1. Exposure Characterization

1.3. Methods of detection and quantification

Methods for the detection and quantification of crotonaldehyde have evolved steadily since the agent was last evaluated by the IARC Monographs programme in Volume 63 (IARC, 1995). Techniques are now available to measure crotonaldehyde in air, water, foodstuffs, and biological specimens. Other methodologies estimate human exposure via metabolites, and both protein and DNA adducts. Table 1.1 summarizes these methods by sample matrix and indicates sample requirements and sensitivity parameters. These techniques are sufficiently sensitive to measure concentrations reliably in ambient air, water, food, and in human biological specimens, and can distinguish background levels from higher exposures (e.g. to combustion products, crotonaldehyde-containing foodstuffs, or in occupational settings). However, sensitivity varies across methods, and not all methods – including National Institute for Occupational Safety and Health (NIOSH) method 3516 (NIOSH, 1994) – have sufficient sensitivity to measure air levels in occupational settings, i.e. at the current American Conference of Governmental Industrial Hygienists (ACGIH) recommended a threshold limit value (TLV) of 0.3 ppm [0.86 mg/m³] (ACGIH, 2020).

1.3.1. Air

Air sampling for the measurement of crotonaldehyde concentrations was most often done by drawing air through impingers or midget bubblers (NIOSH, 1994; Zervas et al., 2002; Zhang et al., 2019a). A significant advance has been the quantitative chemical trapping of crotonaldehyde for the analysis of the corresponding hydrazone by high-performance liquid chromatography (HPLC) (Zhang & Smith, 1999) or gas chromatography (GC) (Otson et al., 1993). 2,4-Dinitrophenylhydrazine (DNPH) can be used in the impinger collection fluid (Zervas et al., 2002) or dried upon glass-fibre filters (OSHA, 1990), passive samplers (Otson et al., 1993), silica gel (Zhang & Smith, 1999; Fung & Long, 2001; Mitova et al., 2016), or octadecane sampling cartridges (Grosjean et al., 1996). Prepared DNPH tubes are available commercially (Williams et al., 1996; Liu et al., 2017). Ahn et al. (2014) used both polyester aluminium film sampling bags and sorbent tubes packed with carbon black to collect the air above fried fish to measure crotonaldehyde levels. Air from the bag was directly analysed by gas chromatography-mass spectrometry (GC-MS) while the crotonaldehyde on sorbent tubes was thermally desorbed before injection. Various forms of GC-MS and liquid chromatography-mass spectrometry (LC-MS) have been employed to detect crotonaldehyde from air samples collected as described above.

1.3.2. Water

Methods for the analysis of crotonaldehyde in water have involved derivatization of samples with pentafluorobenzyl hydroxylamine before hexane extraction and injection into GC equipped with a ⁶³Ni electron-capture detector (ECD) or GC-MS (Glaze et al., 1989). Wang et al. (2009) used DNPH derivatization before HPLC but did not detect crotonaldehyde in any rainwater samples tested (other aldehydes were detected). Baños & Silva (2009) evaluated six solid-phase extraction systems for the analysis of aldehydes in water. They described a continuous DNPH derivatization and pre-concentration step before analysis with LC-MS/MS. However, they found no crotonaldehyde in several samples of swimming pool water in which other aldehydes were detected.

1.3.3. Soil

No data were available to the Working Group.

1.3.4. Food, beverages, and consumer products

Methods for the analysis of crotonaldehyde in food are similar to those used for air, with the exception that crotonaldehyde must either first be extracted from the food matrix, or the headspace above the matrix must be sampled. Granvogl (2014) reported on three different methods involving isotopic dilution that gave good agreement and similar limits of detection and quantification in heat-processed fats and oils, and fried food. In the first method, headspace was sampled directly into the GC-MS. The second method involved derivatization with pentafluorophenylhydrazine, followed by extraction and injection into the GC-MS. The third method involved derivatization with DNPH, followed by extraction and injection into a HLPC-MS system. Because of ease of application, the first method was used for the analysis of food products. The latter two methods were more sensitive than the first method but involved pre-analytical steps.

1.3.5. Biological specimens

Several methods are available for the direct analysis of crotonaldehyde in saliva, urine, and serum, as well as for the analysis of crotonaldehyde metabolites or DNA and protein adducts (Table 1.1). The urinary biomarker N‐acetyl‐S‐(3‐hydroxy-1-methylpropyl)‐L‐cysteine (HMPMA; 3-hydroxy-1-methylpropylmercapturic acid) was commonly analysed. N-Acetyl-S-(3-carboxy-1-methylpropyl)-L-cysteine (CMEMA; 2-carboxy-1-methylethylmercapturic acid) has also been analysed. Both can be detected using LC-MS/MS methods.

No data on a validated biomarker for crotonaldehyde were available to the Working Group.

Table 1.1

Representative methods for the detection and quantification of crotonaldehyde, its metabolites, and its DNA adducts.

1.4. Occurrence and exposure

1.4.1. Environmental and natural occurrence

Crotonaldehyde occurs naturally in a ubiquitous fashion. It is produced endogenously by plants and animals (including humans) as part of lipid peroxidation and metabolism (WHO; IPCS; IOMC, 2008). Crotonaldehyde has been measured in gases emitted by volcanoes (Graedel et al., 1986), but has also been detected as a biogenic emission from pine trees (0.19 µg/m³) and deciduous forests (0.49 µg/m³) (Ciccioli et al., 1993). Scotter et al. (2005) measured levels of crotonaldehyde in the headspace of fungal cultures. Detectable crotonaldehyde levels (mean, 0.106 µg/m³; standard deviation, SD, 0.005 µg/m³) were found in the air of a room when people were exercising, but not when they were resting (< 0.0636 µg/m³) (Mitova et al., 2020).

Crotonaldehyde is found in burned and unburned tobacco (Bagchi et al., 2018), as a combustion product of burning wood and plastic, cooking fires (3.8–91.6 mg/kg fuel), and automobile exhaust (0.07–1.35 ppm [0.20–3.87 mg/m³], depending on engine size and operating conditions) and diesel exhaust (15–27 mg/kWh energy produced, depending on fuel type and operating conditions) (Nishikawa et al., 1987; Zhang & Smith, 1999; Song et al., 2010).

An overview of exposure measurements of crotonaldehyde in outdoor air, indoor air and dust, and water is provided in Table 1.2.

Table 1.2

Concentrations of crotonaldehyde in outdoor air, indoor air and dust, and water.

1.4.2. Exposure in the general population

Important sources of exposure to crotonaldehyde in the general population include tobacco and tobacco-related products, indoor and outdoor air, food, and beverages. Table 1.3 presents concentrations of crotonaldehyde in cigarettes, engine emissions, and other sources. Table 1.4 presents data on levels of crotonaldehyde biomarkers in humans. including from studies of known exposures (e.g. to tobacco products) and from studies in which the exposure source was not characterized (e.g. in children). Studies on DNA adducts in humans (e.g. Chen & Lin, 2009) are further addressed in Section 4.2.1. Table 1.5 presents crotonaldehyde concentrations measured in food and beverages.

Table 1.3

Concentrations of crotonaldehyde in cigarettes, engine emissions, and other sources.

Table 1.4

Levels of crotonaldehyde biomarkers in humans.

Table 1.5

Concentrations of crotonaldehyde in food and beverages.

(a) Tobacco products and tobacco-related products

See Table 1.3 and Table 1.4.

Cigarette smoke is a major source of exposure to crotonaldehyde (Counts et al., 2004; Carmella et al., 2009). The amount of crotonaldehyde measured per cigarette varies widely depending on the source of the tobacco and the sampling protocol (Hammond & O’Connor, 2008; see Table 1.3). The mean concentration of crotonaldehyde in cigarettes from the Chinese market was 42–67 µg/cigarette (Cai et al., 2019). Zhang et al. (2019a) analysed the gas phase of mainstream smoke from 16 different brands of Chinese flue-cured cigarettes and reported an average crotonaldehyde concentration of 13.4 µg/cigarette under the International Organization for Standardization ISO 3308 machine-smoking regimen (35 mL puff volume, 2 second puff duration, 60 second puff interval). Similar concentrations were reported by Ding et al. (2016) and Sampson et al. (2014) when using the ISO regimen, whereas using the “Canadian Intense” protocol (55 mL puff volume, 2 second puff duration, 30 second puff interval) gave values that were 2–5 times higher; however, levels as high as 228 µg/cigarette have been reported previously. Brands originating in the USA appear to contain higher levels of crotonaldehyde, with Ding et al. (2016) reporting average levels of 25–72 [mean, 48] µg/cigarette in 10 USA brands under the “Canadian Intense” protocol. [The Working Group noted that the “Canadian Intense” method may provide higher values that correspond better to human exposure during smoking.] Several research groups have reported lower levels of crotonaldehyde in mainstream smoke when electronic cigarettes were machine-smoked (Farsalinos et al., 2018; Mallock et al., 2018).

Among smokers in the National Health and Nutrition Examination Survey (NHANES) study conducted by the United States Centers for Disease Control and Prevention (CDC), there was an increase in HMPMA concentration with increasing number of cigarettes smoked. Approximately 20% of participants were smokers (Bagchi et al., 2018). The urinary HMPMA concentrations in smokers were about 5 times higher than in non-smokers (1.63 versus 0.313 mg/g creatinine). HMPMA was detected in 99.9% of all urine samples (Bagchi et al., 2018). Median concentrations were 419 and 369 µg/L for the 2011–12 and 2013–14 sampling periods, respectively, while the 95th percentiles were 3700 and 3040 µg/L, respectively (NHANES, 2019). [The Working Group noted that the latter values are likely to include smokers and/or persons with significant occupational exposure.] The lowest concentrations were reported for non-Hispanic Black people (median, 253 µg/g creatinine for non-users and 1070 µg/g creatinine for users of exclusively smoked tobacco products; interquartile range, 195–356 and 489–1870 µg/g creatinine, respectively). These data indicate widespread crotonaldehyde exposure within the population and confirm that tobacco smoke is a major source of exposure (Bagchi et al., 2018; see Table 1.4).

Alwis et al. (2012) analysed urinary HMPMA concentrations in 1203 non-smokers and 347 smokers. They found the average (± SD) concentrations to be 429 µg/L (± 478 µg/L) in non-smokers and 1992 µg/L (± 2009 µg/L) in smokers, a highly significant difference. Carmella et al. (2009) studied HMPMA concentrations in 17 people who quit smoking. They found that concentrations were reduced by 80% when resampling occurred on the next return visit after 3 days (allowing an estimate of the maximum possible half-life of 36 hours for HMPMA) and then remained at approximately this level for the next 56 days of follow-up. Scherer et al. (2006) conducted a study of HMPMA comparing regular-filter cigarettes to those with a charcoal filter. HMPMA concentrations in week 1 were lower in smokers using cigarettes with charcoal filters than in smokers using cigarettes with regular filters. However, the difference disappeared when the groups crossed over after 1 week, although the glutathione-depleting activity of smoke passed through the charcoal filters was significantly less than of smoke passed through regular filters.

Park et al. (2015) studied HMPMA in more than 2200 smokers of five ethnicities. They found a significant difference between the ethnic groups, with native Hawaiians having the highest geometric mean concentrations of HMPMA and Latinos the lowest at 2759 and 2210 pmol/mL urine, respectively. These data strongly suggest an ethnic influence on exposure effect.

Pluym et al. (2015) measured both HMPMA and CMEMA concentrations in three groups: non-smokers, light smokers (≤ 10 cigarettes/day) and heavier smokers (> 10 cigarettes/day). They reported a robust concentration–response relationship for HMPMA but not for CMEMA. Median concentrations in non-smokers were 18.9 (range, 9.7–64.4) µg/g creatinine for HMPMA, and 201 (range, 104–756) µg/g creatinine for CMEMA. These values were 95.9 (range, 55–268) µg/g creatinine and 226 (range, 125–408) µg/g creatinine in light smokers, and 121.7 (range, 57–220) µg/g creatinine and 226 (range, 121–299) µg/g creatinine in heavier smokers. In addition, there was only a weak correlation between HMPMA and CMEMA concentrations, and no correlation between CMEMA and cotinine concentrations.

(b) Indoor air

Indoor cooking can be a source of airborne exposure to crotonaldehyde. Zhang & Smith (1999) studied the emissions from 22 different methods of cooking in China and found that crotonaldehyde production ranged from not detected to 92 mg/kg fuel for wood used in a brick stove with a flue. Relatively large amounts (up to 88 mg/kg fuel; mean, 60 mg/kg fuel) were produced when liquefied petroleum gas was used as fuel while coal and coal briquette fuels produced the lowest levels. Consistent with these data, Weinstein et al. (2020) reported a non-significant 4% reduction in urinary HMPMA concentrations in women in Guatemala when wood-burning stoves were replaced by liquefied petroleum gas-powered stoves (from 193 µg/g creatinine with wood-burning stoves to 186 µg/g creatinine with liquefied petroleum gas). Mitova et al. (2020) found a mean concentration of 2.06 µg/m³ (SD, ± 0.01 µg/m³) in Switzerland where people warmed a cheese dish on an electric hotplate. Ahn et al. (2014) reported that crotonaldehyde concentrations ranged from 4.96 to 51.7 ppb [14.2 to 148 µg/m³] when mackerel were pan-fried using butane as a fuel in the Republic of Korea. Hecht et al. (2015) compared HMPMA concentrations in non-smoking women in Singapore who cooked once per week or less frequently with a wok (including boiling, stir frying, and deep frying) with those who cooked between 2 and 6 times per week and with those who cooked 7 times per week or more frequently. They reported a highly significant trend with increasing wok use, with the groups at either extreme (< 1 meal/week versus > 7 meals/week) having a geometric mean of 894 (95% confidence interval, CI, 749–1067) pmol/mg creatinine versus 1167 (95% CI, 1022–1332) pmol/mg creatinine). There was also an effect of the oil used to cook, with rapeseed oil (829 pmol/mg creatinine) and sunflower oil (1329 pmol/mg creatinine) being the extremes.

Ochs et al. (2016) reported that varnishing a door during apartment renovation was the source of an increase in crotonaldehyde concentrations that peaked at 80 µg/m³ but dissipated rapidly thereafter.

Lu & Zhu (2007) measured crotonaldehyde concentrations aboard six carriages in different trains during the 2004 Spring Festival in China when tens of millions of people used the train system; they reported concentrations of between 2.6 and 3.6 µg/m³.

(c) Outdoor air pollution

Grosjean et al. (1996) reported that concentrations of crotonaldehyde in outdoor air in Los Angeles, California, USA, peaked at about 0.5 ppb [1.4 µg/m³] with an average concentration of 0.3 ppb [0.86 µg/m³]. Concentrations seemed to increase with traffic, consistent with reports of crotonaldehyde in the exhaust of gasoline and diesel engines (Nishikawa et al., 1987; Zervas et al., 2002; Song et al., 2010). Similarly, Dugheri et al. (2019) reported that crotonaldehyde concentrations in four roads with heavy traffic in Florence, Italy, were 0.8–1.3 µg/m³ (mean, 1.0 µg/m³), while in a low-traffic area, the mean concentration was 0.2 µg/m³. The bulk of the crotonaldehyde was found in the vapour phase.

(d) Food and beverages

See Table 1.4 and Table 1.5.

Crotonaldehyde is present in many foodstuffs, including vegetables (Brussels sprouts, cabbages, carrots, cauliflower, celery leaves; at concentrations of 0.02–0.1 ppm [mg/kg]), fruits (apples, grapes, guavas, tomatoes and strawberries; at > 0.01 ppm [mg/kg]), dairy products and meats (milk, bread, cheese, meat, clams and fish), beer, and wine (at 0–0.07 ppm [mg/kg, mg/L]) (Feron et al., 1991; Liu et al., 2020). Whisky and vodka contain from < 0.02 to 0.21 ppm [mg/L] (Miller & Danielson, 1988). Fruit intake was significantly associated with increased urinary HMPMA levels in the NHANES survey (Bagchi et al., 2018).

Recent data indicated that heated cooking oil is a significant source of exposure to crotonaldehyde in food. In a study conducted in Germany, Granvogl (2014) reported that while cooking oils differ intrinsically due to composition, the amount of crotonaldehyde in each oil increases significantly with temperature (100–180 or 220 °C) and heating time. Concentrations of crotonaldehyde in the oils ranged from below 9 µg/kg in unheated oils to 34 mg/kg [34 000 µg/kg] for linseed oil heated to 180 °C for 24 hours. Foods cooked in these oils also contained crotonaldehyde, albeit at lower concentrations. Both potato chips and doughnuts cooked in rapeseed oil contained twice as much crotonaldehyde as those cooked in olive oil (24.8 and 18.2 µg/kg, and 12.6 and < 9 µg/kg, respectively). Liu et al. (2020) measured crotonaldehyde concentrations in clams before and during deep frying in China. They found that the concentration of crotonaldehyde increased with both oil temperature and cooking time, from 0.04 µg/g for fresh clams to 1.46 µg/g for clams fried at 180 °C for 15 minutes. Crotonaldehyde concentrations in pre-marinated control clams also increased over 15 minutes when they were fried at 160 °C.

(e) Exposures in infants and children

See Table 1.4.

1. Regarding infants, El-Metwally et al. (2018) compared urinary concentrations of HMPMA in newborns in cribs versus those born pre-term and placed in incubators (median ages, 16 and 11 days, respectively). Median concentrations did not differ (394 µg/L versus 376 µg/L, respectively), suggesting that there were relatively high crotonaldehyde exposures in neonatal intensive care units (compared with children aged 6–11 years, see above). Boyle et al. (2016) studied 488 pregnant women and reported a 50th percentile HMPMA value of 342 µg/L which was virtually identical to the value of 352 µg/L reported by NHANES for girls and women aged 6–11 years, 12–19 years, and ≥ 20 years (NHANES, 2019). Boyle et al. reported that the highest value measured was 17 700 µg/L (5% of their sample were tobacco smokers).

1.4.3. Occupational exposure

One of the largest current commercial uses of crotonaldehyde is in the production of sorbic acid as a food preservative (E200), and crotonic acid (European Commission, 2013). However, no data could be found on workers’ exposure during this process. A survey conducted by NIOSH (1983) suggested that fewer than 400 workers (metal-plating machine operators in the transportation equipment industry, and separating, filtering, and clarifying machine operators in the chemicals and allied products industry) had potential exposure to crotonaldehyde in the USA, but no measurements were made. Since that time, it has become appreciated that far more workers are exposed to crotonaldehyde via exposure to pyrolysis products. Therefore, studies have been performed in cooks, coke-oven workers, and traffic officers, at toll booths, and particularly on firefighters, but have focused on biological monitoring rather than air concentrations.

The IARC Monographs programme in its previous evaluation of crotonaldehyde (Volume 63; IARC, 1995) noted that a variety of measurements for the compound were made in 24 Finnish businesses and that all measurements were below the Finnish standard at the time of 6 mg/m³. Linnainmaa et al. (1990) found concentrations of 0.23 mg/m³ near a doughnut-frying station in a Finnish bakery. In a chemical plant in the USA, area samples ranged from not detected to 3.2 mg/m³, with two personal samples of 1.9 and 2.1 mg/m³ (NIOSH, 1982). Crotonaldehyde was detected at concentrations of 1–7 mg/m³ in a plant producing aldehydes in Germany. More recently, Zhang et al. (2003) measured exposure to crotonaldehyde via inhalation in parking-garage workers (n = 53) and controls (n = 33) and reported that smoking parking-garage workers had a mean crotonaldehyde air concentration of 0.96 µg/m³ (SD, ± 0.94 µg/m³) and non-smoking parking-garage workers’ mean concentrations were 0.53 µg/m³ (± 0.79 µg/m³). Smoking controls were exposed to crotonaldehyde at 0.29 µg/m³ (± 0.48 µg/m³), and non-smoking controls at 0.25 µg/m³ (± 0.32 µg/m³). Destaillats et al. (2002) measured concentrations at toll booths in San Francisco, USA, and reported concentrations (mean ± SD) of 0.061 ± 0.012 µg/m³ and 0.093 ± 0.002 µg/m³ in the afternoon and 0.147 ± 0.004 µg/m³ in the morning.

For firefighters, Dills et al. (2008) reported crotonaldehyde concentrations as high as 4.3 mg/m³ in the overhaul smoke of a demonstration fire (wood with polyvinyl chloride), when water was used to knock down the fire. In another demonstration-fire study (household materials), Jones et al. (2016) reported concentrations as high as 0.07 ppm [0.2 mg/m³] during the overhaul phase (smouldering) of the exercise. In a third demonstration study, Kirk & Logan (2015) measured concentrations between 1 and 11 µg/m³ off-gassing from a structural firefighting ensemble for 24 hours after four hostile attack evolutions (resin-bonded wood panels).

Frigerio et al. (2020) measured urinary CMEMA and HMPMA concentrations in coke-oven workers, but there was no statistical difference between concentrations in workers and controls, the latter being slightly higher.

1.5. Regulations and guidelines

1.5.1. Exposure limits and guidelines

(a) Occupational exposure

Limits occupational exposure regulations and guidelines for various countries and states are given in Table 1.6. Crotonaldehyde is a potent irritant of the skin, eyes, and mucous membranes throughout the respiratory tract. The ACGIH TLV of 0.86 mg/m³ for crotonaldehyde is based on analogy with formaldehyde as an irritant. The TLV is a ceiling level, i.e. a level that should never be exceeded. Crotonaldehyde is also given a “skin” notation by ACGIH indicating that there are data suggesting that the liquid is well-absorbed through the skin (ACGIH, 2020). Although the TLVs are established to provide professional guidance for practicing industrial hygienists, they have been adopted by many governmental regulatory agencies. The TLV for crotonaldehyde was last updated by the ACGIH in 1998 with the ceiling value being adopted. As can be seen from Table 1.6, values established before 2000 are significantly higher than those promulgated after 2000, the sole exception being United States Occupational Safety and Health Administration (OSHA) and NIOSH. Furthermore, the pre-2000 limits are time-weighted averages as opposed to the ceilings that should never be exceeded for many values set after 2000.

Table 1.6

Occupational exposure limits for crotonaldehyde^a in various countries.

(b) Environmental exposure limits

Crotonaldehyde has not been widely regulated in the environment. As with acrolein and other reactive aldehydes, occupational guidelines for acute exposures (100–300 ppb) [0.29–0.86 mg/m³] are approximately 10 to 100 times the environmental guidelines for acute exposures (1–5 ppb [2.9–14 µg/m³] or for subacute exposures).

In 2008 the National Advisory Committee for Acute Exposure Guideline Levels (AEGLs) for Hazardous Substances of the United States National Academy of Sciences evaluated crotonaldehyde exposure concentrations and times that could be classified as nondisabling (AEGL-1), disabling (AEGL-2), and lethal (AEGL-3) (National Research Council, 2007). These are presented in Table 1.7. Note that AEGL-3, which is lethal, is reached after 10 minutes exposure to crotonaldehyde at 44 000 ppb (44 ppm) [130 mg/m³], whereas exposure for any duration of time from 10 minutes to 8 hours to 190 ppb [0.55 mg/m³] leads to slight eye irritation and discomfort.

Table 1.7

Summary of acute exposure guideline levels for crotonaldehyde.

1.5.2. Reference values for biological monitoring of exposure

There are currently no regulations or guidelines for measuring levels of crotonaldehyde metabolites or other biomarkers in biological samples. While there have been important studies involving metabolites in smokers, there are very few data related to metabolite concentrations, air concentrations, or effect markers (e.g. DNA adducts and metabolites), which are the parameters needed to provide guidance relevant for occupational exposure. In addition, there remain other data gaps that prevent development of such a biological exposure index. This includes data on metabolite elimination half-life, which is needed to recommend the timing of sample collection (ACGIH, 2020). One alternative for guidance is using “population” reference values based on the 95th percentile levels in the general population (ACGIH, 2020). [The Working Group noted that there appeared to be ample data to establish a population value for crotonaldehyde.]

2. Cancer in Humans

2.1. Descriptions of individual studies

See Table 2.1.

One cohort study and three nested case–control studies in cohorts have been published on the relationship between cancer and exposure to crotonaldehyde.

Table 2.1

Epidemiological studies of cancer in humans exposed to crotonaldehyde.

Cohort studies

Bittersohl (1975) recorded cancer cases in a small cohort of 220 workers in an aldehyde factory in the former German Democratic Republic who were diagnosed between 1967 and 1972. Workers who left the factory for whatever reason were not included. Measurements in some factory departments showed values of crotonaldehyde of 1–7 mg/m³. Four different cancer types were observed in nine men (5 cases of squamous cell lung carcinoma, 2 cases of squamous cell carcinoma of the oral cavity, 1 case of adenocarcinoma of the stomach, and 1 case of adenocarcinoma of the colon). Two cases in women (one leukaemia and one cancer of the ovary) were excluded from analysis due to short duration of exposure to aldehydes. There was no formal comparison group; a comparison was made with incidence rates in the general population of the former German Democratic Republic (source not reported). [The Working Group noted that the study design was weak. Not all those ever employed in the factory were included, only those currently employed (possible selection bias), and a small number of cases (9 cases) at four different sites were recorded. Exposure was based on measurements in some unspecified departments and there were multiple undifferentiated exposures experienced by workers. The exposure–disease association was not quantified because comparison rates for the general population were not provided.]

Yuan et al. (2012) and Yuan et al. (2014) published results from two nested case–control studies from the Shanghai Cohort Study, which included 18 244 men residing in one of four small communities in Shanghai and aged 45–65 years at enrolment (1986–1989). The methodology of the two nested case–control studies was very similar. Besides in-person interviews, a spot urine sample was taken from each participant at baseline and stored until laboratory analysis. Lung cancer incidence and mortality data were obtained from annual in-person interviews of all surviving participants, the local cancer registry, and the vital statistics office. Exposure to crotonaldehyde was represented by its urine metabolite HMPMA at enrolment. [The Working Group noted that both studies used a nested case–control design, with a long follow-up and few losses to follow-up. As a measure of exposure, tobacco-specific biomarkers were determined in urine samples. Urine biomarkers were based on single urine samples at enrolment, and smoking status was also collected at enrolment. The rate of histopathological confirmation of lung cancer was moderate, at 65% and 74% of cases for each study respectively. Otherwise, the classification was based on clinical diagnosis.]

In the first study (Yuan et al., 2012), the cohort was followed for 20 years through 2006; loss during follow-up was 4.6%. The aim of the study was to examine the relationship between some volatile carcinogens and toxicants from tobacco smoke and lung cancer development in smokers. A total of 706 cases of lung cancer were identified, of which 574 were in current smokers at baseline. For each case in a smoker, one control was selected, also a smoker, who was alive and free of cancer at the time of cancer diagnosis and matched on age at enrolment, date of urine sample collection, and neighbourhood of residence. After excluding cases and controls whose urine samples were depleted and had missing values for one or more mercapturic acid metabolites, 343 lung cancer cases and 392 controls were included in the analysis (all current smokers at baseline). Urine samples were analysed for mercapturic acids, including a metabolite of crotonaldehyde (HMPMA), as well as for metabolites of polycyclic aromatic hydrocarbons (r-1,t-2,3,c-4-tetrahydroxy1,2,3,4-tetrahydrophenanthrene; PheT), tobacco-specific nitrosamines (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNAL), and nicotine (total cotinine). Smoking duration was 34.4 years for cases and 30.8 years for controls. Lung cancer cases had significantly higher concentrations of HMPMA than did controls (P ˂ 0.001), and HMPMA concentration was positively associated with the daily number of cigarettes smoked and duration of smoking (P ˂ 0.001). Comparing the highest with the lowest quartiles of HMPMA concentration, risk of lung cancer was almost 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 (PheT) and tobacco-specific nitrosamines (NNAL) and/or cotinine, no association was found between HMPMA concentration and lung cancer. [The Working Group noted that there were multiple correlated exposures as measured by biomarkers. The strengths of the study included a relatively large sample size, a sufficiently long follow-up (20 years), few losses to follow-up, that the urinary biomarker HMPMA was collected before disease occurrence, and that smoking status was verified by total cotinine. The nearly two-fold increase in risk of lung cancer associated with the highest quartile of HMPMA concentration when adjusting only for intensity and duration of smoking disappeared with further adjustment for other smoking biomarkers such as cotinine. HMPMA is likely to be a biomarker of smoking. Overall, the study was not informative regarding the carcinogenicity of crotonaldehyde.]

In the second study (Yuan et al., 2014), a similar design as in the paper published in 2012 was applied. Male never-smokers at baseline were included to examine the relationship between environmental exposure to air pollutants, including secondhand smoke, and lung cancer. The follow-up was extended through 2008 (22 years). Loss to follow-up was 5.4%. A total of 80 cases of lung cancer and 82 controls (all never-smokers at baseline) were included in the analysis, after excluding cases with urinary cotinine concentrations above 18 ng/mL (indicating that they may have been smokers) and missing values for cotinine and mercapturic acids. The same biomarkers as in the previous paper were measured, including HMPMA for crotonaldehyde; PheT; 3-OH-Phe (3-hydroxyphenanthrene) and total OH-Phe (total hydroxyphenanthrenes, the sum of 1-, 2-, 3- and 4-OH-Phe) for polycyclic aromatic hydrocarbons; and cotinine for nicotine. Urinary concentrations of HMPMA were similar in both cases and controls. After adjustment for matching factors and urinary cotinine concentration, HMPMA was not associated with elevated risk of lung cancer (fourth quartile versus first quartile OR, 1.00; 95% CI, 0.41–2.41). [The Working Group noted that only internal exposure to crotonaldehyde was assessed. In addition, urinary cotinine represents a short-term biomarker of passive smoking and therefore there may not have been full adjustment for long-term secondhand smoke exposure.]

Grigoryan et al. (2019) published results of a nested case–control study on cancer of the colon or rectum within the cohort study European Prospective Investigation into Cancer and Nutrition, in Italy (EPIC-Italy), with participants recruited from 1993 through 1997. Serum samples were obtained at baseline to detect Cys34 adducts of albumin, as an exposure marker. Cases of colorectal cancer were confirmed by colonoscopy and biopsy. Healthy controls were selected from the cohort, and matched on age, sex, and enrolment year and season. Data on different lifestyle factors were obtained by questionnaire at baseline. After excluding gelled serum samples and samples from two subjects with a high percentage of missing adducts, 57 cases and 72 controls were included in analyses (including 47 matched case–control pairs). Seven Cys34 adducts were associated in a statistically significant manner with colorectal cancer. Five adducts were found to be more abundant in the cases than in controls. One of these was identified as a crotonaldehyde adduct and clustered with the s-methanethiol adduct. These adduct findings may have resulted from the infiltration of gut microbes into the intestinal mucosa and subsequent inflammatory response. [The Working Group noted the small sample size and the lack of information regarding external exposure to crotonaldehyde as limitations of this study.]

3. Cancer in Experimental Animals

In a previous evaluation, the IARC Monographs programme concluded that there was inadequate evidence in experimental animals for the carcinogenicity of crotonaldehyde (IARC, 1995).

Studies on the carcinogenicity of crotonaldehyde in experimental animals are summarized in Table 3.1.

Table 3.1

Studies of carcinogenicity with crotonaldehyde in experimental animals .

4. Mechanistic Evidence

4.1. Absorption, distribution, metabolism, and excretion

The information below pertains to mixtures of the trans- (E-) and cis- (Z-) isomers of crotonaldehyde, unless stated otherwise.

4.1.1. Humans

(a) Exposed humans

Sparse information was available to the Working Group on the absorption and distribution of crotonaldehyde in humans.

The most extensive data on the fate of crotonaldehyde in humans are related to the detection and quantification of urinary crotonaldehyde-specific mercapturates (Fig. 4.1). Numerous studies have reported the use of sensitive analytical methods, primarily based on LC-MS/MS, to assess urinary biomarkers of human exposure to mixtures of volatile organic compounds, including crotonaldehyde (Scherer et al., 2006, 2007; Carmella et al., 2009; Hecht et al., 2010; Alwis et al., 2012; Carmella et al., 2013; Zhang et al., 2014; Hecht et al., 2015; Pluym et al., 2015; Frigerio et al., 2019). These studies have consistently demonstrated the ubiquitous presence of HMPMA in human urine, at statistically significant higher concentrations (3- to 7-fold) in smokers than in non-smokers. Smoking cessation or switching to cigarettes with lower crotonaldehyde delivery resulted in significant reductions in urinary HMPMA concentrations (Scherer et al., 2006, 2007). When measured up to 56 days after smoking cessation, urinary HMPMA concentrations rapidly decreased, from a baseline value of 1965 ± 1001 (mean ± SD) to 265 ± 113 nmol/24 hours after 3 days, and remained approximately constant thereafter (Carmella et al., 2009). Some of these studies (Scherer et al., 2007; Pluym et al., 2015; Frigerio et al., 2019) also reported the detection and quantification of a second crotonaldehyde-derived mercapturate, CMEMA, in human urine. In contrast to rats (see Section 4.1.2), in which CMEMA was found to be a minor urinary metabolite, urinary concentrations of CMEMA in humans were comparable to, or even higher than, those of HMPMA. However, whereas HMPMA concentrations were significantly correlated with smoking status, this was not the case for CMEMA (Scherer et al., 2007; Pluym et al., 2015). Conversely, concentrations of CMEMA (but not HMPMA) were significantly higher in non-smoking gasoline-station attendants than in unexposed workers (Frigerio et al., 2019). [The Working Group noted that the reasons for these discrepancies are not clear. Both HMPMA and CMEMA may also be formed from exposure to crotonaldehyde present in food and ambient air, or formed endogenously. Elevated concentrations of CMEMA might reflect exposure to crotonic acid or crotonates in humans.]

Fig. 4.1

Major pathways of crotonaldehyde metabolism.

A genome-wide association study conducted in samples from more than 2200 smokers from five ethnic groups reported a significant association between urinary HMPMA concentration and a variant on chromosome 12 near the TBX3 gene, which is involved in encoding transcription factors, but the implications of this association with regard to crotonaldehyde metabolism and excretion were not clear (Park et al., 2015). Moreover, no association was detected with chromosome 11, which contains the glutathione S-transferase pi 1 (GSTP1) gene. [These observations suggest that glutathione conjugation with crotonaldehyde, ultimately leading to formation of HMPMA, is mainly a non-enzyme-catalysed process in humans.]

(b) Human cells in vitro

Although crotonaldehyde reacts rapidly with glutathione in vitro (see Section 4.1.2), some degree of enzyme-catalysed conjugation has been demonstrated in vitro with several allelic variants of human GSTP1-1, with catalytic efficiencies (k_cat/K_m) in the range of 12–17 mM^-1 s^-1 (Pal et al., 2000). Consistent with glutathione conjugation, human polymorphonuclear leukocytes had a dose-related decrease in surface and soluble sulfhydryl (SH) groups after treatment with crotonaldehyde in vitro (Witz et al., 1987).

In studies with purified recombinant aldo-keto reductase family 1 B10 (AKRB10), which is expressed in the human colon and small intestine, the enzyme was demonstrated to catalyse the reduction of crotonaldehyde to crotyl alcohol at 0.9 μM, with K_m = 86.7 ± 14.3 μM and V_max = 2647.5 ± 132.2 nmol/mg protein per min, and also the carbonyl reduction of the glutathione–crotonaldehyde conjugate at 0.5 μM, with K_m = 245.7 ± 21.2 μM and V_max = 1900.7 ± 90.9 nmol/mg protein per min (Yan et al., 2007; Zhong et al., 2009). AKRB10 downregulation enhanced the susceptibility of colorectal cancer HCT-8 cells to crotonaldehyde, resulting in rapid cell death (Yan et al., 2007). In a subsequent study, catalytic efficiency for the reduction of crotonaldehyde was 400 times lower for purified recombinant aldo-keto reductase family 1 B1 (AKRB1) (ubiquitously expressed in humans) than for AKRB10. Although AKRB1 appeared to have higher specificity than AKRB10 for glutathione-conjugated carbonyls, data for the glutathione–crotonaldehyde conjugate were not presented (Shen et al., 2011).

4.1.2. Experimental systems

(a) Non-human mammals in vivo

The available data on the absorption, distribution, metabolism, and excretion of crotonaldehyde in experimental animals are few. Nonetheless, protein and DNA adducts of crotonaldehyde have been detected in multiple tissues from rats and mice (see Section 4.2.1), demonstrating that crotonaldehyde undergoes systemic distribution.

In a study with groups of three or four adult male Fischer 344 rats given a single dose of [¹⁴C]-crotonaldehyde (radiochemical purity, > 96%) at 2.6–2.9 mg/kg body weight (bw) in aqueous ethanol by intravenous injection, approximately 31% of the administered radiolabel was excreted as [¹⁴C]-labelled carbon dioxide in the expired air and 37% in the urine within 6 hours after dosing. At the same time-point, the excretion of other volatiles in the breath accounted for approximately 1% of the total radiolabel, whereas the amount of radiolabel associated with blood and selected tissues (skin, muscle, adipose tissue, and liver) accounted for 10% of the total dose administered. At 72 hours after dosing, the elimination of crotonaldehyde as [¹⁴C]-labelled carbon dioxide had increased to approximately 41%, and urinary metabolites accounted for 48% of the administered radiolabel, with negligible (< 0.5%) faecal elimination and low accumulation of [¹⁴C] (< 5% radioactivity) detected in the analysed tissues. The parent crotonaldehyde accounted for > 1% of the urinary excretion of [¹⁴C] and its oxidation product, crotonic acid, for < 2%. The elimination of [¹⁴C] in the breath and urine appeared to be biphasic, with similar half-lives of approximately 2 hours for the initial phase and 13 hours for the second phase estimated for both routes (NTP, 1985).

In a concomitant study, adult male Fischer 344 rats were given [¹⁴C]-labelled crotonaldehyde by gavage as a single dose at 0.7, 3, or 35 mg/kg bw. Absorption from the gastrointestinal tract occurred readily. By 12 hours after dosing, elimination in exhaled air and urine combined accounted for 78% and 60% of the administered radiolabel at the lowest and highest dose, respectively. By 72 hours, 44–49% of the administered dose was excreted in the breath as [¹⁴C]-labelled carbon dioxide, 38–39% in the urine, and 6–7% in the faeces, indicating that the absorption of [¹⁴C]-labelled crotonaldehyde from oral doses was > 93%. Elimination of [¹⁴C] from the tissues and blood was biphasic; there was an initially rapid elimination stage, with half-lives of approximately 1 hour or less, followed by a much slower elimination of the last 10% of the dose, with terminal half-lives of 2.5 days or longer (NTP, 1985).

In an earlier study, groups of male albino and black hooded rats were given a single subcutaneous injection of crotonaldehyde at 0.75 mmol/kg bw [approximately 53 mg/kg bw] in olive oil. Two mercapturate metabolites were identified in urine collected in the 24 hours after dosing. The major metabolites, which accounted for 6–15% of the administered dose, was characterized as HMPMA by hydrolytic conversion to S-(3-hydroxy-1-methylpropyl)-L-cysteine and comparison with a synthetic standard of the latter. The minor urinary metabolite, which was detected occasionally but not quantified, was characterized as CMEMA (Gray & Barnsley, 1971). HMPMA was also detected in the urine of adult male C57BL6/J mice after whole-body exposure to mainstream cigarette smoke (equivalent to 12 cigarettes over 6 hours) but not in the urine of mice exposed to electronic cigarette aerosols (Conklin et al., 2018) or smokeless tobacco extracts in tap water (Malovichko et al., 2019).

The structures of the urinary mercapturates are indicative of Michael-type addition of glutathione to the α,β-unsaturated carbonyl of crotonaldehyde, followed by either reduction or oxidation of the aldehyde group and subsequent catabolism (Fig. 4.1). When given by intraperitoneal injection at a dose of 2 mmol/kg bw [140 mg/kg bw] to male Wistar rats, crotonaldehyde did cause an early decrease in the hepatic glutathione concentrations, as measured 3 hours after dosing. However, the approximate liver glutathione content in rats treated with crotonaldehyde at 0.75 mmol/kg bw was comparable to that of control rats when measured 12 hours after dosing (Oguro et al., 1990).

(b) Non-human mammalian cells in vitro

Upon in vitro incubation with stomach content homogenate from an untreated rat, at an amount equivalent to a dose of 1.8 mg/kg bw, [¹⁴C]-labelled crotonaldehyde remained essentially intact after 2 hours, with 94% of the radioalabel being recovered as the parent compound (assessed by HPLC) and approximately 5% found to be bound to particulate matter (NTP, 1985). In contrast, incubation of [¹⁴C]-labelled crotonaldehyde (approximately 7.33 μg/g) with rat plasma at 37 °C demonstrated that the compound was not stable under these conditions. After 5 minutes, only 42% of the radiolabelled parent compound remained intact, and this had decreased to 15% after 30 minutes. The initial degradation of crotonaldehyde subsequently became much slower, with 8% of the parent compound still present after 20 hours. The reaction products were not identified (NTP, 1985).

Crotonaldehyde reacts readily with SH groups in vitro. It undergoes spontaneous reaction with glutathione, although some degree of enzyme catalysis has also been documented after incubation with rat liver preparations (Boyland & Chasseaud, 1967; Gray & Barnsley, 1971) or with purified glutathione S-transferases (Stenberg et al., 1992; Eisenbrand et al., 1995). In an additional study, rat pulmonary alveolar macrophages exhibited a dose-related decrease in surface and soluble SH groups after treatment with crotonaldehyde in vitro (Witz et al., 1987).

Upon incubation of adult rat lung alveolar cells with crotonaldehyde at 100, 200, or 500 μM for 20 minutes, the effective concentration (EC₅₀) for 50% intracellular glutathione depletion was estimated to be 130 μM. At the crotonaldehyde concentrations used in the study, the rate of glutathione depletion was characteristic of a non-enzymatic second-order reaction for adduct formation (Meacher & Menzel, 1999). [The Working Group noted that the data from this study indicated a key role for molecular reactivity in the process.]

While the reaction between crotonaldehyde and glutathione in buffer solution yields the expected 1,4-addition product (glutathione–crotonaldehyde adduct; GS–CA, Fig. 4.1), this species is only detected at very low levels in cell media. In contrast, a glutathione–crotonaldehyde adduct resulting from subsequent reduction of the aldehyde carbonyl (GS–CA-OH, Fig. 4.1) was clearly identified after a 30-minute incubation of B16-BL6 mouse melanoma cells with crotonaldehyde at 10 μM (Horiyama et al., 2016). The same crotonaldehyde-specific adduct was readily detected (t ≤ 1 minute) in sheep erythrocytes exposed to cigarette smoke extract (Horiyama et al., 2018), indicating that the initially formed glutathione–crotonaldehyde adduct is a substrate for mammalian intracellular carbonyl reductases.

Several studies have also addressed the oxidative metabolism of crotonaldehyde to crotonic acid in rat hepatocytes and rat liver mitochondrial, cytosolic, and microsomal fractions. Crotonaldehyde was consistently found to be both a poor substrate for the liver aldehyde dehydrogenases (ALDHs), with a K_m of 515 μM calculated for the microsomal ALDH, and was a potent inhibitor of the high-affinity mitochondrial and cytosolic ALDH isoforms (Cederbaum & Dicker, 1982; Dicker & Cederbaum, 1984; Mitchell & Petersen, 1993).

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 crotonaldehyde is electrophilic or can be metabolically activated to an electrophile; is genotoxic; induces oxidative stress; induces chronic inflammation; or is immunosuppressive. Insufficient data were available for the evaluation of other key characteristics of carcinogens.

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

(a) Human

(i) Exposed humans

See Table 4.1.

Table 4.1

Crotonaldehyde-derived DNA adducts in exposed humans.

Crotonaldehyde forms α-methyl-γ-hydroxy-1,N²-propano-2′-deoxyguanosine adducts in DNA, of which there are two identified diastereoisomeric forms – 8R,6R and 8S,6S (see Fig. 4.2 and Section 4.2.1.b). These crotonaldehyde adducts were detected in normal human liver at levels ranging from 0.13 to 1.0 adducts/10⁶ deoxyguanosine (Nath & Chung, 1994). In subsequent studies, these adducts were detected in other normal tissues, including in peripheral blood and mammary tissue (Nath et al., 1996); in oral (gingival) tissue (Nath et al., 1998); in liver, lung, and blood cells (Zhang et al., 2006); in placenta, blood cells, and saliva (Chen & Lin, 2009, 2011); in urine samples (Garcia et al., 2013; Zhang et al., 2016a); and in peripheral blood (Alamil et al., 2020). [The Working Group noted that different methods were used in these studies, which may account for differences in levels detected.]

Fig. 4.2

Diastereoisomeric adducts, 8R,6R and 8S,6S.

In studies comparing smokers and non-smokers, adduct levels were significantly elevated in smokers, indicating their formation by crotonaldehyde from tobacco smoke; the presence of adducts in tissues of non-smokers is widely interpreted as being indicative of formation from endogenous sources such as lipid peroxidation (Nath et al., 1996). In a comparison of residents in two areas of Brazil, adduct levels in urine samples were significantly higher in the urban population than in rural residents (Garcia et al., 2013). This was attributed to differences in levels of air pollution as the source of exposure to crotonaldehyde.

In a study from the EPIC-Italy colon cancer cohort, Cys34 adducts of crotonaldehyde in serum albumin were more abundant in cases than in controls, suggesting an inflammatory response involving the generation of crotonaldehyde via lipid peroxidation (Grigoryan et al., 2019). Interestingly, this adduct, along with several other adducts that can result from lipid peroxidation, was also present at significantly higher concentrations in the serum albumin of workers exposed to benzene than in unexposed controls (Grigoryan et al., 2018).

In a study on various smoking-related DNA adducts in different human tissues, crotonaldehyde-derived 1,N²-propano-2′-deoxyguanosine adducts were the most common adducts detected in buccal cells from smokers and in normal lung tissue from lung cancer patients who were smokers, but not in lung tissues of non-smokers (Weng et al., 2018).

(ii) Human cells in vitro

See Table 4.2.

Table 4.2

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

Several studies have demonstrated the formation of crotonaldehyde-derived DNA adducts or DNA damage in human cells treated in vitro with crotonaldehyde. Adducts characteristic of 1,N²-propano-2′-deoxyguanosine were detected by ³²P-postlabelling in the DNA of human xeroderma pigmentosum (XP) fibroblasts treated with crotonaldehyde at 1–100 μM (Wilson et al., 1991). The same range of crotonaldehyde concentrations increased the levels of these adducts in MRC5 cells above the levels already present in untreated cells (Zhang et al., 2016b).

DNA interstrand crosslinks were detected in human lymphocytes and placental DNA treated with crotonaldehyde at 50 mM (Ul Islam et al., 2014, 2016).

Treatment of human HepG2 liver cells with the carcinogen aflatoxin B₁ resulted in the formation of aflatoxin–DNA adducts, and also crotonaldehyde-derived DNA adducts (at a 30-fold higher level) induced by lipid peroxide generation of crotonaldehyde (Weng et al., 2017). Both types of adducts were preferentially formed at codon 249 of the TP53 gene, a hotspot for mutation in hepatocellular carcinoma associated with aflatoxin exposure.

(b) Experimental systems

(i) DNA and protein binding in chemical reactions

Crotonaldehyde is a bifunctional α,β-unsaturated aldehyde (enal) that can form cyclic adducts in DNA, DNA interstrand crosslinks, and DNA–protein crosslinks.

Michael addition of the N²-amino group of deoxyguanosine and of deoxyguanosine residues in DNA, to C3 of crotonaldehyde, followed by ring closure between N1 of deoxyguanosine and C1 of crotonaldehyde forms α-methyl-γ-hydoxy-1,N²-propano-2′-deoxyguanosine adducts, frequently referred to as crotonaldehyde-derived 1,N²-propano-2′-guanosine adducts (Eder et al., 1982; Chung & Hecht, 1983; Chung et al., 1984; Chung et al., 1986b). These are guanine positions that are involved in base pairing in DNA. Chirality at the methyl-bearing carbon atom in the 1,N²-propano ring results in a pair of diastereoisomeric adducts, 8R,6R and 8S,6S (see Fig. 4.2).

Monoclonal antibodies specific for the 8R,6R and 8S,6S stereoisomers have been produced (Foiles et al., 1987). Methods for detecting crotonaldehyde derived DNA adducts using ³²P-postlabelling analysis (Chung et al., 1989, Foiles et al., 1990, Nath et al., 1994, Pan et al., 2006) and mass spectrometry (Doerge et al., 1998, Zhang et al., 2006, Chen & Lin, 2009, Garcia et al., 2013, Zhang et al., 2016b, Alamil et al., 2020) have also been reported.

Reaction of deoxyguanosine with an excess of crotonaldehyde at 80 °C gave rise not only to 1,N²-propano adducts but also to N7,C8 cyclic adducts and 1,N²,7,8 bicyclic adducts (Eder & Hoffman, 1992). Reaction of crotonaldehyde with deoxyadenosine produces 1,N⁶-propano-2′-deoxyadenosine adducts equivalent to the deoxyguanosine adducts (Chen & Chung, 1994).

Crotonaldehyde is a metabolite of N-nitrosopyrrolidine (NPYR), a carcinogenic environmental nitrosamine. α-Acetoxy-NPYR, a synthetic stable precursor to the proposed proximate carcinogen α-hydroxy-NPYR, reacts with DNA to form crotonaldehyde-derived 1,N²-propano-2′-deoxyguanosine and cyclic N7,C8 guanine adducts (Wang et al., 1989, 1998).

Crotonaldehyde-derived 1,N²-propano-2′-deoxyguanosine may also be generated by endogenous processes. Their formation by ω-3 polyunsaturated fatty acids, including docosahexaenoic acid, linoleic acid, and eicosapentaenoic acid (Pan & Chung, 2002), suggests a possible source, as products of lipid peroxidation, of adducts detected in human and animal tissues not knowingly exposed to crotonaldehyde.

The ability of crotonaldehyde to form interstrand crosslinks in DNA depends on the stereochemistry at the C6 position of the 1,N²-propano-2′-deoxyguanosine adduct. It requires a 5′-CpG-3′ (cytosine-phosphate-guanine) sequence where the orientation of the aldehyde within the minor groove favours reaction of the 6R configuration relative to the 6S (Kozekov et al., 2003; Stone et al., 2008; Minko et al., 2009). Molecular modelling studies predict less disruption of the duplex structure, and greater thermodynamic stability for the crosslink formed by the R adduct (Cho et al., 2006a, b, 2007).

Histones, which are rich in basic amino acids such as arginine and lysine, accelerate the reaction of crotonaldehyde with deoxyguanosine and DNA under physiological conditions (Sako et al., 2003; Inagaki et al., 2004). Crotonaldehyde reacts with lysine and histidine in bovine serum albumin (Ichihashi et al., 2001) and can also form DNA–protein crosslinks (Kuykendall & Bogdanffy, 1992). Crotonaldehyde-derived 1,N²-propano-2′-deoxyguanosine adducts crosslink to peptides via Schiff base linkage (Kurtz & Lloyd, 2003).

Several studies have indicated that crotonaldehyde, and crotonaldehyde-derived DNA adducts, can arise from acetaldehyde, a metabolite of alcohol, under physiological conditions or at biologically relevant concentrations of acetaldehyde (Stornetta, et al., 2018), indicating that alcohol exposure is confounding when performing studies of crotonaldehyde–DNA binding. Micromolar concentrations of acetaldehyde in the presence of spermidine led to formation of α-methyl-γ-hydroxy-1,N²-propano-2′-deoxyguanosine adducts in DNA (Theruvathu et al., 2005). Crotonaldehyde can be produced in aqueous solutions of acetaldehyde by aldol condensation. Enzymatic or neutral hydrolysis of DNA in the presence of crotonaldehyde produces paraldol, the dimer of 3-hydroxybutanal (aldol) that, when it reacts with DNA, generates a class of adducts described by Wang et al. (2000). Base treatment of acetaldehyde results in the formation of its trimer, aldoxane, which is in equilibrium with crotonaldehyde in solution. This too can lead to the formation of adducts in DNA (Wang et al., 2001), although it is not known whether aldoxane or paraldol are produced from acetaldehyde in vivo.

(ii) DNA adducts in experimental systems

See Table 4.3 and Table 4.4.

Table 4.3

Detection of crotonaldehyde-derived DNA adducts in non-human mammals in vivo.

Table 4.4

Detection of crotonaldehyde-derived adducts with oligonucleotides and DNA.

After treatment of Fischer 344 rats by gavage with a single dose of crotonaldehyde (200 mg/kg bw), 2.9 adducts/10⁸ nucleotides were detected in the liver; treatment with repeated doses (1 mg/kg bw, five times per week for 6 weeks) resulted in a similar level of adduct formation (2.0 adducts/10⁸ nucleotides) (Eder et al., 1999; Budiawan et al., 2000). No adducts were detected in the livers of untreated rats in these studies (limit of detection, 3 adducts/10⁹ nucleotides), in contrast to studies by other investigators who reported the presence of adducts in the livers of both untreated and treated mice and rats (Chung et al., 1989; Nath & Chung, 1994; Nath et al., 1996; Pan et al., 2006). [The Working Group noted that in one of these studies treatment of rats with N-nitrosopyrrolidine (NPYR) also gave rise to crotonaldehyde-derived 1,N²-propano-2′-deoxyguanosine adducts in liver (Chung et al., 1989).] DNA adducts have also been detected in mouse skin after topical treatment with crotonaldehyde (Chung et al., 1989) and in multiple tissues (lung, kidney, colonic mucosa, prostate, mammary tissue, brain, and leukocytes) of untreated rats and also in the skin of untreated mice (Nath et al., 1996).

Tissues of mice exposed to mainstream tobacco smoke (5 days per week for 12 weeks) were analysed for multiple DNA adducts, including those derived from benzo[a]pyrene, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK), acrolein, and crotonaldehyde (Weng et al., 2018). Adducts derived from crotonaldehyde were detected in the lung and urinary bladder, but not in the heart and liver.

Male Wistar rats were exposed via inhalation to exhaust from either ultra-low sulfur diesel (ULSD) or biodiesel containing 30% rapeseed methyl ester in ULSD. No significant increases in the frequency of lung crotonaldehyde–DNA adducts were observed in either treatment group when compared with rats exposed to filtered air (Douki et al., 2018).

It has also been reported that crotonaldehyde forms 1,N²-propano-2′-deoxyguanosine adducts, as detected by ³²P-postlabelling analysis in Chinese hamster ovary cells (Foiles et al., 1990).

In acellular studies, crotonaldehyde induced the formation of DNA adducts in calf thymus DNA (Chung et al., 1984; Kailasam & Rogers, 2007), as well as in oligonucleosides and mononucleotides (Eder & Hoffman, 1992; Borys-Brzywczy et al., 2005; see Table 4.4).

4.2.2. Is genotoxic

[The information below pertains to mixtures of the trans- (E-) and cis- (Z-) isomers of crotonaldehyde, unless stated otherwise.]

(a) Humans

(i) Exposed humans

No data were available to the Working Group.

(ii) Human cells in vitro

See Table 4.5.

Table 4.5

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

Crotonaldehyde-induced DNA single-strand breaks were observed in human lymphoblastoid (Namalwa) cells (Eisenbrand et al., 1995). Dittberner et al. (1995) obtained a positive result for sister-chromatid exchange, structural chromosomal aberration, and micronucleus formation in both human primary lymphocytes and Namalwa cells treated with crotonaldehyde. However, a negative result was obtained for centromere-positive micronuclei, as detected by fluorescence in situ hybridization (FISH), in both cell lines. [The Working Group noted that this indicates a clastogenic effect.] Additionally, the lymphocytes were only examined for the number of aneuploid metaphases; no significant increase was found (Dittberner et al., 1995).

In three experiments, plasmids containing the supF gene were reacted with crotonaldehyde and then transfected into various human cell types to allow for repair and replication; the supF mutant frequency was subsequently assessed in Escherichia coli and found to be significantly increased in a dose-dependent manner in all cases (Czerny et al., 1998; Kawanishi et al., 1998; Weng et al., 2017). In one study in which the exposed plasmid was transfected into human hepatocellular carcinoma cells (HepG2), crotonaldehyde induced G→C transversions (41%), G→T transversions (37%), deletions (16%), and G→A transitions (6%) (Weng et al., 2017). In another supF shuttle-vector study using normal human fibroblasts (W138-VA13), 85% of the crotonaldehyde-induced mutations were base substitutions (single substitutions, 47%; tandem or multiple substitutions, 38%), 14% were deletions, and 1% were insertions; of the base substitutions, they found that G→T transversions predominated (50%), followed by G→A transitions (23%), and G→C transversions (13%) (Kawanishi et al., 1998). In a study in which the exposed plasmid was transfected into transformed human normal lymphoblasts (GM0621), crotonaldehyde induced primarily deletions (46%), as well as base-pair substitutions (39%), insertions (12%), and inversions (3%); two hot spot deletions were identified, which represented 62% of all deletions (Czerny et al., 1998).

In another study, a DNA vector containing either the 8R,6R or 8S,6S adducts was introduced into human xeroderma pigmentosum A (XPA) cells; both adduct isomers were found to inhibit DNA synthesis, with the 8S,6S adduct being more mutagenic than the 8R,6R isomer (10% versus 5%, respectively). Additionally, for the 8S,6S adduct, G→T transversions were the most common, followed by G→C transversions, and G→A transitions, whereas with the 8R,6R isomer, G→T and G→A were induced at almost the same frequency, followed by G→C (Stein et al., 2006).

(b) Experimental systems

(i) Non-human mammals in vivo

See Table 4.6.

Table 4.6

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

Chromosomal aberrations in the bone marrow were observed in male and female Swiss albino mice exposed to crotonaldehyde as a single intraperitoneal injection, with a significant response seen at sampling times of 6, 12, and 24 hours (Jha et al., 2007). Chromosomal aberrations were observed in spermatozoa analysed 24 hours after exposure to crotonaldehyde (Jha et al., 2007). A significant increase in abnormal sperm head morphology (an end-point used as an indicator of mammalian germ cell mutagens) was observed in male Swiss albino mice in samples obtained 1, 3, and 5 weeks after a single intraperitoneal dose of crotonaldehyde (Jha & Kumar, 2006). Male Swiss albino mice exposed by intraperitoneal injection to crotonaldehyde once daily for 5 days were mated with untreated females during the post-exposure periods in weeks 1, 2, 3, 4, or 5. An increase in the number of dominant lethal mutations (DLMs) and the number of dead implants per female was reported (Jha et al., 2007). From mating week 1, a significant increase in DLMs was induced by the highest dose; for mating weeks 2 and 3, DLMs were induced by all three doses; for mating week 4, DLMs were induced by the highest dose, and from mating week 5, there was a small but non-significant dose-related increase in DLMs (Jha et al., 2007). [The Working Group noted that the examination of these end-points after different post-exposure mating schedules allows for analysis of the sensitivity of the male germ cells at different developmental stages, and that these results indicated that male mouse germ cells appear to be most sensitive to the mutagenic effects of crotonaldehyde when exposed during the repair-proficient spermatid and late spermatocyte stages.]

(ii) Non-human mammalian cells in vitro

See Table 4.7.

Table 4.7

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

In crotonaldehyde-treated primary rat hepatocytes, a significant increase in the frequency of DNA single-strand breaks was observed at 1 mM, as assessed by the alkaline elution assay (Eisenbrand et al., 1995). Crotonaldehyde treatment of primary rat colon and stomach mucosa cells induced DNA damage at 0.4 mM, as assessed by the alkaline comet assay (Gölzer et al., 1996). Higher doses (up to 71.3 mM) failed to elicit a significant increase in the amount of DNA in the comet tail in primary rat hepatocytes when assessed by the comet assay; however, condensed comet heads characteristic of DNA cross links were observed at 28.5 mM (Kuchenmeister et al., 1998). [The Working Group noted that similar comet responses for other cross-linking chemicals have been reported elsewhere (Pfuhler & Wolf, 1996; Merk & Speit, 1999). The Working Group also noted the high concentrations used.] A negative response was obtained for unscheduled DNA synthesis in crotonaldehyde-treated primary rat hepatocytes (Williams et al., 1989). Crotonaldehyde treatment resulted in a significant increase in the frequency of mutations of the Tk gene in mouse lymphoma cells (L5178Y) (Demir et al., 2011), and the Hgprt gene in standard Chinese hamster fibroblasts (V79-4), as well as in V79-4 cells expressing the human aldo-keto reductase enzyme AKR7A2 (Li et al., 2012).

Using shuttle vectors containing either adduct isomer, the 8R,6R and 8S,6S crotonaldehyde-derived 1,N²-propano-2′-guanosine adducts were found to be mutagenic in African green monkey kidney (COS-7) cells, with similar percentage mutagenicity observed for both isomers (i.e. 4.7% and 6.2%, respectively) (Fernandes et al., 2005).

(iii) Non-mammalian experimental systems

See Table 4.8.

Table 4.8

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

In Drosophila melanogaster, a negative result was obtained for sex-linked recessive lethal mutation when crotonaldehyde was administered in the feed, but the result was positive for both sex-linked recessive lethal mutations and heritable translocations when crotonaldehyde was administered by injection (Woodruff et al., 1985). A positive response was observed in the somatic mutation and recombination test (SMART) wing spot mutation assay with crotonaldehyde in the feed (Demir et al., 2013).

Crotonaldehyde has been evaluated in several Salmonella typhimurium strains that are sensitive to base-pair substitutions (i.e. strains TA1535, TA100, and TA104) and frameshift mutations (i.e. strains TA1537, TA1538, and TA98). However, no strains specific to the detection of cross-linking agents (e.g. TA102) were employed. In some cases, tests were only carried out without metabolic activation (−S9); with metabolic activation (+S9), the number of revertants was lowered. In the base-pair substitution strains, crotonaldehyde gave negative results with and without metabolic activation in several plate-incorporation assays with strain TA1535 (Lijinsky & Andrews, 1980; Neudecker et al., 1981; Haworth et al., 1983) and TA100 (Lijinsky & Andrews, 1980; Neudecker et al., 1981); however, in strain TA100 two positive results with and without metabolic activation were also observed (Haworth et al., 1983; Neudecker et al., 1989). When the more sensitive preincubation version of the assay was employed, a negative result was still obtained in strain TA1535 (Grúz et al., 2018). However, in strain TA100 the result was positive with and (when tested) without metabolic activation in five of the six preincubation assays (Lijinsky & Andrews, 1980; Neudecker et al., 1981, 1989; Cooper et al., 1987; Eder et al., 1992; Grúz et al., 2018). A positive response was obtained in strain TA104 without metabolic activation (Marnett et al., 1985). Crotonaldehyde gave negative results with and without metabolic activation in the frameshift strains TA1537, TA1538, and TA98 (Lijinsky & Andrews, 1980; Neudecker et al., 1981, 1989; Haworth et al., 1983; Eder et al., 1992; Grúz et al., 2018). Positive results without metabolic activation were observed in several YG test strains engineered with different polymerases (Grúz et al., 2018). A weak positive response for SOS induction was observed in strain TA1535 (Benamira & Marnett, 1992), and two negatives and a weak positive result were obtained in the SOS chromotest in Escherichia coli when DMSO was used as the solvent (Eder et al., 1992, 1993; Eder & Deininger, 2002); however, when ethanol was used as the solvent in two additional assays, robust positive responses were observed (Eder et al., 1993; Eder & Deininger, 2002). Negative results were obtained for both forward and reverse mutation in Salmonella typhimurium BA9 when the plate-incorporation version was carried out, but robust increases in forward and reverse mutation were observed with the more sensitive preincubation version (Ruiz-Rubio et al., 1984).

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 crotonaldehyde in an acellular study (Kailasam & Rogers, 2007).

4.2.3. Alters DNA repair

A single study on the ability of crotonaldehyde to alter DNA repair was available. Using the host cell reactivation assay, crotonaldehyde was found to inhibit both nucleotide excision repair and base excision repair capacity in human hepatocellular carcinoma cells (HepG2) (Weng et al., 2017). In a subsequent experiment, nucleotide excision repair was instantaneously inhibited when crotonaldehyde was added to cell lysates, indicating that crotonaldehyde reacts with and inhibits proteins that are critical for nucleotide excision repair (Weng et al., 2017).

4.2.4. Induces oxidative stress

(a) Humans

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

In vitro studies in human vein endothelial cells demonstrated that crotonaldehyde (50 μM; 1 hour) increases the formation of reactive oxygen species (Ryu et al., 2013). Crotonaldehyde treatment also increased gene expression and protein levels of haem oxygenase 1 in a dose-dependent manner, consistent with a cellular response to oxidative stress (Lee et al., 2011). In human bronchial epithelial cells, crotonaldehyde decreased concentrations of intracellular glutathione (at up to 10 μM) and increased the formation of reactive oxygen species (at 40 μM) (Liu et al., 2010).

(b) Experimental systems

See Table 4.9.

Table 4.9

Effects of crotonaldehyde on markers of oxidative stress or chronic inflammation in non-human mammals in vivo.

In rats, depletion of hepatic glutathione (a marker of oxidative stress) occurs after acute intraperitoneal administration of crotonaldehyde (Cooper et al., 1992). In male Wistar rats, subchronic oral administration of crotonaldehyde increased production of proinflammatory cytokines and elevated serum malondialdehyde concentrations, indicative of increased lipid peroxidation (Zhang et al., 2019b). In another study in male Wistar rats, subchronic (up to 120 days) oral exposure to crotonaldehyde decreased serum glutathione peroxidase and superoxide dismutase activity and elevated malondialdehyde concentration (Li et al., 2020).

In vitro studies have shown that crotonaldehyde exposure can inhibit glutathione S-transferase activity, resulting in depletion of intracellular glutathione (van Iersel et al., 1996). Crotonaldehyde exposure for 4 hours decreased intracellular glutathione concentration (at 25 μM) and increased reactive oxygen species formation (at ≥ 25 μM) in a rat alveolar macrophage cell line (Yang et al., 2013a).

4.2.5. Induces chronic inflammation

(a) Humans

No data were available to the Working Group.

(b) Experimental systems

See Table 4.9.

In a study of subchronic toxicity (120 days) in rats treated by gavage, crotonaldehyde was associated with myocardial necrosis, cardiac fibrosis, renal tubular epithelial cell oedema, and renal lymphocyte infiltration, suggestive of an inflammatory response (Zhang et al., 2019b). In a study of chronic toxicity in male rats treated by inhalation, crotonaldehyde was associated with a dose-dependent increase in the incidence and severity of inflammation in the nasal respiratory epithelium (JBRC, 2001b). In female mice and rats exposed to crotonaldehyde by inhalation in a study of chronic toxicity, inflammation was seen at 12 and 6 ppm, respectively (JBRC, 2001e, b); see also Section 3. [The Working Group noted that changes in cell proliferation in response to crotonaldehyde exposure has not been evaluated in experimental systems.] Intratracheal instillation of crotonaldehyde resulted in inflammatory cell infiltration, shift in the number of CD4+ and CD8+ T lymphocytes, decreased numbers of mononuclear phagocytes in bronchoalveolar lavage fluid in male Wistar rats (Wang et al., 2018). In a study of subchronic toxicity (up to 120 days) in male Wistar rats, oral exposure to crotonaldehyde (at 4.5 mg/kg bw) resulted in increased inflammatory cell infiltration, as well as increased lung concentrations of TNFα, interleukin 6 (IL6), and IL1β (Li et al., 2020).

4.2.6. Other key characteristics

(a) Is immunosuppressive

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

In cultured human monocytic U937 cells differentiated along the macrophagic line, crotonaldehyde increased the release of IL8 and TNFα (Facchinetti et al., 2007). In cultured human macrophages, human lung fibroblasts, and small airway epithelial cells, crotonaldehyde increased the release of IL8, and this response was mediated via p38 MAPK- and ERK1/2-dependent pathways (Moretto et al., 2009).

Shifts in T-lymphocyte populations, decreased numbers of mononuclear phagocytes in bronchoalveolar lavage fluid, and decreased lung macrophage function were reported in male Wistar rats after intratracheal instillation of crotonaldehyde in the study of Wang et al. (2018) referenced above (see Table 4.9). Crotonaldehyde was found to suppress phagocytic function in cultured rat alveolar macrophages and was associated with a dose-dependent decrease in cell viability (Yang et al., 2013b).

(b) Modulates receptor-mediated effects

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

Crotonaldehyde activated peroxisome proliferator-activated receptor PPARγ and PPARβ/δ luciferase reporter activity in a dose-dependent manner in cultured TSA201 cells derived from human embryonic kidney cells (HEK293) (Matsushita et al., 2019). Crotonaldehyde enhanced thyroid hormone action by modulating thyroid hormone binding to thyroid hormone receptors (TR) resulting in upregulation of gene transcription in cultured human embryonal kidney (TSA 201) cells (Hayashi et al., 2018). In TSA201 cells transfected with the ligand-binding domain of TRα1 or TRβ1 coupled to a luciferase reporter system, it was demonstrated that, in the presence of thyroid hormone, crotonaldehyde induced TRα1-mediated transcription activity while not affecting TRβ1 (Hayashi et al., 2018).

(c) Multiple characteristics

Transcript profiling has been performed in a human monocytic leukaemia THP-1 cell line exposed to crotonaldehyde (Yang et al., 2014). In this system, 342 or 663 genes were statistically significantly differentially expressed after either a 6- or 12-hour exposure, respectively, to crotonaldehyde at 80 μM (Yang et al., 2014). Crotonaldehyde affected the expression of genes related to oxidative stress, including several involved in glutathione metabolism. Haeme oxygenase 1 (HO-1) was also upregulated after crotonaldehyde exposure (Yang et al., 2014). Other pathways dysregulated by crotonaldehyde exposure included those involved in apoptosis and regulating cellular responses to DNA damage (Yang et al., 2014).

Liu et al. (2010) evaluated transcript profiles in human bronchial epithelial cells exposed to crotonaldehyde. Multiple inflammatory responsive genes (e.g. XCL1, CXCL2, CXCL3, CCL2, CSF1, CSF2, NFKBIA, NFKBIZ) were downregulated by crotonaldehyde, whereas fewer genes (CMTM, PAG1, and PTX3) were upregulated. Some genes involved in cytokine production and inflammation (IL6, IL8) were downregulated, whereas HOX-1 was upregulated after treatment with crotonaldehyde (Liu et al., 2010).

5. Summary of Data Reported

6. Evaluation and Rationale

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