Diacetyl: Occurrence, Analysis, and Toxicity

Review pubs.acs.org/JAFC

Diacetyl: Occurrence, Analysis, and Toxicity Takayuki Shibamoto* Department of Environmental Toxicology, University of California, Davis, California 95616, United States ABSTRACT: Diacetyl possesses a butter-like flavor and has been widely used as a flavoring agent. It forms from sugars and lipids via various bacteria and heat treatment in various foods and beverages, such as milk. The toxicity of diacetyl, especially when inhaled, has recently attracted the attention not only of consumers but also of regulatory agencies. Even though accurate quantitative analysis of diacetyl is extremely important in evaluating its possible adverse effects, precise quantitative analysis of diacetyl in foods and beverages, as well as in ambient air, is considerably difficult because it is highly reactive and soluble in water. Among the many analytical methods developed for measuring diacetyl, preparation of 2,3-dimethylquinoxaline followed by gas chromatography has been most commonly used in the analysis of various foods, beverages, and air samples. This mini-review summarizes the formation mechanisms, analytical methods, occurrence, and toxicity of diacetyl. KEYWORDS: diacetyl, α-dicarbonyl compounds, inhalation toxicity, lipids, sugars

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raphy.18 Various less commonly used methods, such as colorimetric,19 fluorometric,20 GC-MS,5 GC-ECD,21 and HPLC-UVD analyses,22,23 have also been reported. The recent development of LC-MS analysis may provide an ideal analytical method for diacetyl in the near future.

INTRODUCTION Diacetyl is a degradation product of various food components, including fatty acids/triglycerides, carbohydrates/sugars, and proteins/amino acids. Formation of diacetyl from sugar degradation had already been reported by the middle of the past century.1 Around that time, diacetyl was found in lipid peroxidation products.2,3 More recent research has shown that diacetyl forms by the action of lactic bacteria.4 Diacetyl is also known to form as a natural product of the action of microorganisms during fermentation in some food products, such as yogurt5 and fermented soybeans.6 Consequently, diacetyl has been found in many foods and beverages, particularly in dairy products. Diacetyl is listed in the FDA’s GRAS (generally regarded as safe) list and has been used widely in the preparation of butter and related food products, at levels of 6−9 μg/g, because it possesses a unique, butter-like flavor with an odor threshold of 50 ppb.7,8 On the other hand, NIOSH proposed limits on diacetyl exposure for factory workers, who might be exposed to vapor-phase diacetyl in related production factories.9−11 Toxicities associated with diacetyl, such as interacting with other factors to cause lung damage12 and playing a role in oxidative stress, have also been reported.13 Determination of toxicity is the first avenue to establishing the safety level of chemicals. Establishing regulatory values of diacetyl, however, is rather difficult because sufficient information, such as actual levels in foods and beverages, vapor-phase levels, formation mechanisms, and toxicities, is required before the safety level can be set. This information is not yet completely known. A number of reviews involved in specific issues of diacetyl, such as analytical and biochemical considerations,14 foodborne microorganisms,15 respiratory sensitizer,16 and brewery fermentation,17 have been published. However, virtually no reviews providing sufficient information on the occurrence, toxicity, and analytical method of diacetyl are available. Analysis of diacetyl is not easy because it is highly reactive, volatile, and water-soluble. The mainstream practice in diacetyl analysis is therefore to prepare a stable compound, such as 2,3dimethylquinoxaline, and then analyze it using gas chromatog© 2014 American Chemical Society

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CHEMISTRY AND FORMATION MECHANISMS OF DIACETYL Physical Nature. Diacetyl (CAS Registry No. 431-03-8) is a simple α-dicarbonyl compound with a molecular weight of 86.0892. Another common name for diacetyl is 2,3butanedione. It is a yellow liquid at room temperature and soluble in most organic solvents and water. Its melting point is between −2 and −4 °C, and its boiling point is 88 °C. Chemical Formation. Many carbonyl compounds, including diacetyl, are known to be formed from lipids upon oxidation. Figure 1 summarizes the generally recognized proposed formation pathways of carbonyl compounds from lipids, which were reported in the early 1980s.24,25 It has also been known since the 1960s that sugars degrade into many low-molecular-weight carbonyl compounds including diacetyl.1,26 Formation of diacetyl in milk by heat treatment had already been demonstrated in the late 1960s.27 Figure 2 shows the proposed formation pathways of diacetyl from sucrose. In these pathways, the first step is tautomerization of a free sugar group, followed by cleavage at keto−enol bonding in acidic or alkaline solution.28 A recent study reported that higher levels of diacetyl were formed from sugars in acidic or basic solutions than in neutral solutions.29 In addition to the formation pathways of α-dicarbonyl compounds shown in Figures 1 and 2, there is a pathway by which a lipid or sugar produces various low-molecular-weight radicals, such as •CH3, •CO, and •CO(CH3), and these radicals subsequently combine to yield diacetyl. This pathway Received: Revised: Accepted: Published: 4048

February April 14, April 16, April 16,

4, 2014 2014 2014 2014

dx.doi.org/10.1021/jf500615u | J. Agric. Food Chem. 2014, 62, 4048−4053

Journal of Agricultural and Food Chemistry

Review

Figure 1. Generally recognized proposed formation pathways of carbonyl compounds from lipids.

Figure 2. Proposed formation pathways of diacetyl from sucrose.

are sugars and lipids.33 Formation of diacetyl from a Maillard model system consisting of L-rhamonse and ammonia was reported in the late 1970s.34 Despite the fact that carbonyl compounds do not contain a nitrogen atom, amine compounds react with a sugar or a lipid to promote the formation of carbonyl compounds, including diacetyl,35 suggesting that amine compounds act as catalysts for sugar or lipid degradation. Maltose, for example, degraded into diacetyl through an Amadori product intermediate when it was incubated with Llysine.36 In this study, diacetyl was recovered as a quinoxaline derivative ranging from 0.08 to 0.14 mmol/mol maltose. Bacterial Formation. Formation of diacetyl by bacterial treatment may follow the pathway shown in Figures 1 and 2

could be proposed when the reaction systems absorb high levels of energy from exposure to high temperatures, as in cooking or photoirradiation.30 In fact, when cod liver oil was irradiated by UV, 27.23 nmol/mg glyoxal and 5.72 nmol/mg methylglyoxal were formed, suggesting that the radicals listed above combined to produce these diacetyl analogues.31 Maillard Reaction. The Maillard reaction is one of the most important reactions that form carbonyl compounds, including diacetyl, in foods. The Maillard reaction occurs between carbonyl compounds, such as sugars and lipids, and nitrogen-containing compounds, such as amino acids. It is generally recognized that nitrogen comes from an amino acid via Strecker degradation.32 The sources of carbonyl compounds 4049



Review

Table 1. Diacetyl Found in Various Foods and Beverages

a

sample

level (μg/g)

objective of analysis

analytical method

ref

heated milk oxidized sardine oil fermented soybean brandy, vinegar, wine, butter fermented soybean curds wine cheese fresh milk orange juice whiting, mackerel, cod roasted coffee sweet cream butter goat’s milk jack cheese yogurt artichoke juice beer selected dairy products

0.005−0.38 1.6−3.1 NRb 2.1−0.3 0.02−0.12 0.5−10 mg/L 4.52 NR 20 μg/g.70 After NIOSH investigated lung disease associated with the butter flavoring used in popcorn, the safety level of diacetyl in ambient air was targeted for restriction by some regulatory agencies. When the inhalation toxicity of a given chemical is assessed, it is extremely important to know the exact amount of that chemical inhaled by the target subjects, whether animal or human. A detailed discussion of diacetyl toxicities associated with occupational health, such as bronchiolitis obliterans,71 is not within the scope of this mini-review.

chemicals was reported in fresh milk, for example, but without quantitative analysis.46 On the other hand, analysis of a volatile sample recovered from fermented soybean curds using a simultaneous steam distillation and extraction apparatus resulted in a quantitative measure of 0.001−0.17 μg/g diacetyl.44 Diacetyl found in 12 brands of beer using a slightly modified quinoxaline derivative ranged from 0.034 to 0.11 μg/ g.52 Diacetyl has been found to be one of the volatile chemicals that contributes the characteristic butter flavor to various foods and beverages. It was reported as one of the most intense volatile compounds, for example, in the aroma of pasteurized AA butter.55 These reports indicate that diacetyl is also present in the headspace of food and beverage samples. Determination of diacetyl in the vapor phase has therefore become important in assessing the flavor quality of butter and related products as well as in evaluating its inhalation toxicity. Among over 120 volatile compounds reported in yogurt, diacetyl was described as one of the major chemicals contributing to the characteristic yogurt flavor.5 Starter distillates, which are used as ingredients in the formulation of various foods, such as cottage cheese, margarine, and sour cream, contained 1.2−22000 μg/g diacetyl in their headspace when analyzed using SPME and GC-MS.53 Amounts (5−600 ppb) of diacetyl vaporized from beer at high temperature were monitored using an automatic flow system after diacetyl was derivatized into 2,3-dimethylquinoxaline.59 Vapor-phase diacetyl in cigarette smoke analyzed using quinoxaline derivative resulted in measurements of 301−433 mg/cigarette in 14 brands of cigarette.60 Recently, between 13.9 and 2835.7 ng/g of diacetyl were reported in the headspace of heated butter and cheese samples using a unique simultaneous purging and extraction apparatus.29 The headspace from spoiled fish samples was successively trapped using a SPME fiber made of carboxen/polydimethylsiloxane.48 Analysis of the trapped sample by GC-MS resulted in the identification of 86 volatile compounds, including diacetyl. The absolute amounts of the volatiles, however, were not reported in this article due to the difficulty of performing quantitative analysis using SPME.61 Later, diacetyl in the headspace of goat’s milk jack cheese during the aging process was successfully determined using static headspace GC with an internal standard.51

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CONCLUSIONS Diacetyl is known as a flavor chemical possessing a butter-like flavor, and it is found in various foods and beverages. It has begun to receive attention as a possible cause of certain lung diseases in the past 5 years. The toxicity of α-dicarbonyl compounds glyoxal and methylglyoxal has been reported frequently, but reports on diacetyl toxicity were very infrequent until the 2000s. After NIOSH reported its inhalation toxicity, limits on diacetyl became a pressing need to protect factory workers. It is therefore important to know the formation mechanisms and occurrence of diacetyl to assess the safety of foods and beverages as well as indoor air containing diacetyl.

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AUTHOR INFORMATION

Corresponding Author

*Phone: (530) 752-4523. Fax: (530) 752-3394. E-mail: [email protected]. Notes

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The authors declare no competing financial interest.

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TOXICITY OF DIACETYL Diacetyl toxicity (mutagenicity) was first reported in 1979 as a positive finding in an Ames assay.62 Later, mutagenicity of diacetyl was reported using a mammalian cell gene mutation assay in L5178Y mouse lymphoma cells.63 Another early study demonstrated that various carbonyl compounds, including diacetyl, induced chromosome loss when they were combined with subacute concentrations of propionitrile.64 Since the recent publication of comprehensive studies of the respiratory toxicity of diacetyl using C57BBI/6 mice,65 occupational health issues among workers in plants associated with diacetyl vapor, such as butter-flavoring production plants, have received much attention.11 Diacetyl has been produced in large amounts (228,000 pounds in 2005) for use as a flavoring agent in food products. It has recently been linked to bronchiolitis obliterans occurring among factory workers.10 A recent review indicated that diacetyl is associated with chronic forms of diffuse parenchymal lung disease.66 When human epithelial lung cells were exposed to diacetyl vapor,

ABBREVIATIONS USED CAS, Chemical Abstracts Service; DAD, diode array detector; FDA, U.S. Food and Drug Administration; FID, flame ionization detector; GC-EC, gas chromatograph−electron capture detector; GC-MS, gas chromatography−mass spectrometry; GC-NPD, gas chromatograph−nitrogen phosphorus detector; GRAS, generally regarded as safe; HPLC-UVD, highperformance liquid chromatograph−ultraviolet detector; IL, interleukin; LC-MS, liquid chromatography−mass spectrometry; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupational Safety and Health Administration; PTR-MS, proton-transfer-reaction mass spectrometry; SPME, solid phase microextraction; TNF-α, tumor necrosis factor alpha

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REFERENCES

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Diacetyl: Occurrence, Analysis, and Toxicity

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