Food Chemistry 314 (2020) 126222

Contents lists available at ScienceDirect

Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem

Chemical hazards in grapes and wine, climate change and challenges to face T
a b a a
Cristina Ubeda , Ruth Hornedo-Ortega , Ana B. Cerezo , M. Carmen Garcia-Parrilla ,
⁎
Ana M. Troncosoa,
a
Departamento de Nutricion y Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García Gonzalez 2, 41012 Sevilla,
Spain
b
MIB, Unité de Recherche Oenologie, EA 4577, USC 1366 INRA, ISVV, Université de Bordeaux, Villenave d Onron, France

A R T I C LE I N FO A B S T R A C T

Keywords: Climate change has an impact on the chemical risks associated to wine consumption related with grape de-
Climate change velopment and microbial contamination. We can classify chemical hazards in wine into two groups: those
Wine present in grapes due to agricultural practices, environmental contamination or fungal growth and those coming
Food safety from fermentation and the winemaking process. The first group includes mycotoxins, whilst the second en-
Biogenic amines
compasses ethyl carbamate, biogenic amines, sulfur dioxide and proteins used as technological ingredients such
Ochratoxin A
as fining material. Usually the effective control of chemical hazards is achieved by assuring that they either are
Sulfites
minimized or absent in the final product since their removal is somewhat difficult and sometimes it may affect
sensory properties, which is a major issue in wine. Interestingly, it is possible to give recommendations to avoid
excess of these compounds, but more research is needed to face future challenges related to climate change and
consumer demands.

1. Overview of chemical hazards in grape and wine
Any food is considered safe if its consumption is not harmful to
human health in the short or long term and it is prepared and consumed
according to its intended use. For the concrete case of wine, moderate
consumption is required within intended use, since excessive ethanol
consumption has serious deleterious effects on health (WHO, 2018).
From a food safety perspective, we have to consider chemical hazards,
different from microbiological hazards in a number of aspects, among
them and most relevant, their inability to be removed by technological
treatments.
Climate plays a substantial role in the selection of viticultural and
enological practices to obtain wine of quality, typicity and safety
standards. Wine is quite safe under the microbiological point of view
since it is free from pathological microorganisms due to the high con-
tent in ethanol (ca. 9–14%) in which most pathogenic bacteria cannot
survive. Regarding chemical hazards, they are very dependent on en-
vironmental conditions, such as climate change. They can be grouped
according to their origin in three classes, as follows, i) those that are
incorporated into the grape as a result of agricultural practices, en-
vironmental conditions or fungal contamination and growth ie., heavy
metals, pesticides or mycotoxins, ii) chemical hazards of micro-
biological origin, ie ethyl carbamate and biogenic amines that are the
product of microbiological activity of yeast and bacteria during fer-
mentation and iii) ingredients used as part of the winemaking process
and that might present a risk to certain sensitive consumers, such as
sulfur dioxide and protein fining material (Marangon, Vincenzi, &
Curioni, 2019). At the same time climate change is behind new issues
related to the increase of alcohol content in wines and residual plant
protection products on mature grapes that can affect fermentation and
consumer’s health. Recently, it has been reported that environmental
contamination can lead to the presence of toxic compounds such as
acrolein and furfural in grapes and in the respective wines (Ferreira
et al., 2018). Hence, there is an array of emerging chemical hazards that
should be controlled to minimize the risks associated with wine con-
sumption. This article aims to review the state of the art of classical and
emerging chemical hazards in wine including toxicological considera-
tions and mitigation strategies.
2. Climate change and impact in grape development and wine
production
Climate change is a real current problem carrying dire consequences
in multiple areas. A recent report from the Intergovernmental Panel on
Climate Change (IPCC) shows that from the pre-industrial period
(1850–1900) the surface mean temperature has risen continuously,

⁎
Corresponding author.
E-mail address: amtroncoso@us.es (A.M. Troncoso).

https://doi.org/10.1016/j.foodchem.2020.126222
Received 5 December 2019; Received in revised form 10 January 2020; Accepted 13 January 2020
Available online 16 January 2020
0308-8146/ © 2020 Elsevier Ltd. All rights reserved.
C. Ubeda, et al. Food Chemistry 314 (2020) 126222

Fig. 1. Land Surface Air Temperature from 1850 to 2018. (Data from: https://data.giss.nasa.gov).

reaching approximately 1 °C above the pre-industrial levels in 2017

(mean increase of 0.2 °C per decade) due to past and current emissions
derived from human activity (IPCC, 2018) (Fig. 1). Agricultural sector
has been one of the most affected by this temperature increase. It is
estimated that the world agricultural yield will be reduced a 6.9% in
2050 because of climate change (Wiebe et al., 2015). This situation has
been caused by an expanded frequency, intensity and duration of heat-
related events such as droughts, heat waves and changes in rainfalls
which are becoming more frequent and extreme (Meehl et al., 2007),
leading to both desertification and field flooding.
Wine production, dependent on the grape, has been substantially
affected by climate change since this fruit is one of the most sensitive
crops to little changes on climatic conditions. In fact, changes on cli-
mate patterns have greater impact on vine development and fruit
composition than the grapevine variety itself or even soil characteristics
(van Leeuwen et al., 2004). Noteworthy there are three variables
strongly related to the wine grape quality, namely, water status, solar
radiation and temperature (van Leeuwen & Darriet, 2016). Overall,
temperature increases lead to juices with a higher sugar content and pH
and lower acidity (Iland, Dry, Proffitt, & Tyerman, 2011) (Fig. 2).
The increase in temperatures has resulted in advanced harvests date
in most of the wine producing countries (De Orduña, 2010, Fig. 2).
Nevertheless, cold climates have taken advantage of this temperature
increases representing an opportunity to expand. Conversely, undesired
consequences would appear in warm wine producing regions, esti-
mating that the production of some current wine styles would be
challenging if not impracticable (Jones, White, Cooper, & Storchmann,
2005).
One of the main consequences of temperature increase is that it can
advance the veraison (Parker, García de Cortzar Atauri, van Leeuwen, &
Chuine, 2011), the onset of ripening, in which the change on berry’s
color as well as the beginning of sugars’ accumulation occurs. Over the
last years, aroma and polyphenolic maturity are also considered in
addition to the traditional measurement of technological variables
(sugar, acidity), leading to longer hang times (De Orduña, 2010). This
represents a huge challenge for the oenologist because sugar accumu-
lation and the formation of important quality minor compounds such as
phenolics and volatile compounds are decoupled (Pons et al., 2017;
Sadras & Moran, 2012) resulting in unbalanced grapes (Fig. 2).
Therefore, this quick berry development means that the oenologist has
to choose either late harvest, giving rise to high alcoholic degree and
bitter wines; or early harvest, resulting in wines with low color density
and poor aroma intensity and complexity, being both rejected by the
consumer. High alcohol degree represents a problem for the consumer Fig. 2. Evolution of primary and secondary metabolites through ripeness. a)
acceptability and for a good management of the fermentation, because Grape harvest at ideal berry maturity with ideal sugar to acid ratio and sec-
high alcohol concentrations are toxic to the yeast and could produce a ondary metabolites development. b) Decoupling of sugar and phenolic and
aromatic accumulation due to high temperatures.
fermentation stop. The above-mentioned negative consequences are
mainly related with the organoleptic and quality properties of wine.

2
C. Ubeda, et al.
However, another major concern is the potential implication that this
steady increase changes in alcohol degree of quality wines, observed
during the last 20 years, could have on consumer s health. Harmful
consumption of alcohol has been highlighted by the World Health Or-
ganization (WHO) as having a significant impact on human health with
a 5.9% of total world deaths and diseases (WHO, 2014). However, the
reduction of alcohol in wine is difficult due to legal restrictions that
only allow the addition of water for the preparations of enzymes and
yeast and not for the dilution of sugar content of the grape must (OIV,
2019). Therefore, alternative techniques are being developed to achieve
the reduction of the alcoholic content such osmosis, nano-filtration
techniques (Schmidtke, Blackman, & Agboola, 2012) or the selection of
yeast that metabolize sugar in glycerol, pyruvic acid and other meta-
bolites in addition to alcohol (Ciani et al., 2016; López-Malo, Chiva,
Rozes, & Guillamon, 2013).
Joined to the increase in alcohol concentration in wines, the in-
crease of ambient temperature also increases pH. Noteworthy, malic
acid content decrease with higher temperatures, and lower acidity is
usually correlated with higher grape pH. This pH increase is proble-
matic since it may favor microbial growth in grapes, fungal con-
tamination and therefore the production of toxins such as ochratoxin A,
present in raw material and consequently in wine and, also, the pro-
liferation of spoilage non-pathogenic yeast strains such as
Brettanomyces. To avoid this situation, it is usual to increment the ad-
dition of antimicrobial treatment to the plant and preservatives to the
wine. Finally, it is important to point that the amount of nitrogenous
compounds increases during ripening (Garde-Cerdán et al., 2009);
therefore, these overripened grapes are expected to present high N
quantities. This could be a potential technological problem because it
would imply higher quantity of fining agent added against unstable
proteins, as well as a health-related problem increasing potential to
form biogenic amines (Ancín-Azpilicueta, Gonzalez-Marco, & Jimenez-
Moreno, 2008).
As regards food safety issues, there are many pathways through
which climate-related factors may impact, not only those related with
changes in temperature and rain patterns, but also with changes in the
transport pathways of complex contaminants (Herrera, Anadón, Iqbal,
Bailly, & Ariño, 2016).
In conclusion, climate change consequences open a new challenging
research field trying to counteract these effects on grapes.
3. Chemical hazards of microbiological origin
3.1. Grape origin
An overripened grape has some risks associated due to higher pH,
lower acidity and higher sugar concentration than expected, thus pro-
moting the development of undesirable microbial growth. Moreover, it
must be taken into account that a late harvest date, in order to favor the
synthesis of secondary metabolites, increases the probability of occa-
sional unexpected rains at the last ripening stages. Thus, the vineyard
humidity may favor fungal proliferation. This is a huge issue because
certain species of fungi produce secondary metabolites named myco-
toxins (Paterson & Lima, 2010), many of them of interest in human
health due to their toxicity. The most important reported mycotoxins in
grape and/or wine are Patulin (PAT), Ochratoxin A (OTA)), Aflatoxin
B1 (AFB1), Alternariol (AOH) and Fumonisin B2 (FB2). All of them
have been found in wines, except for Patulin (Table 1), being Ochra-
toxin A, the most predominant mycotoxin in grapes. Once they are
produced on grapes as a consequence of fungus development they are
transferred to wines, being in general very stable. Many works have
addressed factors influencing OTA presence in wine, but few studies
have been developed on AF, PAT, AOH, and FB2 (Paterson, Venâncio,
Lima, Guilloux-Bénatier, & Rousseaux, 2018).
PAT is produced most notably by the fruit-rotting fungus, Penicillium
expansum and induces gastrointestinal disorders including ulceration,
3
Food Chemistry 314 (2020) 126222
distension and bleeding, congestion and edema of pulmonary, hepatic
and gastrointestinal blood vessels and tissues (Puel, Galtier, & Oswald,
2010). Fortunately, PAT is degraded to some extent during the fer-
mentation process and it has not been detected in wine (Li, Chen,
Zhang, Zhang, & Peng, 2018).
AFB1 is an aflatoxin mainly produced by the fungus Aspergillus
flavus and Aspergillus parasiticus. Aflatoxins (AF) are the most important
mycotoxins with AFB1 being the most potent carcinogenic (hepato-
carcinogen) natural compound known (Paterson et al., 2018). There-
fore, the European Commission set the maximum level of AFB1 in foods
(mainly for groundnut, other oilseeds, tree nuts, dried fruit, rice and
maize) between 2 and 12 µg/kg depending on the food, with the ex-
ception of infant’s food where the maximum is 0.1 µg/kg (European
Commission, 2006). There is not a limit established for AF in wines,
being the studies on the content of AF in wines scarce. However, as can
be seen in Table 1, in the last decade surveys, Romanian wines exceed
pretty much the limits set in the above-mentioned Regulation. Although
currently OTA remains the most prevalent mycotoxin in grapes, inter-
estingly some studies have recently pointed that in some European
areas, AFB1 may eventually replace OTA as the main problem due to
climatic conditions, mainly higher temperatures, which directly affect
fungus development (Paterson & Lima, 2010).
Fumonisins are a group of mycotoxins that have been extensively
studied since they present cancer-promoting activity. Aspergillus niger,
which is involved in FB2 production and commonly found on grains,
has been also described on grape skins. Concretely, Fumonisin B2 (FB2)
has been seldom isolated from grapes and also in wines (Logrieco,
Ferracane, Visconti, & Ritieni, 2010; Mogensen, Larsen, & Nielsen,
2010).
OTA has been described in a number of food products, namely
cereals, vegetables, dried fruits, nuts, meats and, also, in grapes and
wine. It is considered that more than 90 kinds of foodstuffs of both plant
and animal origins, including milk, contribute to the OTA dietary ex-
posure. OTA is the most studied mycotoxin in grape products and pre-
sents the biggest concern since in a European assessment of the con-
tribution of each food commodity to its mean total dietary intake, wine
was identified as the second major source of intake, contributing with a
10% (Miraglia & Brera, 2002). This toxin is produced by the secondary
metabolism of certain fungal species, mainly Aspergillus spp, and is ne-
phrotoxic, genotoxic, teratogenic and carcinogenic for both animals and
humans (Da Rocha, Freire, Maia, Guedes, & Rondina, 2014). Therefore,
it was classified as possible human carcinogen (Group 2B) by the In-
ternational Agency for Research on Cancer (IARC, 1993), however, very
recently OTA has been reclassified as probably carcinogenic to humans
(Group 2A) due to new information regarding genotoxicity of OTA
(formation of OTA DNA adducts), its role in oxidative stress, and the
identification of epigenetic factors. The European Union has established
legal concentration limits in wine (2 µg/Kg) (European Commission,
2006). As can be observed in Table 1, OTA content in wine surveys from
China, Italy, Argentina and Turkey exceed this concentration limit.
A major producer of OTA is Aspergillus section Nigri Aspergillus car-
bonarius. Several studies made in Spain, France, Italy or Portugal about
the occurrence of OTA, point out that the higher producer of this my-
cotoxin is Aspergillus carbonarius but the most isolated is A. niger (Bellí
et al., 2006). OTA was at first found in wines of different countries and
afterwards it was determined in grapes (Bellí et al., 2006). Climate
change is acknowledged as determinant for the OTA occurrence in
grapes (Paterson et al., 2018) together with location and plant health
conditions. Weather, period of harvest, biotic factors, agricultural and
harvesting practices or the type of wine may also impact the final
concentration (Gil-Serna, Vázquez, González-Jaén, & Patiño, 2018).
Noteworthy, winemaking practices such as maceration, can increase
OTA content in the wines (Anli & Bayram, 2009) and consequently is
mostly found in red wines followed by rosé and white wines.
There are control strategies that have been proved to be useful to
avoid the growth of OTA producers fungus on grapes. They can be
C. Ubeda, et al. Food Chemistry 314 (2020) 126222

Table 1
Last decade wine surveys of presence of mycotoxins in wines. Ochratoxin A (OTA), Aflatoxin B1 (AFB1) and B2 (AFB2), Alternariol (AOH), Fumonisin B2 (FB2). nd:
non detected.
Mycotoxin Wine n Location [Range] (µg/L) Reference

OTA
Red wine 20 Turkey 0.39–7.96 Altiokka, Can, Atkoşar, & Aboul-Enein, 2009
White wine 5 0.25–1.80
Red wine 47 Argentina 0.02–4.82 Ponsone et al., 2010
Red wine 1002 Italy 0.580–2.360 Spadaro, Lorè, Garibaldi, & Gullino, 2010
White wine 204 0.056–1.360
Jerez wine 40 Spain 0.039–0.642 Murillo-Arbizu, Amézqueta, González-Peñas, & López de
Cerain, 2010
Red wine 78 Greece 0.07–2.00 Labrinea, Natskoulis, Spiropoulos, Magan, & Tassou, 2011
Red wine 88 Brazil 0.80–0.84 Teixeira et al., 2011
Red wine 97 Spain 0.004–0.179 Quintela,Villarán, de Armentia, & Elejalde, 2011
Red wine 16 Brazil 0.03–0.62 Terra, Prado, Pereira, Ematné, & Batista, 2013
White wine 7 nd-0.03
Red wine 14 France 0.010–0.237 Quintela, Villarán, de Armentia, & Elejalde, 2012
8 Italy 0.050–0.353
6 Australia 0.033–0.072
2 Spain 0.064–0.138
Red wines 30 Portugal 0.41–0.45 Fernandes, Barros, & Câmara, 2013
Red wine 77 China 0.03–5.65 Zhang, Chen, Li, Zhu, & Ma, 2013
White wine 34 0.03–0.07
Red wine 18 Tunissia 0.09–0.94 Lasram, Oueslati, Chebil, Mliki, & Ghorbel, 2013
White wine 7 0.11–1.5
Red wine 183 China nd-0.20 Zhong et al., 2014
White wine 40 nd-0.36
Sweet wine 30 Italy 0.021–1.560 Di Stefano et al., 2015
Red wine 31 EEUU 0.3–2.1 De Jesús et al., 2018
White wine 10 0.6–8.6
AFB2
Red wine 24 Spain 1.25–13.43 Pérez-Ortega, Gilbert-López, García-Reyes, Ramos-Martos, &
Molina-Díaz, 2012
Sweet wines 30 Italy 0.013–0.016 Di Stefano et al., 2015
AFB1
Sweet wines/dessert 30 Italy 0.017–0.035 Di Stefano et al., 2015
wines
Mixed 20 Romania 12.12–33.68 Nistor, Cotan, Cotea, & Niculaua, 2019
AOH
Red wine 6 – 1.2–4.9 Asam, Konitzer, & Rychlik, 2011
Red/white wines 14 Argentina 13–18 Broggi et al., 2013
Red Wine 5 Retail stores Netherlands 2–11 López et al., 2016
Red wine 14 German stores 1.68–7.65 Zwickel, Klaffke, Richards, & Rychlik, 2016
White wine 11 0.65–1.19
FB2
Red wine 45 Italy 0.5–2.4 Logrieco et al., 2010
Mixed 77 Countries mix (Portugal, Spain, China, Italy, 1–20 Mogensen et al., 2010
France, South Africa…)

applied during pre-harvest (field management, use of biological and
chemical materials), harvest and post-harvest (improving drying and
storage conditions) (Amézqueta, González-Peñas, Murillo-Arbizu, & de
Cerain, 2009). Hence, at the vineyard the most applied are: efficient
branch aeration, avoid growing close to the soil, visual inspections of
grapes, storing grapes for less than 8 h, use of fungicides, and during
winemaking: removal of moldy grapes or bunches.
As mentioned above, OTA content in grapes and wines varies ac-
cording to the harvest geographical area. European and African con-
tinents are the most affected, this fact reflected in a survey performed to
asses OTA contamination in European wines (Italy, Spain, Greece,
Hungary, Croatia) in which it was found in 60–80% samples, although
the values were strongly variable (from 0.007 to 2.79 ng/mL) (Bellver
Soto, Fernández-Franzón, Ruiz, & Juan-García, 2014). Moreover, a re-
cent study grouped several works determining OTA in wines employing
appropriate sampling and analytical methods and concluded that only
the 1.2% of the samples analyzed were above legal limits set by the
European Union and some other countries (usually 2 µg/L) (Gil-Serna
et al., 2018). As regards climate change, the effects of high temperature
were associated with higher OTA content in wines from Italy and Spain
with levels above 2 μg/L in a 10% of the samples (De Jesús, Bartley,
Welch, & Berry, 2018). Previously, Soleas, Yan, and Goldberg (2001)
observed a correlation between temperature and the occurrence of OTA
in grapes and wines, concluding that wines from southern European
countries presented higher quantities of OTA than the wines of the
northern European countries.
At the winery there is the possibility of decontamination by yeast-
binding, filtration, addition of fining agents (activated charcoal, ben-
tonite, chitin, egg albumin, gelatine, oakwood pieces, caseinate) or
bioremediation, all of them with limited results (Quintela, Villarán, de
Armentia, & Elejalde, 2013).
Lastly, the development of analytical methodologies for the de-
termination of the multi-mycotoxin occurrence in wines is so far lim-
ited. Recently developed analytical methods make profit of the use of
liquid chromatography tandem mass spectrometry for the identification
and quantification of OTA and other mycotoxins in wine (Dias et al.,
2019). However, a deeper insight on the actual presence of the cocktail
of mycotoxins in wines from different geographical areas is needed.
3.2. Fermentation origin
It is unusual to find pathogenic microorganism in wines, because
this matrix contains components with antimicrobial properties which
prevent the growth of pathogens. This is mainly the case of ethanol

4
C. Ubeda, et al.
(7–24%), but also tartaric and malic acids, high polyphenol content,
low redox potential and the addition of sulfites. As a result, wine is
being recognized as a microbiologically low risk food. Therefore, risk
may come from nonpathogenic microorganisms whose metabolism re-
lease certain toxic products.
Ethyl carbamate (EC), also named urethane, is a probable human
carcinogen compound classified by the International Agency for
Research on Cancer (IARC) as a possible human carcinogen (Group 2B)
in 1974 and upgraded to a probable human carcinogen (Group 2A) in
2007 (IARC, 2007). It is formed during alcoholic fermentation and
storage by a spontaneous chemical reaction of ethanol with carbamyl
compounds, mostly urea, released by yeast metabolism, but also ci-
trulline, released by lactic acid bacteria, and carbamyl phosphate). Urea
and citrulline are in part derived from the yeast metabolism of arginine
(De Orduña, Liu, Patchett, & Pilone, 2000), a major amino acid in
grapes. Therefore, grape varieties with higher content in this amino
acid or submitted to extensive fertilization with nitrogen compounds
are expected to have more potential to develop ethyl carbamate. As
mentioned in the second section of this review, climate change some-
times forces the winemaker to harvest on an advanced date when flavor
development is not achieved; therefore, the addition of nitrogen-based
fertilizers leads to a better volatile compounds formation in the grape
(Gutiérrez-Gamboa, Garde-Cerdán, Carrasco-Quiroz, Martínez-Gil, &
Moreno-Simunovic, 2018). But this fertilization increases amino acid
content in the berry, specially arginine, leading to a high probability of
ethyl carbamate formation in the resulting wines. EC content in wines is
usually controlled and limited but there are no homogenization max-
imum levels worldwide. In Canada and Czech Republic, the limits range
from 30 μg/L for wines to 400 μg/L for fruit brandies and USA has
voluntary targets for wines from 15 to 60 μg/L. In relation to the pre-
sence of ethyl carbamate in stone fruits spirits and marc spirits, the
European Union recommended to take mitigation measures reducing
the levels as much as possible to achieve the level of 1 mg/L. However,
it is unusual to exceed these quantities because strategies to degrade
and prevent the formation of ethyl carbamate are well known. These
include good pre-harvest management, the selection of ethyl carbamate
low producers yeast strains, and lactic acid bacteria, control of tem-
perature increases during fermentation and during storage, addition of
degrading enzymes such as urease, among others (Gowd, Su, Karlovsky,
& Chen, 2018). It can be said that EC is not currently an issue within
wine safety, but emphasis should be made on potential EC formation
over time if urea is present, especially in aged wines. Moreover, the
risks associated to lung cancer development and long-term exposure at
low levels through alcoholic beverages should be considered in depth
(Gowd et al., 2018).
Currently, the main concerning chemicals hazards produced by
microorganisms during winemaking are biogenic amines (BA). BA are
low molecular weight organic bases, formed in fermented food and
beverages by some strains of lactic acid bacteria. They are then the
product of microbial catabolism under stress conditions and their for-
mation involves decarboxylation of amino acids. Biogenic amines pre-
sent biological activity and have many physiological functions such as
regulation of body temperature, stomach pH, and brain activity (Anli &
Bayram, 2009), but when they are consumed in large quantities nega-
tive effects may appear, especially in sensitive individuals. Fermented
foods contain BA in different concentrations depending on several
factors, among them the nature of the raw material, the microbial po-
pulation and the environmental conditions. In general, the main BA
found in wine are histamine, tyramine and putrescine, whose pre-
cursors are the amino acids histidine, tyrosine and ornithine, respec-
tively (Anli & Bayram, 2009). They are mainly produced during mal-
olactic fermentation (MLF) in wine (Landete, Ferrer, Polo, & Pardo,
2005). One of the most studied BA is histamine, which can cause poi-
soning at high levels, with symptoms such as low blood pressure, skin
irritation, headaches, edemas, and rashes typical of allergic reactions.
Other BA such as putrescine and cadaverine may also have toxic effects
5
Food Chemistry 314 (2020) 126222
but with lower activity, however, the coexistence of these BA with
histamine enhances the toxicological effects of the last one, preventing
detoxification of the system (Halász, Barath, Simon-Sarkadi, &
Holzapfel, 1994). Another BA commonly found in fermented foods is
tyramine, whose ingestion may trigger several symptoms such as mi-
graines, headaches and, contrary to the histamine poisoning symptoms,
increased blood pressure, since it favors the release of noradrenaline
(Pegg, 2013). Putrescine can also potentiate the effects of histamine,
and by itself produces hypotension, bradycardia, lockjaw and paresis of
the extremities, as well as acting as tumor promoter, being correlated
with cancer events (Spano et al., 2010). Apart from the toxicological
effects of these BA, it is important to consider that there are individual
sensibilities and also some factors that alter their detoxification me-
chanisms, taking into account that they are degraded in the intestinal
lumen by amino oxidases (Russo et al., 2016). On the other hand,
human gut microbiota could have effects on the pathogenesis of his-
tamine intolerance, explaining the different sensitivity among patients
(Schink et al., 2018). Hence, patients treated with antidepressant drugs
named inhibitors of mono and diamino oxidases (MAOI/DAOI) may
present adverse effects. For these people, the ingestion of a lower dose
of tyramine has much more effect than for a regular person and can get
poisoned with lower amounts of this BA. Also, the simultaneous in-
gestion of BA with alcohol, or the ingestion in the case of im-
munodeficient patients or with some gastrointestinal disorder may
enhance toxicity (Halász et al., 1994). It must be said that every person
has different sensitivity to BA because of their different capacity for
detoxification, which makes the establishment of maximum limits in
foods a difficult task (EFSA, 2011a). In any case, around 1% of the
population has histamine intolerance (Lefèvre, Astier, & Kanny, 2017).
Therefore, the European Food Safety Authority (EFSA) has performed a
qualitative risk assessment on the presence of biogenic amines in fer-
mented products, stating that histamine and tyramine are the most
relevant and toxic, being fermented food of particular concern due to
the potential BA formation (EFSA, 2011a). The panel found no adverse
health effects after exposure to 50 mg histamine for healthy individuals,
but below detectable limits for those with histamine intolerance.
However, different countries have established upper limits of histamine
in wine: 2 mg/L in Germany, 5 mg/L in Finland, 10 mg/L in Australia
and Switzerland, 8 mg/L in France, 3.5 mg/L in Netherlands and 6 mg/
L in Belgium (Smit, Du Toit, & Du Toit, 2008). Consequently, it seems
reasonable to consider a critical limit of 2 mg/L for industries in order
to avoid rejections.
BA are products from the decarboxylation of amino acids of lactic
acid bacteria as a protective mechanism against unfavorable environ-
mental conditions, among them acidic media. This process may take
place during the production of wine, beer, cheese, sausage, fermented
vegetables and vinegar. BA content in wines are reported in a range of
concentrations from a few milligrams per liter up to about 50 mg L−1
depending on the type of wine (red > white) and the quality of the
beverage (Table 2). Table 2 shows BA contents in commercial wines
reported in the literature during the last decade. As can be seen, pu-
trescine remains the main BA in wines and at the same time histamine
values are in many cases above the proposed limits (from 2 to 10 mg/L),
especially for southern countries wines. Interestingly, if a limit of 2 mg/
L is proposed at the EU level a significant portion of European wines
would be out of the legislation (Filipe-Ribeiro et al., 2019).
Only some lactic acid bacteria are able to produce biogenic amines,
being Pediococcus, Lactobacillus, Leuconostoc and Oenococcus spp. the
main genera species implicated in their presence in wine. Oenococcus
oeni, is considered the main responsible of MLF, and although it has the
ability of generating histamine, it is not considered a major producer of
BA. The main BA producers are species that usually do not perform
MLF, but instead spoil the wine and indicate poor winemaking and bad
sanitization practices (Costantini, Vaudano, Pulcini, Carafa, & Garcia-
Moruno, 2019). The formation of biogenic amines depends on three
main factors: availability of free amino acids, presence of
C. Ubeda, et al. Food Chemistry 314 (2020) 126222

Table 2
Last decade surveys on the content of the main biogenic amines present in the wine: Histamine (HIS), Putrescine (PUT) and Tyramine (TYR) after malolactic
fermentation. nd: non detected.
Wine n Location [Range] (mg/L) Biogenic amine Reference

Red wine 7 Italy 0.54–1.82 PUT Del Prete, Costantini, Cecchini, Morassut, & Garcia-Moruno, 2009
0.97 TYR
Red wine 9 Spain 0.05–33 HIS Peña-Gallego, Hernández-Orte, Cacho, & Ferreira., 2009
4.96–35 PUT
0.25–2.53 TYR
Red wine 76 Australia nd-14.5 HIS Bartowsky & Stockley, 2011
1.73–43.37 PUT
nd-5.93 TYR
White wine 24 nd-4.31 HIS
0.83–12.25 PUT
nd-5.65 TYR
Red wine 73 Italy 0.22–7.62 HIS Galgano, Caruso, Perretti, & Favati, 2011
2.23–13.50 PUT
1.14–6.37 TYR
Red wine 100 Austria 0.52–27 HIS Konakovsky et al., 2011
2.93–122 PUT
1.07–10.7 TYR
Red wine 84 France 0.5–14.05 HIS Bach, Le Quere, Vuchot, Grinbaum, & Barnavon, 2012
3.71–48.72 PUT
0.1–12.35 TYR
Red wine 8 Italy 1.01–19.46 HIS Patrignani et al., 2012
1.39–13.38 PUT
2.89–14.27 TYR
Red wine 27 Chile 1.14–10.49 HIS Pineda, Carrasco, Peña-Farfal, Henríquez-Aedo, & Aranda, 2012
7.97–25.97 PUT
2.03–6.38 TYR
Red wine 6 France 1.3–9.4 HIS Romano et al., 2012
Red wine 17 EU Mix 2.2–16.2 HIS Comuzzo Rauhut, Werner, Lagazio, & Zironi, 2013
7.1–19.0 PUT
0.5–37.3 TYR
Red wine 36 Spain 0.06–6.2 HIS Martínez-Pinilla, Guadalupe, Hernández, & Ayestarán, 2013
2.4–25 PUT
0.10–1.4 TYR
Red wine 30 Italy nd-10.8 HIS Martuscelli, Arfelli, Manetta, & Suzzi, 2013
2.4–31.8 PUT
nd-18.8 TYR
White wine 19 0–3.4 HIS
0.8–12.8 PUT
0–6.8 TYR
Mixed 47 Poland 10.09–1639 HIS Papageorgiou, Lambropoulou, Morrison, Namieśnik, & Płotka-Wasylka, 2018
37–1148 PUT
10.21–432 TYR

decarboxylase-positive microorganisms and conditions that allow bac-
terial growth and decarboxylase synthesis and activity (Goñi &
Azpilicueta, 2001). Histamine, tyramine and putrescine are thermo-
stable and are not inactivated by thermal treatments employed in the
food industry, therefore, preventing their presence in the foods is a key
commitment. The final quantity of BA in wine is determined by dif-
ferent factors from the vineyard to the winery storage. Nitrogenous
fertilization, climatic conditions during growth, grape variety, geo-
graphic location or level of maturation are parameters that may cause
changes in the amino acids and therefore in the subsequent amount of
BA (Herbert, Cabrita, Ratola, Laureano, & Alves, 2005). On the other
hand, some factors referred to alcoholic and malolactic fermentations,
high pH, temperature of 22–24 °C, and low sulphur dioxide (SO2)
concentration may also affect the concentration of biogenic amines
(Landete et al., 2005). Additionally, some winemaking practices such as
clarification, crushing or duration of maceration process may increase
the concentration of amino acids and therefore the BA production
(Herbert et al., 2005). Another critical point is ageing, because after this
period the concentrations of BA usually increase (Landete et al., 2005),
specially for histamine and putrescine (Smit, du Toit, Stander, & du
Toit, 2013).
Although the prevention of BA formation is a key point, micro-
biological strategies are currently being developed to prevent or elim-
inate amines once they are already in the fermentation media (Berbegal
et al., 2019). In wine, it has been proved that two strains of Lactobacillus
plantarum as well as some fungi isolated from the vineyard can degrade
tyramine and putrescine (Cueva et al., 2012). Recently, the selection of
specific lactic acid bacteria starters lacking the pathways for BA accu-
mulation have been proposed to carry out the MLF (Barbieri,
Montanari, Gardini, & Tabanelli, 2019).
Concerning the BA content and the effects of climate change, the
excessive fertilization that is applied today in the vineyard to achieve
the flavor development required is causing variations in the amino
acids and increasing the BA concentration in musts (Smit et al., 2013).
Also, the delayed harvest give rise to musts from overripened grapes
with higher contents of nitrogenous compounds that could potentially
increase the production of these compounds by lactic acid bacteria
(Ancín-Azpilicueta et al., 2008; Garde-Cerdán et al., 2009). Finally, the
current tendency to produce lower sulfur wines is increasing the
quantities found of BA in them because lactic acid bacteria producing
BA have more opportunity to grow.
4. Chemical hazards derived from the winemaking process: Food
ingredients
Along the winemaking process, a limited number of food ingredients
such as certain additives and processing aids are employed depending
on many factors, among them the characteristics of the year harvest.

6
C. Ubeda, et al.
The International Organisation of Vine and Wine collects all the ap-
proved oenological practices and treatments, including authorized food
ingredients (OIV, 2019). Among them, different proteins are very useful
for a wide range of purposes since they have a huge variety of chemical
and physical properties. They are employed mainly as clarifying/sta-
bilizing/fining agents. The clarification of a wine is a very important
stabilization step on winemaking, since the addition of fining agents to
the must removes particles and molecules capable of haze formation
and turbidity, usually not soluble proteins and polymeric phenols. The
most commonly employed fining agents are proteins of animal origin,
plant proteins, and inorganic compounds, being the most used egg and
milk proteins: albumin and calcium caseinate, respectively (Peñas, Di
Lorenzo, Uberti, & Restani, 2015). However, the negative effects that
these proteins can cause in a certain segment of the population due to
allergic reactions in susceptible individuals is a real concern and their
use in winemaking is seldom questioned (Stockley & Johnson, 2015).
Quite a number of studies reveal that residual quantities of these pro-
teins remain in the wine (milk and egg white allergens) and may trigger
a reaction on allergic consumers (Tolin, Pasini, Simonato, Mainente, &
Arrigoni, 2012; Weber, Steinhart, & Paschke, 2007), whilst few studies
(Jaeckels et al., 2015; Vassilopoulou et al., 2011) attribute the allergic
effects to intrinsic wine proteins. Nevertheless, the European Union
implemented a regulation to protect the consumers, providing complete
and comprehensive information on the labeling of all fining treatments
based on milk, milk-based or egg, and egg-based products used in grape
must and wine (European Commission, 2012). Regarding the doses
employed, the OIV allows casein, casein blended with potassium car-
bonate or bicarbonate and potassium caseinate from 50 to 500 mg/L for
white wine and for red wine from 50 to 250 mg/L, plus egg derived
products from 30 to 150 mg/L, respectively (OIV, 2014).
Climatic change may also influence the employment of fining agents
since, as mentioned above, the increase of the temperatures is delaying
the date of harvest to ensure the secondary metabolites. This situation
gives rise to grapes with higher concentration in nitrogenous com-
pounds (Garde-Cerdán et al., 2009). This higher concentration in the
overripened grapes makes necessary a higher addition of fining agents/
clarifiers in the must to ensure a proper stabilization. Because of health
concerns, substantial efforts are being directed to the use of alternative
fining agents of plant origins with interesting results (Marangon et al.,
2019). Thus, extracts from Saccharomyces cerevisiae yeast, gluten from
wheat and maize zeins showed good results as fining agents in wine by
themselves and better when combined with bentonite. However, these
alternatives are not commonly employed.
Lysozyme is a hen egg protein commonly added as antimicrobial
additive since it is a potent inhibitor of Gram-positive bacteria, mainly
lactic acid bacteria (Bartowsky, Costello, Villa, & Henschke, 2004). The
addition of lysozyme reduces the needed dose of sulfites, which are the
most widely employed antimicrobial agents in winemaking, but with
demonstrated negative health effects as it will be discussed below. Since
it is an additive it remains in wine although certain fining agents such
as bentonite and metatartaric acid can substantially reduce its con-
centration (Peñas et al., 2015). However, it is acknowledged as an al-
lergenic egg protein and little is known about the effects of its presence
in wine in allergic patients. Despite no specific allergic episodes after
the ingestion of wine containing lysozyme have been described, Weber
et al. (2007) detected the presence of lysozyme in wine by means of
ELISA, warning that allergic reactions against treated wines could not
be excluded. More recently, the European Food Safety Authority (EFSA)
has released a scientific opinion concluding that wines treated with
lysozyme may trigger adverse allergic reactions in susceptible in-
dividuals under the conditions of proposed use (EFSA, 2011b), and as a
consequence, its exemption from labeling is not recommended.
To counteract the potential impact of climatic change, it is usual the
addition of bigger doses of fining agents and preservatives hence
avoiding unwanted microorganism proliferation and subsequent wine
spoilage. The microbiological stability of wines is accomplished mainly
7
Food Chemistry 314 (2020) 126222
by means of SO2, which seems crucial in winemaking due to its good
antimicrobial and antioxidant capacities. It inhibits bacterial growth,
prevents yeast haze formation, undesirable secondary fermentation,
Brettanomyces growth and the development of mycodermic yeasts and
acetic acid bacteria. Bacteria are the most sulfite sensitive micro-
organisms followed by non-Saccharomyces yeasts and Saccharomyces
yeasts (Ribéreau-Gayon, Glories, Maujean, & Dubourdieu, 2006). At the
same time, it exhibits a potent antioxidant activity preventing enzy-
matic (polyphenol oxidase activity) and chemical browning (Santos,
Nunes, Saraiva, & Coimbra, 2012). Moreover, it helps to extract mi-
nerals, organic acids and phenols and it may enhance flavor and color
as well (Guerrero & Cantos-Villar, 2015). Unfortunately, it has health
disadvantages for sensitive individuals and its ingestion may provoke
dermatologic, respiratory, or gastrointestinal signs and symptoms or
severe consequences in asthmatics such as bronchoconstriction. Around
1% of the population are estimated to be “sulfite-sensitive” individuals
(Vally & Thompson, 2003). Therefore, sulfites addition is usually per-
mitted at levels from 150 to 400 mg/L of total SO2 depending on the
type of wine and its content in reducing matter (Pozo-Bayón, Monagas,
Bartolomé, & Moreno-Arribas, 2012). The European Union legislation
sets the limit of total SO2 concentration up to 150 mg/L in red wines
and 200 mg/L in white and rosé wines containing a maximum of 5 g/L
of reducing sugars (European Commission, 2009). Also, the European
Commission established mandatory labeling in products containing
sulfur dioxide and sulfites at concentrations higher than 10 mg kg−1 or
10 mg L–1 (European Commission, 2011), which is the threshold con-
centration able to provoke an adverse reaction in sensitive individuals
(Stockley & Johnson, 2015). Sensitivity reactions, which are mostly
intolerance reactions not immune-mediated, are observed when sulfites
are used as food additives, with wine remaining the main contributor to
the exposure in adults and elderly (EFSA, 2016).
Sulfites have a complex equilibrium in wine and are usually added
in the form of sodium and potassium salts; the active form is molecular
sulphur dioxide whose proportion increases at lower pH levels,
meaning that sulfites are more effective in controlling spoilage in acidic
media (Zoecklein, Fugelsang, Gump, & Nury, 1995). As regards the
influence of climatic change on sulfite addition, an overripened grape
has a higher pH and therefore the amount needed for ensuring wine
stability would be higher, with the corresponding negative effects on
health. Moreover, a substantial portion of added sulfite remains
bounded to different compounds in wine, not being effective as anti-
oxidant or antimicrobial but active as hazard for sensitive population.
Lastly, even though the number of sulfite sensitive individuals is
small, risk perception is high among population and the tendency is to
lower its concentrations in wine. Due to the legal above-mentioned
restrictions and people awareness, the search of alternatives to sulfites
in wine is a hot topic (Lisanti, Blaiotta, Nioi, & Moio, 2019). The search
for valid alternatives is a real challenge since not only microbiological
issues but also protection against oxidation and preserving organoleptic
properties have to be taken into account. There are, so far, a number of
useful chemical alternatives which aim the microbiological stabiliza-
tion, being permitted by the European Union and OIV, such as dimethyl
decarbonate, lysozyme, and sorbic acid, and others with applications
apart from microbiological stabilization, such as phenolic compounds,
chitosan and β-glucanases, that could replace sulfites, all of them not
free of limitations.
Lysozyme, as previously mentioned, is an antimicrobial employed
for the control of lactic acid bacteria during fermentation. However, the
main drawback is that color and phenolic compounds in general may
suffer a negative effect after its application (Bartowsky et al., 2004).
The maximum addition is limited by 500 mg/L in must, while in wine
the same dose must be intended as cumulative (also considering
treatment on must) (European Commission, 2009).
The maximum concentration of the antimicrobial agent dimethyl
dicarbonate (DMDC) added to wines is 200 mg/L; once in solution it is
quickly hydrolysed (into carbon dioxide and methanol) and may react
C. Ubeda, et al.
with different constituents of wine (EFSA, 2015). No detectable re-
sidues can be found in wines placed on the market (European
Commission, 2009). DMDC activity is mainly against yeast, being the
action against undesirable bacteria limited (Costa, Barata, Malfeito-
Ferreira, & Loureiro, 2008). It is important to point out that the action
of this compound in wine produces methanol, being necessary to con-
sider it in the final amount, since this alcohol has health implications,
and therefore, it has legal limits. The EFSA concluded that the exposure
to methanol coming from DMDC at the permitted levels does not con-
stitute a significant additional risk greater than the risk from the natural
occurrence in foods, although more information should be generated on
the nature and quantity of the reaction products resulting from inter-
action of DMDC with the components of beverages (EFSA, 2015).
On the other hand, there are other strategies such as the addition of
permitted substances such as phenolic compounds, chitosan and β-
glucanases that are widely employed as clarifiers during winemaking
and, also present antimicrobial activity (Silva et al., 2018).
The research on alternatives to substitute or more properly to de-
crease sulfite addition in wines is quite intensive and includes chemical
and physical alternatives (Lisanti et al., 2019), although many of them
are not authorized at the moment, since they have to be validated under
the point of view of efficacy, quality and safety. The chemical alter-
natives include the use of Ag nanoparticles (Monge & Moreno-Arribas,
2016), chitosan (Chinnici, Natali, & Riponi, 2014), or bacteriocines
(Rojo-Bezares, Sáenz, Zarazaga, Torres, & Ruiz-Larrea, 2007). All of
them present advantages and drawbacks mainly related with limited
efficacy in wine matrix and toxicity. Natural extracts as a feasible al-
ternative have also been tested such as oenological tannins (Sonni,
Chinnici, Natali, & Riponi, 2011), eucalyptus and almond extracts
(González-Rompinelli et al., 2013; Romano et al., 2012), among others
with limited results. Regarding phenolic compounds, known as potent
antioxidants, several studies have been conducted with hydroxytyrosol,
a compound naturally present in wines (Guerrero et al., 2016), and
more recently with grape stems extracts rich in stilbenes (trans-resver-
atrol and viniferin) with interesting antimicrobial and antioxidant
properties (Raposo et al., 2018).
Apart from the chemical alternatives, there are physical strategies
such as ultrasounds, pulsed electric fields, high pressure, microwave
that seem to be effective against several microorganisms but need fur-
ther validation at industrial scale (Lisanti et al., 2019).
5. Conclusions
Food production in general and wine in particular will likely change
in the future due to different reasons, among them the climatic factor. It
is acknowledged that climate change may compromise the sustainable
production of wines in different geographical regions specially im-
pacting wine quality and tipicity (Berbegal et al., 2019) as well as
safety. The main consequences can be summarized as follows: pro-
liferation of undesired microorganisms, high alcohol content due to
high sugar concentration in grapes, high pH and low acidity, pro-
liferation of new mycotoxins and increase in biogenic amines content.
At the same time, musts and wines are treated with increasing quan-
tities of certain ingredients related with health problems in sensitive
individuals, such as animal proteins or sulfites.
Nevertheless, wine is still considered a low risk product, absent from
microbiological risks due to its ethanol content although a number of
limited chemical risks associated with its consumption are present.
Since chemical safety of foods (toxins, contaminants, residues) is
largely dependent on where they are produced and the environmental
conditions (Herrera et al., 2016), changes in the prevalent mycotoxins
in grapes can be predicted. Toxic mycotoxins such as aflatoxins may be
present at higher temperatures and this situation needs to be addressed
(Paterson et al., 2018).
It is worth to mention the work performed by risk assessment
agencies, such as EFSA, to propose a standardized and harmonious
8
Food Chemistry 314 (2020) 126222
framework for their continuous monitoring and evaluation (Russo
et al., 2016). Finally, biogenic amines production and sulfites addition
should be minimized in order to protect sensitive consumers.
CRediT authorship contribution statement
Cristina Ubeda: Conceptualization, Writing - original draft, Writing
- review & editing. Ruth Hornedo-Ortega: Writing - original draft,
Writing - review & editing. Ana B. Cerezo: Writing - review & editing.
M. Carmen Garcia-Parrilla: Writing - review & editing. Ana M.
Troncoso: Conceptualization, Writing - original draft, Writing - review
& editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
Authors want to thank to the VI Plan Propio de Investigación y
Transferencia of the University of Seville for Dr Cristina Ubeda current
contract (Contract number USE-18644-Z). This work has been funded
by the project 1263469-2018 FEDER-Junta de Andalucía-Universidad
de Sevilla.
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