1. Exposure Characterization

1.4. Occurrence and exposure

1.4.1. Environmental and natural occurrence

The incomplete combustion and heating of cooking oils produce acrolein, as does the photochemical degradation of 1,3-butadiene in the environment. Acrolein may also be formed endogenously (Faroon et al., 2008; see also Nath & Chung, 1994). Zhang et al. (2018) cited several sources of endogenous acrolein formation, the most important of which include the reactions of myeloperoxidase on hydroxyl-amino acids such as threonine, and the oxidation of spermine and spermidine by amine oxidase (Stevens & Maier, 2008), while other endogenous sources include peroxidation of polyunsaturated fatty acids (Uchida et al., 1998a) and oxidative ring opening of the anticancer drug cyclophosphamide and other oxazaphosphorine drugs such as ifosfamide (Brock et al., 1979). No quantitative data on endogenous production of acrolein were available to the Working Group.

Landfill leachate contained acrolein at a concentration of 0.07–2.1 ppm [0.07–2.1 mg/L] (Faroon et al., 2008). The US EPA lists acrolein as a pollutant in National Priority Superfund sites in at least 16 USA states; acrolein was detected at a concentration of 0.006–1.3 ppm [0.006–1.3 mg/L] in groundwater at half of these sites (Faroon et al., 2008). Because acrolein is highly reactive, it is not expected to bioaccumulate, but it can be formed in the environment as a breakdown product of other chemicals, in addition to occurring as a result of the direct emission of acrolein as a combustion product (Faroon et al., 2008).

1.4.2. Exposure in the general population

The most important sources of acrolein exposure in the general population include tobacco use and cooking with oil at high temperatures. Forest and residential fires, vehicle exhaust, and incinerators are other significant sources of acrolein exposure.

(a) Food, beverages, and cooking emissions

Acrolein concentrations measured in food, beverages, and cooking emissions are presented in Table 1.1.

Table 1.1

Concentrations of acrolein in food, beverages, and cooking emissions.

Most food items are not considered to be major sources of acrolein in the general population. However, higher concentrations have been reported in certain food items, including frying fats and oils (mean acrolein concentration, 276 µg/L; maximum, 1389 µg/L; n = 15; see Table 1.1), and cooking food in hot oil has been shown to produce emissions containing acrolein, which can be a significant source of exposure.

An analysis by Umano & Shibamoto (1987) revealed that the two most important factors in the production of acrolein during cooking were cooking duration and cooking temperature, both of which were positively associated with acrolein production; the type of oil (i.e. sunflower, beef fat, soybean, corn, sesame, and olive, in increasing order of acrolein production) was less important. While little acrolein was formed under 240 °C, emissions increased 10-fold when the temperature was increased from 280 to 300 °C, and 3-fold from 300 to 320 °C. Temperatures in home cooking were reported to rarely exceed 200 °C. However, Hecht et al. reported that, among non-smoking Chinese women in Singapore who cook at much higher temperatures or cook more frequently than controls (women randomly selected from the Chinese Health Study), concentrations of urinary acrolein metabolites were about 50% higher than among women who cooked less frequently (see Table 1.2) (Hecht et al., 2010, 2015).

Table 1.2

Levels of acrolein metabolite biomarkers measured in human urine.

Beer typically contains acrolein at a concentration of 1–5 µg/L, although higher concentrations (up to 25 µg/L) are found in the early stages of beer making, before processing to make the final product; the acrolein in other alcoholic drinks ranges from 0.02 to 11 µg/L, (Greenhoff & Wheeler, 1981; Ferreira et al., 2018; Hernandes et al., 2019). A study of 117 alcoholic beverages found that over half had detectable levels of acrolein (limit of detection, 14 µg/L), some at much higher concentrations (Kächele et al., 2014). None of 9 beers, 4 vodkas, and 5 absinthes tested had detectable concentrations, nor did only 21 out of 23 wines tested. However, over 85% of the 15 whiskey samples, 7 tequilas, 28 fruit spirits, and 10 grape marc samples tested were positive; the average acrolein concentration in all the samples was 276 µg/L, but some tequilas, fruit spirits, and grape marc were over 1000 µg/L (Kächele et al., 2014). Rainwater to be used as drinking-water and stored in polyethylene cisterns in Brazil was found to contain acrolein in 75% of the 36 cisterns tested, with concentrations up to 115 µg/L (de Oliveira Moura et al., 2019). No acrolein was detected in 10 bottles of mineral and table water in Germany (Kächele et al., 2014).

(b) Tobacco products and tobacco-related products

Acrolein is present in smoke from cigarettes, cigars, bidis, and hookahs, as well as in emissions from electronic cigarettes and “heatsticks” (Table 1.3). Average concentrations in mainstream smoke from bidis and small cigars are slightly higher than in cigarette smoke. The apparent variability in acrolein yield in mainstream smoke from cigarettes smoked according to the outdated ISO 3308 method is greatly reduced when using the Health Canada Intensive method recommended by WHO, with most products producing 100–200 µg of acrolein/rod. In general, sugars (which are natural components of tobacco and which may also be added during the manufacturing process) increase the emissions of acrolein in tobacco smoke by 20–70% (Talhout et al., 2006). Hookahs (waterpipes, narghile) produce approximately 900 µg of acrolein in mainstream smoke and 1100 µg of acrolein in sidestream smoke per session, which lasts for approximately 1 hour, meaning that secondhand acrolein exposure from waterpipes may exceed that from cigarettes, at 140 µg/rod (Al Rashidi et al., 2008; Daher et al., 2010). Although the fluid in electronic cigarettes (“e-liquid”) does not contain acrolein, it is apparently formed during the heating of the fluid, at an amount that is dependent on the composition of the fluid and the temperature of the coil (Conklin et al., 2018); a single puff contains 3–15 ng of acrolein (Herrington & Myers, 2015). Increasing voltage from 3.8 V to 4.8 V increased the acrolein yield more than 4-fold (Kosmider et al., 2014), and the addition of humectants, sweeteners, and flavourings increased the production of acrolein from nondetectable to several hundred micrograms per gram of e-liquid (Khlystov & Samburova, 2016). [The Working Group noted that newer devices contain voltage/temperature controls that can increase the delivery of nicotine and also enhance acrolein production, indicating that acrolein exposures among current users may be much greater than reflected in the recent literature.] Heatsticks, which have been available in over 40 countries for the past 5 years, each discharge about 5 µg of acrolein in mainstream and 0.7 µg of acrolein in sidestream emissions (Cancelada et al., 2019). The acrolein exposure from the heatsticks is reduced by a factor of about 10 compared with conventional cigarettes (Lachenmeier et al., 2018).

Table 1.3

Concentrations of acrolein in smoke from tobacco products.

While acrolein metabolites (the mercapturic acids HPMA and CEMA) have been detected in the urine of 99% of Americans (Alwis et al., 2015), concentrations of these metabolites were three to five times higher in smokers than in non-smokers (Eckert et al., 2011; Lindner et al., 2011; Alwis et al., 2015; Goniewicz et al., 2018; Table 1.2), with concentrations increasing with the number of cigarettes smoked per day (Lindner et al., 2011) and with increasing urinary concentration of cotinine (a metabolite of nicotine) (Alwis et al., 2015). Acrolein metabolite concentrations were slightly higher in electronic-cigarette smokers than in non-smokers, but four times higher in dual users of cigarettes and electronic cigarettes (Goniewicz et al., 2018). Passive exposure to secondhand smoke led to comparable increases in urinary acrolein metabolites among hookah smokers and non-smokers alike after visiting a hookah lounge or attending a hookah social event at home (Kassem et al., 2018), probably due to the abovementioned high sidestream emission of acrolein from hookahs. Levels of urinary acrolein metabolites were significantly higher in children living with daily hookah smokers than in children from non-smoking homes (Kassem et al., 2014).

Park et al. (2015) reported significantly different concentrations of acrolein metabolites for smokers from different racial and ethnic groups. Similarly, the National Health and Nutrition Examination Survey (NHANES) found that the 25th percentile of the HPMA concentrations for tobacco smokers was greater than the 75th percentile for non-tobacco users, for all age groups, and that HPMA concentrations among non-tobacco users were similar for both sexes, and were lower for non-Hispanic White people and non-Hispanic Black people than for Mexican Americans or for people of other Hispanic origins or for other or multiple ethnicities. However, among Mexican Americans, metabolite concentrations for smokers were much lower (36%) than those of non-Hispanic White people (Alwis et al., 2015).

In Taiwan, China, healthy subjects who chewed betel quid had HPMA concentrations that were significantly elevated, but significantly lower than in cigarette smokers, and those who both smoked cigarettes and chewed betel quid had the highest urinary HPMA levels (3600, 5800, and 8900 pmol/mg creatinine [796, 1282, and 1967 µg/g creatinine], respectively, see Table 1.2 (see also Table 2.1); Tsou et al., 2019). In contrast, in patients with oral squamous cell carcinoma who both smoked cigarettes and chewed betel quid, urinary levels of HPMA were only 7% those of healthy people with matched smoking and betel-quid use history, despite the fact that their NNAL (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol)/creatinine levels were comparable.

(c) Indoor air

(i) In the home

Activities in the home, especially tobacco smoking and cooking with oils and fats heated to high temperatures, are the primary indoor source of acrolein (see Section 1.4.2(a)). Cooking can increase air concentrations of acrolein by 26 to 64 µg/m³ (Seaman et al., 2009). Other indoor sources of acrolein include gas stoves, wood-burning fireplaces and stoves, burning candles, and incense. When indoor air in the home and outdoor air are measured simultaneously, the indoor concentration of acrolein is usually 2–10 times greater than the outdoor concentration. Azuma et al. (2016) reviewed surveys of Japanese homes and reported an average indoor concentration of acrolein of 0.267 µg/m³, which was three times higher than the outdoor concentration, but much lower than that found in homes in other countries. A survey of 130 homes in Beijing, China, reported much higher concentrations, with an average of 2.1 µg/m³, although neither smoking nor cooking occurred during the sampling period (Liu et al., 2014). A study of acrolein concentrations outdoors and inside occupied homes and unoccupied, newly constructed, model homes (expected to have high emissions from construction materials) reported morning indoor concentrations in occupied homes (2–8 µg/m³) that were generally more than 10 times higher than the outdoor concentrations (0.1–0.3 µg/m³) in Davis and surrounding towns in California, USA. Similarly, in new model homes, the indoor concentrations were also 10 times higher than the outdoor concentrations. The outdoor concentrations in occupied homes in Los Angeles averaged 5–10 times higher than those around Davis (0.8–1.7 µg/m³), but indoor concentrations were comparable (Seaman et al., 2007). The greatest increases in indoor acrolein concentrations in occupied homes in all three counties studied (Los Angeles, Placer, Yolo) were associated with cooking with fats and oils. Homes with frequent, regular cooking activity had the highest morning acrolein levels. In four unoccupied new houses, indoor acrolein concentrations were increased by 10-fold compared with those outdoors, although no cooking or smoking had taken place. However, the particle board and lumber used to construct these houses was found to emit acrolein (1–8 ng acrolein/g). The Relationship of Indoor, Outdoor and Personal Air (RIOPA) study of 398 homes in the USA found quite different average acrolein concentrations in the three cities studied. The average concentration in these cities ranged from 1.0 µg/m³ in Elizabeth, New Jersey, and 1.2 µg/m³ in Los Angeles, California, to 3.1 µg/m³ in Houston, Texas (Weisel et al., 2005).

In Prince Edward Island, Canada, acrolein concentrations were consistently two and a half times higher in homes with smokers than in homes without. Similarly, concentrations were higher in homes with new carpets than in those without new carpets. No significance was found for the presence of wood stoves, the type of heating, or painting (Gilbert et al., 2005). Subsequent studies of over 250 homes in Edmonton, Halifax, Regina, and Windsor, Canada, also found that homes with smokers had distinctly higher concentrations of acrolein than homes without, and also that indoor concentrations of acrolein were higher than outdoor concentrations; median indoor concentrations ranged from 1.3 to 8.1 µg/m³, while paired outdoor concentrations were more than 60% lower (ranging from 0.2 to 2.2 µg/m³) (Health Canada, 2020).

Other sources of acrolein in homes include burning incense and using kilns. Burning incense increases acrolein concentrations by 2.67–8.14 ppm/g [6000–19 000 µg/m³ per g] burned (Lin & Wang, 1994). Hirtle et al. (1998) measured acrolein concentrations greater than 20 ppb [46 µg/m³] in three homes with kilns.

Overall, the acrolein concentrations in homes ranged from less than 0.01 to 39 µg/m³, with median concentrations of 1 to 8 µg/m³.

(ii) Primary schools

In a study of 408 primary schools (attended by 6590 students) in France, 14% of the children were found to be exposed to acrolein at concentrations greater than 1.55 µg/m³ in their classrooms (Annesi-Maesano et al., 2012). [The Working Group noted that the aldehyde (acrolein, formaldehyde, and acetaldehyde) concentrations inside the classrooms in this study were greater than the outdoor concentrations in the same cities, which indicates that there might be indoor sources, but these were not identified. Possibilities include smoking by staff or emissions from building materials.] Similarly, a study of seven schoolrooms in Mira Loma, California, USA, reported that acrolein concentrations in the classroom were greater than outdoor concentrations. The authors attributed the higher indoor acrolein concentrations to building elements such as carpet, drywall, and adhesives (Sawant et al., 2004).

(iii) Hospitality sites

Hospitality sites where smoking was permitted had higher indoor concentrations of acrolein. Measurements made in the 1970s and early 1980s in France found acrolein concentrations in cafés to be between 12 and 43 µg/m³. Acrolein concentrations in restaurants and taverns in the Netherlands were between 1 and 8 µg/m³, and concentrations in a car with three smokers increased from 13 µg/m³ with the windows open to ten times that level when the windows were closed (Triebig & Zober, 1984). Löfroth et al. (1989) reported acrolein concentrations on two evenings to be 21 and 24 µg/m³ in a tavern in the USA. [The Working Group noted that the advent of smoke-free regulations has presumably lowered these concentrations substantially.]

(d) Outdoor air pollution

The major sources of acrolein in the outdoor environment are forest fires and exhaust from motor vehicles and aircraft. Acrolein is released directly into the ambient air from vehicle exhaust and is also formed by photo-oxidation of 1,3-butadiene and other hydrocarbons (Faroon et al., 2008,). These reactions comprised an estimated 39% of total acrolein emissions in California, USA, in 2012 (OEHHA, 2018). Other sources of acrolein, which may be important in nearby local areas, include emissions from manufacturing processes such as pulp and paper, coal/gas/oil-fired power plants, waste-disposal emission, and the volatilization of biocides.

The seasonal effect for acrolein is opposite to that for many other pollutants in that concentrations decrease in winter. For example, the median summer concentration measured in several European cites was 2 µg/m³, while the median winter concentration was 0.6 µg/m³ (Campagnolo et al., 2017), which may be partially attributable to the decline in frequency of photochemical reactions with seasonal reduction in solar intensity. Outdoor concentrations of acrolein in the USA are typically 0.5–3.2 ppb [1–7 µg/m³] (Faroon et al., 2008), although acrolein concentrations measured outside 124 homes in Houston, Texas, averaged 17.9 µg/m³ (Weisel et al., 2005). Median concentrations in California were 0.041 µg/m³ in coastal areas, 0.068 µg/m³ in intermediate areas, 0.101 µg/m³ in the San Francisco Bay area, and 0.32 µg/m³ in the Los Angeles air basin (Cahill, 2014); concentrations outside 15 homes averaged 0.60 µg/m³ (Seaman et al., 2007). Based on measurements throughout the state, acrolein exposures in California increased between 2004 (0.51 ppb) [1.2 µg/m³] and 2014 (0.66 ppb) [1.5 µg/m³], although concentrations of volatile organic compounds other than aldehydes have declined, and acrolein emissions from gasoline-related sources decreased by two thirds between 1996 and 2012. The increase in acrolein emissions from non-gasoline related sources in 2012 was attributed primarily to a higher estimate of emissions from waste disposal (OEHHA, 2018).

Exhaust from gasoline- and diesel-powered vehicles is one of the most important, ubiquitous sources of acrolein in outdoor air. With the introduction of engine and fuel improvements due to stricter regulations to reduce exhaust emissions, this contribution has declined in North America and Europe. Schauer et al. (2002) reported that tailpipe emissions of acrolein from several gasoline-powered vehicles equipped with early catalytic converters (1981–1994) were greatly reduced compared with those from vehicles without these converters (1969–1970), from 3800 to 60 µg/km. The estimated acrolein emissions from on-road vehicles in the 48 contiguous states of the USA in 2007 were less than half the estimated emissions in 1996 (10 185 versus 21 266 metric tonnes/year). This decrease was almost entirely due to reductions from gasoline-powered vehicles and was attributed to changes in gasoline formulation and implementation of stricter Tier 2 emission standards for light-duty vehicles (IARC, 2013).

(i) Local sources

Local sources may increase acrolein concentrations. The importance of nearby industry and traffic is illustrated by the results of 2 years of sampling in the Pittsburgh area, Pennsylvania, USA. Four locations were sampled every sixth day: one near downtown (near the city centre) with heavy traffic; one remote from both traffic and industry; and two in residential areas within 0.8 km of heavy industry. In the two residential areas near industry, acrolein concentrations were approximately double those in the rural area, while the downtown area had the highest average and 95th percentile concentrations (Logue et al., 2010). Other evidence of the importance of local sources included measurements made in the vicinity of a petrochemical plant: acrolein concentrations were 640 µg/m³ at a distance of 1 km, and 2000 µg/m³ at 100 m. Concentrations measured 50 m from a perfume factory ranged from 40 to 480 µg/m³ (Izmerov, 1984).

Acrolein is used as a biocide in irrigation canals and volatilizes quickly after application. In the San Joaquin Valley of California, USA, a major agricultural area through which pass the 640 km California Aqueduct and numerous irrigation canals, an estimated 90 tonnes of acrolein were volatilized into the air in 2001 (CEPA, 2002). The estimate for 2012 was 33 tonnes (OEHHA, 2018). [The Working Group noted that no measurements of ambient acrolein concentrations were made while acrolein was in use, but these could affect local concentrations.]

(ii) Diesel and biodiesel

A study of emissions from the engines of two heavy-duty trucks found that both pollution-control technology and fuel were major determinants of acrolein emissions (Cahill & Okamoto, 2012). The truck engine built in 2008 was equipped with a diesel oxidation catalyst/diesel particulate filter, while the truck engine built in 2000 was not, although it complied with the environmental regulations of the time. Emissions from the truck engine without pollution controls (without the catalyst/filter) were 2–10 times greater than those from the engine with these controls, depending on the fuel type used; the difference was least for ultra-low sulfur diesel fuel (ULSD; a petroleum product) and greatest for soy biodiesel blend (50% soy biodiesel and 50% ULSD). More fuels were tested with the 2008 engine than with the 2000 engine. These included: ULSD, a soy biofuel, an animal biofuel, a “renewable” fuel (hydrotreated biofuel), and 50:50 blends of each of the biofuels and ULSD. Acrolein emissions from the renewable fuels (hydrotreated biofuel, and 50:50 hydrotreated biofuel and ULSD) were comparable to those from the petroleum-based fuel (ULSD); the animal biofuel and blend emitted 40% more acrolein than the ULSD fuel, and the soy biofuel emitted the most acrolein (two and a half to three times that of the ULSD).

(iii) Gasoline and other sources of acrolein

Gasoline- and diesel-powered road motor vehicles are the major quantified source of acrolein in outdoor air in Canada. Annual releases from these were estimated to be 209 000 to 2 730 000 kg. However, unquantified but possibly greater sources of acrolein are other vehicles that are not fitted with pollution-control devices, such as aircraft, railway and marine vehicles, as well as off-road motor vehicles, lawnmowers, and snowblowers. Other major anthropogenic sources include the oriented strand board industry (25 664 kg/year), pulp and paper mills (18 735 kg/year), waste incineration (2435 kg/year), and coal-based power plants (467–17 504 kg/year) (WHO, 2002).

A recent evaluation of the sources of acrolein emissions in outdoor air in California, USA, reported that the contribution of gasoline, as both a primary and secondary pollutant, declined significantly from 52% in 1996 to 28% in 2012. Despite this decline, the average exposure to ambient acrolein in California increased from 0.51 to 0.66 ppb [1.2 to 1.5 µg/m³] (OEHHA, 2018). Fig. 1.1 presents the dominant sources of acrolein in three urban and two agricultural areas of California in 2012.

Fig. 1.1

Primary and secondary sources of acrolein, 2012.

1.4.3. Occupational exposure

Workers may be exposed occupationally to acrolein during its manufacture and use as a chemical intermediate (see Section 1.2). However, as for the population at large, workplace exposures to acrolein occur primarily from the formation of acrolein during the incomplete combustion of organic material such as tobacco, cooking oils, gasoline and diesel fuel, and forest and residential fires.

The National Occupational Exposure Survey estimated that approximately 1300 workers were potentially exposed to acrolein in the USA when the study was conducted in 1981–1983. Approximately one third of these workers were mechanics and repairers. Other occupations identified with potential exposure to acrolein included painters and spray painters, machinists, sheet metal workers, chemical technicians, janitors, and water and sewage treatment plant operators (NIOSH, 1990). [The Working Group noted that the survey did not include agricultural production, mining activity, or railroad transportation. During the subsequent 40 years, occupational exposures in manufacturing in the USA have evolved significantly and these numbers have probably changed substantially due to changes in product usage, export of chemical manufacturing, and automation, to name a few examples.] Between 1993 and 2009, 8 cases of acrolein-related illness from pesticide usage were identified in Washington State and California, USA (Rodriguez et al., 2013).

Occupational exposure to acrolein in firefighting, manufacturing, welding, food processing, and traffic-related occupations is presented in Table 1.4 and detailed below.

Table 1.4

Occupational exposure to acrolein.

(a) Firefighting

Firefighters are exposed to high concentrations of acrolein produced during the incomplete combustion of burning materials. Structural fires and wildland fires are fought by distinctly different crews who have different exposure profiles. The exposures of wildland firefighters and urban firefighters are presented in Table 1.4.

The two distinct phases of fighting structural fires are: (i) knockdown, when the visible flames are extinguished; and (ii) overhaul, during which smouldering material is searched for embers and hidden flames. Jankovic et al. (1991) collected short-term personal samples from 22 fires, mostly residential, in the USA and reported that half the samples from during knockdown exceeded the short-term exposure limit (STEL) for acrolein at the time – 300 ppb [690 µg/m³] – and that the maximum value was 3200 ppb [7330 µg/m³]. Their data were similar to those reported by Burgess et al. in 1979 and plotted in the Jankovic publication. Together, these data provided a median of 500 ppb [1100 µg/m³], with a 95th percentile of 5000 ppb [11 000 µg/m³] and a maximum of 15 000 ppb [34 000 µg/m³]. During knockdown, firefighters wear a self-contained breathing apparatus; some samples collected inside the breathing mask measured as high as 900 ppb [2000 µg/m³]. During overhaul, when a self-contained breathing apparatus is not generally worn, measured acrolein concentrations were as high as 200 ppb [500 µg/m³] in the Jankovic publication and 300 ppb [700 µg/m³] in a study of 25 fires in the USA by Bolstad-Johnson et al. (2000). Of the 96 30-minute samples collected by Bolstad-Johnson et al. (2000), only 7 exceeded the limit of detection (11 ppb [25 µg/m³]). The mean for these 7 samples was 123 ppb [282 µg/m³].

Wildland firefighters do not wear respiratory protection. The three types of wildland firefighting are: (i) initial attack – the first day of a fire, during which all but 5% of fires are extinguished; (ii) project fires – the second and successive days of fighting those few fires that continue past the first day; and (iii) prescribed burns – intentionally set and controlled fires in an established area. In the USA, Reinhardt & Ottmar (2004) reported geometric mean (GM) acrolein concentrations of 1 ppb [2 µg/m³] during 13–14 hour shifts for the initial attack day (45 samples) and also for the subsequent days (84 samples), while the GM during prescribed burns was 9 ppb [21 µg/m³] (11.5-hour average shift, 200 samples), and the maximum concentrations were 11, 15, and 60 ppb [25, 34, and 140 µg/m³], respectively. Similar results for prescribed burns in the USA were reported by Slaughter et al. (2004): a time-weighted average (TWA) mean of 10 ppb [23 µg/m³] and a maximum of 41 ppb [94 µg/m³] for 65 samples. Task-specific (~2 hours) concentrations ranged from < 1 ppb [< 2.3 µg/m³] at the engine and 5 ppb [11 µg/m³] while igniting the fire to 30 ppb [69 µg/m³] for the holding boss and 18 ppb [41 µg/m³] for others holding the fire within prescribed boundaries. A 30-minute exposure during direct attack to extinguish flames that had escaped these boundaries was 62 ppb [140 µg/m³] (Reinhardt & Ottmar, 2004).

(b) Manufacturing operations

The manufacture of acrolein can lead to very high exposures of 43–3526 ppb [98–4075 µg/m³] (Izmerov, 1984). Various plastic-manufacturing processes use or produce acrolein. Polyethylene extrusion operations and phenol–formaldehyde resins led to exposures under 13 ppb [< 30 µg/m³] (Tikuisis et al., 1995; Pośniak et al., 2001).

(c) Welding

In a study in Ukraine, Protsenko et al. (1973) found that, while metal untreated with primer emitted no measurable acrolein, some primers coated onto metals resulted in significant acrolein emissions during both gas cutting and automatic submerged arc welding, with acrolein concentrations reaching 447 ppb [1024 µg/m³]. While exposures during welding in new ship outfitting averaged 9 ppb [21 µg/m³], with maximum values reaching 28 ppb [64 µg/m³], exceeding the occupational exposure limit (OEL) for the European Union (EU), exposures during ship repair were even higher, reaching 64 ppb [150 µg/m³], and over half the shipbreaking samples exceeded the EU OEL, with one sample at 600 ppb [1400 µg/m³]. Although in most short-term (15-minute) samples collected in engine and garage repair shops acrolein was not detectable (i.e. < 65 ppb [< 150 µg/m³]), one sample contained acrolein at 260 ppb [595 µg/m³].

(d) Food processing, traffic-related, and other occupations

Exposures (summarized in Table 1.4) measured in restaurant kitchens are highly variable, probably reflecting emissions from cooking fuels. Similarly, those who work near gasoline exhaust, such as bus drivers, garage workers, and highway construction workers, and those who work at or near incineration facilities, have highly variable and significant exposures, from 10 ppb to > 100 ppb [~23 to > 230 µg/m³]. Klochkovskii et al. (1981) reported that 37% of 800 samples collected in quarry operations in an area of the former Soviet Union exceeded permissible limits, and that acrolein concentrations in exhaust gases and workplace air averaged 900–3100 ppb [2100–7100 µg/m³].

(e) Occupational exposure to acrolein from secondhand smoke

Workers, especially hospitality workers, may also be subject to significant exposures to acrolein in places where smoking is permitted. Acrolein concentrations in a tavern in North Carolina, USA, with moderately high levels of secondhand smoke (on average, particles, 430 µg/m³; and nicotine, 66 µg/m³) were measured at 21 µg/m³ and 24 µg/m³ on two sampling trips of 3–4 hours each (Löfroth et al., 1989). In open offices where smoking was allowed in Massachusetts, USA, the 90th percentile of weekly average concentrations of nicotine was 34 µg/m³ (Hammond et al., 1995), so office exposures may exceed 5 ppb [11 µg/m³] acrolein (Mitova et al., 2016). Ayer & Yeager (1982) reported that acrolein concentrations reached > 50 ppm [114 000 µg/m³] in the smoke plume of cigarettes. Thus, secondhand smoke can be an important source of both peak and TWA exposure to acrolein.

(f) Occupational Safety and Health Administration compliance data

OSHA maintains a publicly available database of industrial hygiene samples collected in the USA as part of its compliance monitoring programme, the Chemical Exposure Health Data (OSHA, 2020). The results for 1220 samples and blanks collected by OSHA inspectors and analysed for acrolein between 1984 and 2019 provide some information from inspections for those 35 years (OSHA, 2020). These values should be compared with the 8-hour TWA OSHA permissible exposure limit of 100 ppb [250 µg/m³], the EU OEL of 20 ppb [50 µg/m³] for 8-hour TWA and 50 ppb [114 µg/m³] STEL (for 15 minutes) as well as the American Conference of Governmental Industrial Hygienists (ACGIH) ceiling value of 100 ppb [250 µg/m³]. Only about 10% of the samples were above the limit of detection, and only 3 of the nearly 200 samples collected for less than 1 hour had detectable concentrations of acrolein, but of these 2 were of concern: the 15-minute sample was 115 ppb [263 µg/m³] acrolein and the 24-minute sample was 69 ppb [158 µg/m³], both in excess of the EU short-term limit of 50 ppb [120 µg/m³]; the limit of detection in air for these shorter-timed samples would have been higher than that for the 8 hour samples, but these values were not in the database. Because of the intense irritation caused by acrolein, the ACGIH recommends neither an 8 hour nor a 15-minute STEL, but, rather, a ceiling of 100 ppb [250 µg/m³] that should never be exceeded. [The Working Group noted that, while none of the OSHA samples contained detectable levels of acrolein after such short exposures, the higher concentrations clearly indicated that this recommendation was exceeded for many samples.] Of the samples with detectable levels of acrolein, 40% exceeded the EU OEL of 20 ppb [50 µg/m³], and half of these samples contained acrolein at more than twice that OEL (Table 1.4).

The highest acrolein concentration reported was from samples collected in late 2018 at a company that manufactured plastic pipes and pipe fittings. Four workers wore the sampling equipment for 90–180 minutes and their exposure concentrations were less than detectable, 17, 25, and 240 ppb [39, 57, and 550 µg/m³] (sampling times were 90, 140, 180, and 170 minutes, respectively). Only 17% of the 134 personal samples collected at approximately three dozen plastic-manufacturing establishments were above the limit of detection. Those samples that were detectable ranged from 3 to 240 ppb [7 to 550 µg/m³] acrolein, with an average of 39 ppb [89 µg/m³] and a median of 21 ppb [48 µg/m³]; one 24-minute sample averaged 69 ppb [158 µg/m³], above the EU STEL of 50 ppb [120 µg/m³] (Table 1.4; OSHA, 2020).

Over half of the personal samples collected from food production workers had detectable concentrations of acrolein, and both the mean and median values of those samples (29 and 25 ppb [66 and 57 µg/m³], respectively) exceeded the EU OEL of 20 ppb [50 µg/m³] (OSHA, 2020).

1.5. Regulations and guidelines

1.5.1. Exposure limits and guidelines

(a) Occupational exposure limits

Acrolein is a severe irritant to the eyes, mucous membranes, and the respiratory tract at concentrations lower than 1 ppm, and this is the basis for OELs. At higher concentrations, acrolein can cause pulmonary oedema and death (10 ppm; 23.3 mg/m³) (ATSDR, 2014; ACGIH, 2019).

In 1946, the ACGIH recommended that 8-hour TWA exposure to acrolein should not exceed 0.5 ppm [1100 µg/m³]. This value was lowered to 0.1 ppm [230 µg/m³] in 1963. In 1976, a STEL of 0.3 ppm [690 µg/m³] was added to this recommendation, and in 1998 both the TWA and the STEL were replaced by a ceiling value of 0.1 ppm [230 µg/m³] that should not be exceeded for any duration. These ACGIH threshold limit values were intended as recommendations to industrial hygienists but have been adopted by many countries as OELs directly, by reference, or as the basis upon which national OELs were developed. Currently the EU has an 8-hour TWA OEL of 0.02 ppm or 0.05 mg/m³ and a STEL of 0.05 ppm or 0.12 mg/m³ (European Commission, 2017). Within the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) registration of acrolein, the derived no-effect level (DNEL) of long-term exposed workers was set at 0.2 mg/m³ for both local and systemic effects, and the DNEL for long-term skin exposure at 0.08 mg/kg body weight (bw) per day (ECHA, 2020).

Table 1.5 presents the OELs for various countries. Many countries use the EU OEL of 0.02 ppm [0.05 mg/m³], or the older ACGIH OEL (TWA, 0.1; STEL, 0.3) or the current ACGIH ceiling value of 0.1 ppm [0.23 mg/m³].

Table 1.5

Occupational exposure limits for acrolein in various countries.

(b) Environmental exposure limits

The US EPA reference concentration for inhalation exposures is 2 × 10⁻⁵ mg/m³, and the reference dose for oral exposures is 0.5 µg/kg per day (US EPA, 2003). The US Agency for Toxic Substances and Disease Registry (ATSDR) set the minimal risk level for ingestion of acrolein at 4 µg/kg per day for 15–364 days on the basis of forestomach squamous epithelial hyperplasia in mice (ATSDR, 2007). The International Programme on Chemical Safety tolerable intake levels are 0.17 ppb [0.4 µg/m³] for inhalation exposures and 1.5 µg/mL (corresponding to 7.5 µg/kg bw per day) for drinking-water exposures (IPCS, 1992).

For subchronic exposures, e.g. 8 hours, environmental guidelines were 0.03–4.8 ppb [0.07–11 µg/m³], whereas OELs were 20–100 ppb [0.05–0.23 mg/m³], although some guidelines suggested ceiling values of 100 ppb [230 µg/m³] that should never be exceeded.

The occupational guidelines for acute exposures (50–100 ppb [120–250 µg/m³]) are approximately 10–100 times the environmental guidelines for acute exposures. Acute exposure guideline levels (AEGLs) have been established for acrolein (National Research Council, 2010). The lethal level of exposure (AEGL-3) is reached after 10 minutes of exposure to acrolein at 6.2 ppm [14 000 µg/m³], whereas exposure to acrolein for any duration from 10 minutes to 8 hours at 30 ppb [69 µg/m³] leads to slight eye irritation and discomfort.

Table S1.3 (Annex 1, Supplementary material for acrolein, Section 1, Exposure Characterization, web only; available from: https://publications.iarc.fr/602) presents some guidelines for acrolein concentrations in the air.

1.5.2. Reference values for biological monitoring of exposure

A metabolite of acrolein (the mercapturic acid HPMA) has been measured as an indicator of exposure. The German Committee for the determination of occupational exposure limits (the “MAK-Commission”) suggests a biological reference value for workplace substances (BAR) for HPMA of 600 µg/g creatinine in the urine in non-smokers (Jäger, 2019).

2. Cancer in Humans

2.1. Descriptions of individual studies

See Table 2.1.

Table 2.1

Epidemiological studies of cancer in humans exposed to acrolein.

Six studies – one cohort study, two case–control studies, and three nested case–control studies in cohorts – have been published on the relationship between cancer and exposure to acrolein. Five other studies (mainly case reports) described bladder cancers or leukaemia occurring after use of the pharmaceutical cyclophosphamide (classified in IARC Group 1, carcinogenic to humans) or ifosfamide to treat cancer or autoimmune disease. These studies on pharmaceutical agents were determined by the Working Group to be uninformative because the role of acrolein in causing these cancers could not be distinguished from that of other metabolites. The quality of the exposure assessment in the six studies described below is detailed in Section 1.6.

Bittersohl (1975) reported on a small cohort of 220 workers exposed to multiple aldehydes or aldehyde derivatives including acrolein (in trace amounts) in a factory in the former German Democratic Republic, who were followed up from 1967 to 1972. There were 9 cases of cancer in men (5 squamous cell lung carcinomas, 2 squamous cell carcinomas of the oral cavity, 1 adenocarcinoma of the stomach, and 1 adenocarcinoma of the colon) and 2 cases in women (1 leukaemia and 1 cancer of ovary). There was no formal comparison group except a narrative comparison with incidence rates in the general population, source unspecified. [The Working Group noted that although cancer rates were reported to be higher in the cohort than in the population of the German Democratic Republic, the study did not quantify any excess, nor specify the population rate in the German Democratic Republic. Exposure was poorly defined, and no attempt was made to assess exposure (semi-) quantitatively by measurements of duration. No inference can be made regarding the association between acrolein exposure and cancer risk.]

In an occupational nested case–control study among male chemical workers in the USA, Ott et al. (1989a) reported on 129 workers who died from lymphohaematopoietic cancer and their controls (matched on hire decades), with the time scale being time since hire. Information on multiple chemical exposures was available (Ott et al., 1989b), with expert assessment of individual exposures based on jobs, including acrolein. Positive associations between acrolein exposure and non-Hodgkin lymphoma (NHL), multiple myeloma, and leukaemia were reported, based on small numbers of exposed cases (n = 6). Given the small sample size and multiple exposures, no inference was possible. [The Working Group noted that matching was based on hire decades. Implications for potential bias were not discussed in the paper. In addition, the exposure assessment was insufficient, limited to dichotomous (ever/never) classification, based on production records and not measured exposure, and exposure encompassed multiple chemicals in addition to acrolein.]

Yuan et al. (2012, 2014) published the results of two nested case–control studies within a cohort of 18 244 Chinese men enrolled in 1986–1989 in Shanghai, China. Besides in-person interviews, a spot urine sample was taken from each participant at baseline and stored until laboratory analysis. Incident cases of and deaths from lung cancer were identified through annual in-person interviews of all surviving participants, the local cancer registry, and the vital statistics office. The first study (Yuan et al., 2012) was a nested case–control study on lung cancer, limited to current smokers at enrolment, and based on follow-up through 2006. Urinary biomarkers related to smoking habits were measured at enrolment, including HPMA (an acrolein-derived, mercapturic acid metabolite), NNAL, cotinine and others. Overall, 343 cases and 392 controls were included in the analysis, after exclusion of cases and controls for whom urine samples were depleted or values for one or more mercapturic acid metabolites were missing. One control per case was selected from among cohort members who were current smokers at enrolment, free of cancer, and alive at the time of the cancer diagnosis of the index case, and further matched on age at enrolment, date of biological specimen collection, and neighbourhood of residence at recruitment. Comparing the highest with the lowest quartiles, risk of lung cancer associated with HPMA levels doubled in models adjusting for matching factors and number of cigarettes smoked per day and years of cigarette smoking at baseline. In models with further adjustment for metabolites of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines (NNAL) and/or cotinine, no association was found between HPMA and lung cancer. [The Working Group noted that there were multiple correlated exposures (biomarkers). Strengths of the study included: a relatively large sample and long follow-up (20 years); few losses to follow-up (4.6%); urinary biomarkers collected before disease occurrence; and self-reported smoking status verified by urinary cotinine. The 2-fold increase in risk of lung cancer was associated with the highest quartile of HPMA concentration, adjusted for only intensity and duration of smoking. However, this effect disappeared with further adjustment for other smoking biomarkers, indicating that acrolein represented a biomarker of smoking. The Working Group judged that this study was uninformative for an evaluation of the carcinogenicity of acrolein.]

The second study (Yuan et al., 2014) had a similar study design but extended follow-up through 2008 and included only never-smokers at baseline (82 cases of lung cancer and 83 controls; same design as in the Yuan et al., 2012). The same urinary biomarkers as in the previous paper were measured. There was no association between quartile of urinary HPMA concentration and lung cancer in never-smokers (fourth quartile versus first quartile: OR, 1.13; 95% CI, 0.47–2.75) in analysis adjusting for matching factors and urinary cotinine level. [The Working Group noted that only internal exposure was assessed, and since the participants were all non-smokers, the source of external exposure to acrolein was unclear. The Working Group also noted that urinary cotinine represents a short-term biomarker of passive smoking and therefore may not fully adjust for long-term secondhand smoke exposure.]

Tsou et al. (2019) measured acrolein–DNA adducts in buccal swabs from patients (n = 97) with cancer of the oral cavity. Acrolein–DNA adducts were also measured in buccal swabs from 230 healthy controls. Additionally, HPMA and NNAL were measured in the urine of the same 97 patients with cancer of the oral cavity and 230 healthy controls. For the patients with cancer, Tsou et al. (2019) also compared DNA–adduct levels in cancer biopsies with those in adjacent normal tissue collected from buccal swabs. Levels of acrolein–DNA adducts in buccal cells were 1.4 times higher in cases than in controls (P < 0.001). The ratio was 1.3 among smokers and betel-quid chewers only (P < 0.05). Levels of acrolein–DNA adducts were 1.8 times higher in cancer biopsy specimens than in buccal swabs from adjacent normal tissue (P < 0.01). However, there was no significant difference in levels of acrolein–DNA adducts among healthy controls with different cigarette smoking or betel-quid chewing histories. Smoking and betel-quid chewing were associated with significantly higher levels of HPMA. Levels of urinary HPMA were lower among cases (0.7 µmol/g creatinine) than among controls (7.1 µmol/g creatinine) (P < 0.001), with a similar difference observed when only smokers and chewers were considered. There was no adjustment for covariates. [The Working Group noted that, overall, the paper suggests that HPMA (but not acrolein–DNA adducts) is associated with smoking and betel-quid chewing, and acrolein–DNA adducts are associated with oral cancer (cross-sectionally). There were lower levels of HPMA in the urine of cases than in controls (irrespective of smoking/chewing status). The cross-sectional nature of the study and the fact that specimens were collected after cancer diagnosis in cases make causal inference difficult.]

Hong et al. (2020) in a case–control study in Taiwan, China, included 62 patients with urothelial carcinoma and 43 healthy controls. All cases and none of the controls had chronic kidney disease (CKD), the rationale being that CKD patients have a high risk of bladder cancer and altered metabolism that increases susceptibility to chemical exposures. Urinary HPMA, plasma acrolein–protein conjugates, DNA adducts formed by acrolein, and TP53 mutations in frozen tissue samples were measured. Tumour biopsies showed levels of acrolein–DNA adducts that were 1.2 times higher than those in adjacent normal tissue in urothelial carcinoma patients overall (P < 0.005). The same ratio and P value were also found in cases and controls who were non-smokers. Levels of acrolein–DNA adducts were correlated with CKD severity. Also, levels of plasma acrolein–protein conjugates were twice as high in cases as in controls (P < 0.001). Similar results were observed for acrolein–protein conjugates in plasma in study participants with different degrees of severity of CKD and in non-smokers. Urinary HPMA levels were lower in cases (0.83 µmol/g creatinine) than in controls (1.16 µmol/g creatinine) (P = 0.023), this observation being attributed to binding of HPMA to glutathione (GSH) as a cellular defence mechanism. [The Working Group noted that controls were not described, and cases were all affected by CKD. The only endogenous exposure considered was due to kidney failure, while external exposure to smoking was considered only as a confounder. The study also had a small sample size, considerable age difference between cases and controls, and short follow-up period. There appeared to be a disproportionate number of non-smokers included: all controls and 79% of cases.]

3. Cancer in Experimental Animals

In previous evaluations, the IARC Monographs programme concluded that there was inadequate evidence in experimental animals for the carcinogenicity of acrolein (e.g. IARC, 1995).

Studies of carcinogenicity with acrolein in experimental animals are summarized in Table 3.1.

Table 3.1

Studies of carcinogenicity with acrolein in experimental animals.

4. Mechanistic Evidence

4.1. Absorption, distribution, metabolism, and excretion

4.1.1. Humans

(a) Exposed humans

No data on the absorption or distribution of acrolein by inhalation were available to the Working Group.

The main metabolic pathways of acrolein are depicted in Fig. 4.1.

Fig. 4.1

The main pathways of acrolein metabolism.

Two acrolein-derived mercapturic acids, HPMA and CEMA, were found in the urine of both smokers and non-smokers, HPMA being consistently the more common. Tobacco smokers showed significantly higher levels of both HPMA and CEMA (Alwis et al., 2012, 2015). A significant increase in acrolein-derived urinary mercapturic acids was also reported shortly after being served heat-processed food containing acrolein (Wang et al., 2019; Watzek et al., 2012). These mercapturic acids were also found in a limited exploratory toxicokinetic study on a single subject within 24 hours after oral uptake of acrolein at a dose of 7.5 μg/kg bw in drinking-water. For HPMA and CEMA, respectively, elimination half-times were 8.9 hours and 11.8 hours, and maximum urinary concentrations reached 2 hours after ingestion were 1.61 and 1.05 μmol/g creatinine (Watzek et al., 2012). A similar elimination half-time for acrolein (9 hours) based on urinary metabolite HPMA profile was reported in a study on subjects who were served fried food containing acrolein (Wang et al., 2019).

Acrolein can be produced endogenously, including as a result of lipid peroxidation (Nath & Chung, 1994; Stevens & Maier, 2008).

Acrolein can be excreted unchanged in exhaled air (Andreoli et al., 2003; Ligor et al., 2008; Ruenz et al., 2019).

Free acrolein was also found in the urine (Al-Rawithi et al., 1998; Takamoto et al., 2004) and saliva (Korneva et al., 1991) of patients treated with cyclophosphamide; acrolein is a metabolite of cyclophosphamide. Once formed, acrolein appeared to be rapidly excreted in urine because its urinary concentration peaked shortly (1–12 hours) after treatment with cyclophosphamide (Takamoto et al., 2004).

A role of glutathione S-transferases (GSTs) in detoxification of acrolein was demonstrated by a randomized clinical trial in which a significant increase in the excretion of HPMA was observed in individuals who received 2-phenethyl isocyanate, an inducer of GST mu 1 (GSTM1) and GST theta 1 (GSTT1), compared with controls (Yuan et al., 2016). The role of GSH and GSTs is discussed further below (see Section 4.1.2).

(b) In vitro

A low absorption rate of 0.480 ± 0.417 μg/cm² in 30 minutes was observed in experiments with human skin in vitro at 153 ppm (351 mg/m³) of acrolein in air (Thredgold et al., 2020).

The reaction of acrolein with GSH in vitro is efficiently catalysed by human GST ε, μ, and π, the last one isolated from human placenta being the most catalytically active (Berhane & Mannervik, 1990). Significant differences were found in catalytic efficiency (k_cat/K_m) between four allelic variants of the π isoenzyme (hGSTP1-1) (Pal et al., 2000). However, in a search for genetic variants related to acrolein metabolism to mercapturic acids (GST polymorphism) by a genome-wide association study, no association with HPMA levels in smokers after adjusting for total nicotine equivalents was found (Park et al., 2015). [The Working Group noted that these results, together with the known high electrophilic reactivity of acrolein, suggest that its conjugation with GSH leading eventually to the excretion of HPMA is mainly a spontaneous non-catalysed process.]

Acrolein can be reduced by human aldo-keto reductases with catalytic efficiencies that vary greatly among the superfamily members. Thus, aldose reductase (EC 1.1.1.21) catalysed acrolein reduction with k_cat/K_m = 1.09 μM⁻¹ min⁻¹ and was significantly induced (7–20-fold) towards a variety of aldehydes by acrolein (Kolb et al., 1994). Human aldo-keto reductase AKR1A showed a much lower catalytic activity (k_cat/K_m = 0.29 × 10⁻³ μM⁻¹ min⁻¹ (Kurahashi et al., 2014), whereas AKR1B1 and ABR1B10 showed k_cat/K_m values of 0.12 and 1.07 μM⁻¹ min⁻¹, respectively (Shen et al., 2011). AKR1B1, which is ubiquitously expressed in humans, also efficiently reduced the acrolein–GSH conjugate (S-(3-oxopropyl)glutathione, OPSG) with k_cat/K_m = 0.355 μM⁻¹ min⁻¹, whereas AKR1B10 expressed mainly in the gastrointestinal tract showed a much lower catalytic efficiency, k_cat/K_m = 0.004 μM⁻¹ min⁻¹ (Shen et al., 2011). Downregulation of the AKR1B10 gene increased the susceptibility of a colorectal cancer cell line to cytotoxicity caused by acrolein (Yan et al., 2007).

4.1.2. Experimental systems

(a) In vivo

Due to high electrophilicity and solubility in water, a significant portion of inhaled acrolein is taken up in the upper respiratory tract. Experiments on Fischer 344 rats with surgically isolated upper respiratory tract in vivo showed that the nasal uptake efficiency decreased with increasing acrolein concentration, time of exposure, and inspired air flow rate (Morris, 1996; Struve et al., 2008). At the inspired air flow rate of 100 mL/minute, the uptake efficiency averaged over an 80-minute exposure period was 98%, 68%, and 50% at 0.6, 1.8, and 3.6 ppm, respectively. At 300 mL/minute these values fell to 85%, 48%, and 38%, respectively (Struve et al., 2008). Somewhat lower time-averaged values were obtained earlier by Morris (1996), namely, 62%, 38%, and 28% at the exposure concentrations 0.87, 4.4, and 8.7 ppm, respectively (inspiratory flow rate, 200 mL/minute).

GSH concentrations in nasal epithelium were markedly lowered in a concentration-dependent manner in rats exposed for 80 minutes. However, when the rats were pre-exposed to acrolein at 3.6 ppm during 14 days (6 hours per day, 5 days per week), the depletion was nearly compensated by an adaptive response (Struve et al., 2008). A marked depletion in rat nasal GSH was also reported earlier by Lam et al. (1985). [The Working Group noted that these results indicate a marked influence of tissue reactivity on uptake in the upper respiratory tract.]

Mercapturic acids, namely, HPMA and CEMA, were identified in the urine of rats dosed subcutaneously (Kaye, 1973; HPMA only) or orally with acrolein (Draminski et al., 1983; CEMA only), as well as in mice after inhalation and intraperitoneal injection (Linhart et al., 1996). Due to its high electrophilic reactivity, acrolein forms protein adducts in vivo (Gan & Ansari, 1989; Kautiainen et al., 1989; see also Section 4.2.1). A gradual accumulation of protein-adducted acrolein was reported in mice exposed to acrolein by inhalation at 1.5 ppm for 30 minutes twice per day for 3 weeks. At the same time, a gradual increase in urinary HPMA excretion was observed (Tully et al., 2014).

The metabolism and disposition of [2,3-¹⁴C]acrolein was studied in male and female Sprague-Dawley rats treated by oral and intravenous administration (Parent et al., 1996a, 1998). The rats were divided into five groups of 5 males and 5 females and were given a single dose of [2,3-¹⁴C]acrolein intravenously at 2.5 mg/kg bw, or orally by gavage at 2.5 or 15 mg/kg bw. One group of rats was pre-exposed to unlabelled acrolein for 14 days at 2.5 mg/kg-day before oral administration of [2,3-¹⁴C]acrolein at 2.5 mg/kg bw. Urine, faeces, and expired air were collected for 7 days. In all exposure groups, about 26–31% of the radiolabel was exhaled as carbon dioxide while < 1.2% was tissue-bound. Rats given a single intravenous injection of [2,3-¹⁴C]acrolein at 2.5 mg/kg bw excreted 66–69% of the radiolabel in urine and < 2% in faeces. The main urinary metabolites were identified by HPLC/MS analysis using authentic standards as 3-hydroxypropanoic acid, HPMA, CEMA, and N-acetyl-S-(2-carboxy-2-hydroxyethyl)-L-cysteine (2-carboxy-2-hydroxyethylmercapturic acid, CHEMA) and traces of malonic acid. After oral doses, less radiolabel was excreted in the urine (lower dose, 52%; higher dose, 36.5%) and more in the faeces (lower dose, 13%; higher dose, 31%). Two additional urinary metabolites, oxalic and malonic acid, were identified (Parent et al., 1998). No significant effect on the excretion pattern was observed after pre-treatment with acrolein. The main portion of radiolabel was excreted within 48 hours after dosing, but excretion was delayed in the group receiving the higher oral dose. The analysis of faeces did not reveal any distinct peaks in the excretion of radiolabel over time. [The Working Group noted that faeces probably contained polymers of acrolein or polysaccharide, or protein adducts resulting from the reaction of acrolein with food components.]

A computational fluid dynamics model was developed to predict nasal dosimetry of acrolein in rats and humans using parameters adjusted to fit experimental uptake efficiency data from Struve et al. (2008) and Morris (1996). In humans, calculated nasal uptake efficiencies for inhaled acrolein were 16% and 28% at exposure concentrations of 3.6 ppm and 0.6 ppm, respectively, and were consistently lower than those in rats. These predictions capture the overall trend of increased uptake when exposure concentrations decrease (Schroeter et al., 2008). [The Working Group noted that because of oral breathing, delivery of acrolein to the lower respiratory tract could be higher in humans than in rats, which are obligate nasal breathers.]

(b) In vitro

Acrolein reacts spontaneously with GSH to form OPSG (Esterbauer et al., 1975; Mitchell & Petersen, 1989; Horiyama et al., 2016), which is subsequently oxidized by rat liver aldehyde dehydrogenase (ALDH) to S-(2-carboxyethyl)glutathione (CESG) and, in a lesser extent, reduced by rat liver alcohol dehydrogenase (ADH) to S-(3-hydroxypropyl)glutathione (HPSG) as the affinity of ADH (K_m = 877 μM) was low compared with the high-affinity cytosolic (K_m = 310 μM) and mitochondrial (K_m = 198 μM) ALDH forms (Mitchell & Petersen, 1989). Rat AKR7A1 catalysed reduction of both acrolein and its GSH conjugate. Chinese hamster V79 cells expressing rat AKR7A1 were efficiently protected against acrolein-induced mutations (Gardner et al., 2004) (see Section 4.2.2b).

The carbonyl group of acrolein can be oxidized by ALDH and reduced by aldo-keto reductases (AKR). Recombinant mouse ALDH1a1 and ALDH 3a1 efficiently oxidized acrolein to acrylic acid, ALDH1a1 showing comparable catalytic efficiency (V_max/K_m >> 23) but a higher affinity (K_m = 23.2 μM) than ALDH3a1 (K_m = 464 μM) (Makia et al., 2011). Significant catalytic ALDH activities were found in the microsomes, cytosol, and mitochondria of rat liver (Rikans, 1987). In mitochondria, two different ALDH activities were found: a high-affinity one with K_m = 0.017 mM, V_max = 42.2 nmol min⁻¹ mg⁻¹, and a low-affinity one with K_m = 0.430 mM, V_max = 29.2 nmol min⁻¹ mg⁻¹. Similarly, in the cytosolic fraction, there was a high-affinity ALDH form with K_m = 0.026 mM, V_max = 14.9 nmol min⁻¹ mg⁻¹, and a low-affinity form with K_m = 0.725 mM, V_max = 7.1 nmol min⁻¹ mg⁻¹. In the microsomes, a single low-affinity ALDH activity with K_m = 1.5 mM and V_max = 30.5 nmol min⁻¹ mg⁻¹ was reported. Hence, the low K_m ALDH in mitochondria was found to have the highest metabolic activity (Rikans, 1987). [The Working Group noted that both oxidation by ALDHs and reduction by AKRs are important detoxication pathways in the metabolism of acrolein.]

Metabolic activation of acrolein to glycidaldehyde and its detoxification to acrylic acid were described in rat liver and lung preparations by Patel et al. (1980). Notably, oxidation to acrylic acid was not observed in the lung preparations. Glycidaldehyde is a substrate for epoxide hydrolases as well as for cytosolic GSTs in rat lung and liver (Patel et al., 1980). However, metabolic activation was not necessary for conjugation with GSH. A weak increase in GSH conjugation as measured by GSH depletion was observed only when cytochrome P450 (CYP) in rat liver microsomes was induced by pre-treatment of rats with phenobarbital (Garle & Fry, 1989). Experiments with [¹⁴C]-labelled acrolein proved its covalent association with rat microsomal CYP and further metabolism to an epoxide (Marinello et al., 1984). [The Working Group noted that conjugation of glycidaldehyde with GSH should lead to urinary CHEMA, a confirmed metabolite of acrolein.]

4.2. Evidence relevant to key characteristics of carcinogens

This section summarizes the evidence for the key characteristics of carcinogens (Smith et al., 2016), including whether acrolein is electrophilic or can be metabolically activated to an electrophile; is genotoxic; alters DNA repair or causes genomic instability; induces oxidative stress; is immunosuppressive; induces chronic inflammation; alters cell proliferation, cell death, or nutrient supply; induces epigenetic alterations; modulates receptor-mediated effects; and causes immortalization.

4.2.1. Is electrophilic or can be metabolically activated to an electrophile

(a) DNA binding

(i) Studies in humans

Acrolein is a chemically reactive aldehyde that directly interacts with DNA as a result of its α,β-unsaturated carbonyl function. As further described in Section 4.2.1(b), it forms four isomeric α- and γ-hydroxy-1,N²-propano-2′-deoxyguanosine adducts (α-OH-PdG and γ-OH-PdG, two of each), and their ring-opened precursors (Chung et al., 1999). Acrolein-induced DNA adducts have been found in various tissues in studies in humans, including lung, buccal cells, leukocytes, peripheral blood, liver tissues, sputum, brain tissues, bladder, and urothelial mucosa (Weng et al., 2018; Zhang et al., 2007; Yang et al., 2019a; Chung et al., 2012; Nath et al., 1998; Bessette et al., 2009; Wang et al., 2019; Tsou et al., 2019; Zhang et al., 2011; Yin et al., 2013; McDiarmid et al., 1991; Alamil et al., 2020; Nath & Chung, 1994; Fu et al., 2018; Chen & Lin, 2011; Liu et al., 2005; Lee et al., 2014; Hong et al., 2020; see Table 4.1 and Table 2.1). Furthermore, significantly higher levels of acrolein–DNA adducts were found in bladder tumour tissues, hepatocellular carcinoma tissues, and brain tissues from patients with Alzheimer disease (Liu et al., 2005; Lee et al., 2014; Fu et al., 2018; see Table 4.1 and Table 2.1).

Table 4.1

Acrolein-derived DNA adducts in exposed humans.

Acrolein–DNA adduct formation has been detected in the leukocytes of 40% of a group of patients treated with cyclophosphamide compared with none of the controls (McDiarmid et al., 1991). Several studies reported higher levels of acrolein–dG adducts in the buccal cells and lung tissues of tobacco smokers (Nath et al., 1998; Zhang et al., 2007; Weng et al., 2018). Similar results have been reported using immunochemical, ³²P-postlabelling 2D thin-layer chromatography/high-performance liquid chromatography (TLC/HPLC) and LC-MS/MS methods for measuring acrolein–dG adducts in buccal cells (Nath et al., 1998; Weng et al., 2018; Wang et al., 2019). [The Working Group noted that different methods were used in these studies, which may account for differences in levels detected.] Using the immunochemical method and ³²P-postlabelling 2D TLC/HPLC, Weng et al. (2018) reported that γ-OH-PdG accumulated significantly more in smokers than in non-smokers (Weng et al., 2018). Using the LC-MS/MS method, Chung et al. (2012) also confirmed that γ-OH-PdG is the major acrolein–DNA adduct formed in the human lung tissues. Alamil et al. (2020) reported higher levels of acrolein–DNA adducts in peripheral blood in a smoker than in a non-smoker. On the other hand, it has been reported that two isomers, α- and γ-OH-PdG, formed almost equally in the lung tissues of smokers and non-smokers; and that the level of acrolein–DNA adducts in smokers is not significantly different from that in non-smokers (Ma et al., 2019; Yang et al., 2019a). The levels of acrolein–dG adducts detected were about 10–100 times lower than those reported by other laboratories, and the levels of acrolein–DNA adducts in leukocytes and lungs were similar (Chung et al., 2012; Ma et al., 2019; Zhang et al., 2011; Weng et al., 2018; Yang et al., 2019a; Alamil et al., 2020). [Since tobacco smoke contains substantial amounts of acrolein (see Section 1.4.2(b)), the Working Group noted that the lack of differences in acrolein–DNA adduct formation in both lung tissues and leukocytes of smokers and non-smokers may be explained by other exposure sources.]

(ii) Human cells in vitro

There is ample evidence demonstrating that acrolein can adduct DNA in various primary human cells and in cultured human cell lines in vitro (Wilson et al., 1991; Feng et al., 2006; Pan et al., 2009, 2012, 2016; Greenspan et al., 2012; Wang et al., 2012; see Table 4.2). Feng et al. (2006) reported that acrolein treatment in normal human bronchial epithelial cells and normal human lung fibroblasts induces acrolein–DNA adducts that were preferentially formed at lung cancer TP53 mutational hotspots, and that acrolein preferentially adducts guanines at cytosine methylation CpG sites. Wang et al. (2009a, 2012), using shuttle vectors containing the supF gene, showed that cytosine methylation at CpG sites enhanced acrolein–DNA adduct formation and mutations at these sites; and that in human lung cells, acrolein induced γ-OH-PdG (95%) and α-OH-PdG (5%). These studies also investigated subsequent mutagenesis as well as effects on DNA repair (see Sections 4.2.2 and 4.2.3).

Table 4.2

Acrolein-derived DNA adducts in human cells in vitro.

(iii) Experimental systems: reactions with deoxyribonucleosides

Acrolein is a strong electrophile and readily undergoes reactions with deoxyribonucleosides forming covalent adducts via Michael addition. The reactions of acrolein with deoxyguanosine, deoxyadenosine, and deoxycytidine have been well studied. The electron-rich purine bases are more reactive towards acrolein than are pyrimidine bases. These reactions involve an initial nucleophilic attack of a nitrogen in the bases to the terminal (β) olefinic carbon of acrolein, followed by the addition of a second nitrogen to the aldehydic carbon, leading to the formation of a new ring structure. The end products consist of a class of structurally unique cyclic adducts (Chung et al., 1986). Specifically, upon reaction with deoxyguanosine, acrolein yields cyclic 1,N²-propano-2′-deoxyguanosine (PdG) adducts as a pair of regioisomers, designated as α and γ-OH-PdG (formerly as Acr–dG 1/2 and 3, respectively), depending on which deoxyguanosine nitrogen is involved in the Michael addition (Chung et al., 1984; Fig. 4.2). The α-isomers are a pair of diastereomers that exist in equilibrium due to interconversion via ring opening. The reaction of acrolein with deoxyadenosine yields cyclic 1,N⁶-propano-2′-deoxyadenosine derivatives (1,N⁶-PdA) with the possible formation of either 9- or 7-OH substituted regioisomers (Sodum & Shapiro, 1988, Smith et al., 1990a; Pawłowicz et al., 2006a); however, studies were mostly focused on the 9-OH-isomer (Fig. 4.2). The 9-OH-1,N⁶-PdA adduct can further react with another acrolein molecule, forming a 2:1 adduct (Pawłowicz et al., 2006a); [the Working Group noted that such adducts are unlikely to be formed under physiological conditions in vivo]. In addition to the above-mentioned adducts, the exocyclic amino group in deoxyadenosine can be involved in two Michael additions with two acrolein molecules, followed by intramolecular aldol condensation, which gives rise to a 6-(3-formyl-1,2,5,6-tetrahydropyridyl) substituted adduct (Pawłowicz et al., 2006b). The reaction of acrolein with deoxycytidine forms a 3,N⁴-substituted cyclic adduct (7-hydroxy-3,N⁴-propano-2′-deoxycytidine) as a pair of diastereomers (Chenna & Iden, 1993). However, only one of the two possible regioisomers, the one resulting from Michael addition of the endocyclic N3 to the acrolein β-carbon, has been described (Fig. 4.2). Alkylated adducts, sometimes 2:1 adducts with deoxyadenosine and thymidine, which result from Michael addition to acrolein without subsequent ring closure, have also been described; these appear to be minor products (Lutz et al., 1982; Chenna et al., 1992; Pawłowicz et al., 2006a; Pawłowicz & Kronberg, 2008). Interestingly, under strenuous conditions (DMSO at 100 °C for 5 days) γ-OH-PdG, one of the cyclic adducts of acrolein with deoxyguanosine, can further react with another molecule of deoxyguanosine forming a cyclic bis-nucleoside, γ-OH-PdG–dG (Kozekov et al., 2001). [The Working Group noted that, despite the somewhat harsh conditions, the identification of the bis-nucleoside adduct suggests the possibility that interstrand dG–acrolein–dG crosslinks can be formed in duplex DNA.] Table 4.3 summarizes the reported reaction conditions between acrolein and deoxyribonucleosides/deoxyribonucleotides and the identity of the resulting adducts.

Fig. 4.2

Structures of the major acrolein–deoxyribonucleoside adducts.

Table 4.3

Detection of acrolein-derived adducts with deoxynucleosides or deoxynucleotides in acellular systems.

(iv) Experimental systems: reactions with DNA in vitro

Using synthetic adducts from the reactions with deoxyribonucleosides as reference standards, several studies, mostly with calf thymus DNA, have shown that acrolein can also modify DNA, forming some of the same adducts as with deoxyribonucleosides. Adducts formed in the acrolein-modified DNA have been detected and quantified, mainly after hydrolysis, by a variety of methods, including HPLC with fluorescence detection, ³²P-postlabelling, immune-based assays, or LC-MS/MS (Chung et al., 1984; Liu et al., 2005; Pawłowicz et al., 2006a; Pawłowicz & Kronberg, 2008; Pan et al., 2012; Chen et al., 2019a). The levels of adduct modification in these reactions are considerably lower than those with the monomers; however, the levels of modification may be significantly increased using denatured or single-stranded DNA, or oligomers. As the most nucleophilic base in DNA, guanine reacts to the greatest extent, in what constitutes a major pathway of DNA modification by acrolein.

Unlike its reactions with the monomers, the formation of cyclic adducts by acrolein with deoxyguanosine and deoxyadenosine in DNA appears to be regioselective. For example, γ-OH-PdG predominates over the α-isomer in DNA (Chung et al., 1984). Similarly, 9-OH-1,N⁶-PdA was reported to be the product in acrolein-modified DNA, not the 7-OH-isomer (Smith et al., 1990a). Studies were carried out to shed light onto the molecular basis for the regioselectivity. Possible explanations involve the tertiary structure of DNA and/or an intermediacy of the Schiff’s base between acrolein and amines (Chung et al., 2012). The 2:1 adduct of acrolein with deoxyadenosine, but not thymidine or deoxycytidine, was also observed in the reactions with DNA in vitro (Pawłowicz et al., 2006b; Pawłowicz & Kronberg, 2008). The formation of cyclic adducts of acrolein involves covalent binding with the nitrogens that participate in hydrogen bonding in the double helical structure of DNA.

Interestingly, the cyclic bis-nucleoside adduct of γ-OH-PdG (γ-OH-PdG–dG) described above was also found in a DNA duplex containing γ-OH-PdG in a 5′-CpG sequence context with the exocyclic amino group of deoxyguanosine in the opposite strand, resulting from interstrand crosslinking in oligonucleotide or DNA (Kozekov et al., 2001, 2010; Minko et al., 2009). Although the crosslinking product can undergo reversible reaction, it was sufficiently stable to be isolated for structural characterization. Table 4.4 summarizes the reactions of acrolein with oligomers and DNA.

Table 4.4

Detection of acrolein-derived DNA adducts with oligonucleotides and DNA.

(v) Experimental systems: DNA adduct formation in tissues and cells

See Table 4.5 and Table 4.6.

Table 4.5

Detection of acrolein-derived DNA adducts in experimental animals in vivo.

Table 4.6

Detection of acrolein-derived DNA adducts in experimental systems in vitro.

Most in vivo studies of the acrolein-derived DNA adducts in cells and tissues have focused on γ-OH-PdG. The only acrolein-derived DNA adduct other than γ-OH-PdG reported to be formed in vivo is 9-OH-1,N⁶-PdA (Kawai et al., 2003). It has been shown that γ-OH-PdG can be formed in DNA in vivo from acrolein derived from two major sources: environmental exposure, such as tobacco smoke; and endogenous production, such as lipid peroxidation and polyamine oxidation. Although diet may also be a possible source, its importance has been questioned by a study in which integrated quantitative structure–activity relationship–physiologically based kinetic/dynamic (QSAR-PBK/D) modelling was used to predict formation of γ-OH-PdG (Kiwamoto et al., 2015). As acrolein is an oxidation product of lipid peroxidation from ω-3 and -6 polyunsaturated fatty acids, the acrolein-derived adducts can be formed upon incubation of these fatty acids in the presence of deoxyguanosine under oxidative conditions (Pan & Chung, 2002; Kawai et al., 2003). As lipid peroxidation occurs continuously in vivo as part of normal physiological processes, acrolein-derived DNA adducts are constantly formed in cellular DNA as endogenous background lesions. Several methods have been developed to detect acrolein-derived DNA adducts in vivo, including ³²P-postlabelling, LC-MS/MS, and immunohistochemistry. The availability of monoclonal antibodies against acrolein-derived deoxyadenosine and deoxyguanosine adducts has facilitated the development of immune-based methods, such as immunohistochemistry, immunocytochemistry, and dot blot, for detecting these adducts in cells and tissues (Kawai et al., 2003 and Pan et al., 2012). However, it is generally agreed that LC-MS/MS is by far the most specific and most sensitive method for adduct detection and identification in vivo.

Acrolein-derived DNA adducts, including γ-OH-PdG, have been detected in various experimental animals in vivo (see Table 4.5). γ-OH-PdG was detected by a ³²P-postlabelling method in DNA of peripheral blood lymphocytes obtained from a dog given a therapeutic oral dose of cyclophosphamide at 6.6 mg/kg (Wilson et al., 1991). Studies later showed γ-OH-PdG is an endogenous background DNA lesion in livers of rodents and humans without known treatment and exposure (Nath & Chung, 1994; Nath et al., 1996). γ-OH-PdG was also detected in rats and mice given control feed (Fu et al., 2018; Chen et al., 2019a). Exposure of cockerels to acrolein (1 and 10 ppm) for 6 hours via inhalation gave rise to γ-OH-PdG in the aortic DNA (Penn et al., 2001). Exposure to tobacco smoke (mainstream, ~75 mg/m³, 6 hours per day, 5 days per week, for 12 weeks; or sidestream, 500 µg/m³, 6 hours per day, 5 days per week, for 8 or 16 weeks) and automobile exhaust was shown to induce γ-OH-PdG formation in the rodent lung (Lee et al., 2015; Weng et al., 2018; Douki et al., 2018). A small, but significant, increase in levels of acrolein-derived DNA adducts was found in the lung DNA of rats exposed to diesel exhaust; however, the data on the specific identity of the adduct were not reported (Douki et al., 2018). The notion that DNA adducts of acrolein can be derived from endogenous sources, such as lipid peroxidation, has been reinforced by recent studies showing that the levels of γ-OH-PdG are significantly increased in liver DNA of mice fed a high-fat diet (Coia et al., 2018). This study further demonstrated that the elevated hepatic formation of γ-OH-PdG in mice fed a high-fat diet parallels the increased risk of developing hepatocellular carcinoma in these mice. The only other acrolein-derived DNA adduct in vivo so far reported is 9-OH-1,N⁶-PdA. This adduct was found in rat kidney, using an iron-induced kidney carcinogenesis model under oxidative stress conditions in which rats were exposed to ferric nitrilotriacetate (Kawai et al., 2003). However, the structural identity of the adduct was not unequivocally established in this study because the adduct was detected by a monoclonal antibody raised against acrolein-modified DNA, not specifically 9-OH-1,N⁶-PdA.

Acrolein-derived DNA adducts, including γ-OH-PdG, have also been assessed in various experimental cell types in vitro (see Table 4.6). Using a monoclonal antibody developed against crotonaldehyde-derived cyclic deoxyguanosine adducts structurally analogous to γ-OH-PdG (Foiles et al., 1987), an early study demonstrated the detection of γ-OH-PdG in Salmonella typhimurium strains TA100 and TA104 exposed to acrolein at the concentration range in which mutations were induced (Foiles et al., 1989). The first study detecting γ-OH-PdG in mammalian cells was reported using enzyme-linked immunosorbent assay (ELISA) in Chinese hamster ovary cells exposed to acrolein at a high concentration (1 mM) (Foiles et al., 1990). This concentration, however, was too toxic for scoring mutations. Later, monoclonal antibodies were raised against 1,N⁶-PdA, using acrolein-modified DNA (Kawai et al., 2003), and against γ-OH-PdG, using specifically γ-OH-PdG-conjugated bovine serum albumin (Pan et al., 2012; see Table 4.4). More recently, a DNA adductomics approach was applied to the study of γ-OH-PdG in the soil bacterium Sphingobium spp. strain KK22 (Kanaly et al., 2015). This study demonstrated the potential of LC-MS/MS in DNA adductomics as a promising tool to study γ-OH-PdG and other related adducts in cells.

(b) Interactions with cellular proteins

(i) Reactions with amino acids and proteins in vitro

See Table 4.7.

Table 4.7

Reactions of acrolein with amino acids and proteins.

Acrolein shows a strong propensity to react with amino acids or proteins via Michael addition, considerably more so than with DNA bases. Cysteines and the thiols of amino acids and proteins are the major sites for covalent binding with acrolein. Because the thiols are known to play important roles in enzyme activities and redox homeostasis, their facile interactions with acrolein can profoundly alter cellular functions. On the other hand, compounds with the mercapto (-SH) group, like GSH and cysteine, are widely used as effective scavengers of acrolein, with aim of reducing its adverse effects in cells or animals (Rees & Tarlow, 1967; Gurtoo et al., 1981; Wildenauer & Oehlmann, 1982).

The N-alkylation of proteins by acrolein may also occur. These reactions, through the side-chain amino group of lysine or a ring nitrogen of histidine, are kinetically less favourable than conjugation with -SH groups. Unlike reactions with cysteines, N-alkylation is irreversible, and the end products are usually quite stable (Cai et al., 2009). Reactions of acrolein with lysine have been investigated extensively with 3-formyl-3,4-dehydropiperidine (FDP), a 2:1 adduct, as a notable product that may serve as a potential biomarker of acrolein exposure detectable by a monoclonal antibody (Uchida et al., 1998a, b). The formation of FDP lysine adducts in histone has been associated with the inhibition of chromatin assembly mediated by acrolein (Fang et al., 2016). Furthermore, acrolein can form a Schiff base with the amine of lysine, followed by Michael addition yielding N-(3-methylpyridium)lysine via 2:1 addition (Furuhata et al., 2003; Kaminskas et al., 2005) and intra- and inter-protein crosslinks (Burcham & Pyke, 2006; Ishii et al., 2007; Minko et al., 2008). In addition to lysine, acrolein can also react with histidine by nucleophilic attack on the imidazole ring nitrogen (Pocker & Janjić, 1988; Maeshima et al., 2012). A recent study demonstrated that acrolein may be one of the aldehydes in tobacco smoke responsible for the inhibition of the enzymes involved in DNA repair by targeting these proteins via direct binding (Weng et al., 2018). Acrolein is a major metabolic product of certain anticancer drugs, such as cyclophosphamide, and early studies showed that the bladder toxicity of cyclophosphamide can be effectively attenuated by GSH or other SH-containing small compounds, whereas its therapeutic efficacy was not affected by GSH (Gurtoo et al., 1981). The reaction products were studied and compared between acrolein versus 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and a synthetic peptide 128 (Carbone et al., 1997). Ample evidence shows that dithiothreitol and hydralazine also inhibit acrolein-induced cellular toxicity through their interactions with acrolein (Rees & Tarlow, 1967; Cox et al., 1988; Burcham et al., 2000; Burcham & Pyke, 2006; Chen et al., 2016). The chemical basis for the inhibition is the -SH conjugation with the former and formation of a hydrazone derivative with the latter; both reactions can effectively block acrolein’s ability to bind cellular target proteins.

The identification of the binding sites of acrolein to protein is important because this knowledge may help understand the molecular basis underlying the toxicity caused by acrolein. To this end, LC-MS/MS-based proteomic methods have been developed in the past decade (Spiess et al., 2011; Coffey & Gronert, 2016; Afonso et al., 2018; Chen, Liu et al., 2019b). The application of proteomics in the determination of protein binding sites has been demonstrated with the use of model proteins as well as in cells treated with acrolein (Table 4.7).

(ii) Protein binding in human cells in vitro

Enhanced protein binding of acrolein has been demonstrated in exposed human bronchial epithelial cells (Caito et al., 2010), in human serum albumin (Colombo et al., 2010) and with the lactate dehydrogenase isozymes in human saliva (Avezov et al., 2014). Further investigations have revealed effects on protein function. For example, acrolein formed Michael adducts with sirtuin 1 (SIRT1) and reduced its activity (Caito et al., 2010). The evidence for protein dysfunction is ample; for example, Biswal et al. (2003) showed that acrolein modified c-JUN, preventing its dimerization and consequently preventing AP-1-promoter binding, and that acrolein modified B[a]P-induced TP53 and reduced its transcription transactivation activity. In human T cells, acrolein caused modification at Cys-61 and Arg-307 sites in p50 and IkB phosphorylation, consequently preventing DNA binding of NF-kB and reducing the expression of interleukins IL2 and IL10, interferon gamma (INFγ), tumour necrosis factor α (TNFα), and granulocyte-macrophage colony-stimulating factor. In human lung cells, acrolein at noncytotoxic levels can cause acrolein–Cys binding and consequently Hsp90 crosslinks (Burcham et al., 2007).

(iii) Protein binding in experimental animal cells and tissues

See Table 4.8.

Table 4.8

Detection of acrolein-derived adducts in proteins in experimental animal cells and tissues.

To identify target proteins and binding sites in cells and tissues of rodents exposed to acrolein the methods currently used include immunohistochemistry, immunocytochemistry, Western blot, and LC-MS/MS. Because direct exposure to acrolein can cause overt toxicity, studies in vivo are often carried out with cancer chemotherapeutics, cigarette smoke, ethanol, and diet as indirect sources of acrolein (Gurtoo et al., 1981; Wildenauer & Oehlmann, 1982; Günther et al., 2008; Conklin et al., 2009; Chen et al., 2016). The availability of a monoclonal antibody to acrolein-modified keyhole limpet haemocyanin, with the lysine binding as an epitope, has greatly facilitated studies of acrolein-bound proteins in cells and tissues (Uchida et al., 1998a, b). The antibody was specifically developed for lysine-adducted proteins. In recent years, LC-MS/MS-based proteomics has also been used to identify hundreds, if not thousands, of protein targets in cells and tissues (Spiess et al., 2011; Chavez et al., 2011; Han et al., 2012; Chen et al., 2019b; Table 4.8).

4.2.2. Is genotoxic

(a) Humans

(i) Exposed humans

No data were available to the Working Group.

(ii) Human cells in vitro

See Table 4.9.

Table 4.9

Genetic and related effects of acrolein in human cells in vitro.

Using the alkaline elution assay, acrolein-induced DNA strand breaks were observed in primary human bronchial epithelial cells (Grafström et al., 1986, 1988), human normal skin fibroblasts (CRL 1508) as well as xeroderma pigmentosum fibroblasts (Dypbukt et al., 1993), human myeloid leukaemia cells (K562) (Crook et al., 1986), and human lymphoblastoid cells (Namalwa) (Eisenbrand et al., 1995). [The Working Group noted that some of these experiments (Grafström et al., 1986; Dypbukt et al., 1993) were carried out at concentrations of acrolein that induced excessive cytotoxicity.] The frequency of phosphorylated H2AX proteins (γH2AX), an indicator of DNA double-strand breaks, was found to be significantly increased in acrolein-treated lung epithelial adenocarcinoma cells (A549) (Zhang et al., 2017) and human bronchial epithelial cells (BEAS-2B) (Zhang et al., 2020), and positive results were obtained in the comet assay for DNA damage in human normal lung fibroblasts (IMR-90) (Luo et al., 2013), A549 cells (Zhang et al., 2018), BEAS-2B cells (Zhang et al., 2020), human Burkitt lymphoma B lymphocytes (Raji) (Yang et al., 1999a), liver hepatoma cells (HepG2) (Li et al., 2008a), and retinal epithelial cells (ARPE-19) (Li et al., 2008b). [The Working Group noted that one experiment (Yang et al., 1999a) was carried out with acrolein at concentrations up to 500 µM with no measure of cytotoxicity.]

Acrolein-induced DNA–protein crosslinks were reported in bronchial epithelial cells (Grafström et al., 1986, 1988), in HepG2 cells (Li et al., 2008b), and in Burkitt lymphoma cells (EBV-BL) (Costa et al., 1997), but a negative result was reported in human promyelocytic leukaemia cells at a concentration (i.e. 100 μM) that resulted in a study-specific cell viability of 58% (Schoenfeld & Witz, 2000). [The Working Group noted that some of these experiments (Grafström et al., 1986; Schoenfeld & Witz, 2000) were carried out at concentrations of acrolein that induced excessive cytotoxicity.] Additionally, a negative result was reported in BEAS-2B cells exposed to acrolein at 7.5 μM; however, at this same concentration acrolein significantly enhanced the level of DNA–protein crosslinks observed when co-administered with formaldehyde (Zhang et al., 2020).

Acrolein induced a dose-dependent increase in HPRT mutant frequency in human DNA-repair-deficient xeroderma pigmentosum fibroblasts (Curren et al., 1988) and normal human bronchial epithelial cells (BEAS-2B) (Zhang et al., 2020), but failed to elicit a positive response in normal human fibroblasts when tested up to 2 µM (Curren et al., 1988). A positive result was obtained for micronucleus formation in lung A549 cells (Zhang et al., 2018) and BEAS-2B cells (Zhang et al., 2020), and for sister-chromatid exchanges in human primary lymphocytes (Wilmer et al., 1986). All studies in human cells were carried out in the absence of exogenous metabolic activation.

In eight experiments, plasmids containing the supF gene were reacted with acrolein and were then transfected into various human cell types to allow for repair and replication; the supF mutant frequency was subsequently assessed in Escherichia coli. Six experiments reported positive results (Feng et al., 2006; Kawanishi et al., 1998; Wang et al., 2009a, 2013a; Lee et al., 2014) and two experiments reported negative results (Kim et al., 2007). In one of these studies, Feng et al. (2006) sequenced mutations in the recovered plasmid from normal human lung fibroblasts and found that > 50% of the acrolein-induced base substitutions in the supF gene were G→T transversions. In the supF gene of acrolein-reacted plasmids recovered from human lung fibroblasts (CCL-202), primarily G→T transversions (53%) were observed, followed by G→A transitions (30%), and G→C transversions (12%); moreover, they found that mutational hotspots occurred in sequences with runs of Gs, and that the mutations across the supF gene mapped to the same sequence locations as those where the acrolein-derived adducts formed (Wang et al., 2009a). In another supF shuttle vector study, of the acrolein-exposed plasmids recovered from a transformed normal human fibroblast cell line (W138VA13), 76% of mutations were base substitutions (46% single substitutions, 30% tandem or multiple substitutions), 21% were deletions, and 2% were insertions. Of the base substitutions, it was found that G→T predominated (44%), followed by G→A (24%), and G→C (12%) (Kawanishi et al., 1998).

A study in human xeroderma pigmentosum group V (XPV) cells transfected with a plasmid containing the α-OH-PdG adduct found that there was inaccurate translesion synthesis by both polymerases η and κ (Yang et al., 2003). Only marginal miscoding (< 1%) was observed for translesion synthesis across the γ-OH-PdG adduct in normal human fibroblasts, HeLa cells, xeroderma pigmentosum group A (XPA), and group V (XPV) cells (Yang et al., 2002a; Yoon et al., 2018). Another study in XPA cells transfected with plasmids containing either the α- or the γ-OH-PdG adduct found that the α-OH-PdG adduct strongly blocked DNA synthesis and induced base-pair substitutions (predominantly G→T) with an overall miscoding frequency of 10.4–12.5%, whereas the γ-OH-PdG adduct had neither effect (Yang et al., 2002b).

In one acellular study, human DNA polymerase ι was found to replicate past γ-OH-PdG in an error-free manner (Washington et al., 2004a), whereas in another acellular study, γ-OH-PdG was found to cause a significant replication block to human polymerase η (i.e. 100 times lower efficiency than dGTP), and caused misincorporation frequencies of approximately 10⁻² to 10⁻¹ (Minko et al., 2003).

(b) Experimental systems

(i) Non-human mammals in vivo

See Table 4.10.

Table 4.10

Genetic and related effects of acrolein in non-human mammals in vivo.

A negative result was obtained for formation of DNA–protein crosslinks in the nasal respiratory mucosa of male Fischer 344 rats exposed to acrolein by inhalation for 6 hours; however, acrolein enhanced the level of DNA–protein crosslinks when rats were co-exposed to both acrolein and formaldehyde (Lam et al., 1985). No significant increase in the frequency of dominant lethal mutations was observed in male ICR/Ha Swiss mice exposed to acrolein as a single intraperitoneal injection (Epstein et al., 1972). In the micronucleus assay, a significant increase of 1.4-fold in the frequency of micronucleated polychromatic erythrocytes was observed in the bone marrow of male Sprague-Dawley rats treated with acrolein at 5 mg/kg bw per day by gavage, six times per week, for 30 days (Aydın et al., 2018). There was no dose-dependent increase in the frequency of micronucleated normochromatic erythrocytes in male and female B6C3F₁ mice exposed to acrolein at 10 mg/kg bw per day by gavage for 14 weeks. However, a significant increase of 2-fold in the frequency of micronucleus formation was observed in the female mice at 5 mg/kg bw per day (Irwin, 2006).

(ii) Non-human mammalian cells in vitro

See Table 4.11.

Table 4.11

Genetic and related effects of acrolein in non-human mammalian cells in vitro.

An increase in the frequency of DNA strand breaks was observed via the alkaline elution assay in Chinese hamster ovary (K1) cells (Deaton et al., 1993) and mouse leukaemia (L1210) cells, although the latter study noted that the tested dose caused substantial toxicity (Eder et al., 1993). An alkaline comet assay in mouse Leydig cells gave a positive result for DNA damage (i.e. comet tail intensity) at the lowest concentration tested (i.e. 7.4 µM) (Yildizbayrak et al., 2020). At a dose that was higher by nearly 6000-fold (i.e. 44.1 mM), an alkaline comet assay in rat primary hepatocytes gave a negative response when cells were analysed for comet tail length/intensity. However, 94% of cells had a condensed nucleus characteristic of compounds that cause DNA and/or protein crosslinks (Kuchenmeister et al., 1998). Acrolein-induced DNA–protein crosslinks were also observed in African green monkey kidney cells (CV-1) (Permana & Snapka, 1994) and in rat nasal mucosal cells (Lam et al., 1985). [The Working Group noted that these experiments were carried out with acrolein at high concentrations that either induced excessive cytotoxicity (Kuchenmeister et al., 1998; Lam et al., 1985), or at which cytotoxicity was not assessed (Permana & Snapka, 1994).]

Acrolein was found to be mutagenic, with a positive result for Hprt mutations in two assays in Chinese hamster lung fibroblasts (V79) (Smith et al., 1990b; Gardner et al., 2004). However, a negative result was obtained in V79 cells that express the rat aldo-keto reductase enzyme AKR7A1 (Gardner et al., 2004). [The Working Group noted that AKR7A1 catalyses the reduction of acrolein to alcohols, indicating that rat AKR7A1 protects against acrolein-induced mutagenicity (see Section 4.1.2b).] The frequency of acrolein-induced Hprt mutants was also analysed in Chinese hamster ovary cells, with one study reporting a positive response at 30 µM (Cai et al., 1999). Another study reported elevated mutant frequencies at some doses, but with no clear dose–response relationship when acrolein was tested at up to 89 µM with and without metabolic activation (rat liver S9) (Parent et al., 1991b). An additional study reported negative results for Hprt mutations in Chinese hamster ovary cells (Foiles et al., 1990). A significant increase in the frequency of Tk^+/− mutations was reported in mouse lymphoma (L5178Y) cells (Demir et al., 2011), but a negative response was reported for the induction of cII mutations in mouse embryonic fibroblasts from the Big Blue mouse (Kim et al., 2007). Chromosomal aberrations and sister-chromatid exchanges were both assessed in two different studies in Chinese hamster ovary cells, with both reporting a negative response for chromosomal aberrations, and a positive result for sister-chromatid exchanges (Au et al., 1980; Galloway et al., 1987).

Using shuttle vectors containing either adduct isomer, the α- and γ-OH-PdG adducts were found to be mutagenic in African green monkey kidney (COS-7) cells, with a similar percentage mutagenicity observed for both isomers (i.e. 8.3% and 7.4%, respectively) (Sanchez et al., 2003). The γ-OH-PdG adduct was found to be significantly mutagenic in plasmid-transfected COS-7 cells; primarily transversions were observed, but also transition mutations (Kanuri et al., 2002).

(iii) Non-mammalian experimental systems

See Table 4.12.

Table 4.12

Genetic and related effects of acrolein in non-mammalian experimental systems.

In Drosophila melanogaster, largely positive results were obtained in SMART eye and wing spot mutation studies after exposure to acrolein in feed (Sierra et al., 1991; Demir et al., 2013; Vogel & Nivard, 1993), or via inhalation (Vogel & Nivard, 1993). Acrolein was also tested in Drosophila for the ability to induce sex-linked recessive lethal mutations, with negative results for all four feeding assays, but when acrolein was administered by injection, two out of three assays gave positive results (Zimmering et al., 1985, 1989; Sierra et al., 1991; Barros, et al., 1994a, b). Acrolein did not induce sex chromosome loss in Drosophila when administered either by injection or via feed (Sierra et al., 1991).

In Saccharomyces cerevisiae, acrolein did not induce DNA strand breaks and interstrand crosslinks in one study (Fleer & Brendel, 1982), or reverse mutations in another study (Izard, 1973).

Acrolein has been evaluated in multiple assays in several Salmonella tester strains sensitive to base-pair substitutions (i.e. TA1535, TA100, TA104) and frameshift mutations (i.e. TA1537, TA1538, TA97, and TA98). However, only one assay was carried out in TA102, a strain that is used specifically for the detection of crosslinking agents. In the TA1535 base-pair substitution strain, a negative response was observed in the SOS induction assay (Benamira & Marnett, 1992) and the results were negative for reverse mutation (Hales, 1982; Haworth et al., 1983; Florin et al., 1980; Loquet et al., 1981; Lijinsky & Andrews, 1980; Irwin, 2006). In the TA100 strain, the results were mixed positive (Parent et al., 1996b; Haworth et al., 1983; Foiles et al., 1989; Eder et al., 1993; Khudoley et al., 1987; Eder et al., 1990; Lutz et al., 1982) or negative (Florin et al., 1980; Loquet et al., 1981; Lijinsky & Andrews, 1980; Basu & Marnett, 1984; Irwin, 2006), with the positive responses mainly occurring without metabolic activation (rat liver S9). Notably, only one pre-incubation assay was carried out with TA100 and a negative result was reported (Irwin, 2006). However, a positive result was obtained in TA100 when acrolein was tested in a liquid suspension assay (Lutz et al., 1982). Of the two assays reported in TA104, both gave positive results without metabolic activation (S9) (Foiles et al., 1989; Marnett et al., 1985). In the frameshift strains, all three TA1537 assays gave negative results (Haworth et al., 1983; Florin et al., 1980; Lijinsky & Andrews, 1980), both results in TA1538 were negative (Lijinsky & Andrews, 1980; Irwin, 2006), the one TA97 experiment gave negative results (using the vapour protocol) (Irwin, 2006), and four positive results (Lijinsky & Andrews, 1980; Parent et al.,1996b; Claxton, 1985; Khudoley et al., 1987) and six negative results were reported in TA98 (Haworth et al., 1983; Florin et al., 1980; Loquet et al., 1981; Basu & Marnett,1984; Irwin, 2006). A negative result was obtained in the crosslink strain TA102, but the highest tested dose was not reported (Marnett et al., 1985). The more sensitive pre-incubation version of the Ames assay was not carried out with any frameshift strains without metabolic activation.

In E. coli, a positive result for DNA-histone crosslinks was reported (Kuykendall & Bogdanffy, 1992). Several studies reported positive results for acrolein in the SOS chromotest (Eder et al., 1990, 1993; Eder & Deininger, 2002), whereas a negative response was observed in the SOS chromotest when DMSO was used as the solvent. Additional studies in E. coli reported positive results for reverse mutations (Nunoshiba & Yamamoto, 1999; Hemminki et al., 1980), as well as one experiment with a negative result without metabolic activation and a weak positive result with metabolic activation (Parent et al., 1996b). In one study, three different plasmids containing different mutational targets in the lacZ gene were reacted with acrolein and then transfected into E. coli for mutant frequency assessment; positive results were observed for all three mutation types (i.e. A→C, A→T, and A→G) (Dylewska et al., 2017). An increase in DNA damage, assessed via a fluorescence-based screen quantifying changes in DNA melting/annealing behaviour, was observed in calf thymus DNA reacted with acrolein in an acellular system (Kailasam & Rogers, 2007).

In the study of Kanuri et al. (2002), described above, the γ-OH-PdG adduct was found to be significantly less mutagenic in E. coli than in COS-7 cells transfected with the same plasmid (i.e. 0.96% mutations in E. coli versus 6.3–7.4% in COS-7). In E. coli, a study by Yang et al. (2001) found that DNA polymerase III catalysed translesion synthesis across the γ-OH-PdG adduct in an error-free manner, but that DNA polymerase I did so in an error-prone manner, with incorporation frequencies opposite the γ-OH-PdG adduct of 93% for deoxyadenosine triphosphate (dATP), 88% for deoxyguanosine triphosphate (dGTP), 7% for deoxycytidine triphosphate (dCTP), and 5% for deoxythymidine triphosphate (dTTP). Additionally, γ-OH-PdG was found to inhibit DNA synthesis in E. coli (Yang et al., 2001). In another study with E. coli transformed with bacteriophage vectors containing an 8-hydroxy-1,N²-propano-2′-deoxyguanosine (OH-PdG) adduct (no stereochemistry specified), the correct base was inserted under all conditions (VanderVeen et al., 2001).

In an acellular study, γ-OH-PdG was found to cause a significant replication block to yeast polymerase η (i.e. 190 times lower efficiency than deoxyguanosine), although incorporation opposite the adduct was relatively accurate (Minko et al., 2003). In an acellular study, both α- and γ-OH-PdG caused a significant replication block to yeast DNA pol η, with α-OH-PdG being a significantly stronger blocking lesion as pairing with dCTP was strongly inhibited (Sanchez et al., 2003). When assayed for nucleotide incorporation frequency, dCTP was primarily incorporated across from both lesions, but extension with other deoxynucleoside triphosphates (dNTPs) was also observed at almost identical ratios for both stereoisomers (Sanchez et al., 2003). In other acellular studies, yeast Rev1 was demonstrated to replicate past γ-OH-PdG in an error-free manner (Washington et al., 2004b; Nair et al., 2008).

In an acellular study with bacteriophage DNA polymerase T7⁻ and HIV-1 reverse transcriptase, OH-PdG adducts (stereochemistry not specified) were found to be miscoding, with dATP being preferentially incorporated instead of dCTP (Zang et al., 2005). In another acellular study, Sulfolobus solfataricus Dpo4, the prototypic Y-family DNA polymerase, was capable of bypassing γ-OH-PdG adducts in a primarily error-free manner (Shanmugam et al., 2013).

4.2.3. Alters DNA repair

(a) Humans

No studies on exposed humans were available to the Working Group.

Acrolein was found to inhibit the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT) in human bronchial fibroblasts in two studies (Krokan et al., 1985; Grafström et al., 1986). [The Working Group noted that, as aldehydes are highly reactive towards thiols, this inhibition is probably due to acrolein reacting with and inhibiting the methyl-acceptor cysteine residue in MGMT (Grafström et al., 1986).] In a study using human normal skin fibroblasts and DNA-repair deficient XPA fibroblasts, it was concluded that acrolein inhibited nucleotide excision repair since there was an accumulation of DNA single-strand breaks in acrolein-treated normal skin fibroblasts, which only increased after a recovery period in fresh medium (Dypbukt et al., 1993). Indeed, several studies found that acrolein treatment causes concentration-dependent inhibition of nucleotide excision repair in primary normal human lung fibroblasts (NHLFs) (Feng et al., 2006; Wang et al., 2012), primary normal human bronchial epithelial cells (NHBEs), human lung adenocarcinoma cells (A549s) (Wang et al., 2012), and in immortalized human urothelial (UROtsa) cells (Lee et al., 2014). Acrolein also causes concentration-dependent inhibition of base excision repair in NHBEs, NHLFs, A549s (Wang et al., 2012), and UROtsa cells (Lee et al., 2014), and of mismatch repair in HeLa (epithelial adenocarcinoma) cells (Wang et al., 2012). A subgenotoxic concentration of acrolein (i.e. 50 µM) has also been demonstrated to inhibit the repair of gamma-irradiation–induced DNA damage in human B-lymphoid cells, and the repair inhibition increased with acrolein dose (Yang et al., 1999b).

Acrolein treatment reduced the expression level of certain DNA repair genes in A549 cells (Sarkar, 2019). Other studies did not find an effect on gene expression but showed that acrolein reacts rapidly with and directly inhibits DNA repair proteins (Wang et al., 2012; Lee et al., 2014). More specifically, in NHBE, NHLF, A549, and UROtsa cells, acrolein treatment caused a dose-dependent reduction in the expression of repair proteins (i.e. XPA, XPC, human 8-oxoguanine DNA glycosylase (hOGG1), PMS2, and MLH1) that are crucial for nucleotide excision repair, base excision repair, and mismatch repair (Wang et al., 2012; Lee et al., 2014). Pre-treatment of cells with proteasome inhibitors reduced the level of protein degradation, and pre-treatment with an autophagy inhibitor caused partial reduction in the degradation of DNA repair proteins; however, repair capacity was not rescued (Wang et al., 2012; Lee et al., 2014). [The Working Group noted that these results indicate that acrolein protein modification alone is capable of causing DNA-repair protein dysfunction, and that this modification results in DNA-repair protein degradation both by proteasomes and by autophagy; see also Section 4.2.1(a).]

Wang et al. (2012) found that both α-OH-PdG and γ-OH-PdG adducts were not efficiently repaired in acrolein-exposed NHBEs and NHLFs. A study using HeLa whole-cell extracts found that α-OH-PdG and γ-OH-PdG adducts were not efficiently removed by base excision repair (Yang et al., 2002b). In a study of nuclear extracts from unexposed human normal skin fibroblasts and DNA-repair deficient human XPA cells transfected with acrolein-treated plasmids, it was found that acrolein–dG adducts (i.e. a mixture of α-OH-PdG and γ-OH-PdG) are substrates for nucleotide excision repair proteins, but are repaired at a much slower rate than other similar adducts, and that this is probably because of poor recognition and/or excision of the lesions in DNA (Choudhury et al., 2013).

(b) Experimental systems

No data were available to the Working Group.

4.2.4. Induces oxidative stress

(a) Humans

No in vivo data were available to the Working Group.

In vitro studies using human retinal pigmented epithelial and lung fibroblast cell lines have demonstrated that acrolein induces a variety of biochemical changes, including decreased nuclear protein levels of nuclear factor erythroid 2-related factor 2 (NRF2; [NFE2L2, nuclear factor, erythroid 2-like 2]) (retinal pigmented epithelial cells only), decreased superoxide dismutase and glutathione peroxidase activities, lowered cellular GSH levels, and increased generation of reactive oxygen species (ROS) and protein carbonyls (Jia et al., 2007, 2009; Li et al., 2008a). Haem oxygenase-1 (HO-1 [HMOX1]) gene expression is induced in human bronchial epithelial cells (HBE1 cells) after acrolein exposure, and acrolein-induced HO-1 protein levels are attenuated by pan-protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K) inhibitors (Zhang & Forman, 2008). Exposure of human cultured liver (HepG2) or retinal pigment epithelial cells to acrolein results in endoplasmic reticulum stress, mitochondrial disruption, and oxidative stress (Li et al., 2008a, b; Mohammad et al., 2012). Human primary bronchial epithelial cells exposed to acrolein vapour (0.1 and 0.2 ppm) for 30 minutes had increased IL17 expression (Johanson et al., 2020).

(b) Experimental systems

See Table 4.13.

Table 4.13

Effects of acrolein on markers of oxidative stress in non-human mammals in vivo.

Multiple in vivo studies in rodents have shown that acrolein administration via multiple routes of exposure, including oral administration, inhalation, and intraperitoneal injection, results in decreased tissue GSH concentrations (Arumugam et al., 1997; Aydın et al., 2018; Cassee et al., 1996; Cichocki et al., 2014; Cooper et al., 1992; Gurtoo et al., 1981; Kim et al., 2018). Oral and parenteral rodent studies have shown evidence of lipid peroxidation or protein carbonyl production after short-term (up to 1 month) exposure (Aydın et al., 2018; Rom et al., 2017; Sun et al., 2014; Yousefipour et al., 2013, 2017). A significant increase in levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG) has been reported in the mouse lung after inhalation of acrolein (Kim et al., 2018). Intraperitoneal exposure of wildtype and gp91^phox knockout mice with acrolein at 0.5 μg/kg provided evidence that increased oxygen radical generation occurs via NAD(P)H oxidase activation (Yousefipour et al., 2013). In vitro studies with bovine pulmonary artery endothelial cells have likewise shown that acrolein causes increased generation of oxygen radicals by NAD(P)H oxidase activation (Jaimes et al., 2004).

4.2.5. Is immunosuppressive

(a) Humans

No data in exposed humans were available to the Working Group.

In vitro studies show that acrolein exposure is associated with apoptosis and necrosis in human alveolar macrophages and with inhibition of IL1β, TNF, and IL12 release from cells (Li et al., 1997). Human T cells treated with acrolein also demonstrated suppressed cytokine production and T-cell responses (Lambert et al., 2005). Human alveolar macrophages infected with Mycobacterium tuberculosis and exposed to acrolein have a reduced ability to clear these bacteria (Shang et al., 2011).

(b) Experimental systems

See Table 4.14.

Table 4.14

Immunosuppression after acrolein exposure in non-human mammals in vivo.

Multiple studies in rodents have assessed whether acrolein inhalation alters bacterial-induced mortality, bactericidal activity, or innate immune function (Aranyi et al., 1986; Astry & Jakab, 1983; Jakab, 1993; Danyal et al., 2016; Hristova et al., 2012; Leach et al., 1987). Most of these studies have used short-term exposures (e.g. < 10 days).

Splenic cells isolated from naïve female C57/BL6 mice that were subsequently exposed to acrolein exhibited decreased T- and B-cell proliferation (Poirier et al., 2002). Immunosuppression by acrolein has been attributed to GSH depletion and interactions with redox-sensitive signalling pathways such as NF-κB or JNK (Lambert et al., 2005; Valacchi et al., 2005; Kasahara et al., 2008).

4.2.6. Induces chronic inflammation

(a) Humans

No data were available to the Working Group.

(b) Experimental systems

See Table 4.15.

Table 4.15

Inflammatory responses after acrolein exposure in non-human mammals in vivo.

Chronic inhalation (6 hours per day, 5 days per week, for 104 weeks) of acrolein was associated with mild inflammation in the nasal respiratory epithelium in rats and mice (JBRC, 2016d, e, f; see also Section 3). A 1-year study in hamsters treated with acrolein by inhalation (7 hours per day, 5 days per week, for 52 weeks) was also associated with mild inflammation in the nasal respiratory epithelium (Feron & Kruysse, 1977; see Table 3.1). [The Working Group noted that changes in cell proliferation in response to acrolein exposure have not been evaluated in experimental systems.] Multiple studies in rodents with short-term or subchronic exposures to acrolein via inhalation have shown that acrolein produces airway inflammation (Johanson et al., 2020; Kasahara et al., 2008; Wang et al., 2009b; Liu et al., 2009a, b; Sithu et al., 2010). Accumulation of monocytes, macrophages, and lymphocytes in the lung interstitium and mucous cell metaplasia are common features seen in many rodent inhalation studies with acrolein (Kutzman et al., 1985; Borchers et al., 1999, 2007, 2008). Interstitial inflammation, neutrophil infiltration, congestion, and oedema were reported in mouse lung (Kim et al., 2018). Increased inflammation has also been reported in rat respiratory epithelial cells and in the rat, hamster, and rabbit olfactory epithelium after acrolein inhalation (Feron et al., 1978; Dorman et al., 2008). Mucus hypersecretion has been observed in rats after acrolein inhalation (Chen et al., 2013a), and effects on bronchoalveolar lavage fluid have variously been observed in studies in mice and rats (O’Brien et al., 2016; Johanson et al., 2020; Snow et al., 2017). Oropharyngeal administration of acrolein in mice results in pulmonary inflammation as shown by the associated increase in elevated macrophage and neutrophil counts in the bronchoalveolar lavage fluid, and increased expression of production of cytokines, including interleukins IL1α, IL1β, IL6, IL17, and TNF, IFNγ, and monocyte chemotactic protein 1 (MCP-1) (Ong et al., 2012).

Some in vivo studies in rodents have investigated the role of acrolein in cyclophosphamide-induced inflammation and haemorrhagic cystitis. These studies rely on an injection of acrolein directly into the urinary bladder (Batista et al., 2006, 2007; Bjorling et al., 2007; Macedo et al., 2008; Merriam et al., 2008; Wang et al., 2013b). [The Working Group noted that these studies use a route of exposure that is unlikely to occur in humans and they involve acute exposures.]

4.2.7. Alters cell proliferation, cell death, or nutrient supply

(a) Humans

No data in exposed humans were available to the Working Group.

In human cell lines, several studies suggested that acrolein is capable of inhibiting tumour suppressor genes and activating proto-oncogenes either by directly binding and modulating the protein or by disrupting signalling cascades that promote cell proliferation. Acrolein inhibited both DNA-binding activity and luciferase-reporter activity of the tumour suppressor TP53, in a B[a]P induction study using human lung adenocarcinoma cells (A549) (Biswal et al., 2003). The inhibitory effect of acrolein occurred in the absence of altered TP53 protein levels under basal or induced conditions (i.e. a 48-hour pre-treatment with B[a]P), which is probably the result of direct binding of the TP53 protein by acrolein, as well as the alteration of the intracellular redox status.

Acrolein was demonstrated to both covalently modify and inhibit phosphatase and tensin homologue (PTEN) in MCF-7 breast ductal carcinoma cancer cells (Covey et al., 2010). Perturbation of Wnt/β-catenin signalling in human embryonic kidney cells (HEK-293), which favour the retention of active protein kinase AKT, was demonstrated in both time- and dose-dependent manners. Acrolein inactivation of PTEN lead to an increase in activity of the proto-oncogene AKT, which can increase cellular proliferation and survival (Covey et al., 2010). AKT activity was further explored in a human colon carcinoma cell line (HCT 116), and in MCF-7 cells: acrolein was generated endogenously as a by-product of myeloperoxidase catalysis (quantified spectrophotometrically) and resulted in the accumulation of higher amounts of phospho-Ser⁴⁷³AKT; when a PI3K inhibitor (wortmannin) or a myeloperoxidase inhibitor (resorcinol) were added, phospho-Ser⁴⁷³AKT formation was suppressed (Al-Salihi et al., 2015).

Acrolein caused differential inhibition and modification (covalent adducts) of pyruvate kinase, the enzyme involved in the last step of anaerobic glycolysis, in MCF-7 cells and in a cell-free system. This change in activity has been reported during the transformation of cells to a proliferative or tumorigenic phenotype (Sousa et al., 2019).

(b) Experimental systems

A significant increase in the incidence and/or severity of respiratory tract metaplasia and hyperplasia was observed in B6D2F₁/Crlj mice and F344/DuCrlCrlj rats exposed to acrolein by inhalation for 2 years (JBRC, 2016a, b, c, d, e, f) and is discussed in Sections 3.1 and 3.2 of the present monograph.

Feron & Kruysse (1977) reported an increase in epithelial metaplasia of the nasal cavity epithelium in Syrian golden hamsters repeatedly inhaling acrolein vapour (4 ppm) for 7 hours per day, 5 days per week, for 52 weeks. In a subacute toxicity study (6 hours per day, 5 days per week, for 13 weeks) in hamsters, rats, and rabbits, squamous metaplasia was only observed in rats treated with the intermediate dose of 1.4 ppm (Feron et al., 1978). [The Working Group noted high mortality in the group at the higher dose.]

Fischer 344 rats treated with acrolein (0.6 or 1.8 ppm) by inhalation for up to 65 days presented with respiratory epithelial hyperplasia and squamous metaplasia (Dorman et al., 2008). In the most sensitive location, the lateral wall, respiratory epithelial cell proliferation occurred in the two highest dose groups as detected by proliferating cell nuclear antigen (PCNA) immunohistochemistry (Dorman et al., 2008). In a separate inhalational study, acrolein (3 ppm) induced goblet cell hyperplasia in the bronchial epithelium in lungs of male Sprague-Dawley rats exposed for 6 hours per day, 7 days per week, for 2 weeks (Liu et al., 2009b). Acrolein (≥ 0.1 µM) elicited a similar increase in goblet cell number in a differentiated lung epithelium model, which mirrored, to some extent, the goblet cell hyperplasia observed in animal inhalation models and after human chronic exposure (Haswell et al., 2010).

In Sprague-Dawley rats, acrolein (3 ppm) inhalation for 3 weeks led to metaplastic, dysplastic, and hyperplastic changes in the mucous, respiratory, and olfactory epithelium of the nasal cavity (Leach et al., 1987). These changes were prominent on the septum and in the anterior and ventral areas.

In Sprague-Dawley rats given a single exposure or a sustained 3-day exposure to acrolein at 0.2 or 0.6 ppm via inhalation, a concentration-dependent increase in the proportion of 5-bromo-2′-deoxyuridine (BrdU)-labelled nasal epithelial, tracheal epithelial, or free lung cells was observed (Roemer et al., 1993). Although significantly increased compared with control at both time-points, the single exposure elicited a stronger proliferative response (Roemer et al., 1993). Similar treatment-related proliferative increases were measured by both BrdU and PCNA labelling in nasal epithelium of albino Wistar rats that were treated (≤ 0.67 ppm) for 6 hours per day, for 3 days (Cassee et al., 1996). These rats also presented with slight disarrangement, necrosis, thickening, and desquamation of respiratory/transitional epithelium (Cassee et al., 1996). [The Working Group noted necrosis associated with the highest dose.]

A single inhalational exposure (5 ppm for 10 minutes) of BALB/c mice to acrolein led to a sustained increase in levels of vascular endothelial growth factor protein that persisted for 8 weeks (Kim et al., 2019). A single inhalation exposure of Sprague-Dawley rats to acrolein (3 ppm for a 12-day period of 5 days of treatment, 2 days of rest, and another 5 days of treatment) significantly activated the Ras/ERK pathway in bronchial epithelial cells, which functions downstream of epidermal growth factor. This finding was accompanied by an increase in goblet cell hyperplasia and metaplasia, which were significantly inhibited by simvastatin, a Ras inhibitor (Chen et al., 2010).

In oral gavage studies in B6C3F₁ mice and F334/N rats, acrolein treatment led to lesions associated with uncontrolled cell growth. Squamous epithelial hyperplasia in the forestomach and hyperplasia of bone marrow cells were observed in rats treated with acrolein at ≤ 10 mg/kg bw 5 days a week for 2 weeks; mice in the dose groups treated with ≤ 10 mg/kg bw developed squamous epithelial hyperplasia of the forestomach (Irwin, 2006). [The Working Group noted the high mortality in the groups of rats and mice at the highest dose.]

Forestomach epithelial hyperplasia was observed in male and female F344/N rats and B6C3F₁ mice given acrolein (≤ 10 mg/kg bw) by gavage once per day, 5 days per week, for 14 weeks (Auerbach et al., 2008). The pro-toxicants, allyl acetate and allyl alcohol, which are metabolized to acrolein, were also investigated. Periportal hepatocyte hypertrophy was observed in rats treated with allyl acetate and allyl alcohol, but not acrolein. Both species treated with the highest dose of allyl acetate exhibited forestomach epithelial necrosis. [The Working Group noted the 100% mortality of this dose group for all species and sexes; the Working Group also noted low (93.3%) purity of allyl acetate.]

In a mouse model of intestinal cancer, Apc^min/+ mice were either treated with water or dextran sodium sulfate to induce a model of colitis. Colonocytes isolated from mice treated with dextran sodium sulfate were found to have covalent acrolein–protein adducts on the PTEN tumour suppressor from endogenously generated acrolein (myeloperoxidase catalysis), which corresponded with the activation of the Akt protooncogene in these samples (Al-Salihi et al., 2015).

In studies in hypertension-resistant and salt-induced rats treated with acrolein (≤ 1.4 ppm) via inhalation for 6 hours per day, 5 days per week, for 62 days, bronchiolar epithelial hyperplasia was reported that was sometimes accompanied by squamous metaplasia and fibrosis (Kutzman et al., 1984). [The Working Group noted the toxicity associated with the highest dose, and the model of hypertension that was used for this study.]

4.2.8. Other key characteristics of carcinogens

(a) Induces epigenetic alterations

Several studies in experimental systems investigated the effect of acrolein on histone modification. Acrolein inhibited acetylation of the N-terminal tails of cytosolic histones H3 and H4 in vitro, compromising chromatin assembly in immortalized human bronchial epithelial and lung adenocarcinoma cell lines (Chen et al., 2013b). Interestingly, the effect of acrolein was specific to unmodified and newly synthesized histones; post-translational modifications seemed to protect the histone from being targeted. The mechanism behind these phenomena was further investigated by the same research group. Fang et al. (2016) determined that acrolein reacts and forms covalent adducts with lysine residues in an immortalized human bronchial epithelial cell line (BEAS-2B), including those residues important for chromatin assembly, therefore preventing these sites from undergoing physiological modifications (see Section 4.2.1). Promoter histone modifications of the FasL gene were enhanced by acrolein in the human liver hepatocarcinoma HepG2 cell line and in primary rat hepatocytes both alone and when co-treated with the HIV antiretroviral zidovudine (Ghare et al., 2016). When the acrolein scavenger hydralazine was added to the experiment, promoter-associated epigenetic changes were inhibited. Global DNA methylation and accumulation of DNA damage because of silencing of DNA repair genes was observed in acrolein-treated C57BL/6 mouse bladder tissue and in cultured mouse bladder muscle cells (Haldar et al., 2015, 2016). Cox et al. (1988) showed that DNA methylase isolated from the liver and urothelium of rats (strain not reported), treated with acrolein, was inhibited by 30–50% but the mechanism behind the inhibition was unclear.

(b) Modulates receptor-mediated effects

Several receptors appear to be activated or modulated by acrolein, although the studies are limited in both number and specificity. Thyroid hormone co-treatment with acrolein, administered both as a single compound and as a component of cigarette smoke, acts as a partial agonist for the thyroid receptor through recruitment of the nuclear coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SCR1) (Hayashi et al., 2018). Again, independently or as a component of cigarette smoke extract, acrolein was able to recruit GRIP1 or SCR1, but this time to peroxisome proliferator-activated receptor-α (PPARα) to induce transcriptional changes (Matsushita et al., 2019).

In male Fischer 344 rats given acrolein intraperitoneally with phenobarbital, α-, 2β-, 6β-, 16α-, and 16β-hydroxylation of testosterone and androstenedione was decreased (Cooper et al., 1992). This was the result of acrolein impairing the induction of CYP by 45%.

(c) Causes immortalization

Acrolein significantly increased soft agar anchorage-independent-growth colony formation, a characteristic of tumorigenic cell transformation, in immortalized human bronchial epithelial cells (BEAS-2B) and bladder urothelial cells (UROtsa) (Lee et al., 2015).

(d) Multiple characteristics

Gene expression changes in response to acrolein exposure were investigated in several studies. Data suggested a coordination of several of the key characteristics, namely induces oxidative stress, induces chronic inflammation and, to some degree, alters DNA repair in epithelial tissue or cells.

In normal human bronchial epithelial cells treated with acrolein for up to 24 hours, a combination of high-content screening and genome-wide transcriptomics revealed induction of genes associated with cellular stress followed by proliferation, and to a lesser extent, senescence networks (Gonzalez-Suarez et al., 2014). Interestingly, NRF2 was consistently activated despite the lack of observed increases in ROS. Furthermore, an increase in phosphorylation of histone 3 (pH3) levels was not accompanied by changes in cell number, suggesting the presence of cell cycle arrest at G₂/M. Rats exposed for 6 hours to acrolein by inhalation (nose-only) exhibited similar patterns of protein and gene expression (Gonzalez-Suarez et al., 2014). In addition to the nuclear accumulation of Nrf2 protein, antioxidant genes (i.e. NAD(P)H quinone dehydrogenase 1, Nqo1; catalytic subunit of glutamyl cysteine ligase, Gclc; and haem oxygenase 1, Hmox1) were upregulated at much lower acrolein concentrations than those required to induce the expression of proinflammatory genes (i.e. chemokine-induced neutrophil chemoattractant-1, Cinc1; and interleukin 6, Il6) (Cichocki et al., 2014).

Three studies investigated the transcriptional response to acrolein in human adenocarcinoma lung epithelial (A549) cells at various time-points. Over the course of 4 hours, a strong initial downregulation of genes was observed, possibly in response to DNA damage, followed by an increase in gene upregulation in which pro-inflammatory and pro-apoptotic pathways were dominant (Thompson & Burcham, 2008). Overall, these results indicate a dysregulation in several key characteristics of carcinogens including apoptosis, cell cycle control, and cell signalling. In a 2-hour exposure study in the same cells (A549), acrolein given alone or as a mixture with other short-chain aldehydes resulted in only one upregulated gene, HMOX1, a key gene in oxidative stress response (Cheah et al., 2013). A 24-hour treatment of A549 cells with acrolein at half maximal inhibitory concentration (IC₅₀) induced a robust expression of DNA repair genes, but this failed to rescue cells from apoptosis, even after acrolein washout and a recovery period (Sarkar, 2019)

5. Summary of Data Reported

6. Evaluation and Rationale

References

• ACGIH (2019). Acrolein. Threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati (OH), USA: American Conference of Governmental Industrial Hygienists.
• Afonso CB, Sousa BC, Pitt AR, Spickett CM (2018). A mass spectrometry approach for the identification and localization of small aldehyde modifications of proteins. Arch Biochem Biophys. 646:38–45. 10.1016/j.abb.2018.03.026 [PubMed: 29580947] [CrossRef]
• Al Rashidi M, Shihadeh A, Saliba NA (2008). Volatile aldehydes in the mainstream smoke of the narghile waterpipe. Food Chem Toxicol. 46(11):3546–9. 10.1016/j.fct.2008.09.007 [PMC free article: PMC2662371] [PubMed: 18834915] [CrossRef]
• Al-Rawithi S, El-Yazigi A, Ernst P, Al-Fiar F, Nicholls PJ (1998). Urinary excretion and pharmacokinetics of acrolein and its parent drug cyclophosphamide in bone marrow transplant patients. Bone Marrow Transplant. 22(5):485–90. 10.1038/sj.bmt.1701355 [PubMed: 9733272] [CrossRef]
• Al-Salihi M, Reichert E, Fitzpatrick FA (2015). Influence of myeloperoxidase on colon tumor occurrence in inflamed versus non-inflamed colons of Apc^(Min/+) mice. Redox Biol. 6:218–25. 10.1016/j.redox.2015.07.013 [PMC free article: PMC4536298] [PubMed: 26262998] [CrossRef]
• Alamil H, Lechevrel M, Lagadu S, Galanti L, Dagher Z, Delépée R (2020). A validated UHPLC-MS/MS method for simultaneous quantification of 9 exocyclic DNA adducts induced by 8 aldehydes. J Pharm Biomed Anal. 179:113007. 10.1016/j.jpba.2019.113007 [PubMed: 31796220] [CrossRef]
• Alberta Environment (2011). Assessment report on acrolein for developing ambient air quality objectives. Edmonton (AB), Canada: Alberta Environment. Available from: https://open​.alberta​.ca/publications/9781460105849, accessed 13 May 2021.
• Alwis KU, Blount BC, Britt AS, Patel D, Ashley DL (2012). Simultaneous analysis of 28 urinary VOC metabolites using ultra high performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry (UPLC-ESI/MSMS). Anal Chim Acta. 750:152–60. 10.1016/j.aca.2012.04.009 [PubMed: 23062436] [CrossRef]
• Alwis KU, deCastro BR, Morrow JC, Blount BC (2015). Acrolein exposure in U.S. tobacco smokers and non-tobacco users: NHANES 2005–2006. Environ Health Perspect. 123(12):1302–8. 10.1289/ehp.1409251 [PMC free article: PMC4671235] [PubMed: 26024353] [CrossRef]
• Andreoli R, Manini P, Corradi M, Mutti A, Niessen WM (2003). Determination of patterns of biologically relevant aldehydes in exhaled breath condensate of healthy subjects by liquid chromatography/atmospheric chemical ionization tandem mass spectrometry. Rapid Commun Mass Spectrom. 17(7):637–45. 10.1002/rcm.960 [PMC free article: PMC1455504] [PubMed: 12661015] [CrossRef]
• Annesi-Maesano I, Hulin M, Lavaud F, Raherison C, Kopferschmitt C, de Blay F, et al. (2012). Poor air quality in classrooms related to asthma and rhinitis in primary schoolchildren of the French 6 Cities Study. Thorax. 67(8):682–8. 10.1136/thoraxjnl-2011-200391 [PMC free article: PMC3402758] [PubMed: 22436169] [CrossRef]
• Aranyi C, O’Shea WJ, Graham JA, Miller FJ (1986). The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fundam Appl Toxicol. 6(4):713–20. 10.1016/0272-0590(86)90184-3 [PubMed: 3519345] [CrossRef]
• Arntz D, Fischer A, Höpp M, Jacobi S, Sauer J, Ohara T, et al. (2007). Acrolein and methacrolein. Ullmann’s Encyclopedia of Industrial Chemistry. Weinheim, Germany: Wiley-VCH Verlag; pp. 329–46.
• Arumugam N, Sivakumar V, Thanislass J, Devaraj H (1997). Effects of acrolein on rat liver antioxidant defense system. Indian J Exp Biol. 35(12):1373–4. [PubMed: 9567773]
• Astry CL, Jakab GJ (1983). The effects of acrolein exposure on pulmonary antibacterial defenses. Toxicol Appl Pharmacol. 67(1):49–54. 10.1016/0041-008X(83)90243-0 [PubMed: 6845357] [CrossRef]
• ATSDR (2007). Toxicological profile for Acrolein. Atlanta (GA), USA: Agency for Toxic Substances and Disease Registry. Available from: https://wwwn​.cdc.gov​/TSP/ToxProfiles/ToxProfiles​.aspx?id=557&tid=102, accessed 14 May 2021.
• ATSDR (2014). Medical management guidelines for acrolein. Atlanta (GA), USA: Agency for Toxic Substances and Disease Registry. Available from: https://www​.atsdr.cdc​.gov/MHMI/mmg124.pdf, accessed 14 May 2021.
• Au W, Sokova OI, Kopnin B, Arrighi FE (1980). Cytogenetic toxicity of cyclophosphamide and its metabolites in vitro. Cytogenet Cell Genet. 26(2–4):108–16. 10.1159/000131432 [PubMed: 7389408] [CrossRef]
• Auerbach SS, Mahler J, Travlos GS, Irwin RD (2008). A comparative 90-day toxicity study of allyl acetate, allyl alcohol and acrolein. Toxicology. 253(1–3):79–88. 10.1016/j.tox.2008.08.014 [PMC free article: PMC2665691] [PubMed: 18817840] [CrossRef]
• Avezov K, Reznick AZ, Aizenbud D (2014). LDH enzyme activity in human saliva: the effect of exposure to cigarette smoke and its different components. Arch Oral Biol. 59(2):142–8. 10.1016/j.archoralbio.2013.11.003 [PubMed: 24370185] [CrossRef]
• Aydın B, Atlı Şekeroğlu Z, Şekeroğlu V (2018). Acrolein-induced oxidative stress and genotoxicity in rats: protective effects of whey protein and conjugated linoleic acid. Drug Chem Toxicol. 41(2):225–31. 10.1080/01480545.2017.1354872 [PubMed: 28771065] [CrossRef]
• Ayer HE, Yeager DW (1982). Irritants in cigarette smoke plumes. Am J Public Health. 72(11):1283–5. 10.2105/AJPH.72.11.1283 [PMC free article: PMC1650438] [PubMed: 7125032] [CrossRef]
• Azuma K, Uchiyama I, Uchiyama S, Kunugita N (2016). Assessment of inhalation exposure to indoor air pollutants: Screening for health risks of multiple pollutants in Japanese dwellings. Environ Res. 145:39–49. 10.1016/j.envres.2015.11.015 [PubMed: 26618504] [CrossRef]
• Barros AR, Comendador MA, Sierra LM (1994a). Acrolein genotoxicity in Drosophila melanogaster. II. Influence of mus201 and mus308 mutations. Mutat Res. 306(1):1–8. 10.1016/0027-5107(94)90162-7 [PubMed: 7512197] [CrossRef]
• Barros AR, Sierra LM, Comendador MA (1994b). Acrolein genotoxicity in Drosophila melanogaster. III. Effects of metabolism modification. Mutat Res. 321(3):119–26. 10.1016/0165-1218(94)90035-3 [PubMed: 7513061] [CrossRef]
• Basu AK, Marnett LJ (1984). Molecular requirements for the mutagenicity of malondialdehyde and related acroleins. Cancer Res. 44(7):2848–54. [PubMed: 6372997]
• Batista CK, Brito GA, Souza ML, Leitão BT, Cunha FQ, Ribeiro RA (2006). A model of hemorrhagic cystitis induced with acrolein in mice. Braz J Med Biol Res. 39(11):1475–81. 10.1590/S0100-879X2006001100011 [PubMed: 17146560] [CrossRef]
• Batista CK, Mota JM, Souza ML, Leitão BT, Souza MH, Brito GA, et al. (2007). Amifostine and glutathione prevent ifosfamide- and acrolein-induced hemorrhagic cystitis. Cancer Chemother Pharmacol. 59(1):71–7. 10.1007/s00280-006-0248-z [PubMed: 16708234] [CrossRef]
• Belloc-Santaliestra M, van der Haar R, Molinero-Ruiz E (2015). Occupational exposure assessment of highway toll station workers to vehicle engine exhaust. J Occup Environ Hyg. 12(1):51–61. 10.1080/15459624.2014.935781 [PubMed: 25411914] [CrossRef]
• Benamira M, Marnett LJ (1992). The lipid peroxidation product 4-hydroxynonenal is a potent inducer of the SOS response. Mutat Res. 293(1):1–10. 10.1016/0921-8777(92)90002-K [PubMed: 1383804] [CrossRef]
• Berhane K, Mannervik B (1990). Inactivation of the genotoxic aldehyde acrolein by human glutathione transferases of classes alpha, mu, and pi. Mol Pharmacol. 37(2):251–4. [PubMed: 2304453]
• Bessette EE, Goodenough AK, Langouët S, Yasa I, Kozekov ID, Spivack SD, et al. (2009). Screening for DNA adducts by data-dependent constant neutral loss-triple stage mass spectrometry with a linear quadrupole ion trap mass spectrometer. Anal Chem. 81(2):809–19. 10.1021/ac802096p [PMC free article: PMC2646368] [PubMed: 19086795] [CrossRef]
• Biswal S, Maxwell T, Rangasamy T, Kehrer JP (2003). Modulation of benzo[a]pyrene-induced p53 DNA activity by acrolein. Carcinogenesis. 24(8):1401–6. 10.1093/carcin/bgg061 [PubMed: 12807757] [CrossRef]
• Bittersohl G (1975). Epidemiological research on cancer risk by aldol and aliphatic aldehydes. Environ Qual Saf. 4:235–8. [PubMed: 1193059]
• Bjorling DE, Elkahwaji JE, Bushman W, Janda LM, Boldon K, Hopkins WJ, et al. (2007). Acute acrolein-induced cystitis in mice. BJU Int. 99(6):1523–9. 10.1111/j.1464-410X.2007.06773.x [PubMed: 17346276] [CrossRef]
• Blasch K, Kolivosky J, Hill B (2016). Occupational exposures among personnel working near combined burn pit and incinerator operations at Bagram Airfield, Afghanistan. Inhal Toxicol. 28(5):216–25. 10.3109/08958378.2016.1145768 [PubMed: 27092584] [CrossRef]
• Bolstad-Johnson DM, Burgess JL, Crutchfield CD, Storment S, Gerkin R, Wilson JR (2000). Characterization of firefighter exposures during fire overhaul. AIHAJ. 61(5):636–41. 10.1080/15298660008984572 [PubMed: 11071414] [CrossRef]
• Borchers MT, Wesselkamper S, Wert SE, Shapiro SD, Leikauf GD (1999). Monocyte inflammation augments acrolein-induced Muc5ac expression in mouse lung. Am J Physiol. 277(3):L489–97. 10​.1152/ajplung.1999.277.3.L489 [PubMed: 10484456]
• Borchers MT, Wesselkamper SC, Eppert BL, Motz GT, Sartor MA, Tomlinson CR, et al. (2008). Nonredundant functions of αβ and γδ T cells in acrolein-induced pulmonary pathology. Toxicol Sci. 105(1):188–99. 10.1093/toxsci/kfn106 [PMC free article: PMC2734302] [PubMed: 18515264] [CrossRef]
• Borchers MT, Wesselkamper SC, Harris NL, Deshmukh H, Beckman E, Vitucci M, et al. (2007). CD8⁺ T cells contribute to macrophage accumulation and airspace enlargement following repeated irritant exposure. Exp Mol Pathol. 83(3):301–10. 10.1016/j.yexmp.2007.08.020 [PMC free article: PMC2140237] [PubMed: 17950725] [CrossRef]
• Borgerding MF, Bodnar JA, Wingate DE (2000). The 1999 Massachusetts benchmark study; final report. Brown & Williamson. Available from: https://www​.industrydocuments​.ucsf.edu/tobacco​/docs/#id=rfdx0057, accessed 17 May 2021.
• Boyle EB, Viet SM, Wright DJ, Merrill LS, Alwis KU, Blount BC, et al. (2016). Assessment of exposure to VOCs among pregnant women in the National Children’s Study. Int J Environ Res Public Health. 13(4):376. 10.3390/ijerph13040376 [PMC free article: PMC4847038] [PubMed: 27043585] [CrossRef]
• Brock N, Stekar J, Pohl J, Niemeyer U, Scheffler G (1979). Acrolein, the causative factor of urotoxic side-effects of cyclophosphamide, ifosfamide, trofosfamide and sufosfamide. Arzneimittelforschung. 29(4):659–61. [PubMed: 114192]
• Brzeźnicki S, Gromiec J (2002). [Exposure to selected aldehydes among municipal transport bus drivers]. Med Pr. 53(2):115–7. [Polish] [PubMed: 12116900]
• Burcham PC, Kerr PG, Fontaine F (2000). The antihypertensive hydralazine is an efficient scavenger of acrolein. Redox Rep. 5(1):47–9. 10.1179/rer.2000.5.1.47 [PubMed: 10905545] [CrossRef]
• Burcham PC, Pyke SM (2006). Hydralazine inhibits rapid acrolein-induced protein oligomerization: role of aldehyde scavenging and adduct trapping in cross-link blocking and cytoprotection. Mol Pharmacol. 69(3):1056–65. 10.1124/mol.105.018168 [PubMed: 16368895] [CrossRef]
• Burcham PC, Raso A, Thompson C, Tan D (2007). Intermolecular protein cross-linking during acrolein toxicity: efficacy of carbonyl scavengers as inhibitors of heat shock protein-90 cross-linking in A549 cells. Chem Res Toxicol. 20(11):1629–37. 10.1021/tx700192e [PubMed: 17907782] [CrossRef]
• Cahill TM (2014). Ambient acrolein concentrations in coastal, remote, and urban regions in California. Environ Sci Technol. 48(15):8507–13. 10.1021/es5014533 [PubMed: 24992452] [CrossRef]
• Cahill TM, Okamoto RA (2012). Emissions of acrolein and other aldehydes from biodiesel-fueled heavy-duty vehicles. Environ Sci Technol. 46(15):8382–8. 10.1021/es301659u [PubMed: 22746209] [CrossRef]
• Cai J, Bhatnagar A, Pierce WM Jr (2009). Protein modification by acrolein: formation and stability of cysteine adducts. Chem Res Toxicol. 22(4):708–16. 10.1021/tx800465m [PMC free article: PMC2929760] [PubMed: 19231900] [CrossRef]
• Cai Y, Wu MH, Ludeman SM, Grdina DJ, Dolan ME (1999). Role of O6-alkylguanine-DNA alkyltransferase in protecting against cyclophosphamide-induced toxicity and mutagenicity. Cancer Res. 59(13):3059–63. [PubMed: 10397244]
• Caito S, Rajendrasozhan S, Cook S, Chung S, Yao H, Friedman AE, et al. (2010). SIRT1 is a redox-sensitive deacetylase that is post-translationally modified by oxidants and carbonyl stress. FASEB J. 24(9):3145–59. 10.1096/fj.09-151308 [PMC free article: PMC2923349] [PubMed: 20385619] [CrossRef]
• Campagnolo D, Saraga DE, Cattaneo A, Spinazzè A, Mandin C, Mabilia R, et al. (2017). VOCs and aldehydes source identification in European office buildings - The OFFICAIR study. Build Environ. 115:18–24. 10.1016/j.buildenv.2017.01.009 [CrossRef]
• Cancelada L, Sleiman M, Tang X, Russell ML, Montesinos VN, Litter MI, et al. (2019). Heated tobacco products: volatile emissions and their predicted impact on indoor air quality. Environ Sci Technol. 53(13):7866–76. 10.1021/acs.est.9b02544 [PubMed: 31150216] [CrossRef]
• Carbone V, Salzano A, Pucci P, Fiume I, Pocsfalvi G, Sannolo N, et al. (1997). In vitro reactivity of the antineoplastic drug carmustin and acrolein with model peptides. J Pept Res. 49(6):586–95. 10.1111/j.1399-3011.1997.tb01167.x [PubMed: 9266487] [CrossRef]
• Cassee FR, Groten JP, Feron VJ (1996). Changes in the nasal epithelium of rats exposed by inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundam Appl Toxicol. 29(2):208–18. 10.1006/faat.1996.0024 [PubMed: 8742318] [CrossRef]
• Cecil TL, Brewer TM, Young M, Holman MR (2017). Acrolein yields in mainstream smoke from commercial cigarette and little cigar tobacco products. Nicotine Tob Res. 19(7):865–70. 10.1093/ntr/ntx003 [PubMed: 28339569] [CrossRef]
• CEPA (2002). Pesticide volatile organic compound emissions inventory 2002 update: Estimated emissions January-December 2001. Sacramento (CA), USA: California Environmental Protection Agency.
• Chavez JD, Wu J, Bisson W, Maier CS (2011). Site-specific proteomic analysis of lipoxidation adducts in cardiac mitochondria reveals chemical diversity of 2-alkenal adduction. J Proteomics. 74(11):2417–29. 10.1016/j.jprot.2011.03.031 [PMC free article: PMC3199298] [PubMed: 21513823] [CrossRef]
• Cheah NP, Pennings JL, Vermeulen JP, van Schooten FJ, Opperhuizen A (2013). In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 27(3):1072–81. 10.1016/j.tiv.2013.02.003 [PubMed: 23416264] [CrossRef]
• Chem Sources (2020). Chem Sources Online, Chemical Sources International, Inc. Available from: https://www​.chemsources.com, accessed 10 May 2020.
• Chemical Abstracts Service (2020). SciFinder^®: acrolein commercial sources. Columbus (OH), USA: American Chemical Society.
• Chen D, Fang L, Li H, Tang MS, Jin C (2013b). Cigarette smoke component acrolein modulates chromatin assembly by inhibiting histone acetylation. J Biol Chem. 288(30):21678–87. 10.1074/jbc.M113.476630 [PMC free article: PMC3724627] [PubMed: 23770671] [CrossRef]
• Chen H, Krishnamachari S, Guo J, Yao L, Murugan P, Weight CJ, et al. (2019a). Quantitation of lipid peroxidation product DNA adducts in human prostate by tandem mass spectrometry: a method that mitigates artifacts. Chem Res Toxicol. 32(9):1850–62. 10.1074/jbc.M113.476630 [PMC free article: PMC6746595] [PubMed: 31361128] [CrossRef]
• Chen HJ, Lin WP (2011). Quantitative analysis of multiple exocyclic DNA adducts in human salivary DNA by stable isotope dilution nanoflow liquid chromatography-nanospray ionization tandem mass spectrometry. Anal Chem. 83(22):8543–51. 10.1021/ac201874d [PubMed: 21958347] [CrossRef]
• Chen P, Deng Z, Wang T, Chen L, Li J, Feng Y, et al. (2013a). The potential interaction of MARCKS-related peptide and diltiazem on acrolein-induced airway mucus hypersecretion in rats. Int Immunopharmacol. 17(3):625–32. 10.1016/j.intimp.2013.08.001 [PubMed: 24012931] [CrossRef]
• Chen WY, Zhang J, Ghare S, Barve S, McClain C, Joshi-Barve S (2016). Acrolein is a pathogenic mediator of alcoholic liver disease and the scavenger hydralazine is protective in mice. Cell Mol Gastroenterol Hepatol. 2(5):685–700. 10.1016/j.jcmgh.2016.05.010 [PMC free article: PMC5042858] [PubMed: 28119953] [CrossRef]
• Chen Y, Liu Y, Hou X, Ye Z, Wang C (2019b). Quantitative and site-specific chemoproteomic profiling of targets of acrolein. Chem Res Toxicol. 32(3):467–73. 10.1021/acs.chemrestox.8b00343 [PubMed: 30604966] [CrossRef]
• Chen YJ, Chen P, Wang HX, Wang T, Chen L, Wang X, et al. (2010). Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. Int Immunopharmacol. 10(6):685–93. 10.1016/j.intimp.2010.03.012 [PubMed: 20359552] [CrossRef]
• Chenna A, Iden CR (1993). Characterization of 2 ʹ-deoxycytidine and 2ʹ-deoxyuridine adducts formed in reactions with acrolein and 2-bromoacrolein. Chem Res Toxicol. 6(3):261–8. 10.1021/tx00033a003 [PubMed: 8318647] [CrossRef]
• Chenna A, Rieger RA, Iden CR (1992). Characterization of thymidine adducts formed by acrolein and 2-bromoacrolein. Carcinogenesis. 13(12):2361–5. 10.1093/carcin/13.12.2361 [PubMed: 1473245] [CrossRef]
• Chiu WA, Guyton KZ, Martin MT, Reif DM, Rusyn I (2018). Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups. ALTEX. 35(1):51–64. 10.14573/altex.1703231 [PMC free article: PMC5783793] [PubMed: 28738424] [CrossRef]
• Choudhury S, Dyba M, Pan J, Roy R, Chung FL (2013). Repair kinetics of acrolein- and (E)-4-hydroxy-2-nonenal-derived DNA adducts in human colon cell extracts. Mutat Res. 751–752:15–23. 10.1016/j.mrfmmm.2013.09.004 [PMC free article: PMC4188536] [PubMed: 24113140] [CrossRef]
• Chung FL, Hecht SS, Palladino G (1986). Formation of cyclic nucleic acid adducts from some simple α,β-unsaturated carbonyl compounds and cyclic nitrosamines. IARC Sci Publ. 1986(70):207–25. [PubMed: 3793173]
• Chung FL, Wu MY, Basudan A, Dyba M, Nath RG (2012). Regioselective formation of acrolein-derived cyclic 1,N²-propanodeoxyguanosine adducts mediated by amino acids, proteins, and cell lysates. Chem Res Toxicol. 25(9):1921–8. 10.1021/tx3002252 [PMC free article: PMC3535281] [PubMed: 22853434] [CrossRef]
• Chung FL, Young R, Hecht SS (1984). Formation of cyclic 1,N²-propanodeoxyguanosine adducts in DNA upon reaction with acrolein or crotonaldehyde. Cancer Res. 44(3):990–5. [PubMed: 6318992]
• Chung FL, Zhang L, Ocando JE, Nath RG (1999). Role of 1,N²-propanodeoxyguanosine adducts as endogenous DNA lesions in rodents and humans. In: Singer B, Bartsch H, editors. Exocyclic DNA adducts in mutagenesis and carcinogenesis. IARC Sci Publ. 150:45–54. [PubMed: 10626207]
• Cichocki JA, Smith GJ, Morris JB (2014). Tissue sensitivity of the rat upper and lower extrapulmonary airways to the inhaled electrophilic air pollutants diacetyl and acrolein. Toxicol Sci. 142(1):126–36. 10.1093/toxsci/kfu165 [PubMed: 25145656] [CrossRef]
• Claxton LD (1985). Assessment of bacterial mutagenicity methods for volatile and semivolatile compounds and mixtures. Environ Int. 11(2–4):375–82. 10.1016/0160-4120(85)90032-7 [CrossRef]
• Coffey CM, Gronert S (2016). A cleavable biotin tagging reagent that enables the enrichment and identification of carbonylation sites in proteins. Anal Bioanal Chem. 408(3):865–74. 10.1007/s00216-015-9176-2 [PubMed: 26613796] [CrossRef]
• Cohen SM, Garland EM, St John M, Okamura T, Smith RA (1992). Acrolein initiates rat urinary bladder carcinogenesis. Cancer Res. 52(13):3577–81. [PubMed: 1617627]
• Coia H, Ma N, Hou Y, Dyba MD, Fu Y, Cruz MI, et al. (2018). Prevention of lipid peroxidation-derived cyclic DNA adduct and mutation in high-fat diet-induced hepatocarcinogenesis by Theaphenon E. Cancer Prev Res (Phila). 11(10):665–76. 10.1158/1940-6207.CAPR-18-0160 [PMC free article: PMC6171362] [PubMed: 30131435] [CrossRef]
• Collin S, Osman M, Delcambre S, El-Zayat AI, Dufour JP (1993). Investigation of volatile flavor compounds in fresh and ripened Domiati cheeses. J Agric Food Chem. 41(10):1659–63. 10.1021/jf00034a027 [CrossRef]
• Colombo G, Aldini G, Orioli M, Giustarini D, Gornati R, Rossi R, et al. (2010). Water-soluble α,β-unsaturated aldehydes of cigarette smoke induce carbonylation of human serum albumin. Antioxid Redox Signal. 12(3):349–64. 10.1089/ars.2009.2806 [PubMed: 19686037] [CrossRef]
• Conklin DJ, Haberzettl P, Prough RA, Bhatnagar A (2009). Glutathione-S-transferase P protects against endothelial dysfunction induced by exposure to tobacco smoke. Am J Physiol Heart Circ Physiol. 296(5):H1586–97. 10.1152/ajpheart.00867.2008 [PMC free article: PMC2685347] [PubMed: 19270193] [CrossRef]
• Conklin DJ, Ogunwale MA, Chen Y, Theis WS, Nantz MH, Fu X-A, et al. (2018). Electronic cigarette-generated aldehydes: the contribution of e-liquid components to their formation and the use of urinary aldehyde metabolites as biomarkers of exposure. Aerosol Sci Technol. 52(11):1219–32. 10.1080/02786826.2018.1500013 [PMC free article: PMC6711607] [PubMed: 31456604] [CrossRef]
• Connor BF, Rose DL, Noriega MC, Murtagh LK, Abney SR (1996). Methods of analysis by the U.S. Geological Survey National Water Quality Laboratory -- determination of 86 volatile organic compounds in water by gas chromatography/mass spectrometry, including detections less than reporting limits. U.S. Geological Survey Open-File Report 97-829. Available from: https://www​.nemi.gov​/methods/method_summary/8933/, accessed 31 May 2021.
• Cooper KO, Witz G, Witmer C (1992). The effects of α,β-unsaturated aldehydes on hepatic thiols and thiol-containing enzymes. Fundam Appl Toxicol. 19(3):343–9. 10.1016/0272-0590(92)90172-E [PubMed: 1334014] [CrossRef]
• Costa M, Zhitkovich A, Harris M, Paustenbach D, Gargas M (1997). DNA-protein cross-links produced by various chemicals in cultured human lymphoma cells. J Toxicol Environ Health. 50(5):433–49. 10.1080/00984109708984000 [PubMed: 9140463] [CrossRef]
• Covey TM, Edes K, Coombs GS, Virshup DM, Fitzpatrick FA (2010). Alkylation of the tumor suppressor PTEN activates Akt and β-catenin signalling: a mechanism linking inflammation and oxidative stress with cancer. PLoS One. 5(10):e13545. 10.1371/journal.pone.0013545 [PMC free article: PMC2958828] [PubMed: 20975834] [CrossRef]
• Cox R, Goorha S, Irving CC (1988). Inhibition of DNA methylase activity by acrolein. Carcinogenesis. 9(3):463–5. 10.1093/carcin/9.3.463 [PubMed: 3345585] [CrossRef]
• Crook TR, Souhami RL, McLean AE (1986). Cytotoxicity, DNA cross-linking, and single strand breaks induced by activated cyclophosphamide and acrolein in human leukemia cells. Cancer Res. 46(10):5029–34. [PubMed: 3463409]
• Curren RD, Yang LL, Conklin PM, Grafstrom RC, Harris CC (1988). Mutagenesis of xeroderma pigmentosum fibroblasts by acrolein. Mutat Res. 209(1–2):17–22. 10.1016/0165-7992(88)90104-2 [PubMed: 3173398] [CrossRef]
• Curylo J, Wardencki W (2005). Determination of acetaldehyde and acrolein in raw spirits by capillary isotachophoresis after derivatization. Anal Lett. 38(10):1659–69. 10.1081/AL-200065818 [CrossRef]
• Daher N, Saleh R, Jaroudi E, Sheheitli H, Badr T, Sepetdjian E, et al. (2010). Comparison of carcinogen, carbon monoxide, and ultrafine particle emissions from narghile waterpipe and cigarette smoking: sidestream smoke measurements and assessment of second-hand smoke emission factors. Atmos Environ (1994). 44(1):8–14. 10.1016/j.atmosenv.2009.10.004 [PMC free article: PMC2801144] [PubMed: 20161525] [CrossRef]
• Dalle-Donne I, Carini M, Vistoli G, Gamberoni L, Giustarini D, Colombo R, et al. (2007). Actin Cys374 as a nucleophilic target of α,β-unsaturated aldehydes. Free Radic Biol Med. 42(5):583–98. 10.1016/j.freeradbiomed.2006.11.026 [PubMed: 17291982] [CrossRef]
• Danyal K, de Jong W, O’Brien E, Bauer RA, Heppner DE, Little AC, et al. (2016). Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR. Am J Physiol Lung Cell Mol Physiol. 311(5):L913–23. 10.1152/ajplung.00276.2016 [PMC free article: PMC5130541] [PubMed: 27612966] [CrossRef]
• de Oliveira Moura T, Oliveira Santana F, Palmeira Campos V, de Oliveira IB, Medeiros YDP (2019). Inorganic and organic contaminants in drinking water stored in polyethylene cisterns. Food Chem. 273:45–51. 10.1016/j.foodchem.2018.03.104 [PubMed: 30292373] [CrossRef]
• Deaton AP, Dozier MM, Lake RS, Heck JD (1993). Acute DNA strand breaks (SB) induced by acrolein are distinguished from those induced by other aldehydes by modulators of active oxygen (abstract). Environ Mol Mutag. 21(Suppl):16.
• Demir E, Kaya B, Soriano C, Creus A, Marcos R (2011). Genotoxic analysis of four lipid-peroxidation products in the mouse lymphoma assay. Mutat Res. 726(2):98–103. 10.1016/j.mrgentox.2011.07.001 [PubMed: 21763450] [CrossRef]
• Demir E, Turna F, Kaya B, Creus A, Marcos R (2013). Mutagenic/recombinogenic effects of four lipid peroxidation products in Drosophila. Food Chem Toxicol. 53:221–7. 10.1016/j.fct.2012.11.053 [PubMed: 23238235] [CrossRef]
• Destaillats H, Spaulding RS, Charles MJ (2002). Ambient air measurement of acrolein and other carbonyls at the Oakland-San Francisco Bay Bridge toll plaza. Environ Sci Technol. 36(10):2227–35. 10.1021/es011394c [PubMed: 12038834] [CrossRef]
• Dorman DC, Struve MF, Wong BA, Marshall MW, Gross EA, Willson GA (2008). Respiratory tract responses in male rats following subchronic acrolein inhalation. Inhal Toxicol. 20(3):205–16. 10.1080/08958370701864151 [PubMed: 18300043] [CrossRef]
• Douki T, Corbière C, Preterre D, Martin PJ, Lecureur V, André V, et al. (2018). Comparative study of diesel and biodiesel exhausts on lung oxidative stress and genotoxicity in rats. Environ Pollut. 235:514–24. 10.1016/j.envpol.2017.12.077 [PubMed: 29324381] [CrossRef]
• Draminski W, Eder E, Henschler D (1983). A new pathway of acrolein metabolism in rats. Arch Toxicol. 52(3):243–7. 10.1007/BF00333903 [PubMed: 6860146] [CrossRef]
• Dylewska M, Kuśmierek JT, Pilżys T, Poznański J, Maciejewska AM (2017). 1,N⁶-α-hydroxypropanoadenine, the acrolein adduct to adenine, is a substrate for AlkB dioxygenase. Biochem J. 474(11):1837–52. 10.1042/BCJ20161008 [PubMed: 28408432] [CrossRef]
• Dypbukt JM, Atzori L, Edman CC, Grafström RC (1993). Thiol status and cytopathological effects of acrolein in normal and xeroderma pigmentosum skin fibroblasts. Carcinogenesis. 14(5):975–80. 10.1093/carcin/14.5.975 [PubMed: 8504492] [CrossRef]
• ECHA (2020). Acrylaldehyde. Helsinki, Finland: European Chemicals Agency. Available from: https://echa​.europa.eu​/da/substance-information​/-/substanceinfo/100.003.141, accessed 10 September 2020.
• Eckert E, Schmid K, Schaller B, Hiddemann-Koca K, Drexler H, Göen T (2011). Mercapturic acids as metabolites of alkylating substances in urine samples of German inhabitants. Int J Hyg Environ Health. 214(3):196–204. 10.1016/j.ijheh.2011.03.001 [PubMed: 21459667] [CrossRef]
• Eder E, Deininger C (2002). The influence of the solvents DMSO and ethanol on the genotoxicity of α,β-unsaturated aldehydes in the SOS chromotest. Mutat Res. 516(1–2):81–9. 10.1016/S1383-5718(02)00026-8 [PubMed: 11943614] [CrossRef]
• Eder E, Hoffman C, Bastian H, Deininger C, Scheckenbach S (1990). Molecular mechanisms of DNA damage initiated by alpha, beta-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity. Environ Health Perspect. 88:99–106. 10.1289/ehp.908899 [PMC free article: PMC1568033] [PubMed: 2272339] [CrossRef]
• Eder E, Scheckenbach S, Deininger C, Hoffman C (1993). The possible role of α,β-unsaturated carbonyl compounds in mutagenesis and carcinogenesis. Toxicol Lett. 67(1–3):87–103. 10.1016/0378-4274(93)90048-3 [PubMed: 8451772] [CrossRef]
• Eisenbrand G, Schuhmacher J, Gölzer P (1995). The influence of glutathione and detoxifying enzymes on DNA damage induced by 2-alkenals in primary rat hepatocytes and human lymphoblastoid cells. Chem Res Toxicol. 8(1):40–6. 10.1021/tx00043a005 [PubMed: 7703365] [CrossRef]
• Eldridge A, Betson TR, Gama MV, McAdam K (2015). Variation in tobacco and mainstream smoke toxicant yields from selected commercial cigarette products. Regul Toxicol Pharmacol. 71(3):409–27. 10.1016/j.yrtph.2015.01.006 [PubMed: 25620723] [CrossRef]
• Epstein SS, Arnold E, Andrea J, Bass W, Bishop Y (1972). Detection of chemical mutagens by the dominant lethal assay in the mouse. Toxicol Appl Pharmacol. 23(2):288–325. 10.1016/0041-008X(72)90192-5 [PubMed: 5074577] [CrossRef]
• Esterbauer H, Zollner H, Scholz N (1975). Reaction of glutathione with conjugated carbonyls. Z Naturforsch C Biosci. 30(4):466–73. 10.1515/znc-1975-7-808 [PubMed: 241172] [CrossRef]
• Etzkorn WG (2009). Acrolein and derivatives. In: Kirk-Othmer encyclopedia of chemical technology. .
• Etzkorn WG, Kurland JJ, Neilsen WD (1991). Acrolein and derivatives. In: Kroschwitz J, Howe-Grant M, editors. Kirk-Othmer encyclopedia of chemical technology. 4th ed. Vol. 1. New York (NY), USA: John Wiley; pp.232–251.
• European Commission (2017). Commission Directive (EU) 2017/164 of 31 January 2017 establishing a fourth list of indicative occupational exposure limit values pursuant to Council Directive 98/24/EC, and amending Commission Directives 91/322/EEC, 2000/39/EC and 2009/161/EU. OJ L 27/115. Available from: https://eur-lex​.europa​.eu/legal-content/EN​/TXT/PDF/?uri=CELEX​:32017L0164&from=FI, accessed 20 May 2021.
• Fang L, Chen D, Yu C, Li H, Brocato J, Huang L, et al. (2016). Mechanisms underlying acrolein-mediated inhibition of chromatin assembly. Mol Cell Biol. 36(23):2995–3008. 10.1128/MCB.00448-16 [PMC free article: PMC5108886] [PubMed: 27669733] [CrossRef]
• Faroon O, Roney N, Taylor J, Ashizawa A, Lumpkin MH, Plewak DJ (2008). Acrolein environmental levels and potential for human exposure. Toxicol Ind Health. 24(8):543–64. 10.1177/0748233708098124 [PubMed: 19039083] [CrossRef]
• Feng Z, Hu W, Hu Y, Tang MS (2006). Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl Acad Sci USA. 103(42):15404–9. 10.1073/pnas.0607031103 [PMC free article: PMC1592536] [PubMed: 17030796] [CrossRef]
• Feron VJ, Kruysse A (1977). Effects of exposure to acrolein vapor in hamsters simultaneously treated with benzo[a]pyrene or diethylnitrosamine. J Toxicol Environ Health. 3(3):379–94. 10.1080/15287397709529571 [PubMed: 926195] [CrossRef]
• Feron VJ, Kruysse A, Til HP, Immel HR (1978). Repeated exposure to acrolein vapour: subacute studies in hamsters, rats and rabbits. Toxicology. 9(1–2):47–57. 10.1016/0300-483X(78)90030-6 [PubMed: 653741] [CrossRef]
• Feron VJ, Til HP, de Vrijer F, Woutersen RA, Cassee FR, van Bladeren PJ (1991). Aldehydes: occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat Res. 259(3–4):363–85. 10.1016/0165-1218(91)90128-9 [PubMed: 2017217] [CrossRef]
• Ferreira DC, Nicolli KP, Souza-Silva ÉA, Manfroi V, Zini CA, Welke JE (2018). Carbonyl compounds in different stages of vinification and exposure risk assessment through Merlot wine consumption. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 35(12):2315–31. 10.1080/19440049.2018.1539530 [PubMed: 30427283] [CrossRef]
• Fleer R, Brendel M (1982). Toxicity, interstrand cross-links and DNA fragmentation induced by ‘activated’ cyclophosphamide in yeast: comparative studies on 4-hydroperoxy-cyclophosphamide, its monofunctional analogon, acrolein, phosphoramide mustard, and nor-nitrogen mustard. Chem Biol Interact. 39(1):1–15. 10.1016/0009-2797(82)90002-3 [PubMed: 7037214] [CrossRef]
• Florin I, Rutberg L, Curvall M, Enzell CR (1980). Screening of tobacco smoke constituents for mutagenicity using the Ames’ test. Toxicology. 15(3):219–32. 10.1016/0300-483X(80)90055-4 [PubMed: 7008261] [CrossRef]
• Foiles PG, Akerkar SA, Chung FL (1989). Application of an immunoassay for cyclic acrolein deoxyguanosine adducts to assess their formation in DNA of Salmonella typhimurium under conditions of mutation induction by acrolein. Carcinogenesis. 10(1):87–90. 10.1093/carcin/10.1.87 [PubMed: 2642752] [CrossRef]
• Foiles PG, Akerkar SA, Miglietta LM, Chung FL (1990). Formation of cyclic deoxyguanosine adducts in Chinese hamster ovary cells by acrolein and crotonaldehyde. Carcinogenesis. 11(11):2059–61. 10.1093/carcin/11.11.2059 [PubMed: 2225341] [CrossRef]
• Foiles PG, Chung FL, Hecht SS (1987). Development of a monoclonal antibody-based immunoassay for cyclic DNA adducts resulting from exposure to crotonaldehyde. Cancer Res. 47(2):360–3. [PubMed: 3791227]
• Fu Y, Silverstein S, McCutcheon JN, Dyba M, Nath RG, Aggarwal M, et al. (2018). An endogenous DNA adduct as a prognostic biomarker for hepatocarcinogenesis and its prevention by Theaphenon E in mice. Hepatology. 67(1):159–70. 10.1002/hep.29380 [PMC free article: PMC5912673] [PubMed: 28718980] [CrossRef]
• Furuhata A, Ishii T, Kumazawa S, Yamada T, Nakayama T, Uchida K (2003). Nε-(3-methylpyridinium)lysine, a major antigenic adduct generated in acrolein-modified protein. J Biol Chem. 278(49):48658–65. 10.1074/jbc.M309401200 [PubMed: 14504272] [CrossRef]
• Furuhata A, Nakamura M, Osawa T, Uchida K (2002). Thiolation of protein-bound carcinogenic aldehyde. An electrophilic acrolein-lysine adduct that covalently binds to thiols. J Biol Chem. 277(31):27919–26. 10.1074/jbc.M202794200 [PubMed: 12032148] [CrossRef]
• Galloway SM, Armstrong MJ, Reuben C, Colman S, Brown B, Cannon C, et al. (1987). Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: evaluations of 108 chemicals. Environ Mol Mutagen. 10(S10):1–35. 10.1002/em.2850100502 [PubMed: 3319609] [CrossRef]
• Gan JC, Ansari GA (1989). Inactivation of plasma alpha 1-proteinase inhibitor by acrolein: adduct formation with lysine and histidine residues. Mol Toxicol. 2(3):137–45. [PubMed: 2518664]
• Gardner R, Kazi S, Ellis EM (2004). Detoxication of the environmental pollutant acrolein by a rat liver aldo-keto reductase. Toxicol Lett. 148(1–2):65–72. 10.1016/j.toxlet.2003.12.056 [PubMed: 15019089] [CrossRef]
• Garle MJ, Fry JR (1989). Detection of reactive metabolites in vitro. Toxicology. 54(1):101–10. 10.1016/0300-483X(89)90082-6 [PubMed: 2916240] [CrossRef]
• Ghare SS, Donde H, Chen WY, Barker DF, Gobejishvilli L, McClain CJ, et al. (2016). Acrolein enhances epigenetic modifications, FasL expression and hepatocyte toxicity induced by anti-HIV drug Zidovudine. Toxicol In Vitro. 35:66–76. 10.1016/j.tiv.2016.05.013 [PMC free article: PMC4938746] [PubMed: 27238871] [CrossRef]
• Gilbert NL, Guay M, David Miller J, Judek S, Chan CC, Dales RE (2005). Levels and determinants of formaldehyde, acetaldehyde, and acrolein in residential indoor air in Prince Edward Island, Canada. Environ Res. 99(1):11–7. 10.1016/j.envres.2004.09.009 [PubMed: 16053923] [CrossRef]
• Goniewicz ML, Smith DM, Edwards KC, Blount BC, Caldwell KL, Feng J, et al. (2018). Comparison of nicotine and toxicant exposure in users of electronic cigarettes and combustible cigarettes [For data in Table 1.2, see Supplement eTable 2]. JAMA Netw Open. 1(8):e185937. 10.1001/jamanetworkopen.2018.5937 [PMC free article: PMC6324349] [PubMed: 30646298] [CrossRef]
• Gonzalez-Suarez I, Sewer A, Walker P, Mathis C, Ellis S, Woodhouse H, et al. (2014). Systems biology approach for evaluating the biological impact of environmental toxicants in vitro. Chem Res Toxicol. 27(3):367–76. 10.1021/tx400405s [PubMed: 24428674] [CrossRef]
• Government of India (2015). Draft Amendment Proposals. The Factories (Amendment) Act, 2015. New Delhi, India: Ministry of Labour & Employment. Available from: https://labour​.gov.in​/sites/default/files/factory_act_draft​.pdf.
• Government of Ontario (2020). Current occupational exposure limits for Ontario workplaces required under Regulation 833. Acrolein. Toronto (ON), Canada: Ontario Ministry of Labour, Training and Skills Development. Available from: https://www​.labour.gov​.on.ca/english/hs/pubs/oel_table.php, accessed 20 May 2021.
• Grafström RC, Curren RD, Yang LL, Harris CC (1986). Aldehyde-induced inhibition of DNA repair and potentiation of N-nitrosocompound-induced mutagenesis in cultured human cells. Prog Clin Biol Res. 209A:255–64. [PubMed: 3749045]
• Grafström RC, Dypbukt JM, Willey JC, Sundqvist K, Edman C, Atzori L, et al. (1988). Pathobiological effects of acrolein in cultured human bronchial epithelial cells. Cancer Res. 48(7):1717–21. [PubMed: 3349453]
• Greenhoff K, Wheeler RE (1981). Analysis of beer carbonyls at the part per billion level by combined liquid chromatography and high pressure liquid chromatography. J Inst Brew. 86(1):35–41. 10.1002/j.2050-0416.1981.tb03982.x [CrossRef]
• Greenspan EJ, Lee H, Dyba M, Pan J, Mekambi K, Johnson T, et al. (2012). High-throughput, quantitative analysis of acrolein-derived DNA adducts in human oral cells by immunohistochemistry. J Histochem Cytochem. 60(11):844–53. 10.1369/0022155412459759 [PMC free article: PMC3524569] [PubMed: 22899861] [CrossRef]
• Günther M, Wagner E, Ogris M (2008). Acrolein: unwanted side product or contribution to antiangiogenic properties of metronomic cyclophosphamide therapy? J Cell Mol Med. 12(6B):2704–16. 10.1111/j.1582-4934.2008.00255.x [PMC free article: PMC3828885] [PubMed: 18266977] [CrossRef]
• Gurtoo HL, Hipkens JH, Sharma SD (1981). Role of glutathione in the metabolism-dependent toxicity and chemotherapy of cyclophosphamide. Cancer Res. 41(9 Pt 1):3584–91. [PubMed: 7260917]
• Hahn JU (1993). 2-Propenal. Air monitoring methods. The MAK-collection for occupational health and safety. In: Kettrup A, editor. Analyses of hazardous substances in air. Vol 2. Hoboken (NJ), USA: John Wiley; pp. 147–57.
• Haldar S, Dru C, Choudhury D, Mishra R, Fernandez A, Biondi S, et al. (2015). Inflammation and pyroptosis mediate muscle expansion in an interleukin-1β (IL-1β)-dependent manner. J Biol Chem. 290(10):6574–83. 10.1074/jbc.M114.617886 [PMC free article: PMC4358290] [PubMed: 25596528] [CrossRef]
• Haldar S, Dru C, Mishra R, Tripathi M, Duong F, Angara B, et al. (2016). Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. Sci Rep. 6(1):39257. 10.1038/srep39257 [PMC free article: PMC5171776] [PubMed: 27995963] [CrossRef]
• Hales BF (1982). Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein. Cancer Res. 42(8):3016–21. [PubMed: 7046914]
• Hammond SK, Sorensen G, Youngstrom R, Ockene JK (1995). Occupational exposure to environmental tobacco smoke. JAMA. 274(12):956–60. 10.1001/jama.1995.03530120048040 [PubMed: 7674526] [CrossRef]
• Han B, Hare M, Wickramasekara S, Fang Y, Maier CS (2012). A comparative ‘bottom up’ proteomics strategy for the site-specific identification and quantification of protein modifications by electrophilic lipids. J Proteomics. 75(18):5724–33. 10.1016/j.jprot.2012.07.029 [PMC free article: PMC3468693] [PubMed: 22842153] [CrossRef]
• Haswell LE, Hewitt K, Thorne D, Richter A, Gaça MD (2010). Cigarette smoke total particulate matter increases mucous secreting cell numbers in vitro: a potential model of goblet cell hyperplasia. Toxicol In Vitro. 24(3):981–7. 10.1016/j.tiv.2009.12.019 [PubMed: 20060463] [CrossRef]
• Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E (1983). Salmonella mutagenicity test results for 250 chemicals. Environ Mutagen. 5(Suppl 1):1–142. 10.1002/em.2860050703 [PubMed: 6365529] [CrossRef]
• Hayashi M, Futawaka K, Matsushita M, Hatai M, Yoshikawa N, Nakamura K, et al. (2018). Cigarette smoke extract disrupts transcriptional activities mediated by thyroid hormones and its receptors. Biol Pharm Bull. 41(3):383–93. 10.1248/bpb.b17-00735 [PubMed: 29491215] [CrossRef]
• Health Canada (2020). Residential indoor air quality guidelines: acrolein. For public consultation. Consultation period ends August 11. 2020. Available from: https://www​.canada.ca​/content/dam/hc-sc/documents​/programs/consultation-residential-indoor-air-quality-guidelines-acrolein​/document/acrolein-consultation-en.pdf, accessed 21 May 2021.
• Hecht SS, Koh WP, Wang R, Chen M, Carmella SG, Murphy SE, et al. (2015). Elevated levels of mercapturic acids of acrolein and crotonaldehyde in the urine of Chinese women in Singapore who regularly cook at home. PLoS One. 10(3):e0120023. 10.1371/journal.pone.0120023 [PMC free article: PMC4373935] [PubMed: 25807518] [CrossRef]
• Hecht SS, Seow A, Wang M, Wang R, Meng L, Koh WP, et al. (2010). Elevated levels of volatile organic carcinogen and toxicant biomarkers in Chinese women who regularly cook at home. Cancer Epidemiol Biomarkers Prev. 19(5):1185–92. 10.1158/1055-9965.EPI-09-1291 [PMC free article: PMC2866160] [PubMed: 20406956] [CrossRef]
• Hemminki K, Falck K, Vainio H (1980). Comparison of alkylation rates and mutagenicity of directly acting industrial and laboratory chemicals: epoxides, glycidyl ethers, methylating and ethylating agents, halogenated hydrocarbons, hydrazine derivatives, aldehydes, thiuram and dithiocarbamate derivatives. Arch Toxicol. 46(3–4):277–85. 10.1007/BF00310445 [PubMed: 7236006] [CrossRef]
• Hernandes KC, Souza-Silva ÉA, Assumpção CF, Zini CA, Welke JE (2019). Validation of an analytical method using HS-SPME-GC/MS-SIM to assess the exposure risk to carbonyl compounds and furan derivatives through beer consumption. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 36(12):1808–21. 10.1080/19440049.2019.1672897 [PubMed: 31596176] [CrossRef]
• Herrington JS, Myers C (2015). Electronic cigarette solutions and resultant aerosol profiles. J Chromatogr A. 1418:192–9. 10.1016/j.chroma.2015.09.034 [PubMed: 26422308] [CrossRef]
• Hess LG, Kurtz AN, Stanton DB (1978). Acrolein and derivatives. In: Mark HF, Othmer DF, Overberger CG, Seaborg GT, Grayson M, editors. Kirk-Othmer encyclopedia of chemical technology. 3rd ed. Vol. 1. New York (NY), USA: John Wiley; pp. 277–97.
• Hirtle B, Teschke K, van Netten C, Brauer M (1998). Kiln emissions and potters’ exposures. Am Ind Hyg Assoc J. 59(10):706–14. 10.1080/15428119891010884 [PubMed: 9794068] [CrossRef]
• Hoffmann D, Sanghvi LD, Wynder EL (1974). Comparative chemical analysis of Indian bidi and American cigarette smoke. Int J Cancer. 14(1):49–53. 10.1002/ijc.2910140107 [PubMed: 4617708] [CrossRef]
• Hong JH, Lee PAH, Lu YC, Huang CY, Chen CH, Chiang CH, et al. (2020). Acrolein contributes to urothelial carcinomas in patients with chronic kidney disease. Urol Oncol. 38(5):465–75. 10.1016/j.urolonc.2020.02.017 [PubMed: 32199754] [CrossRef]
• Horiyama S, Hatai M, Takahashi Y, Date S, Masujima T, Honda C, et al. (2016). Intracellular metabolism of α,β-unsaturated carbonyl compounds, acrolein, crotonaldehyde and methyl vinyl ketone, active toxicants in cigarette smoke: participation of glutathione conjugation ability and aldehyde-ketone sensitive reductase activity. Chem Pharm Bull (Tokyo). 64(6):585–93. 10.1248/cpb.c15-00986 [PubMed: 27250793] [CrossRef]
• Hristova M, Spiess PC, Kasahara DI, Randall MJ, Deng B, van der Vliet A (2012). The tobacco smoke component, acrolein, suppresses innate macrophage responses by direct alkylation of c-Jun N-terminal kinase. Am J Respir Cell Mol Biol. 46(1):23–33. 10.1165/rcmb.2011-0134OC [PMC free article: PMC3262655] [PubMed: 21778411] [CrossRef]
• IARC (1979). Acrolein. In: Some monomers, plastics and synthetic elastomers, and acrolein. IARC Monogr Eval Carcinog Risk Chem Hum, 19:479–494. Available from: https:​//publications.iarc.fr/37 [PubMed: 374236]
• IARC (1985). Acrolein. In: Allyl compounds, aldehydes, epoxides and peroxides. IARC Monogr Eval Carcinog Risk Chem Hum, 36:133–161. Available from: https:​//publications.iarc.fr/54 [PubMed: 3864730]
• IARC (1995). Acrolein. In: Dry cleaning, some chlorinated solvents and other industrial chemicals. IARC Monogr Eval Carcinog Risks Hum, 63:337–372. Available from: https:​//publications.iarc.fr/81 [PMC free article: PMC7681564] [PubMed: 9139128]
• IARC (1999). Part 1. In: Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. IARC Monogr Eval Carcinog Risks Hum, 71:1–315. Available from: https:​//publications.iarc.fr/89 [PMC free article: PMC7681305] [PubMed: 10507919]
• IARC (2013). Annex: Emissions standards for light- and heavy-duty vehicles. In: Diesel and gasoline engine exhausts and some nitroarenes. IARC Monogr Eval Carcinog Risks Hum, 105:1–703. Available from: https:​//publications.iarc.fr/129
• IARC (2019). Report of the Advisory Group to Recommend Priorities for the IARC Monographs during 2020–2024. Lyon, France: International Agency for Research on Cancer. Available from: https:​//publications.iarc.fr/129, accessed 21 May 2021.
• IFA (2020). Acrolein. GESTIS International Limit Values database. Germany: Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (Institute for Occupational Safety and Health of the German Social Accident Insurance). Available from: https://www​.dguv.de/ifa​/gestis/gestis-internationale-grenzwerte-fuer-chemische-substanzen-limit-values-for-chemical-agents/index-2.jsp, accessed 22 October 2020.
• IOHA (2018). Latin America occupational exposure limits. Available from: http://ioha​.net/wp-content​/uploads/2018/08​/7-Latin-America-OELs-Dias-Jr.pdf.
• IPCS (1992). Acrolein. Environmental health criteria 127. Geneva, Switzerland: United Nations Environment Programme, International Labour Organization, World Health Organization. Available from: http://www​.inchem.org​/documents/ehc/ehc/ehc127.htm, accessed 31 May 2021.
• Irwin RD (2006). NTP technical report on the comparative toxicity studies of allyl acetate (CAS No. 591-87-7), allyl alcohol (CAS No. 107-18-6) and acrolein (CAS No. 107-02-8) administered by gavage to F344/N rats and B6C3F₁ mice. Toxic Rep Ser. 48:1–H10. [PubMed: 17160105]
• Ishii T, Yamada T, Mori T, Kumazawa S, Uchida K, Nakayama T (2007). Characterization of acrolein-induced protein cross-links. Free Radic Res. 41(11):1253–60. 10.1080/10715760701678652 [PubMed: 17922343] [CrossRef]
• ISO (2013). International Standard ISO 19701:2013. Methods for sampling and analysis of fire effluents, Geneva, Switzerland: International Organization for Standardization. Available from: https://www​.iso.org/standard/51334.html, accessed 21 May 2021.
• ISO (2015). International Standard ISO 19702:2015. Guidance for sampling and analysis of toxic gases and vapours in fire effluents using Fourier Transform Infrared (FTIR) spectroscopy, Geneva, Switzerland: International Organization for Standardization.
• ISO (2018). International Standard ISO 21160:2018. Cigarettes — Determination of selected carbonyls in the mainstream smoke of cigarettes — Method using high performance liquid chromatography, Geneva, Switzerland: International Organization for Standardization. Available from: https://www​.iso.org/standard/69993.html, accessed 21 May 2021.
• Izard C (1973). [Mutagenic effects of acrolein and its two epoxides, glycidol and glycidal, on Saccharomyces cerevisiae]. C R Acad Hebd Seances Acad Sci D. 276(23):3037–40.[French] [PubMed: 4198809]
• Izmerov NF, editor (1984). Acrolein. In: Scientific reviews of Soviet literature on toxicity and hazards of chemicals). Geneva, Switzerland: United Nations Environment Programme, International Register of Potentially Toxic Chemicals.
• Jäger T (2019). Acrolein (2-propenal) [BAT value documentation, 2015]. In: The MAK-collection for occupational health and safety. John Wiley.
• Jaimes EA, DeMaster EG, Tian RX, Raij L (2004). Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler Thromb Vasc Biol. 24(6):1031–6. 10.1161/01.ATV.0000127083.88549.58 [PubMed: 15059808] [CrossRef]
• Jakab GJ (1993). The toxicologic interactions resulting from inhalation of carbon black and acrolein on pulmonary antibacterial and antiviral defenses. Toxicol Appl Pharmacol. 121(2):167–75. 10.1006/taap.1993.1142 [PubMed: 8346533] [CrossRef]
• Jankovic J, Jones W, Burkhart J, Noonan G (1991). Environmental study of firefighters. Ann Occup Hyg. 35(6):581–602. [PubMed: 1768008]
• JBRC (2016a). Summary of inhalation carcinogenicity study of acrolein in B6D2F₁ mice. Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association.
• JBRC (2016b). Summary of inhalation carcinogenicity study of acrolein in B6D2F₁/Crlj mice (tables). Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association. Available from: https://anzeninfo​.mhlw​.go.jp/user/anzen/kag​/pdf/gan/0817TABLE.pdf, accessed 25 May 2021. [Japanese]
• JBRC (2016c). Summary of inhalation carcinogenicity study of acrolein in B6D2F₁/Crlj mice (text). Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association. Available from: https://anzeninfo​.mhlw​.go.jp/user/anzen/kag​/pdf/gan/0817MAIN.pdf, accessed 25 May 2021. [Japanese]
• JBRC (2016d). Summary of inhalation carcinogenicity study of acrolein in F344 rats. Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association.
• JBRC (2016e). Summary of inhalation carcinogenicity study of acrolein in F344/DuCrlCrlj rats (tables). Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association. Available from: https://anzeninfo​.mhlw​.go.jp/user/anzen/kag​/pdf/gan/0816TABLE.pdf, accessed 25 May 2021. [Japanese]
• JBRC (2016f). Summary of inhalation carcinogenicity study of acrolein in F344/DuCrlCrlj rats (text). Hadano, Japan: Japan Bioassay Research Center, Japan Industrial Safety and Health Association. Available from: https://anzeninfo​.mhlw​.go.jp/user/anzen/kag​/pdf/gan/0816MAIN.pdf, accessed 25 May 2021. [Japanese]
• Jia L, Liu Z, Sun L, Miller SS, Ames BN, Cotman CW, et al. (2007). Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: protection by (R)-α-lipoic acid. Invest Ophthalmol Vis Sci. 48(1):339–48. 10.1167/iovs.06-0248 [PMC free article: PMC2597695] [PubMed: 17197552] [CrossRef]
• Jia L, Zhang Z, Zhai L, Bai Y (2009). Protective effect of lipoic acid against acrolein-induced cytotoxicity in IMR-90 human fibroblasts. J Nutr Sci Vitaminol (Tokyo). 55(2):126–30. 10.3177/jnsv.55.126 [PubMed: 19436138] [CrossRef]
• JIS (1998). Japanese Industrial Standard JIS K 0089:1998. Methods for determination of acrolein in flue gas. Tokyo, Japan: Japanese Standards Association.
• Johanson G, Dwivedi AM, Ernstgård L, Palmberg L, Ganguly K, Chen LC, et al. (2020). Analysis of acrolein exposure induced pulmonary response in seven inbred mouse strains and human primary bronchial epithelial cells cultured at air-liquid interface. BioMed Res Int. 2020:3259723. 10.1155/2020/3259723 [PMC free article: PMC7582059] [PubMed: 33110918] [CrossRef]
• Kächele M, Monakhova YB, Kuballa T, Lachenmeier DW (2014). NMR investigation of acrolein stability in hydroalcoholic solution as a foundation for the valid HS-SPME/GC-MS quantification of the unsaturated aldehyde in beverages. Anal Chim Acta. 820:112–8. 10.1016/j.aca.2014.02.030 [PubMed: 24745744] [CrossRef]
• Kailasam S, Rogers KR (2007). A fluorescence-based screening assay for DNA damage induced by genotoxic industrial chemicals. Chemosphere. 66(1):165–71. 10.1016/j.chemosphere.2006.05.035 [PubMed: 16820187] [CrossRef]
• Kaminskas LM, Pyke SM, Burcham PC (2005). Differences in lysine adduction by acrolein and methyl vinyl ketone: implications for cytotoxicity in cultured hepatocytes. Chem Res Toxicol. 18(11):1627–33. 10.1021/tx0502387 [PubMed: 16300370] [CrossRef]
• Kanaly RA, Micheletto R, Matsuda T, Utsuno Y, Ozeki Y, Hamamura N (2015). Application of DNA adductomics to soil bacterium Sphingobium sp. strain KK22. MicrobiologyOpen. 4(5):841–56. 10.1002/mbo3.283 [PMC free article: PMC4618615] [PubMed: 26305056] [CrossRef]
• Kanuri M, Minko IG, Nechev LV, Harris TM, Harris CM, Lloyd RS (2002). Error prone translesion synthesis past γ-hydroxypropano deoxyguanosine, the primary acrolein-derived adduct in mammalian cells. J Biol Chem. 277(21):18257–65. 10.1074/jbc.M112419200 [PubMed: 11889127] [CrossRef]
• Kasahara DI, Poynter ME, Othman Z, Hemenway D, van der Vliet A (2008). Acrolein inhalation suppresses lipopolysaccharide-induced inflammatory cytokine production but does not affect acute airways neutrophilia. J Immunol. 181(1):736–45. 10.4049/jimmunol.181.1.736 [PMC free article: PMC3031871] [PubMed: 18566440] [CrossRef]
• Kassem NO, Daffa RM, Liles S, Jackson SR, Kassem NO, Younis MA, et al. (2014). Children’s exposure to secondhand and thirdhand smoke carcinogens and toxicants in homes of hookah smokers. Nicotine Tob Res. 16(7):961–75. 10.1093/ntr/ntu016 [PMC free article: PMC4072898] [PubMed: 24590387] [CrossRef]
• Kassem NOF, Kassem NO, Liles S, Zarth AT, Jackson SR, Daffa RM, et al. (2018). Acrolein exposure in hookah smokers and non-smokers exposed to hookah tobacco secondhand smoke: implications for regulating hookah tobacco products. Nicotine Tob Res. 20(4):492–501. 10.1093/ntr/ntx133 [PMC free article: PMC5896480] [PubMed: 28591850] [CrossRef]
• Kautiainen A, Törnqvist M, Svensson K, Osterman-Golkar S (1989). Adducts of malonaldehyde and a few other aldehydes to hemoglobin. Carcinogenesis. 10(11):2123–30. 10.1093/carcin/10.11.2123 [PubMed: 2805232] [CrossRef]
• Kawai Y, Furuhata A, Toyokuni S, Aratani Y, Uchida K (2003). Formation of acrolein-derived 2ʹ-deoxyadenosine adduct in an iron-induced carcinogenesis model. J Biol Chem. 278(50):50346–54. 10.1074/jbc.M309057200 [PubMed: 14522963] [CrossRef]
• Kawanishi M, Matsuda T, Nakayama A, Takebe H, Matsui S, Yagi T (1998). Molecular analysis of mutations induced by acrolein in human fibroblast cells using supF shuttle vector plasmids. Mutat Res. 417(2–3):65–73. 10.1016/S1383-5718(98)00093-X [PubMed: 9733921] [CrossRef]
• Kaye CM (1973). Biosynthesis of mercapturic acids from allyl alcohol, allyl esters and acrolein. Biochem J. 134(4):1093–101. 10.1042/bj1341093 [PMC free article: PMC1177918] [PubMed: 4762754] [CrossRef]
• Khlystov A, Samburova V (2016). Flavoring compounds dominate toxic aldehyde production during e-cigarette vaping. Environ Sci Technol. 50(23):13080–5. 10.1021/acs.est.6b05145 [PubMed: 27934275] [CrossRef]
• Khudoley VV, Mizgireuv I, Pliss GB (1987). The study of mutagenic activity of carcinogens and other chemical agents with Salmonella typhimurium assays: testing of 126 compounds. Arch Geschwulstforsch. 57(6):453–62. [PubMed: 3435224]
• Kim BG, Lee PH, Lee SH, Hong J, Jang AS (2019). Claudins, VEGF, Nrf2, Keap1, and nonspecific airway hyper-reactivity are increased in mice co-exposed to allergen and acrolein. Chem Res Toxicol. 32(1):139–45. 10.1021/acs.chemrestox.8b00239 [PubMed: 30608172] [CrossRef]
• Kim JK, Park JH, Ku HJ, Kim SH, Lim YJ, Park JW, et al. (2018). Naringin protects acrolein-induced pulmonary injuries through modulating apoptotic signalling and inflammation signaling pathways in mice. J Nutr Biochem. 59:10–6. 10.1016/j.jnutbio.2018.05.012 [PubMed: 29957300] [CrossRef]
• Kim SI, Pfeifer GP, Besaratinia A (2007). Lack of mutagenicity of acrolein-induced DNA adducts in mouse and human cells. Cancer Res. 67(24):11640–7. 10.1158/0008-5472.CAN-07-2528 [PubMed: 18089793] [CrossRef]
• Kiwamoto R, Spenkelink A, Rietjens IMCM, Punt A (2015). An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes. Toxicol Appl Pharmacol. 282(1):108–17. 10.1016/j.taap.2014.10.014 [PubMed: 25448044] [CrossRef]
• Klochkovskii SP, Lukashenko RD, Podvysotskii KS, Kagramanyan NP (1981). [Acrolein and formaldehyde content in the air of quarries]. Bezop Tr Prom-sti. 12:38. [Russian]
• Kolb NS, Hunsaker LA, Vander Jagt DL (1994). Aldose reductase-catalyzed reduction of acrolein: implications in cyclophosphamide toxicity. Mol Pharmacol. 45(4):797–801. [PubMed: 8183257]
• Korneva EN, Shcherbakov VM, Kravchenko LV, Chikvashvili BSh, Devichenskiĭ VM, Semenov SIu, et al. (1991). [Comparative study of the effectiveness of the classical and modified Cooper protocol for breast cancer chemotherapy]. Vopr Med Khim. 37(6):47–50. [Russian] PMID:18126141812614 [PubMed: 1812614]
• Kosmider L, Sobczak A, Fik M, Knysak J, Zaciera M, Kurek J, et al. (2014). Carbonyl compounds in electronic cigarette vapors: effects of nicotine solvent and battery output voltage. Nicotine Tob Res. 16(10):1319–26. 10.1093/ntr/ntu078 [PMC free article: PMC4838028] [PubMed: 24832759] [CrossRef]
• Kozekov ID, Nechev LV, Sanchez A, Harris CM, Lloyd RS, Harris TM (2001). Interchain cross-linking of DNA mediated by the principal adduct of acrolein. Chem Res Toxicol. 14(11):1482–5. 10.1021/tx010127h [PubMed: 11712904] [CrossRef]
• Kozekov ID, Turesky RJ, Alas GR, Harris CM, Harris TM, Rizzo CJ (2010). Formation of deoxyguanosine cross-links from calf thymus DNA treated with acrolein and 4-hydroxy-2-nonenal. Chem Res Toxicol. 23(11):1701–13. 10.1021/tx100179g [PMC free article: PMC2990652] [PubMed: 20964440] [CrossRef]
• Krokan H, Grafstrom RC, Sundqvist K, Esterbauer H, Harris CC (1985). Cytotoxicity, thiol depletion and inhibition of O⁶-methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts. Carcinogenesis. 6(12):1755–9. 10.1093/carcin/6.12.1755 [PubMed: 4064250] [CrossRef]
• Kuchenmeister F, Schmezer P, Engelhardt G (1998). Genotoxic bifunctional aldehydes produce specific images in the comet assay. Mutat Res. 419(1–3):69–78. 10.1016/S1383-5718(98)00125-9 [PubMed: 9804897] [CrossRef]
• Kurahashi T, Kwon M, Homma T, Saito Y, Lee J, Takahashi M, et al. (2014). Reductive detoxification of acrolein as a potential role for aldehyde reductase (AKR1A) in mammals. Biochem Biophys Res Commun. 452(1):136–41. 10.1016/j.bbrc.2014.08.072 [PubMed: 25152401] [CrossRef]
• Kutzman RS, Popenoe EA, Schmaeler M, Drew RT (1985). Changes in rat lung structure and composition as a result of subchronic exposure to acrolein. Toxicology. 34(2):139–51. 10.1016/0300-483X(85)90163-5 [PubMed: 3969686] [CrossRef]
• Kutzman RS, Wehner RW, Haber SB (1984). Selected responses of hypertension-sensitive and resistant rats to inhaled acrolein. Toxicology. 31(1):53–65. 10.1016/0300-483X(84)90155-0 [PubMed: 6729836] [CrossRef]
• Kuykendall JR, Bogdanffy MS (1992). Efficiency of DNA-histone crosslinking induced by saturated and unsaturated aldehydes in vitro. Mutat Res. 283(2):131–6. 10.1016/0165-7992(92)90145-8 [PubMed: 1381490] [CrossRef]
• Lachenmeier DW, Anderson P, Rehm J (2018). Heat-not-burn tobacco products: the devil in disguise or a considerable risk reduction? Int J Alcohol Drug Res. 7(2):8–11. 10.7895/ijadr.250 [CrossRef]
• Lam CW, Casanova M, Heck HD (1985). Depletion of nasal mucosal glutathione by acrolein and enhancement of formaldehyde-induced DNA-protein cross-linking by simultaneous exposure to acrolein. Arch Toxicol. 58(2):67–71. 10.1007/BF00348311 [PubMed: 4091658] [CrossRef]
• Lambert C, McCue J, Portas M, Ouyang Y, Li J, Rosano TG, et al. (2005). Acrolein in cigarette smoke inhibits T-cell responses. J Allergy Clin Immunol. 116(4):916–22. 10.1016/j.jaci.2005.05.046 [PubMed: 16210070] [CrossRef]
• Lane RH, Smathers JL (1991). Monitoring aldehyde production during frying by reversed-phase liquid chromatography. J Assoc Off Anal Chem. 74(6):957–60. 10.1093/jaoac/74.6.957 [PubMed: 1757421] [CrossRef]
• Leach CL, Hatoum NS, Ratajczak HV, Gerhart JM (1987). The pathologic and immunologic effects of inhaled acrolein in rats. Toxicol Lett. 39(2–3):189–98. 10.1016/0378-4274(87)90232-3 [PubMed: 3686549] [CrossRef]
• Lee HW, Wang HT, Weng MW, Chin C, Huang W, Lepor H, et al. (2015). Cigarette side-stream smoke lung and bladder carcinogenesis: inducing mutagenic acrolein-DNA adducts, inhibiting DNA repair and enhancing anchorage-independent-growth cell transformation. Oncotarget. 6(32):33226–36. 10.18632/oncotarget.5429 [PMC free article: PMC4741761] [PubMed: 26431382] [CrossRef]
• Lee HW, Wang HT, Weng MW, Hu Y, Chen WS, Chou D, et al. (2014). Acrolein- and 4-aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget. 5(11):3526–40. 10.18632/oncotarget.1954 [PMC free article: PMC4116500] [PubMed: 24939871] [CrossRef]
• Li L, Hamilton RF Jr, Taylor DE, Holian A (1997). Acrolein-induced cell death in human alveolar macrophages. Toxicol Appl Pharmacol. 145(2):331–9. 10.1006/taap.1997.8189 [PubMed: 9266806] [CrossRef]
• Li L, Jiang L, Geng C, Cao J, Zhong L (2008b). The role of oxidative stress in acrolein-induced DNA damage in HepG2 cells. Free Radic Res. 42(4):354–61. 10.1080/10715760802008114 [PubMed: 18404534] [CrossRef]
• Li X, Liu Z, Luo C, Jia H, Sun L, Hou B, et al. (2008a). Lipoamide protects retinal pigment epithelial cells from oxidative stress and mitochondrial dysfunction. Free Radic Biol Med. 44(7):1465–74. 10.1016/j.freeradbiomed.2008.01.004 [PMC free article: PMC2597696] [PubMed: 18258206] [CrossRef]
• Lide DR, editor (1993). CRC handbook of chemistry and physics. 74th ed.. Boca Raton (FL), USA: CRC Press Inc.; pp. 3-27.
• Ligor T, Ligor M, Amann A, Ager C, Bachler M, Dzien A, et al. (2008). The analysis of healthy volunteers’ exhaled breath by the use of solid-phase microextraction and GC-MS. J Breath Res. 2(4):046006. 10.1088/1752-7155/2/4/046006 [PubMed: 21386193] [CrossRef]
• Lijinsky W (1988). Chronic studies in rodents of vinyl acetate and compounds related to acrolein. Ann N Y Acad Sci. 534(1):246–54. 10.1111/j.1749-6632.1988.tb30114.x [PubMed: 3389658] [CrossRef]
• Lijinsky W, Andrews AW (1980). Mutagenicity of vinyl compounds in Salmonella typhimurium. Teratog Carcinog Mutagen. 1(3):259–67. 10.1002/tcm.1770010303 [PubMed: 6119816] [CrossRef]
• Lijinsky W, Reuber MD (1987). Chronic carcinogenesis studies of acrolein and related compounds. Toxicol Ind Health. 3(3):337–45. 10.1177/074823378700300306 [PubMed: 3686537] [CrossRef]
• Lilić A, Wei T, Bennici S, Devaux JF, Dubois JL, Auroux A (2017). A comparative study of basic, amphoteric, and acidic catalysts in the oxidative coupling of methanol and ethanol for acrolein production. ChemSusChem. 10(17):3459–72. 10.1002/cssc.201701040 [PubMed: 28686350] [CrossRef]
• Lim HH, Shin HS (2012). Simple determination of acrolein in surface and drinking water by headspace SPME GC-MS. Chromatographia. 75:943–8. 10.1007/s10337-012-2274-9 [CrossRef]
• Lin JM, Wang LH (1994). Gaseous aliphatic aldehydes in Chinese incense smoke. Bull Environ Contam Toxicol. 53:374–81. 10.1007/BF00197229 [PubMed: 7919714] [CrossRef]
• Lindner D, Smith S, Leroy CM, Tricker AR (2011). Comparison of exposure to selected cigarette smoke constituents in adult smokers and nonsmokers in a European, multicenter, observational study. Cancer Epidemiol Biomarkers Prev. 20(7):1524–36. 10.1158/1055-9965.EPI-10-1186 [PubMed: 21613391] [CrossRef]
• Linhart I, Frantík E, Vodičková L, Vosmanská M, Šmejkal J, Mitera J (1996). Biotransformation of acrolein in rat: excretion of mercapturic acids after inhalation and intraperitoneal injection. Toxicol Appl Pharmacol. 136(1):155–60. 10.1006/taap.1996.0019 [PubMed: 8560469] [CrossRef]
• Liu DS, Liu WJ, Chen L, Ou XM, Wang T, Feng YL, et al. (2009b). Rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist, attenuates acrolein-induced airway mucus hypersecretion in rats. Toxicology. 260(1–3):112–9. 10.1016/j.tox.2009.03.016 [PubMed: 19464576] [CrossRef]
• Liu DS, Wang T, Han SX, Dong JJ, Liao ZL, He GM, et al. (2009a). p38 MAPK and MMP-9 cooperatively regulate mucus overproduction in mice exposed to acrolein fog. Int Immunopharmacol. 9(10):1228–35. 10.1016/j.intimp.2009.07.005 [PubMed: 19631294] [CrossRef]
• Liu Q, Liu Y, Zhang M (2014). Source apportionment of personal exposure to carbonyl compounds and BTEX at homes in Beijing, China. Aerosol Air Qual Res. 14(1):330–7. 10.4209/aaqr.2013.01.0005 [CrossRef]
• Liu X, Lovell MA, Lynn BC (2005). Development of a method for quantification of acrolein-deoxyguanosine adducts in DNA using isotope dilution-capillary LC/MS/MS and its application to human brain tissue. Anal Chem. 77(18):5982–9. 10.1021/ac050624t [PubMed: 16159131] [CrossRef]
• Löfroth G, Burton RM, Forehand L, Hammond SK, Seila RL, Zweidinger RB (1989). Characterization of environmental tobacco smoke. Environ Sci Technol. 23(5):610–4. 10.1021/es00063a015 [CrossRef]
• Logue JM, Small MJ, Stern D, Maranche J, Robinson AL (2010). Spatial variation in ambient air toxics concentrations and health risks between industrial-influenced, urban, and rural sites. J Air Waste Manag Assoc. 60(3):271–86. 10.3155/1047-3289.60.3.271 [PubMed: 20397557] [CrossRef]
• Loquet C, Toussaint G, LeTalaer JY (1981). Studies on mutagenic constituents of apple brandy and various alcoholic beverages collected in western France, a high incidence area for oesophageal cancer. Mutat Res. 88(2):155–64. 10.1016/0165-1218(81)90014-8 [PubMed: 7012608] [CrossRef]
• Luo C, Li Y, Yang L, Feng Z, Li Y, Long J, et al. (2013). A cigarette component acrolein induces accelerated senescence in human diploid fibroblast IMR-90 cells. Biogerontology. 14(5):503–11. 10.1007/s10522-013-9454-3 [PubMed: 24026667] [CrossRef]
• Lutz D, Eder E, Neudecker T, Heschler D (1982). Structure-mutagenicity relationship in α,β-unsaturated carbonylic compounds and their corresponding allylic alcohols. Mutat Res. 93(2):305–15. 10.1016/0027-5107(82)90146-4 [CrossRef]
• Ma B, Stepanov I, Hecht SS (2019). Recent studies on DNA adducts resulting from human exposure to tobacco smoke. Toxics. 7(1):16. 10.3390/toxics7010016 [PMC free article: PMC6468371] [PubMed: 30893918] [CrossRef]
• Macedo FY, Baltazar F, Mourão LC, Almeida PR, Mota JM, Schmitt FC, et al. (2008). Induction of COX-2 expression by acrolein in the rat model of hemorrhagic cystitis. Exp Toxicol Pathol. 59(6):425–30. 10.1016/j.etp.2007.10.010 [PubMed: 18234483] [CrossRef]
• Maeshima T, Honda K, Chikazawa M, Shibata T, Kawai Y, Akagawa M, et al. (2012). Quantitative analysis of acrolein-specific adducts generated during lipid peroxidation-modification of proteins in vitro: identification of N(τ)-(3-propanal)histidine as the major adduct. Chem Res Toxicol. 25(7):1384–92. 10.1021/tx3000818 [PubMed: 22716039] [CrossRef]
• Makia NL, Bojang P, Falkner KC, Conklin DJ, Prough RA (2011). Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation. Chem Biol Interact. 191(1–3):278–87. 10.1016/j.cbi.2011.01.013 [PMC free article: PMC4409133] [PubMed: 21256123] [CrossRef]
• Marinello AJ, Bansal SK, Paul B, Koser PL, Love J, Struck RF, et al. (1984). Metabolism and binding of cyclophosphamide and its metabolite acrolein to rat hepatic microsomal cytochrome P-450. Cancer Res. 44(10):4615–21. [PubMed: 6380709]
• Marnett LJ, Hurd HK, Hollstein MC, Levin DE, Esterbauer H, Ames BN (1985). Naturally occurring carbonyl compounds are mutagens in Salmonella tester strain TA104. Mutat Res. 148(1–2):25–34. 10.1016/0027-5107(85)90204-0 [PubMed: 3881660] [CrossRef]
• Matsushita M, Futawaka K, Hayashi M, Murakami K, Mitsutani M, Hatai M, et al. (2019). Cigarette smoke extract modulates functions of peroxisome proliferator-activated receptors. Biol Pharm Bull. 42(10):1628–36. 10.1248/bpb.b18-00991 [PubMed: 31582651] [CrossRef]
• McDiarmid MA, Iype PT, Kolodner K, Jacobson-Kram D, Strickland PT (1991). Evidence for acrolein-modified DNA in peripheral blood leukocytes of cancer patients treated with cyclophosphamide. Mutat Res. 248(1):93–9. 10.1016/0027-5107(91)90091-2 [PubMed: 2030715] [CrossRef]
• Merriam FV, Wang ZY, Guerios SD, Bjorling DE (2008). Cannabinoid receptor 2 is increased in acutely and chronically inflamed bladder of rats. Neurosci Lett. 445(1):130–4. 10.1016/j.neulet.2008.08.076 [PMC free article: PMC2592089] [PubMed: 18778751] [CrossRef]
• Merriam FV, Wang ZY, Hillard CJ, Stuhr KL, Bjorling DE (2011). Inhibition of fatty acid amide hydrolase suppresses referred hyperalgesia induced by bladder inflammation. BJU Int. 108(7):1145–9. 10.1111/j.1464-410X.2010.09583.x [PMC free article: PMC3505723] [PubMed: 20804480] [CrossRef]
• Miller BE, Danielson ND (1988). Derivatization of vinyl aldehydes with anthrone prior to high-performance liquid chromatography with fluorometric detection. Anal Chem. 60(7):622–6. 10.1021/ac00158a004 [CrossRef]
• Minko IG, Kozekov ID, Harris TM, Rizzo CJ, Lloyd RS, Stone MP (2009). Chemistry and biology of DNA containing 1,N²-deoxyguanosine adducts of the α,β-unsaturated aldehydes acrolein, crotonaldehyde, and 4-hydroxynonenal. Chem Res Toxicol. 22(5):759–78. 10.1021/tx9000489 [PMC free article: PMC2685875] [PubMed: 19397281] [CrossRef]
• Minko IG, Kozekov ID, Kozekova A, Harris TM, Rizzo CJ, Lloyd RS (2008). Mutagenic potential of DNA-peptide crosslinks mediated by acrolein-derived DNA adducts. Mutat Res. 637(1–2):161–72. 10.1016/j.mrfmmm.2007.08.001 [PMC free article: PMC3181171] [PubMed: 17868748] [CrossRef]
• Minko IG, Washington MT, Kanuri M, Prakash L, Prakash S, Lloyd RS (2003). Translesion synthesis past acrolein-derived DNA adduct, γ-hydroxypropanodeoxyguanosine, by yeast and human DNA polymerase η. J Biol Chem. 278(2):784–90. 10.1074/jbc.M207774200 [PubMed: 12401796] [CrossRef]
• Mitacek EJ, Brunnemann KD, Polednak AP, Limsila T, Bhothisuwan K, Hummel CF (2002). Rising leukemia rates in Thailand: the possible role of benzene and related compounds in cigarette smoke. Oncol Rep. 9(6):1399–403. 10.3892/or.9.6.1399 [PubMed: 12375055] [CrossRef]
• Mitchell DY, Petersen DR (1989). Metabolism of the glutathione-acrolein adduct, S-(2-aldehydo-ethyl)glutathione, by rat liver alcohol and aldehyde dehydrogenase. J Pharmacol Exp Ther. 251(1):193–8. [PubMed: 2795457]
• Mitova MI, Campelos PB, Goujon-Ginglinger CG, Maeder S, Mottier N, Rouget EGR, et al. (2016). Comparison of the impact of the Tobacco Heating System 2.2 and a cigarette on indoor air quality. Regul Toxicol Pharmacol. 80:91–101. 10.1016/j.yrtph.2016.06.005 [PubMed: 27311683] [CrossRef]
• Mohammad MK, Avila D, Zhang J, Barve S, Arteel G, McClain C, et al. (2012). Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol. 265(1):73–82. 10.1016/j.taap.2012.09.021 [PMC free article: PMC3501104] [PubMed: 23026831] [CrossRef]
• Morris JB (1996). Uptake of acrolein in the upper respiratory tract of the F344 rat. Inhal Toxicol. 8(4):387–403. 10.3109/08958379609052914 [CrossRef]
• Nair DT, Johnson RE, Prakash L, Prakash S, Aggarwal AK (2008). Protein-template-directed synthesis across an acrolein-derived DNA adduct by yeast Rev1 DNA polymerase. Structure. 16(2):239–45. 10.1016/j.str.2007.12.009 [PubMed: 18275815] [CrossRef]
• Nath RG, Chung FL (1994). Detection of exocyclic 1,N²-propanodeoxyguanosine adducts as common DNA lesions in rodents and humans. Proc Natl Acad Sci USA. 91(16):7491–5. 10.1073/pnas.91.16.7491 [PMC free article: PMC44427] [PubMed: 8052609] [CrossRef]
• Nath RG, Ocando JE, Chung FL (1996). Detection of 1, N²-propanodeoxyguanosine adducts as potential endogenous DNA lesions in rodent and human tissues. Cancer Res. 56(3):452–6. [PubMed: 8564951]
• Nath RG, Ocando JE, Guttenplan JB, Chung FL (1998). 1,N²-propanodeoxyguanosine adducts: potential new biomarkers of smoking-induced DNA damage in human oral tissue. Cancer Res. 58(4):581–4. [PubMed: 9485001]
• National Research Council (2010). Acute exposure guideline levels for selected airborne chemicals: volume 8, pp. 13–48. Washington (DC), USA: National Academies Press. Available from: https://www​.nap.edu/catalog​/12770/acute-exposure-guideline-levels-for-selected-airborne-chemicals-volume-8, accessed 26 May 2021.
• NCBI (2020). Compound summary for acrolein. PubChem Open Chemistry Database. Bethesda (MD), USA: National Center for Biotechnology Information, United States National Library of Medicine. Available from: https://pubchem​.ncbi​.nlm.nih.gov/compound/Acrolein.
• Neghab M, Delikhoon M, Norouzian Baghani A, Hassanzadeh J (2017). Exposure to cooking fumes and acute reversible decrement in lung functional capacity. Int J Occup Environ Med. 8(4):207–16. 10.15171/ijoem.2017.1100 [PMC free article: PMC6679607] [PubMed: 28970595] [CrossRef]
• Neumüller O-A (1979). Römpps Chemie-Lexikon. 8th Ed., Vol. 1. Stuttgart, Germany: Franckh’sche Verlagshandlung, W. Keller & Co.; p. 54. [German]
• NIOSH (1990). National Occupational Exposure Survey. Cincinnati (OH), USA: National Institute for Occupational Safety and Health. Available from: https://www​.cdc.gov/noes/default.html, accessed 26 May 2021.
• Nunoshiba T, Yamamoto K (1999). Role of glutathione on acrolein-induced cytotoxicity and mutagenicity in Escherichia coli. Mutat Res. 442(1):1–8. 10.1016/S1383-5718(99)00052-2 [PubMed: 10366767] [CrossRef]
• O’Brien E, Spiess PC, Habibovic A, Hristova M, Bauer RA, Randall MJ, et al. (2016). Inhalation of the reactive aldehyde acrolein promotes antigen sensitization to ovalbumin and enhances neutrophilic inflammation. J Immunotoxicol. 13(2):191–7. 10.3109/1547691X.2015.1033571 [PMC free article: PMC4678038] [PubMed: 25875327] [CrossRef]
• O’Neil MJ, editor (2013). The Merck index. An encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station (NJ), USA: Merck and Co., Inc.
• OEHHA (2018). Gasoline-related air pollutants in California. Trends in exposure and health risk 1996 to 2004. Sacramento (CA), USA: Office of Environmental Health Hazard Assessment, California Environmental Protection Agency. Available from: https://oehha​.ca.gov​/media/downloads/air​/report/oehhagasolinereportjanuary2018final.pdf, accessed September 2020.
• Ong FH, Henry PJ, Burcham PC (2012). Prior exposure to acrolein accelerates pulmonary inflammation in influenza A-infected mice. Toxicol Lett. 212(3):241–51. 10.1016/j.toxlet.2012.06.003 [PubMed: 22705057] [CrossRef]
• OSHA (2020). Acrolein. Chemical exposure health data. Washington (DC), USA: Occupational Safety and Health Administration. Available from: https://www​.osha.gov​/opengov/healthsamples.html, accessed September 2020.
• Osório VM, de Lourdes Cardeal Z (2011). Determination of acrolein in french fries by solid-phase microextraction gas chromatography and mass spectrometry. J Chromatogr A. 1218(21):3332–6. 10.1016/j.chroma.2010.11.068 [PubMed: 21168848] [CrossRef]
• Ott MG, Teta MJ, Greenberg HL (1989a). Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Am J Ind Med. 16(6):631–43. 10.1002/ajim.4700160603 [PubMed: 2556914] [CrossRef]
• Ott MG, Teta MJ, Greenberg HL (1989b). Assessment of exposure to chemicals in a complex work environment. Am J Ind Med. 16(6):617–30. 10.1002/ajim.4700160602 [PubMed: 2596485] [CrossRef]
• Pal A, Hu X, Zimniak P, Singh SV (2000). Catalytic efficiencies of allelic variants of human glutathione S-transferase Pi in the glutathione conjugation of α,β-unsaturated aldehydes. Cancer Lett. 154(1):39–43. 10.1016/S0304-3835(00)00390-6 [PubMed: 10799737] [CrossRef]
• Pan J, Awoyemi B, Xuan Z, Vohra P, Wang HT, Dyba M, et al. (2012). Detection of acrolein-derived cyclic DNA adducts in human cells by monoclonal antibodies. Chem Res Toxicol. 25(12):2788–95. 10.1021/tx3004104 [PMC free article: PMC3561715] [PubMed: 23126278] [CrossRef]
• Pan J, Chung FL (2002). Formation of cyclic deoxyguanosine adducts from ω-3 and ω-6 polyunsaturated fatty acids under oxidative conditions. Chem Res Toxicol. 15(3):367–72. 10.1021/tx010136q [PubMed: 11896684] [CrossRef]
• Pan J, Keffer J, Emami A, Ma X, Lan R, Goldman R, et al. (2009). Acrolein-derived DNA adduct formation in human colon cancer cells: its role in apoptosis induction by docosahexaenoic acid. Chem Res Toxicol. 22(5):798–806. 10.1021/tx800355k [PMC free article: PMC2683896] [PubMed: 19341237] [CrossRef]
• Pan J, Sinclair E, Xuan Z, Dyba M, Fu Y, Sen S, et al. (2016). Nucleotide excision repair deficiency increases levels of acrolein-derived cyclic DNA adduct and sensitizes cells to apoptosis induced by docosahexaenoic acid and acrolein. Mutat Res. 789:33–8. 10.1016/j.mrfmmm.2016.02.011 [PMC free article: PMC5896306] [PubMed: 27036235] [CrossRef]
• Panosyan AG, Mamikonyan GV, Torosyan M, Gabrielyan ES, Mkhitaryan SA, Tirakyan MR, et al. (2001). Determination of the composition of volatiles in cognac (brandy) by headspace gas chromatography–mass spectrometry. J Anal Chem. 56(10):945–52. 10.1023/A:1012365629636 [CrossRef]
• Parent RA, Caravello HE, Harbell JW (1991b). Gene mutation assay of acrolein in the CHO/HGPRT test system. J Appl Toxicol. 11(2):91–5. 10.1002/jat.2550110204 [PubMed: 2061556] [CrossRef]
• Parent RA, Caravello HE, Long JE (1991a). Oncogenicity study of acrolein in mice. J Am Coll Toxicol. 10(6):647–59. 10.3109/10915819109078657 [CrossRef]
• Parent RA, Caravello HE, Long JE (1992). Two-year toxicity and carcinogenicity study of acrolein in rats. J Appl Toxicol. 12(2):131–9. 10.1002/jat.2550120210 [PubMed: 1556380] [CrossRef]
• Parent RA, Caravello HE, San RH (1996b). Mutagenic activity of acrolein in S. typhimurium and E. coli. J Appl Toxicol. 16(2):103–8. 10.1002/(SICI)1099-1263(199603)16:2<103::AID-JAT318>3.0.CO;2-Q [PubMed: 8935782] [CrossRef]
• Parent RA, Caravello HE, Sharp DE (1996a). Metabolism and distribution of [2,3-¹⁴C]acrolein in Sprague-Dawley rats. J Appl Toxicol. 16(5):449–57. 10.1002/(SICI)1099-1263(199609)16:5<449::AID-JAT369>3.0.CO;2-9 [PubMed: 8889798] [CrossRef]
• Parent RA, Paust DE, Schrimpf MK, Talaat RE, Doane RA, Caravello HE, et al. (1998). Metabolism and distribution of [2,3-¹⁴C]acrolein in Sprague-Dawley rats. II. Identification of urinary and fecal metabolites. Toxicol Sci. 43(2):110–20. 10.1006/toxs.1998.2462 [PubMed: 9710952] [CrossRef]
• Park SL, Carmella SG, Chen M, Patel Y, Stram DO, Haiman CA, et al. (2015). Mercapturic acids derived from the toxicants acrolein and crotonaldehyde in the urine of cigarette smokers from five ethnic groups with differing risks for lung cancer. PLoS One. 10(6):e0124841. 10.1371/journal.pone.0124841 [PMC free article: PMC4460074] [PubMed: 26053186] [CrossRef]
• Patel JM, Wood JC, Leibman KC (1980). The biotransformation of allyl alcohol and acrolein in rat liver and lung preparations. Drug Metab Dispos. 8(5):305–8. [PubMed: 6107226]
• Pawłowicz AJ, Kronberg L (2008). Characterization of adducts formed in reactions of acrolein with thymidine and calf thymus DNA. Chem Biodivers. 5(1):177–88. 10.1002/cbdv.200890009 [PubMed: 18205121] [CrossRef]
• Pawłowicz AJ, Munter T, Klika KD, Kronberg L (2006a). Reaction of acrolein with 2ʹ-deoxyadenosine and 9-ethyladenine–formation of cyclic adducts. Bioorg Chem. 34(1):39–48. 10.1016/j.bioorg.2005.10.006 [PubMed: 16343591] [CrossRef]
• Pawłowicz AJ, Munter T, Zhao Y, Kronberg L (2006b). Formation of acrolein adducts with 2ʹ-deoxyadenosine in calf thymus DNA. Chem Res Toxicol. 19(4):571–6. 10.1021/tx0503496 [PubMed: 16608169] [CrossRef]
• Penn A, Nath R, Pan J, Chen L, Widmer K, Henk W, et al. (2001). 1,N²-propanodeoxyguanosine adduct formation in aortic DNA following inhalation of acrolein. Environ Health Perspect. 109(3):219–24. [PMC free article: PMC1240238] [PubMed: 11333181]
• Permana PA, Snapka RM (1994). Aldehyde-induced protein–DNA crosslinks disrupt specific stages of SV40 DNA replication. Carcinogenesis. 15(5):1031–6. 10.1093/carcin/15.5.1031 [PubMed: 8200064] [CrossRef]
• Pocker Y, Janjić N (1988). Differential modification of specificity in carbonic anhydrase catalysis. J Biol Chem. 263(13):6169–76. [PubMed: 3129421]
• Poirier M, Fournier M, Brousseau P, Morin A (2002). Effects of volatile aromatics, aldehydes, and phenols in tobacco smoke on viability and proliferation of mouse lymphocytes. J Toxicol Environ Health A. 65(19):1437–51. 10.1080/00984100290071342 [PubMed: 12396875] [CrossRef]
• Pośniak M, Kozieł E, Jezewska A (2001). Occupational exposure to harmful chemical substances while processing phenol-formaldehyde resins. Int J Occup Saf Ergon. 7(3):263–76. 10.1080/10803548.2001.11076490 [PubMed: 11543697] [CrossRef]
• Protsenko GA, Danilov VI, Timchenko AN, Nenartovich AV, Trubilko VI, Savchenkov VA (1973). Working conditions when metals to which primer has been applied are welded evaluated from the health and hygiene aspect. Avt Svarka. 2:65–8.
• Redtenbacher J (1843). Ueber die Zerlegungsprodukte des Glyceryloxydes durch trockene Destillation. Justus Liebigs Ann Chem. 47(2):113–48. 10.1002/jlac.18430470202 [CrossRef]
• Rees KR, Tarlow MJ (1967). The hepatotoxic action of allyl formate. Biochem J. 104(3):757–61. 10.1042/bj1040757 [PMC free article: PMC1271216] [PubMed: 6049921] [CrossRef]
• Regal Intelligence (2020). Global acrolein market analysis 2020 with top companies, production, consumption, price and growth rate. Available from https://www​.regalintelligence​.com/report​/17523/Acrolein-Market, accessed 21 May 2021.
• Reinhardt TE, Ottmar RD (2004). Baseline measurements of smoke exposure among wildland firefighters. J Occup Environ Hyg. 1(9):593–606. 10.1080/15459620490490101 [PubMed: 15559331] [CrossRef]
• Rikans LE (1987). The oxidation of acrolein by rat liver aldehyde dehydrogenases. Relation to allyl alcohol hepatotoxicity. Drug Metab Dispos. 15(3):356–62. [PubMed: 2886311]
• Rodriguez L, Prado J, Holland A, Beckman J, Calvert GM; Centers for Disease Control and Prevention (CDC) (2013). Notes from the field: acute pesticide-related illness resulting from occupational exposure to acrolein - Washington and California, 1993–2009. MMWR Morb Mortal Wkly Rep. 62(16):313–4. [PMC free article: PMC4604963] [PubMed: 23615676]
• Roemer E, Anton HJ, Kindt R (1993). Cell proliferation in the respiratory tract of the rat after acute inhalation of formaldehyde or acrolein. J Appl Toxicol. 13(2):103–7. 10.1002/jat.2550130206 [PubMed: 8486908] [CrossRef]
• Rom O, Korach-Rechtman H, Hayek T, Danin-Poleg Y, Bar H, Kashi Y, et al. (2017). Acrolein increases macrophage atherogenicity in association with gut microbiota remodeling in atherosclerotic mice: protective role for the polyphenol-rich pomegranate juice. Arch Toxicol. 91(4):1709–25. 10.1007/s00204-016-1859-8 [PubMed: 27696135] [CrossRef]
• Ruenz M, Goerke K, Bakuradze T, Abraham K, Lampen A, Eisenbrand G, et al. (2019). Sustained human background exposure to acrolein evidenced by monitoring urinary exposure biomarkers. Mol Nutr Food Res. 63(24):e1900849. 10.1002/mnfr.201900849 [PubMed: 31752044] [CrossRef]
• Ruprecht A, De Marco C, Saffari A, Pozzi P, Mazza R, Veronese C, et al. (2017). Environmental pollution and emission factors of electronic cigarettes, heat-not-burn tobacco products, and conventional cigarettes. Aerosol Sci Technol. 51(6):674–84. 10.1080/02786826.2017.1300231 [CrossRef]
• Saison D, De Schutter DP, Delvaux F, Delvaux FR (2009). Determination of carbonyl compounds in beer by derivatisation and headspace solid-phase microextraction in combination with gas chromatography and mass spectrometry. J Chromatogr A. 1216(26):5061–8. 10.1016/j.chroma.2009.04.077 [PubMed: 19450805] [CrossRef]
• Salaman MH, Roe FJC (1956). Further tests for tumour-initiating activity: N,N-di-(2-chloroethyl)-p-aminophenylbutyric acid (CB1348) as an initiator of skin tumour formation in the mouse. Br J Cancer. 10(2):363–78. 10.1038/bjc.1956.42 [PMC free article: PMC2073810] [PubMed: 13364128] [CrossRef]
• Sanchez AM, Minko IG, Kurtz AJ, Kanuri M, Moriya M, Lloyd RS (2003). Comparative evaluation of the bioreactivity and mutagenic spectra of acrolein-derived α-HOPdG and γ-HOPdG regioisomeric deoxyguanosine adducts. Chem Res Toxicol. 16(8):1019–28. 10.1021/tx034066u [PubMed: 12924930] [CrossRef]
• Sarkar P (2019). Response of DNA damage genes in acrolein-treated lung adenocarcinoma cells. Mol Cell Biochem. 450(1–2):187–98. 10.1007/s11010-018-3385-x [PubMed: 29968166] [CrossRef]
• Sawant AA, Na K, Zhu X, Cocker K, Butt S, Song C, et al. (2004). Characterization of PM_2.5 and selected gas-phase compounds at multiple indoor and outdoor sites in Mira Loma, California. Atmos Environ. 38(37):6269–78. 10.1016/j.atmosenv.2004.08.043 [CrossRef]
• Sax NI, Lewis RJ (1987). Hawley’s condensed chemical dictionary. 11th ed. New York (NY), USA: Van Nostrand Reinhold.; p. 18.
• Schauer JJ, Kleeman MJ, Cass GR, Simoneit BRT (2002). Measurement of emissions from air pollution sources. 5. C₁–C₃₂ organic compounds from gasoline-powered motor vehicles. Environ Sci Technol. 36(6):1169–80. 10.1021/es0108077 [PubMed: 11944666] [CrossRef]
• Schoenfeld HA, Witz G (2000). Structure–activity relationships in the induction of DNA–protein cross-links by hematotoxic ring-opened benzene metabolites and related compounds in HL60 cells. Toxicol Lett. 116(1–2):79–88. 10.1016/S0378-4274(00)00203-4 [PubMed: 10906425] [CrossRef]
• Schroeter JD, Kimbell JS, Gross EA, Willson GA, Dorman DC, Tan YM, et al. (2008). Application of physiological computational fluid dynamics models to predict interspecies nasal dosimetry of inhaled acrolein. Inhal Toxicol. 20(3):227–43. 10.1080/08958370701864235 [PubMed: 18300045] [CrossRef]
• Seaman VY, Bennett DH, Cahill TM (2007). Origin, occurrence, and source emission rate of acrolein in residential indoor air. Environ Sci Technol. 41(20):6940–6. 10.1021/es0707299 [PubMed: 17993132] [CrossRef]
• Seaman VY, Bennett DH, Cahill TM (2009). Indoor acrolein emission and decay rates resulting from domestic cooking events. Atmos Environ. 43(39):6199–204. 10.1016/j.atmosenv.2009.08.043 [CrossRef]
• Shang S, Ordway D, Henao-Tamayo M, Bai X, Oberley-Deegan R, Shanley C, et al. (2011). Cigarette smoke increases susceptibility to tuberculosis–evidence from in vivo and in vitro models. J Infect Dis. 203(9):1240–8. 10.1093/infdis/jir009 [PubMed: 21357942] [CrossRef]
• Shanmugam G, Minko IG, Banerjee S, Christov PP, Kozekov ID, Rizzo CJ, et al. (2013). Ring-opening of the γ-OH-PdG adduct promotes error-free bypass by the Sulfolobus solfataricus DNA polymerase Dpo4. Chem Res Toxicol. 26(9):1348–60. 10.1021/tx400200b [PMC free article: PMC3775444] [PubMed: 23947567] [CrossRef]
• Shen Y, Zhong L, Johnson S, Cao D (2011). Human aldo-keto reductases 1B1 and 1B10: a comparative study on their enzyme activity toward electrophilic carbonyl compounds. Chem Biol Interact. 191(1–3):192–8. 10.1016/j.cbi.2011.02.004 [PMC free article: PMC3103604] [PubMed: 21329684] [CrossRef]
• Shibamoto T (2008). Acrolein. In: Stadler RH, Lineback DR, editors. Process-induced food toxicants: occurrence, formation, mitigation, and health risks. Hoboken (NJ), USA: Wiley. pp. 51–73. Available from: https:​//onlinelibrary​.wiley.com/doi/abs/10​.1002/9780470430101.ch2b, accessed 25 May 2021.
• Sierra LM, Barros AR, García M, Ferreiro JA, Comendador MA (1991). Acrolein genotoxicity in Drosophila melanogaster. I. Somatic and germinal mutagenesis under proficient repair conditions. Mutat Res. 260(3):247–56. 10.1016/0165-1218(91)90033-I [PubMed: 1908054] [CrossRef]
• Sithu SD, Srivastava S, Siddiqui MA, Vladykovskaya E, Riggs DW, Conklin DJ, et al. (2010). Exposure to acrolein by inhalation causes platelet activation. Toxicol Appl Pharmacol. 248(2):100–10. 10.1016/j.taap.2010.07.013 [PMC free article: PMC2946419] [PubMed: 20678513] [CrossRef]
• Slaughter JC, Koenig JQ, Reinhardt TE (2004). Association between lung function and exposure to smoke among firefighters at prescribed burns. J Occup Environ Hyg. 1(1):45–9. 10.1080/15459620490264490 [PubMed: 15202156] [CrossRef]
• Smith MT, Guyton KZ, Gibbons CF, Fritz JM, Portier CJ, Rusyn I, et al. (2016). Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis. Environ Health Perspect. 124(6):713–21. 10.1289/ehp.1509912 [PMC free article: PMC4892922] [PubMed: 26600562] [CrossRef]
• Smith RA, Cohen SM, Lawson TA (1990b). Acrolein mutagenicity in the V79 assay. Carcinogenesis. 11(3):497–8. 10.1093/carcin/11.3.497 [PubMed: 2311195] [CrossRef]
• Smith RA, Williamson DS, Cerny RL, Cohen SM (1990a). Detection of 1,N⁶-propanodeoxyadenosine in acrolein-modified polydeoxyadenylic acid and DNA by ³²P postlabeling. Cancer Res. 50(10):3005–12.10.1016/0304-3835(88)90267-4 [PubMed: 2334905] [CrossRef]
• Snow SJ, McGee MA, Henriquez A, Richards JE, Schladweiler MC, Ledbetter AD, et al. (2017). Respiratory effects and systemic stress response following acute acrolein inhalation in rats. Toxicol Sci. 158(2):454–64. 10.1093/toxsci/kfx108 [PMC free article: PMC6515527] [PubMed: 28541489] [CrossRef]
• Sodum R, Shapiro R (1988). Reaction of acrolein with cytosine and adenine derivatives. Bioorg Chem. 16(3):272–82. 10.1016/0045-2068(88)90015-6 [CrossRef]
• Sousa BC, Ahmed T, Dann WL, Ashman J, Guy A, Durand T, et al. (2019). Short-chain lipid peroxidation products form covalent adducts with pyruvate kinase and inhibit its activity in vitro and in breast cancer cells. Free Radic Biol Med. 144:223–33. 10.1016/j.freeradbiomed.2019.05.028 [PubMed: 31173844] [CrossRef]
• South Africa Department of Labour (1995). Occupational Health and Safety Act, 1993. Hazardous Chemical Substances Regulations, 1995. Lyttleton, South Africa: South Africa Department of Labour. Available from: https://labourguide​.co​.za/healthsafety/791-hazardous-chemical-substance-reg-1995/file.
• Spiess PC, Deng B, Hondal RJ, Matthews DE, van der Vliet A (2011). Proteomic profiling of acrolein adducts in human lung epithelial cells. J Proteomics. 74(11):2380–94. 10.1016/j.jprot.2011.05.039 [PMC free article: PMC3196826] [PubMed: 21704744] [CrossRef]
• State of California (2020). Table AC-1. Permissible exposure limits for chemical contaminants. USA: State of California, Department of Industrial Relations. Available from: https://www​.dir.ca.gov​/title8/5155table_ac1.html, accessed 28 May 2021.
• Steiner PE, Steele R, Koch F (1943). The possible carcinogenicity of overcooked meats, heated cholesterol, acrolein, and heated sesame oil. Cancer Res. 3:100–7.
• Stevens JF, Maier CS (2008). Acrolein: sources, metabolism, and biomolecular interactions relevant to human health and disease. Mol Nutr Food Res. 52(1):7–25. 10.1002/mnfr.200700412 [PMC free article: PMC2423340] [PubMed: 18203133] [CrossRef]
• Struve MF, Wong VA, Marshall MW, Kimbell JS, Schroeter JD, Dorman DC (2008). Nasal uptake of inhaled acrolein in rats. Inhal Toxicol. 20(3):217–25. 10.1080/08958370701864219 [PubMed: 18300044] [CrossRef]
• Sun Y, Ito S, Nishio N, Tanaka Y, Chen N, Isobe K (2014). Acrolein induced both pulmonary inflammation and the death of lung epithelial cells. Toxicol Lett. 229(2):384–92. 10.1016/j.toxlet.2014.06.021 [PubMed: 24999835] [CrossRef]
• Svendsen K, Jensen HN, Sivertsen I, Sjaastad AK (2002). Exposure to cooking fumes in restaurant kitchens in Norway. Ann Occup Hyg. 46(4):395–400. [PubMed: 12176708]
• Takamoto S, Sakura N, Namera A, Yashiki M (2004). Monitoring of urinary acrolein concentration in patients receiving cyclophosphamide and ifosphamide. J Chromatogr B Analyt Technol Biomed Life Sci. 806(1):59–63. 10.1016/j.jchromb.2004.02.008 [PubMed: 15149612] [CrossRef]
• Talhout R, Opperhuizen A, van Amsterdam JG (2006). Sugars as tobacco ingredient: effects on mainstream smoke composition. Food Chem Toxicol. 44(11):1789–98. 10.1016/j.fct.2006.06.016 [PubMed: 16904804] [CrossRef]
• Thakore KN, Gan JC, Ansari GA (1994). Rapid plasma clearance of albumin-acrolein adduct in rats. Toxicol Lett. 71(1):27–37. 10.1016/0378-4274(94)90195-3 [PubMed: 8140586] [CrossRef]
• Thompson CA, Burcham PC (2008). Genome-wide transcriptional responses to acrolein. Chem Res Toxicol. 21(12):2245–56. 10.1021/tx8001934 [PubMed: 19548348] [CrossRef]
• Thredgold L, Gaskin S, Heath L, Pisaniello D, Logan M, Baxter C (2020). Understanding skin absorption of common aldehyde vapours from exposure during hazardous material incidents. J Expo Sci Environ Epidemiol. 30(3):537–46. 10.1038/s41370-019-0127-4 [PubMed: 30770841] [CrossRef]
• Tikuisis T, Phibbs MR, Sonnenberg KL (1995). Quantitation of employee exposure to emission products generated by commercial-scale processing of polyethylene. Am Ind Hyg Assoc J. 56(8):809–14. 10.1080/15428119591016647 [PubMed: 7653436] [CrossRef]
• Triebig G, Zober MA (1984). Indoor air pollution by smoke constituents–a survey. Prev Med. 13(6):570–81. 10.1016/S0091-7435(84)80007-9 [PubMed: 6399372] [CrossRef]
• Tsou HH, Hu CH, Liu JH, Liu CJ, Lee CH, Liu TY, et al. (2019). Acrolein is involved in the synergistic potential of cigarette smoking–and betel quid chewing–related human oral cancer. Cancer Epidemiol Biomarkers Prev. 28(5):954–62. 10.1158/1055-9965.Epi-18-1033 [PubMed: 30842129] [CrossRef]
• Tully M, Zheng L, Acosta G, Tian R, Shi R (2014). Acute systemic accumulation of acrolein in mice by inhalation at a concentration similar to that in cigarette smoke. Neurosci Bull. 30(6):1017–24. 10.1007/s12264-014-1480-x [PMC free article: PMC4397909] [PubMed: 25446876] [CrossRef]
• Uchida K, Kanematsu M, Morimitsu Y, Osawa T, Noguchi N, Niki E (1998a). Acrolein is a product of lipid peroxidation reaction. Formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins. J Biol Chem. 273(26):16058–66. 10.1016/0378-4274(94)90195-3 [PubMed: 9632657] [CrossRef]
• Uchida K, Kanematsu M, Sakai K, Matsuda T, Hattori N, Mizuno Y, et al. (1998b). Protein-bound acrolein: potential markers for oxidative stress. Proc Natl Acad Sci USA. 95(9):4882–7. 10.1073/pnas.95.9.4882 [PMC free article: PMC20182] [PubMed: 9560197] [CrossRef]
• Umano K, Shibamoto T (1987). Analysis of acrolein from heated cooking oils and beef fat. J Agric Food Chem. 35(6):909–12. 10.1021/jf00078a014 [CrossRef]
• US EPA (1984a). Method 603. Acrolein and acrylonitrile. Appendix A to Part 136. Methods for organic chemical analysis of municipal and industrial wastewater. United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-08/documents/method_603_1984.pdf, accessed 28 May 2021.
• US EPA (1984b). Method 624. Purgeables. Appendix A to Part 136. Methods for organic chemical analysis of municipal and industrial wastewater. United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-10/documents/method_624_1984.pdf, accessed 28 May 2021.
• US EPA (1984c). Method 1624, Revision B. Volatile organic compounds by isotope dilution GC/MS. Appendix A to Part 136. United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-10/documents/method_1624b_1984​.pdf, accessed 28 May 2021.
• US EPA (1994). Method 8316. Acrylamide, acrylonitrile and acrolein by high performance, liquid chromatography (HPLC). United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-07/documents/epa-8316.pdf, accessed 28 May 2021.
• US EPA (2003). Method 5030C. Purge-and-trap for aqueous samples. United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-07/documents/epa-5030c.pdf, accessed 28 May 2021.
• US EPA (2007). Method 8015C. Nonhalogenated organics by gas chromatography. United States Environmental Protection Agency. Available from: https://www​.epa.gov/sites​/production/files​/2015-12/documents/8015c.pdf, accessed 28 May 2021.
• US EPA (2020). Acrolein. ToxCast/Tox21 summary files. Chemistry Dashboard. United States Environmental Protection Agency. Available from: https://comptox​.epa.gov​/dashboard/dsstoxdb​/results?search=DTXSID5020023#invitrodb, accessed 6 July 2020.
• Valacchi G, Pagnin E, Phung A, Nardini M, Schock BC, Cross CE, et al. (2005). Inhibition of NFκB activation and IL-8 expression in human bronchial epithelial cells by acrolein. Antioxid Redox Signal. 7(1–2):25–31. 10.1089/ars.2005.7.25 [PubMed: 15650393] [CrossRef]
• VanderVeen LA, Hashim MF, Nechev LV, Harris TM, Harris CM, Marnett LJ (2001). Evaluation of the mutagenic potential of the principal DNA adduct of acrolein. J Biol Chem. 276(12):9066–70. 10.1074/jbc.M008900200 [PubMed: 11106660] [CrossRef]
• VDI (2008). Guideline VDI 3862 Part 5. Gaseous emission measurement. Measurement of lower aldehydes especially acrolein with the 2-HMP-method. GC-method. Düsseldorf, Germany: Verein Deutscher Ingenieure e.V.
• Verschueren K (1983). Handbook of environmental data on organic chemicals. 2nd ed. New York (NY), USA: Van Nostrand Reinhold; pp. 157–60.
• Vogel EW, Nivard MJM (1993). Performance of 181 chemicals in a Drosophila assay predominantly monitoring interchromosomal mitotic recombination. Mutagenesis. 8(1):57–81. 10.1093/mutage/8.1.57 [PubMed: 8450769] [CrossRef]
• Von Tungeln LS, Yi P, Bucci TJ, Samokyszyn VM, Chou MW, Kadlubar FF, et al. (2002). Tumorigenicity of chloral hydrate, trichloroacetic acid, trichloroethanol, malondialdehyde, 4-hydroxy-2-nonenal, crotonaldehyde, and acrolein in the B6C3F₁ neonatal mouse. Cancer Lett. 185(1):13–9. 10.1016/S0304-3835(02)00231-8 [PubMed: 12142074] [CrossRef]
• Wang CC, Weng TI, Wu ET, Wu MH, Yang RS, Liu SH (2013b). Involvement of interleukin-6-regulated nitric oxide synthase in hemorrhagic cystitis and impaired bladder contractions in young rats induced by acrolein, a urinary metabolite of cyclophosphamide. Toxicol Sci. 131(1):302–10. 10.1093/toxsci/kfs270 [PubMed: 22961095] [CrossRef]
• Wang HT, Hu Y, Tong D, Huang J, Gu L, Wu XR, et al. (2012). Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility. J Biol Chem. 287(15):12379–86. 10.1074/jbc.M111.329623 [PMC free article: PMC3320987] [PubMed: 22275365] [CrossRef]
• Wang HT, Weng MW, Chen WC, Yobin M, Pan J, Chung FL, et al. (2013a). Effect of CpG methylation at different sequence context on acrolein- and BPDE-DNA binding and mutagenesis. Carcinogenesis. 34(1):220–7. 10.1093/carcin/bgs323 [PMC free article: PMC3534198] [PubMed: 23042304] [CrossRef]
• Wang HT, Zhang S, Hu Y, Tang MS (2009a). Mutagenicity and sequence specificity of acrolein-DNA adducts. Chem Res Toxicol. 22(3):511–7. 10.1021/tx800369y [PMC free article: PMC4606861] [PubMed: 19146376] [CrossRef]
• Wang T, Liu Y, Chen L, Wang X, Hu XR, Feng YL, et al. (2009b). Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats. Eur Respir J. 33(5):1122–32. 10.1183/09031936.00055908 [PubMed: 19129291] [CrossRef]
• Wang TW, Liu JH, Tsou HH, Liu TY, Wang HT (2019). Identification of acrolein metabolites in human buccal cells, blood, and urine after consumption of commercial fried food. Food Sci Nutr. 7(5):1668–76. 10.1002/fsn3.1001 [PMC free article: PMC6526626] [PubMed: 31139379] [CrossRef]
• Wardencki W, Sowiński P, Curyło J (2003). Evaluation of headspace solid-phase microextraction for the analysis of volatile carbonyl compounds in spirits and alcoholic beverages. J Chromatogr A. 984(1):89–96. 10.1016/S0021-9673(02)01741-7 [PubMed: 12564679] [CrossRef]
• Washington MT, Minko IG, Johnson RE, Haracska L, Harris TM, Lloyd RS, et al. (2004b). Efficient and error-free replication past a minor-groove N²-guanine adduct by the sequential action of yeast Rev1 and DNA polymerase zeta. Mol Cell Biol. 24(16):6900–6. 10.1128/MCB.24.16.6900-6906.2004 [PMC free article: PMC479736] [PubMed: 15282292] [CrossRef]
• Washington MT, Minko IG, Johnson RE, Wolfle WT, Harris TM, Lloyd RS, et al. (2004a). Efficient and error-free replication past a minor-groove DNA adduct by the sequential action of human DNA polymerases ι and κ . Mol Cell Biol. 24(13):5687–93. 10.1128/MCB.24.13.5687-5693.2004 [PMC free article: PMC480884] [PubMed: 15199127] [CrossRef]
• Watzek N, Scherbl D, Feld J, Berger F, Doroshyenko O, Fuhr U, et al. (2012). Profiling of mercapturic acids of acrolein and acrylamide in human urine after consumption of potato crisps. Mol Nutr Food Res. 56(12):1825–37. 10.1002/mnfr.201200323 [PubMed: 23109489] [CrossRef]
• Weinstein JR, Asteria-Peñaloza R, Diaz-Artiga A, Davila G, Hammond SK, Ryde IT, et al. (2017). Exposure to polycyclic aromatic hydrocarbons and volatile organic compounds among recently pregnant rural Guatemalan women cooking and heating with solid fuels. Int J Hyg Environ Health. 220(4):726–35. 10.1016/j.ijheh.2017.03.002 [PMC free article: PMC5474125] [PubMed: 28320639] [CrossRef]
• Weisel CP, Zhang J, Turpin BJ, Morandi MT, Colome S, Stock TH, et al. (2005). Relationships of indoor, outdoor, and personal air (RIOPA): Part I. Collection methods and descriptive analyses. Res Rep Health Eff Inst. (130 Pt 1):1–107, discussion 109–27. [PubMed: 16454009]
• Weng MW, Lee HW, Park SH, Hu Y, Wang HT, Chen LC, et al. (2018). Aldehydes are the predominant forces inducing DNA damage and inhibiting DNA repair in tobacco smoke carcinogenesis. Proc Natl Acad Sci USA. 115(27):E6152–61. 10.1073/pnas.1804869115 [PMC free article: PMC6142211] [PubMed: 29915082] [CrossRef]
• WHO (2002). Acrolein. Concise International Chemical Assessment Document 43. Geneva, Switzerland: World Health Organization. Available from: https://apps​.who.int​/iris/bitstream/handle​/10665/42490/a75363​.pdf?sequence=1&isAllowed=y, accessed 3 May 2022.
• WHO (2012). Standard operating procedure for intense smoking of cigarettes. Geneva, Switzerland: World Health Organization, Tobacco Laboratory Network.
• Wildenauer DB, Oehlmann CE (1982). Interaction of cyclophosphamide metabolites with membrane proteins: an in vitro study with rabbit liver microsomes and human red blood cells. Effect of thiols. Biochem Pharmacol. 31(22):3535–41. 10.1016/0006-2952(82)90572-X [PubMed: 7181935] [CrossRef]
• Wilmer JL, Erexson GL, Kligerman AD (1986). Attenuation of cytogenetic damage by 2-mercaptoethanesulfonate in cultured human lymphocytes exposed to cyclophosphamide and its reactive metabolites. Cancer Res. 46(1):203–10. [abstract] [PubMed: 3079586]
• Wilson VL, Foiles PG, Chung FL, Povey AC, Frank AA, Harris CC (1991). Detection of acrolein and crotonaldehyde DNA adducts in cultured human cells and canine peripheral blood lymphocytes by ³²P-postlabeling and nucleotide chromatography. Carcinogenesis. 12(8):1483–90. 10.1093/carcin/12.8.1483 [PubMed: 1860170] [CrossRef]
• Yan R, Zu X, Ma J, Liu Z, Adeyanju M, Cao D (2007). Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: implication for cancer intervention. Int J Cancer. 121(10):2301–6. 10.1002/ijc.22933 [PubMed: 17597105] [CrossRef]
• Yang IY, Chan G, Miller H, Huang Y, Torres MC, Johnson F, et al. (2002b). Mutagenesis by acrolein-derived propanodeoxyguanosine adducts in human cells. Biochemistry. 41(46):13826–32. 10.1021/bi0264723 [PubMed: 12427046] [CrossRef]
• Yang IY, Hossain M, Miller H, Khullar S, Johnson F, Grollman A, et al. (2001). Responses to the major acrolein-derived deoxyguanosine adduct in Escherichia coli. J Biol Chem. 276(12):9071–6. 10.1074/jbc.M008918200 [PubMed: 11124950] [CrossRef]
• Yang IY, Johnson F, Grollman AP, Moriya M (2002a). Genotoxic mechanism for the major acrolein-derived deoxyguanosine adduct in human cells. Chem Res Toxicol. 15(2):160–4. 10.1021/tx010123c [PubMed: 11849041] [CrossRef]
• Yang IY, Miller H, Wang Z, Frank EG, Ohmori H, Hanaoka F, et al. (2003). Mammalian translesion DNA synthesis across an acrolein-derived deoxyguanosine adduct. Participation of DNA polymerase η in error-prone synthesis in human cells. J Biol Chem. 278(16):13989–94. 10.1074/jbc.M212535200 [PubMed: 12584190] [CrossRef]
• Yang J, Balbo S, Villalta PW, Hecht SS (2019a). Analysis of acrolein-derived 1,N²-propanodeoxyguanosine adducts in human lung DNA from smokers and nonsmokers. Chem Res Toxicol. 32(2):318–25. 10.1021/acs.chemrestox.8b00326 [PMC free article: PMC6644703] [PubMed: 30644728] [CrossRef]
• Yang K, Fang JL, Li D, Chung FL, Hemminki K (1999b). 32P-Postlabelling with high-performance liquid chromatography for analysis of abundant DNA adducts in human tissues. In: Singer B, Bartsch H, editors. Exocyclic DNA adducts in mutagenesis and carcinogenesis. IARC Sci Publ. 150:205–7. [PubMed: 10626222]
• Yang Q, Hergenhahn M, Weninger A, Bartsch H (1999a). Cigarette smoke induces direct DNA damage in the human B-lymphoid cell line Raji. Carcinogenesis. 20(9):1769–75. 10.1093/carcin/20.9.1769 [PubMed: 10469623] [CrossRef]
• Yang Y, Ji D, Sun J, Wang Y, Yao D, Zhao S, et al. (2019b). Ambient volatile organic compounds in a suburban site between Beijing and Tianjin: concentration levels, source apportionment and health risk assessment. Sci Total Environ. 695:133889. 10.1016/j.scitotenv.2019.133889 [PubMed: 31426000] [CrossRef]
• Yildizbayrak N, Orta-Yilmaz B, Aydin Y, Erkan M (2020). Acrolein exerts a genotoxic effect in the Leydig cells by stimulating DNA damage-induced apoptosis. Environ Sci Pollut Res Int. 27(13):15869–77. 10.1007/s11356-020-08124-5 [PubMed: 32090303] [CrossRef]
• Yin R, Liu S, Zhao C, Lu M, Tang MS, Wang H (2013). An ammonium bicarbonate-enhanced stable isotope dilution UHPLC-MS/MS method for sensitive and accurate quantification of acrolein-DNA adducts in human leukocytes. Anal Chem. 85(6):3190–7. 10.1021/ac3034695 [PubMed: 23431959] [CrossRef]
• Yoon JH, Hodge RP, Hackfeld LC, Park J, Roy Choudhury J, Prakash S, et al. (2018). Genetic control of predominantly error-free replication through an acrolein-derived minor-groove DNA adduct. J Biol Chem. 293(8):2949–58. 10.1074/jbc.RA117.000962 [PMC free article: PMC5827445] [PubMed: 29330301] [CrossRef]
• Yousefipour Z, Chug N, Marek K, Nesbary A, Mathew J, Ranganna K, et al. (2017). Contribution of PPARγ in modulation of acrolein-induced inflammatory signalling in gp91^phox knock-out mice. Biochem Cell Biol. 95(4):482–90. 10.1139/bcb-2016-0198 [PubMed: 28376311] [CrossRef]
• Yousefipour Z, Zhang C, Monfareed M, Walker J, Newaz M (2013). Acrolein-induced oxidative stress in NAD(P)H oxidase subunit gp91phox knock-out mice and its modulation of NFκB and CD36. J Health Care Poor Underserved. 24(4 Suppl):118–31. 10.1353/hpu.2014.0002 [PubMed: 24241266] [CrossRef]
• Yuan JM, Butler LM, Gao YT, Murphy SE, Carmella SG, Wang R, et al. (2014). Urinary metabolites of a polycyclic aromatic hydrocarbon and volatile organic compounds in relation to lung cancer development in lifelong never smokers in the Shanghai Cohort Study. Carcinogenesis. 35(2):339–45. 10.1093/carcin/bgt352 [PMC free article: PMC3908750] [PubMed: 24148823] [CrossRef]
• Yuan JM, Gao YT, Wang R, Chen M, Carmella SG, Hecht SS (2012). Urinary levels of volatile organic carcinogen and toxicant biomarkers in relation to lung cancer development in smokers. Carcinogenesis. 33(4):804–9. 10.1093/carcin/bgs026 [PMC free article: PMC3384073] [PubMed: 22298640] [CrossRef]
• Yuan JM, Murphy SE, Stepanov I, Wang R, Carmella SG, Nelson HH, et al. (2016). 2-Phenethyl isothiocyanate, glutathione S-transferase M1 and T1 polymorphisms, and detoxification of volatile organic carcinogens and toxicants in tobacco smoke. Cancer Prev Res (Phila). 9(7):598–606. 10.1158/1940-6207.CAPR-16-0032 [PMC free article: PMC4930697] [PubMed: 27099270] [CrossRef]
• Zang H, Harris TM, Guengerich FP (2005). Kinetics of nucleotide incorporation opposite DNA bulky guanine N² adducts by processive bacteriophage T7 DNA polymerase (exonuclease⁻) and HIV-1 reverse transcriptase. J Biol Chem. 280(2):1165–78. 10.1074/jbc.M405996200 [PubMed: 15533946] [CrossRef]
• Zhang H, Forman HJ (2008). Acrolein induces heme oxygenase-1 through PKC-δ and PI3K in human bronchial epithelial cells. Am J Respir Cell Mol Biol. 38(4):483–90. 10.1165/rcmb.2007-0260OC [PubMed: 18048804] [CrossRef]
• Zhang S, Balbo S, Wang M, Hecht SS (2011). Analysis of acrolein-derived 1,N²-propanodeoxyguanosine adducts in human leukocyte DNA from smokers and nonsmokers. Chem Res Toxicol. 24(1):119–24. 10.1021/tx100321y [PMC free article: PMC3064499] [PubMed: 21090699] [CrossRef]
• Zhang S, Chen H, Wang A, Liu Y, Hou H, Hu Q (2017). Assessment of genotoxicity of four volatile pollutants from cigarette smoke based on the in vitro γH2AX assay using high content screening. Environ Toxicol Pharmacol. 55:30–6. 10.1016/j.etap.2017.07.005 [PubMed: 28818740] [CrossRef]
• Zhang S, Chen H, Wang A, Liu Y, Hou H, Hu Q (2018). Combined effects of co-exposure to formaldehyde and acrolein mixtures on cytotoxicity and genotoxicity in vitro. Environ Sci Pollut Res Int. 25(25):25306–14. 10.1007/s11356-018-2584-z [PubMed: 29946839] [CrossRef]
• Zhang S, Chen H, Zhang J, Li J, Hou H, Hu Q (2020). The multiplex interactions and molecular mechanism on genotoxicity induced by formaldehyde and acrolein mixtures on human bronchial epithelial BEAS-2B cells. Environ Int. 143(July):105943. 10.1016/j.envint.2020.105943 [PubMed: 32659531] [CrossRef]
• Zhang S, Villalta PW, Wang M, Hecht SS (2007). Detection and quantitation of acrolein-derived 1,N²-propanodeoxyguanosine adducts in human lung by liquid chromatography-electrospray ionization-tandem mass spectrometry. Chem Res Toxicol. 20(4):565–71. 10.1021/tx700023z [PMC free article: PMC2518976] [PubMed: 17385896] [CrossRef]
• Zimmering S, Mason JM, Valencia R (1989). Chemical mutagenesis testing in Drosophila. VII. Results of 22 coded compounds tested in larval feeding experiments. Environ Mol Mutagen. 14(4):245–51. 10.1002/em.2850140406 [PubMed: 2583131] [CrossRef]
• Zimmering S, Mason JM, Valencia R, Woodruff RC (1985). Chemical mutagenesis testing in Drosophila. II. Results of 20 coded compounds tested for the National Toxicology Program. Environ Mutagen. 7(1):87–100. 10.1002/em.2860070105 [PubMed: 3917911] [CrossRef]
• Zion Market Research (2019). Acrolein market: global industry perspective, comprehensive analysis, and forecast, 2018–2025. Available from: https://www​.zionmarketresearch​.com/report/acrolein-market, accessed 9 September 2020.