International Journal of Environmental Research and Public Health

Review Forest Volatile Organic Compounds and Their Effects on Human Health: A State-of-the-Art Review

Michele Antonelli 1,2,*, Davide Donelli 3,4 , Grazia Barbieri 5, Marco Valussi 6, Valentina Maggini 3 and Fabio Firenzuoli 3 1 Terme di Monticelli, 43022 Monticelli Terme PR, Italy 2 Institute of Public Health, University of Parma, 43125 Parma PR, Italy 3 CERFIT, Careggi University Hospital, 50139 Firenze FI, Italy; [email protected] (D.D.); valentina.maggini@unifi.it (V.M.); fabio.firenzuoli@unifi.it (F.F.) 4 AUSL-IRCCS Reggio Emilia, 42122 Reggio Emilia RE, Italy 5 Binini Partners S.r.l. Engineering and Architecture, 42121 Reggio Emilia RE, Italy; [email protected] 6 European Herbal and Traditional Medicine Practitioners Association (EHTPA), Norwich NR3 1HG, UK; [email protected] * Correspondence: [email protected]



Received: 9 August 2020; Accepted: 4 September 2020; Published: 7 September 2020


Abstract: The aim of this research work is to analyze the chemistry and diversity of forest VOCs (volatile organic compounds) and to outline their evidence-based effects on health. This research work was designed as a narrative overview of the scientific literature. Inhaling forest VOCs like limonene and pinene can result in useful antioxidant and anti-inflammatory effects on the airways, and the pharmacological activity of some terpenes absorbed through inhalation may be also beneficial to promote brain functions by decreasing mental fatigue, inducing relaxation, and improving cognitive performance and mood. The tree composition can markedly influence the concentration of specific VOCs in the forest air, which also exhibits cyclic diurnal variations. Moreover, beneficial psychological and physiological effects of visiting a forest cannot be solely attributed to VOC inhalation but are due to a global and integrated stimulation of the five senses, induced by all specific characteristics of the natural environment, with the visual component probably playing a fundamental role in the overall effect. Globally, these findings can have useful implications for individual wellbeing, public health, and landscape design. Further clinical and environmental studies are advised, since the majority of the existing evidence is derived from laboratory findings.

Keywords: biogenic volatile organic compounds; phytoncides; pinene; limonene; forest; public health; preventive medicine; review

1. Introduction

1.1. Forest Volatile Organic Compounds (VOCs): Background and Natural Functions The first systematic analysis of the importance and role of volatile organic compounds (VOCs) emitted by plants in the atmosphere above forests was probably performed from the perspective of atmospheric chemists who were interested in the effects of VOCs on atmospheric composition and climate. In two seminal articles [1,2], the Dutch scientist Fritz Went and his colleagues hypothesized that the blue haze observed above many forests was caused at least partially by volatile organic compounds emitted by plants (forest VOCs) and went on to estimate the impact that biogenic emissions have on the global balance of organic compounds released into the atmosphere, compared to anthropogenic production. The first estimate of global terpene emissions was 175 millions of tons C/year [1], but more

Int. J. Environ. Res. Public Health 2020, 17, 6506; doi:10.3390/ijerph17186506 www.mdpi.com/journal/ijerph Int. J. Environ. Res. Public Health 2020, 17, 6506 2 of 36 recent evaluations state that worldwide biogenic VOC (BVOC) emissions into the atmosphere could amount to around 1 billion of tons C/year [3]. Forests seem to be the greatest BVOC emitters. Specifically, tropical trees appear to be responsible for around 80% of terpenoid emissions and for around 50% of other BVOC emissions, while other tree species seem to contribute to around 10% of total BVOC emissions [3]. BVOCs form 80% to 90% of total VOC emissions in the atmosphere each year [4,5]. Some forest VOCs are also defined as “phytoncides” and this term, first introduced in the last century by the Russian biologist Boris Petrovich Tokin, derives from the combination of two words: “phyton”, which refers to plants and botany in ancient Greek, plus the suffix “cide”, which indicates “killing” or “exterminating”, thus underscoring the antimicrobial and insecticidal activity of these substances [6,7]. However, the term “phytoncide” may be misleading because, due its broad definition and etymology, it can indicate either plant-derived volatile substances with antiparasitic properties or any (volatile and nonvolatile) antimicrobial/insecticidal compound released by plants, any volatile VOC, or, in some cases, essential oils obtained from aromatic woods. In order to avoid potential misunderstandings, in this research work, which is focused on biogenic volatile substances found in forest air, the term “forest VOCs” will be preferred over the less specific “phytoncide”, and BVOCs will be defined as any organic compound, except carbon dioxide and monoxide, emitted by plants and having vapor pressure high enough to be vaporized in relevant amounts. Usually, the definition excludes dimethyl sulfide and methane because it is still debated as to whether they are produced by terrestrial plants [8]. More than 1000 different BVOCs are released from plant flowers, vegetative parts, or roots [9]. These substances are largely lipophilic products with molecular masses under 300 Da, and the vast majority are isoprenoids, including hemiterpenes (C5H8) such as isoprene, monoterpenes (C10H16), irregular acyclic homoterpenes (C11H18 or C16H26), and sesquiterpenes (C15H24), both as hydrocarbons and as oxygenated compounds; there is also a number of low-molecular-weight molecules, especially C1 and C2 oxygenated compounds, such as methanol and acetaldehyde, and C6H10 fatty acid derivatives, including lipoxygenase pathway products such as green leaf volatiles (henceforth GLVs), plus benzenoids and phenylpropanoids [5,9–13]. Many BVOCs are common to phylogenetically distant plant species [14]. For instance, only some plant species, even belonging to taxonomically distant taxa (like Bryophyta and Quercus), emit isoprene, while in close taxa, there can be both emitters (Quercus spp.) and non-emitters (Acer spp.) [11], thus suggesting that metabolic pathways related to their production have been highly preserved during evolution [14]. From the perspective of plant physiology, BVOCs can be divided into constitutive and inducible compounds. All plants can potentially synthesize volatile isoprenoids if triggered by abiotic and biotic stress factors, but only some species can do this constitutively [15]. Constitutive forest VOCs are already synthesized in the organism and either stored in specialized • structures or constantly emitted without any form of storage [16]. They are emitted at baseline levels and are mainly made of terpenoids, plus shikimate derivatives and polyketides [5]. Inducible forest VOCs (herbivore-induced plant volatiles; henceforth HIPVs) are compounds • whose synthesis is increased or initiated de-novo after herbivore attacks but also after stimulation by abiotic stressors. They have some metabolic costs but they make the plant phenotypically plastic and herbivore adaptation more unlikely to occur [5]. HIPVs comprise isoprenoids, products of the lipoxygenase (LOX) pathway, such as GLVs, some carotenoid derivatives, indoles and phenolics, and phytohormones such as ethylene, jasmonic acid, and others [17,18]. It is hypothesized that forest VOCs are not only involved in some plant-related physiological functions (biogenic stress response, adaptation to climate changes), but they also have a central role in forest ecosystems (interplant communication, antimicrobial and insecticidal activity against parasites, influence on animals’ feeding behaviors as well as on underwood environmental conditions) [19]. Thus, forest VOCs can have several functions for plant physiology [18]; the most important of them are summarized in Table1 and Figure1. Int. J. Environ. Res. Public Health 2020, 17, x 3 of 37

conditions) [19]. Thus, forest VOCs can have several functions for plant physiology [18]; the most important of them are summarized in Table 1 and Figure 1.

Table 1. Functions of constitutive and herbivore-induced forest Volatile Organic Compounds (VOCs). Int. J. Environ. Res. Public Health 2020, 17, 6506 3 of 36 Constitutive Forest VOCs Herbivore-Induced Plant Volatiles (HIPVs) Reduction of abiotic stress. Isoprene and monoterpenes Reduction of abiotic stress. Isoprene and increaseTable general 1. Functions thermal of tolerance constitutive of photosynthesis, and herbivore-induced monoterpenes forest Volatile increase Organic general Compounds thermal (VOCs). tolerance of protect photosynthetic apparatus and its activity under photosynthesis, protect photosynthetic apparatus and high-temperatureConstitutive stress by stabilizing Forest VOCs the thylakoid its Herbivore-Induced activity under high Plant-temperature Volatiles (HIPVs) stress by membranesReduction and of abiotic quenching stress. IsopreneReactive and Oxyge monoterpenesn Species Reductionstabilizing of the abiotic thylakoid stress. Isoprenemembranes and monoterpenesand quenching increase general thermal(ROS tolerance) of photosynthesis, increase generalReactive thermal Oxygen tolerance Species of photosynthesis, (ROS) protect photosynthetic apparatus and its activity under protect photosynthetic apparatus and its activity under Defenhigh-temperaturese against herbivores. stress byComprises stabilizing toxic, the thylakoid repellent, Defenhigh-temperaturese against herbivores, stress by stabilizing mainly indirectly the thylakoid but also antimembranes-nutritive and constitutive quenching ReactiveBVOCs Oxygen(biogenic Species Volatile (ROS) membranesdirectly. HIPVs and quenching and volatile Reactive compounds Oxygen Species that (ROS)attract, OrganicDefense Compounds against herbivores.) or HIPVs, Comprises as well toxic,as growth repellent, and Defensenourish against, or otherwise herbivores, favor mainly another indirectly organism but also that anti-nutritivereproductive constitutive BVOCsreducers (biogenic Volatile directly. HIPVsreduces and volatile herbivore compounds pressure that attract, InterOrganic-plant Compounds) signaling. HIPVs, or HIPVs, especially as well as Green growth Leaf and nourish,Inter- or and otherwise intra-plant favor signaling. another organism HIPVs, that especially reduces reproductive reducers herbivore pressure Volatiles (GLVs), and constitutive BVOCs can travel GLVs, and constitutive BVOCs can travel from a Inter- and intra-plant signaling. HIPVs, especially GLVs, from Inter-planta herbivore signaling.-damaged HIPVs, part especiallyto other plants Green Leaf(both herbivore-damaged part to an undamaged one, or to and constitutive BVOCs can travel from a conspecificVolatiles (GLVs), and andheterospecific), constitutive BVOCs activating can travel defen fromse a other plants (both conspecific and heterospecific), herbivore-damaged part to an undamaged one, or to other herbivore-damaged part to other plants (both conspecific genes and priming a more vigorous response after an activatingplants defen (bothse conspecific genes and and priming heterospecific), a more vigorous and heterospecific), activating defense genes and priming a attack activating defenseresponse genes and after priming an attack a more vigorous more vigorous response after an attack Defense against microbial pathogens Defensresponsee against after microbial an attack pathogens Allelopathy.Defense Inhibition against of microbial competing pathogens species’ seed Defense against microbial pathogens

Allelopathy.germination Inhibition and of competingcompetition species’ seed Attraction germinationof pollinators and and competition seed dispersers Attraction of pollinators and seed dispersers

Figure 1. BVOCs’ functions in relation to biotic and abiotic stresses. Adapted from FigureLaothawornkitkul 1. BVOCs’ functions et al. (2009) in relation [8]. to biotic and abiotic stresses. Adapted from Laothawornkitkul et al. (2009) [8]. 1.2. Non-Tree-Derived Forest BVOCs 1.2. NonIn temperate-Tree-Derived forests, Forest the BVOCs canopy layer of trees acts as the largest emission source of BVOCs [19] and, in general, from a quantitative point of view, plant leaves with their canals, oil glands, and glandular trichomes are the major emitters of these volatile compounds [8,10]. However, all plant organs and tissues produce BVOCs: leaves, flowers, and fruits release them into the atmosphere, whereas roots secrete them into the soil. Moreover, wood, phloem, and bark of trunks can serve as pools of stored BVOCs [19]. Int. J. Environ. Res. Public Health 2020, 17, 6506 4 of 36

Nevertheless, BVOCs are not exclusively tree-derived: soil bacteria, mycorrhizal fungi, and other rhizosphere microbes can also emit BVOCs, but it is not easy to evaluate the exact contribution of these non-plant sources of BVOCs in the soil or their role in the rhizosphere. This is because their emissions cannot be easily separated from those of the roots [19] and because of experimental difficulties [8]. These limits notwithstanding, one study showed that the emission of sesquiterpenes (in particular, (–)-thujopsene) by fungi (Laccaria bicolor) can interact with the ability of Populus trees to develop their root system (in particular, with the proliferation of their lateral roots) [20]. One research article reported that, in the Amazonian rainforest, soil microorganisms can emit large amounts of sesquiterpenes, and these emissions strongly influence atmospheric chemistry near the soil surface and under the canopy, to an extent comparable with canopy emissions themselves [21]. Šimpraga and colleagues reported that there is no similar assessment for temperate and boreal forests, but there are limited data on bacterial VOC profiles (rich in alkenes, alcohols, ketones, and terpenes) and fungal VOC profiles (dominated by alcohols, benzenoids, aldehydes, and ketones) [19]. Apart from soil-derived emission, other, quantitatively less important, BVOC emissions in the forest can originate from understorey vegetation. In an article relative to subarctic forests of Betula pubescens ssp. czerepanovii (mountain birch), the authors found that BVOCs emitted by the understorey vegetation of Rhododendron tomentosum are adsorbed by tree stands growing above them, thus affecting the volatile emission profile of mountain birches [22]. Overall, as suggested by these limited data, trees are considered as the major emitters of BVOCs in temperate forests and the contribution of non-tree emitters is still difficult to properly characterize in sufficient detail, thus probably having a more indirect effect on the composition of the forest air. For these reasons, it was decided to focus this review on tree-derived forest VOCs.

1.3. Research Aim The primary aim of this research work is to outline evidence-based physiological effects of forest VOCs in order to evaluate their potential integrated action on health. A secondary aim is to propose strategies to effectively and sustainably harness any of their beneficial effects in real-life contexts. Among all forest VOCs, it has been decided to focus our attention on pinene and limonene due to their wide uses and applications, as well as to the fact that their effects on health have been better studied [23,24]. The chemistry and diversity of forest VOCs (volatile organic compounds) is also analyzed for better comprehensiveness.

2. Materials and Methods This research work was designed as an overview of the scientific literature with a critical discussion of retrieved evidence [25]. General recommendations to improve the quality of narrative reviews were taken into account for better structuring this research [26,27]. Scientific databases like Medline, PsycINFO, Cochrane Library, and Google Scholar were searched for articles on the topic with relevant keywords, including “volatile organic compound*”, “forest air”, “forest atmosphere”, “forest bathing”, “phytoncide*”, “pinene”, “limonene”, “psycho*”, “neuro*”, “endocrine*”, “hormone*” “immune*”, “prevention”, “inflammation”, “stress”, and “health”. The search yielded 4159 results (1211 from Medline, 200 from PsycINFO, 158 from Cochrane Library, and 2590 from Google Scholar) and, after article screening, 147 studies were considered eligible to be included and discussed in this review. Considering that evidence on the topic is limited, cross-disciplinary, and highly heterogeneous, it was decided to structure the article as a narrative qualitative synthesis of the scientific literature in order to provide the reader with a state-of-the art dynamic description of the topic, stemming from a combination of retrieved evidence with the specific professional background and expertise of each author. Beyond the basis of available evidence, it was decided to collect and discuss ideas, hypotheses, current examples, and future perspectives for research and practice. In particular, the focus on health effects of forest VOCs (especially limonene and pinene) led to highlighting their potential activity on stress and inflammation. Finally, three levels of discussion were considered, with a wide range Int. J. Environ. Res. Public Health 2020, 17, 6506 5 of 36 of implications varying from clinical activities to policymaking: individual wellbeing, public health, and landscape design.

3. Results

3.1. Biochemistry of Forest VOCs Forest VOCs are the product of many different metabolic pathways: the isoprenoids are the most important group of metabolites in terms of diversity of compounds and quantities of emissions, but the products of the LOX pathway as well as shikimate derivatives are also highly relevant. MainInt. biosynthetic J. Environ. Res. Public pathways Health 20 for20, 1 BVOCs7, x are graphically displayed in Figure2. 6 of 37

FigureFigure 2. Main 2. Main biosynthetic biosynthetic pathways pathways for for BVOCs.BVOCs. In In green green and and yellow yellow colors, colors, the the methylerythritol methylerythritol phosphatephospha (MEP)te (MEP and) and mevalonate mevalonate ( (MVA)MVA) pathways pathways to isoprenoids, to isoprenoids, respectively, respectively, in blue incolor blue, the color, the lipoxygenaselipoxygenase ( (LOX)LOX) pathway pathway to to GLVs, GLVs, and and in in purple purple color color,, the the shikimate shikimate pathway pathway to aromatic to aromatic compounds.compounds. Adapted Adapted from from Ma Maffeiffei et et al. al.(2011) (2011) [[17]17]..

3.1.1.3.2. Isoprenoids A Qualitative and Quantitative Analysis of Forest VOC Emissions TheThe volatile composition isoprenoids of forest include VOCs (probably isoprene the (C5), key VOC monoterpenes source [11]) is (C10), expected homoterpenes to consist mainly (C11 or C16),of and constitutive sesquiterpenes compounds, (C15), but, and since they it all cannot derive be from excluded the precursor that, at any dimethylallyl given moment diphosphate, some (DMAPP)individual and plants its isomer in the isopentenylforest may be diphosphate under herbivore (IPP). attack These or abiotic precursors stress, and are provided synthesized that the by two separaterate of pathways, VOC emissions one active can be in many plastids times (the higher deoxyxylulose-5-phosphate than baseline after a herbivore (DXP), attack also [29], known a part of as the the total forest emissions can consist of biotic and abiotic-induced VOCs. This can be important for methylerythritol phosphate (MEP) pathway), and the second in the cytosol of the secretory cells the evaluation of biological activities of forest VOCs because the range of biotic-induced compounds themselves (the mevalonate (MVA) pathway) [17]. In fact, IPP and DMAPP seem to originate in the is often highly different from that of constitutive ones and can be also different from the abiotic- plastidsinduced from ones the MEP[29,30]. pathway, If seen from while the leucoplasts plants’ functional contain point the enzymesof view, VOCs for the thus first comprise steps of all monoterpene volatile biosynthesis.constitutive In defen the MVAse compounds pathway, (volatile DMAPP phytoanticipins, accepts one IPP or (by phytoncides prenyltransferase—PT),, as defined by Tokin), leading plus to the productionvolatile ofinducible farnesyl defen diphosphatese compounds (FPP) (volatile and, consequently,phytoalexins or to HIPVs) sesquiterpenoids and non-defen (although,se compounds in some instances,(attractants there of is apollinator very small and production of seed dispersals). of monoterpenes) and to the homoterpene DMTT. In the MEP pathway,The the hemiterpenebiochemical composition isoprene is ofsynthesized forest air tendsfrom DMAPP to follow alone diurnal by terpenevariations, synthase with BVOCs or cyclase concentration usually peaking early in the afternoon and, especially in summertime, even in the morning (around 2 h after dawn), and it can be markedly influenced by several factors, including meteorological conditions, altitude, seasons, sunlight exposure, and tree types [31,32]. For example, it has been demonstrated that the air of forests dominated by conifer trees has a higher concentration of VOCs if compared to that of forests with more deciduous trees [31]. However, beyond these differences, it is estimated that, from a biochemical point of view, the majority of forest VOCs are isoprene and terpenes, especially monoterpenes, including limonene or pinene [33]. Specifically, according to Guenther and colleagues [3], isoprene dominates the emissions, with around 50% of the

Int. J. Environ. Res. Public Health 2020, 17, 6506 6 of 36

(TPS), and the fusion of DMAPP to one or more IPPs leads to the production of geranyl diphosphate (GPP) (precursor of the monoterpenoids) and geranyl geranyl diphosphate (GGPP), which leads to the synthesis of diterpenes from which the homoterpene TMTT derives. Although the MEP pathway is plastid-located, the enzymes necessary for sesquiterpene synthesis are cytosolic. Hence, MEP-derived IPP or DMAPP need to travel from plastids to the cytosol [17,18]. The biosynthesis of the homoterpenes DMNT and TMTT follows a less direct pathway. DMNT derives from the oxidative degradation of (E)-nerolidol (a C15-alcohol), and TMTT from the oxidative degradation of (E,E)-geranyl linalool (a C20-alcohol) [28].

3.1.2. Oxylipins Oxylipins are products of the lipoxygenase (LOX) pathway. They derive from the polyunsaturated C18 fatty acids of the chloroplast membrane (such as 13-hydroperoxylinolenic acid), which, in times of stress or damage, are cleaved by 9-LOX and 13-LOX pathways to give highly reactive products like 6-carbon aldehydes and alcohols (GLVs) and derivatives of jasmonic acid such as methyl jasmonate [9].

3.1.3. Shikimate Pathway Another important group of BVOCs consists of compounds containing an aromatic ring, such as indole (derived from reactions of modified amino acids or their precursors) or the derivatives of phenylalanine, either via the phenylpropanoid pathway (eugenol and methyl chavicol) or the benzoate pathway (methyl salicylate) [17] (Figure2).

3.2. A Qualitative and Quantitative Analysis of Forest VOC Emissions The composition of forest VOCs (probably the key VOC source [11]) is expected to consist mainly of constitutive compounds, but, since it cannot be excluded that, at any given moment, some individual plants in the forest may be under herbivore attack or abiotic stress, and provided that the rate of VOC emissions can be many times higher than baseline after a herbivore attack [29], a part of the total forest emissions can consist of biotic and abiotic-induced VOCs. This can be important for the evaluation of biological activities of forest VOCs because the range of biotic-induced compounds is often highly different from that of constitutive ones and can be also different from the abiotic-induced ones [29,30]. If seen from the plants’ functional point of view, VOCs thus comprise all volatile constitutive defense compounds (volatile phytoanticipins, or phytoncides, as defined by Tokin), plus volatile inducible defense compounds (volatile phytoalexins or HIPVs) and non-defense compounds (attractants of pollinator and of seed dispersals). The biochemical composition of forest air tends to follow diurnal variations, with BVOCs concentration usually peaking early in the afternoon and, especially in summertime, even in the morning (around 2 h after dawn), and it can be markedly influenced by several factors, including meteorological conditions, altitude, seasons, sunlight exposure, and tree types [31,32]. For example, it has been demonstrated that the air of forests dominated by conifer trees has a higher concentration of VOCs if compared to that of forests with more deciduous trees [31]. However, beyond these differences, it is estimated that, from a biochemical point of view, the majority of forest VOCs are isoprene and terpenes, especially monoterpenes, including limonene or pinene [33]. Specifically, according to Guenther and colleagues [3], isoprene dominates the emissions, with around 50% of the total BVOC emissions of 1 billion tons C/year. C1 and C2 oxygenated compounds such as methanol and acetaldehyde and C10 hydrocarbons such as α-pinene, β-pinene, (E)-β-ocimene, and d-limonene contribute to another 30%, while the remaining 20% is dominated by 20 compounds (mostly terpenoids), with the other 100 compounds accounting for a mere 3%. Evidence from research done on open-field emissions of both conifer and deciduous forests [34–36], and on un-detached leaves or branchlets [30,37], supports these estimates, indicating that, apart from isoprene, the most common and dominant forest VOCs in terms of percentage of the total emissions are monoterpenes such as α-pinene, d-limonene, and β-pinene, followed by sabinene, myrcene, Int. J. Environ. Res. Public Health 2020, 17, 6506 7 of 36 and camphene. Monoterpenes’ global annual emissions amount to 330–480 million tons, with an average atmospheric concentration above forests from some pmol/mol to several nmol/mol. Other quantitatively important forests VOCs such as GLVs and acetaldehyde are emitted in quantities of around 260 million tons and show atmospheric concentrations of around 1–3 nmol/mol [11,16]. From a quantitative point of view, studies which aimed to determine the atmospheric concentration of some categories of BVOCs under forest canopy reported heterogeneous findings, probably due to a significant influence of the abovementioned factors on the forest air composition: approximately, on the basis of available evidence, the total amount of terpenes can vary from a minimum of 3.5 to a maximum of 56.0 µg/m3, isoprene can range from 0.1 to 28.0 µg/m3, and monoterpenes may have an average concentration of 4.5 µg/m3, whereas the amount of LOX pathway products is usually below the upper threshold of 3.4 µg/m3 [16,31,32,34,38–44] (Figure3). In particular, if we only consider monoterpenes, the concentration range of seven of them under the canopy of a Scots pine forest was reported in a study [44] (Figure4). For example, limonene concentration can vary from 0.81 to 8.10 µg/m3, while α-pinene can reach higher concentrations in pine forest air, up to 13.05 µg/m3 [44]. However, as reported in a review endorsed by the World Health Organization (WHO), measured concentrations of limonene in the air of different forest areas across the world (Europe, North America, and Asia) can largelyInt. J. Environ. vary Res. and Public even Health reach 2020 values, 17, x of 12.2 g/m3 [45]. Therefore, it is important to consider this high8 of 37 degree of variability when studying health and environmental effects of forest VOCs.

Figure 3. Atmospheric concentration of BVOCs under forest canopy [16,31,32,34,38–44]. Abbreviations: Tot. terpenes = total concentration of terpenes; LOX = products of the lipoxygenase (LOX) pathway. Figure 3. Atmospheric concentration of BVOCs under forest canopy [16,31,32,34,38–44]. Abbreviations: Tot. terpenes = total concentration of terpenes; LOX = products of the lipoxygenase (LOX) pathway.

Figure 4. Atmospheric concentrations of seven monoterpenes under the canopy of a Scots pine forest [44].

Int. J. Environ. Res. Public Health 2020, 17, x 8 of 37

Figure 3. Atmospheric concentration of BVOCs under forest canopy [16,31,32,34,38–44]. Abbreviations: Tot. terpenes = total concentration of terpenes; LOX = products of the lipoxygenase (LOX) pathway. Int. J. Environ. Res. Public Health 2020, 17, 6506 8 of 36

Figure 4. Atmospheric concentrations of seven monoterpenes under the canopy of a Scots pine forest [44]. Figure 4. Atmospheric concentrations of seven monoterpenes under the canopy of a Scots pine forest Studies on emissions from plants after artificial lesions [46,47], or experiments performed using [44]. techniques such as branch enclosures, which are likely to produce stress in the plant [48], show the presence of GLVs like cis-3-hexen-1-ol, cis-3-hexenyl acetate, cis-3-hexenyl butyrate, and cis-3-hexenyl valerate, although there are contradictory examples [49]. This fits well with the fact that C6 volatiles (aldehydes, alcohols, and their derivatives) such as GLVs are derived from cell membrane denaturation [12]. Not only direct physical stress but also temperature variations can affect the release of BVOCs. GLVs, as well as C1 and C2 oxygenated compound emissions, can increase during heat stress and might continue even for a long time after the temperature has returned to normal levels. Trees with specific storage structures (such as resin ducts in most of the conifers) are less affected by changes in temperature and are moderate isoprenoid emitters, unless these structures are damaged by insects, fires, strong wind, or high humidity. Most deciduous species do not have such structures and release BVOCs directly from mesophyll cells in a more light- and temperature-dependent manner (in particular, Fagaceae and Salicaceae)[12]. However, the most typical compounds emitted after biotic stress are the homoterpenes TMTT and DMNT [17]. Overall, the diversity of BVOCs is certainly much higher, and this is represented in Table2, in descending order of quantity of emissions [4,16,30,34,35,37,42,46–51]. Int. J. Environ. Res. Public Health 2020, 17, x 9 of 37

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[46,47], This stress or fitsvariations experiments in well the withplant can theperformed affect[48], fact showthe that release usingtheC6 volatilestechniques (aldehydes, such as branchalcohols, enclosures, and their derivatives)which are likely such to as produc GLVs eare stress derived in the from plant cell [48], membrane show the volatilespresenceoftechniques BVOCs. (aldehydes, of GLVs, GLVssuch as as like alcohols,branch well cis -as 3enclosures,- hexenC1and and their-1 -C2ol, derivatives)which oxygenated cis-3 -arehexenyl likely such compound acetate, to as produc GLVs cisemissions, aree- 3stress- hexenylderived in can the from butyrate, increase plant cell [48], membrane andduring show cis -heat 3the- denaturationpresence of [12]. GLVs Not like only cis-3-hexen-1-ol, direct physical stress cis-3-hexenyl but also temperature acetate, cis-3-hexenyl variations can butyrate, affect the and release cis-3- denaturationhexenylstresspresence and valerate, ofmight [12]. GLVs althougNot continue like onlyh cis-3-hexen-1-ol, directthere even arephysicalfor contradictorya long stress cis-3-hexenyltime but af examplester also the temperature temperatureacetate, [49]. Thiscis-3-hexenyl variati fitshas well returnedons withcan butyrate, affect theto normal fact the and thatrelease levels.cis-3- C6 ofhexenyl BVOCs. valerate, GLVs, as although well as C1there and are C2 contradictory oxygenated compoundexamples [49]. emissions, This fits can well increase with the during fact that heat C6 ofvolatilesTreeshexenyl BVOCs. with (aldehydes, valerate, GLVs, specific as although storagewellalcohols, as C1structuresthere and and aretheir C2 contradictory (such oxygenatedderivatives) as resin compound examples suchducts as in GLVs most [49]. emissions, ofareThis the derived fits conifers) can well increasefrom with are cell lessthe during membrane factaffected that heat C6by stressvolatiles and might(aldehydes, continue alcohols, even forand a theirlong derivativestime after the) such temperature as GLVs arehas derived returned from to normal cell membrane levels. stressdenaturationchangesvolatiles and inmight(aldehydes, temperature [12]. continue Not onlyalcohols, andeven direct are forand physicalmoderate a theirlong derivativesstresstime isopreno after but alsotheid) such emitters, temperature as GLVs unless arevariatihas these derived returnedons structures can from to affect normal cell are the membrane damaged releaselevels. Treesdenaturation with specific [12]. storage Not only structures direct physical (such as stress resin but ducts also in temperature most of the variations conifers) arecan less affect affected the release by Treesofbydenaturation BVOCs. insects, with specificGLVs, fires, [12]. strongas storage Not well only wind, as structur C1direct or and highes physical C2 (such humidity. oxygenated as stress resin Mostbut ducts compound also deciduous in temperature most emissions, of species the variations conifers) do can not increase arehave can less affect such during affected thestructures release heat by changesof BVOCs. in temperature GLVs, as well and as are C1 moderate and C2 oxygenated isoprenoid emitters,compound unless emissions, these structurescan increase are during damaged heat changesstressandof BVOCs. andrelease in mighttemperature GLVs, BVOCs continue as welldirectly and even as are C1 fromformoderate and a longmesophyll C2 oxygenatedisoprenoidtime after cells the emitters,compoundin temperature a more unless emissions,light- hasthese and returned structures cantemperature-dependent increase to normal are duringdamaged levels. heat bystress insects, and fires, might strong continue wind, even or high for ahumidity. long time Most after deciduous the temperature species has do returnednot have suchto normal structures levels. byTreesmannerstress insects, with and (in fires,specific might particular, strong continuestorage wind Fagaceae structur ,even or high andfores humidity.a(suchSalicaceae long as time resin) Most[12]. af terducts deciduousHowever, the in temperature most thespecies of mostthe has cdoonifers) typical notreturned have arecompounds suchlessto normal affected structures emitted levels. by andTrees release with specific BVOCs storage directly structures from mesophyll (such as cellsresin inducts a more in most light- of the and conifers) temperature-dependent are less affected by andchangesafterTrees release biotic with in temperature BVOCsspecificstress are storage directly the and homoterpenes structuresare from moderate mesophyll (such TMTT isoprenoid as cells resinand DMNT inducts emitters, a more in [17]. most unless light of- the theseand conifers) temperaturestructures are lessare-dependent damagedaffected by mannerchanges (in in particular, temperature Fagaceae and are and moderate Salicaceae isopreno) [12]. However,id emitters, the unless most thesetypical structures compounds are emitteddamaged mannerbychanges insects,Overall, (in infires, particular temperature the strong diversity, Fagaceaewind and of, or are BVOCsand high moderate Salicaceae humidity. is certainly isopreno) [12]. Most much However, iddeciduous emitters, higher, the speciesandunless most this typicalthesedo is notrepresented structures havecompounds such inare structures Table emitteddamaged 2, in afterby insects,biotic stress fires, are strong the homoterpeneswind, or high humidity.TMTT and Most DMNT deciduous [17]. species do not have such structures afteranddescendingby insects, releasebiotic stress fires, BVOCsorder are strong of the directly quantity homoterpeneswind, from ofor emissionshigh mesophyll humidity.TMTT [4,16,30,34,35,37,42,46–51]. and cells Most DMNT in deciduous a more[17]. light species- and do temperature not have such-dependent structures andOverall, release theBVOCs diversity directly of BVOCs from ismesophyll certainly muchcells in higher, a more and light- this isand represented temperature-dependent in Table 2, in mannerandOverall, release (in particular the BVOCs diversity, Fagaceaedirectly of BVOCs andfrom Salicaceae ismesophyll certainly) [12]. muchcells However, inhigher, a more theand light-most this istypicaland represented temperature-dependent compounds in Table emitted 2, in descendingmanner (in order particular, of quantity Fagaceae of emissions and Salicaceae [4,16,30,34,35,37,42,46) [12]. However, –the51]. most typical compounds emitted descendingaftermanner bioticTable (in stress order2. particular, Forest areof quantity theBVOCs Fagaceaehomoterpenes and of emissions theirand chemicalSalicaceae TMTT [4,16,30,34,35,37,42,46 andcharacterist) [12]. DMNT However,ics [17]. listed –the51]. on most the basis typical of the compounds magnitude emitted of after emissionsbiotic stress (in descendingare the homoterpenes order). TMTT and DMNT [17]. afterOverall,Table biotic 2. stressForestthe diversity are BVOCs the homoterpenesof and BVOCs their chemical is certainly TMTT characteristics and much DMNT higher, listed [17]. and on thethis basis is represented of the magnitude in Table of 2, in TableOverall, 2. Forest the diversityBVOCs and of theirBVOCs chemical is certainly characteristics much higher, listed onand the this basis is represented of the magnitude in Table of 2, in descendingemissions order (in descending of quantity order). of emissions [4,16,30,34,35,37,42,46Boiling–51]. descending order of quantity of emissions [4,16,30,34,35,37,42,46–51]. Molar descendingemissions Chemical order(in descending of quantity order). of emissions [4,16,30,34,35,37,42,46–51].CAS Point Molecule IUPAC Formula Structure Boilin Mass I/C 1 C/D 2 E 3 P 4 Family numberCA (at 760 Int. J. Environ. Res. Public Health 2020, 17, 6506 Table 2. Forest BVOCs and their chemical characteristics listedBoilin g on the basis(g/mol) of the magnitude of 9 of 36 Table 2. Forest BVOCs and their chemical characteristCASics listedmmHg) on the Molar basis of the magnitude of MoleculemissionsTableChemical 2. (in Forest descending BVOCs order). and their chemical characteristics listedPointg on the basis of the magnitudeC/D of emissions (in descendingIUPAC order). Formula Structure nuS MolarMass I/C 1 E 3 P 4 Molecule emissionsChemicalFamily (in descending 2- order). (atPoint 760 C/D2 IUPAC Formula Structure mbnu Boilin (g/mol)Mass I/C 1 E 3 P 4 e Family methylbu CA (atmmH 760 2 Table 2. Forest BVOCs and their chemicalIsoprene characteristicsIsoprenoids listed onC5H8 the basis of the magnitude78-79-5mber Boiling34.1g of°C emissions(g/mol)68.12 (inC descendingD **** +++ order). ta-1,3- S mmHBoilingg) MolarMolar Molecul ChemicalChemical CASer PointPoint Molar C/D Chemical CAS Point 1 1 2 3 3 4 4 Molecule IUPACIUPAC2diene- FormulaFormula Structure nu g) MassMass I/CI/C 1 C/D 2 E E 3 P P 4 Moleculee FamilyFamily IUPAC Formula Structure number78- (at(at 760 760 Mass I/C C/D2 E P Family methylb2- numbermb (at 760 (g/mol)(g/mol)Boiling *** Chemical Isoprene Isoprenoids C5H8 7879-- CAS34.1mmHmmHg) °C 68.12(g/mol) C DMolar Mass+++ 1 2 3 4 Molecule IUPACmethylbuta-1,3- Formula Structure er mmHg) Point (at 760 **** I/C C/D E P Family Isoprenecis-3- Isoprenoids C5H8 795- number34.1g) °C 68.12 C D (g/mol)+++ uta(dieneZ-)-hex-3-1,32-- mmHg) * Hexen-1- GLVs 2- 2- C6H12O 928-96-15 156.5 °C 100.16 I D *** +++ dienemethylbuen-1-ol 78- cisIsoprene-3ol- Isoprenoids methylbmethylbu C5H8 78-79-5928 34.1 °C 68.12 C D ******* +++ Isoprene Isoprenoids 2-methylbuta-1,3-dieneIsopreneIsoprene IsoprenoidsIsoprenoids (Z)-ta-1,3-hex- C5H8C5H8C5H8 78-79-579- 78-79-5 34.1156.534.1 °C °C 68.1268.12 34.1 ◦CC C D D 68.12**** ++++++ C D **** +++ Hexencis-3- - GLVs utata-1,3--1,3- C6H12O 928-96- 100.16 I D **** +++ 3(Z-en)-dienehex-1-ol- 5 156.5°C Hexen1-ol - GLVs dienediene C6H12O -961 - 100.16 I D *** +++ 3-en-1-ol °C 1-cis-3-ol (Z)-hex-3- 1 ciscis-3--3- GLVs C6H10O 6789-80-6928678 126 °C 98.14 I D *** +++ Hexenalcis-3- (Z(Z)-)-hex-3-hexenal- 156.5 cis-3-Hexen-1-ol GLVs (Z)-hex-3-en-1-olHexencisHexen-1--3-- GLVsGLVs (Z)(Z-)-hex-3-hex- C6H12OC6H12OC6H12O 928-96-1678-969--928-96-1 156.5 °C 100.16100.16 156.5 ◦CI I D D 100.16****** ++++++ I D *** +++ Hexen-1- GLVsGLVs 3-enen-1-ol-1-ol C6H10OC6H12O 928-96-1 126156.5°C °C °C 98.14100.16 I I D D ****** ++++++ Hexenalcis1--ol3ol- (Z)3-en-1-ol-enalhex- 8091- - ol GLVs C6H10O 126 °C 98.14 I D *** +++ Hexenal 3-enal 806- cis-3- [(Z)-hex- 678 3686 cisHexenyl-3- GLVs [(Z)(Z)3-enyl]--hexhex-- C8H14O2 3681-71-89- 174.2 °C 142.2 I D *** +++ cis-3- GLVs (Z)-hex-3- C6H10OC8H14O 3681- 126174.2 °C 98.14 I D *** +++ HexenalHexenylcisacetatecis-3--3- GLVsGLVs [(Z)33(Z)-hex-3---enyl]acetateenal-hex - C6H10O 6789-80-680- 126 °C 142.298.14 I I D D ****** ++++++ cis-3-Hexenal GLVs (Z)-hex-3-enalHexenal GLVs enal C6H10O C8H14OC6H10O2 6789-80-6711--6789-80-6 174.2°C126 °C 98.14 126 ◦CI D 98.14*** +++ I D *** +++ HexenylacetateHexenal GLVs 3acetate-enyl]enal 6 142.2 I D *** +++ 2 718- °C acetate acetate 368 (4R)-1- 8 cis-3- [(Z)(4R)-hex-1-- methyl-4- C8H14O 1- 174.2 Hexenylcis-3- GLVs methyl(4R)3-[(Z)-hex-enyl]-1-- 659 142.2 I D *** +++ dcis-3--d- Monoterpene [(Z)-hex-prop-1- 2 65996-98-71- °C acetateHexenyl MonoterpeneGLVs methyl4acetate-prop3-enyl]- C8H14O2C10H16 3681-71-865996- 175.4175.4174.2 °C 136.23142.2 C,I I D *** +/+++/++++++ LimoneLimoneneHexenyld- hydrocarbonsGLVs 3-enyl]en-2- C10H16C8H14O2 3681-71-887 174.2 °C 136.23142.2 C, II D D ****** +++ Monoterpene acetate Monoterpenehydrocarbons 41--propenacetate-2- 9698-- 175.4°C +/+++ d-Limonene (4R)-1-methyl-4-prop-1-en-2-ylcyclohexeneLimoneacetatene (4R)ylcycloheacetate-1- C10H16 C10H16 65996-98-7136.23 175.4 C,C I D 136.23*** C, I D *** +/+++ hydrocarbons hydrocarbons ylcycloh1-en-2- 987- °C ◦ + ne methylxene- 659 d- ylcyclohexene 7 Monoterpene 4-prop(4R)-1-- 96- 175.4 +/++ Limone exene2,6,6(4R)-1-2,6,6-- C10H16 136.23 C, I D *** hydrocarbons 1methyl-4--en-2- 67798- °C + ne trimethy2,6,6methyl-4-trimethyl- α-d- MonoterpeneMonoterpene ylcyclohprop-1- 67762-73-65996-98-677627 - +/++ Monoterpene α-Pinened- Monoterpene trimethylbicyclo[bicyclo[3.prop-1- C10H16C10H16 65996-98- 156175.4156 °C °C °C 136.23136.23 C,C, I I D D ****** +/+++ α-Pinene 2,6,6-trimethylbicyclo[3.1.1]hept-2-enePineneLimoneneα- Monoterpenehydrocarbonshydrocarbons exeneen-2- C10H16C10H16 62737- 67762-73-6- 175.4 °C 136.23 156 ◦CC, I D 136.23*** +/++++/+++ C, I D *** +/+++ hydrocarbons Limonene hydrocarbons lbicyclo[3.1.1]heen-2- C10H16 67 156 °C 136.23 C, I D *** Pinene hydrocarbons ylcyclohe1.1]hept- 73- + 2,6,6ylcyclohe- 6 pt3.1.1]he-22-ene-ene 677 trimethyxene 6 α- Monoterpene pt-2-xeneene 62- +/++ lbicyclo[(3E)-3,7- C10H16 156 °C 136.23 C, I D *** Pinene hydrocarbons 2,6,6- 37773- + Int. J. Environ. Res. Public Health(3E)dimethy3.1.1]he 202,6,6--203,7, 1- 7, x 10 of 37 Monoterpene Int.(E) J.- βEnviron.- Monoterpene Res. Public Health trimethyl2020, 17, x 37796- 175.2 10 of 37 (E)-β-Ocimene (3E)-3,7-dimethylocta-1,3,6-trieneMonoterpene dimethyptloctatrimethyl-2-ene- C10H16C10H16 67762-73-3779-61-1136.23 175.2 C,C I D 136.23** +/++ C, I D ** +/++ hydrocarbons Ocimene(E)α-Pinene-β- MonoterpenehydrocarbonsMonoterpene bicyclo[3. C10H16 67762-73-619-- 175.2°C156 °C 136.23 ◦ C, I D *** +/+++ Int.α -PineneJ. Environ. Res.hydrocarbons Public Health locta 1,3,3bicyclo[3.1,3,62020--, 17, xC10H16 C10H16 6 156 °C 136.23136.23 C, C,I I D D ** ***10 +/++of+/+++ 37 Ocimene hydrocarbonshydrocarbons (3E)1.1]hept--3,7- 6116- °C trimethy1,3,6triene1,3,31.1]hept--- 377 dimethy2-ene 4701 (E)1,8-β- - MonoterpenoiMonoterpene trimethytrienel-2-ene2- C10H18 9- 176.4175.2 locta1,3,3- C10H16 -47082- 154.25136.23 C, I D ** +/++ OcimeneCineole1,8- Monoterpenoihydrocarbonsd ethers oxabicycl-2- C10H18O 61- 176.4°C trimethy1,3,6- -826 - 154.25 C, I D ** Cineole d ethers oxabicyc O 470 °C Monoterpenoid 1,8- Monoterpenoi lo[2.2.2]l-2- C10H18 16 176.4 1,8-Cineole 1,3,3-trimethyl-2-oxabicyclo[2.2.2]octanelo[2.2.2]triene C10H18O -82-470-82-6154.25 176.4 C,C I D 154.25** C, I D ** ethers Cineole d ethers oxabicycoctane O °C ◦ octane 6 lo[2.2.2]1,7,7- 1,7,7- trimethyoctane trimethy 76- Campho Monoterpenoi lbicyclo[1,7,7- C10H16 76- 205.7 Monoterpenoid Campho Monoterpenoi lbicyclo[ C10H16 22- 205.7 152.23 ** r d ketones trimethy2.2.1]he O 22- °C 152.23 ** Camphor 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one r d ketones 2.2.1]he C10H16OO 762 - 76-22-2°C 205.7 ◦C 152.23 ** ketones Campho Monoterpenoi lbicyclo[ptan-2- C10H16 2 205.7 ptan-2- 22- 152.23 ** r d ketones 2.2.1]heone O °C one 2 ptan3,7--2- 3,7- dimethyone 78- Monoterpenoid Monoterpenoi dimethy C10H18 78- 197.5 Linalool 3,7-dimethylocta-1,6-dien-3-olLinalool Monoterpenoi locta3,7-- C10H18OC10H18 70- 78-70-6197.5 154.25 197.5 C,◦C L D 154.25** +/++ C, L D ** +/++ alcohol Linalool d alcohol locta- O 70- °C 154.25 C, L D ** +/++ d alcohol 1,6dimethy-dien- O 786 - °C Monoterpenoi 1,6-dien- C10H18 6 197.5 Linalool locta3-ol - 70- 154.25 C, L D ** +/++ d alcohol 3-ol O °C 1,6-1dien- - 6 1- methyl3-ol - methyl- Aromatic 41-- 99- p- Aromatic 4- 99- p- monoterpene propanmethyl- C10H14 87- 177 °C 134.22 C D ** Cymene monoterpene propan- C10H14 87- 177 °C 134.22 C D ** Cymene hydrocarbonsAromatic 24-- 996 - p- hydrocarbons 2- 6 monoterpene ylbenzepropan- C10H14 87- 177 °C 134.22 C D ** Cymene ylbenze hydrocarbons ne2- 6 ne ylbenze4- 4- methyline methyli dene4--1- 338 dene-1- 338 Sabinen Monoterpene propanmethyli- 7- Sabinen Monoterpene propan- C10H16 7- 164 °C 136.23 C D ** e hydrocarbons dene2- -1- C10H16 41338- 164 °C 136.23 C D ** e hydrocarbons 2- 41- Sabinen Monoterpene ylbicyclpropan- 75- ylbicycl C10H16 5 164 °C 136.23 C D ** e hydrocarbons o[3.1.0]h2- 41- o[3.1.0]h ylbicyclexane 5 exane (1R,4E,9o[3.1.0]h (1R,4E,9 exaneS)- S)- (1R,4E,94,11,11- 4,11,11- trimethyS)- β- trimethy 87- β- Sesquiterpene 4,11,11l-8- - 87- Caryoph Sesquiterpene l-8- C15H24 44- NA 204.35 C, I D ** +/++ Caryoph hydrocarbons trimethymethyli C15H24 44- NA 204.35 C, I D ** +/++ ylleneβ- hydrocarbons methyli 875 - yllene Sesquiterpene denebicl-8- 5 Caryoph denebic C15H24 44- NA 204.35 C, I D ** +/++ hydrocarbons yclo[7.2.methyli yllene yclo[7.2. 5 0]undecdenebic- 0]undec- yclo[7.2.4-ene 4-ene 0]undec7- - 7- methyl4-ene - methyl- 37-- 123 β- Monoterpene 3- 123 β- Monoterpene methylimethyl- C10H16 -35- 167 °C 136.23 C D ** Myrcene hydrocarbons methyli C10H16 -35- 167 °C 136.23 C D ** Myrcene hydrocarbons deneocta3- 1233 β- Monoterpene deneocta 3 methyli-1,6- C10H16 -35- 167 °C 136.23 C D ** Myrcene hydrocarbons -1,6- deneoctadiene 3 diene -6,61,6-- 6,6- dimethydiene dimethy l6,6-2-- l-2- 127 Monoterpene dimethymethyli 127 166.0 β-Pinene Monoterpene methyli C10H16 -91- 166.0 136.234 C, I D ** β-Pinene hydrocarbons denebicl-2- C10H16 -91- °C 136.234 C, I D ** hydrocarbons denebic 1273 °C Monoterpene yclo[3.1.methyli 3 166.0 β-Pinene yclo[3.1. C10H16 -91- 136.234 C, I D ** hydrocarbons 1]heptandenebic °C 1]heptan 3 yclo[3.1.e 3,7,7e - 1]heptan 748 trimethy3,7,7- β 3- Monoterpene e 74806- 171.4 lbicyclo[trimethy C10H16 136.234 C D ** β 3- Monoterpene 3,7,7- 06- 171.4 Carene hydrocarbons lbicyclo[ C10H16 04748- °C 136.234 C D ** Carene hydrocarbons trimethy4.1.0]he 04- °C β 3- Monoterpene 4.1.0]he 065 - 171.4 ptlbicyclo[-3-ene C10H16 5 136.234 C D ** Carene hydrocarbons pt-3-ene 04- °C 4.1.0]he 5 pt-3-ene

Int. J. Environ. Res. Public Health 2020, 17, x 10 of 37

1,3,3- Int. J. Environ. Res. Public Healthtrimethy 2020, 17, x 10 of 37 470 1,8- Monoterpenoi l-2- C10H18 176.4 Int. J. Environ. Res. Public Health 2020, 17, x -82- 154.25 C, I D ** 10 of 37 Cineole d ethers oxabicyc1,3,3- O °C 6 trimethylo[2.2.2] 470 1,8- Monoterpenoi octane1,3,3l-2- - C10H18 176.4 -82- 154.25 C, I D ** Cineole d ethers oxabicyctrimethy1,7,7- O °C Int. J. Environ. Res. Public Health 2020, 17, x 4706 10 of 37 1,8- Monoterpenoi trimethylo[2.2.2]l-2- C10H18 176.4 -7682-- 154.25 C, I D ** CamphoCineole Monoterpenoid ethers lbicyclo[oxabicycoctane C10H16O 205.7°C 1,3,3- 226 - 152.23 ** r d ketones 2.2.1]helo[2.2.2]1,7,7- O °C trimethy 2 trimethyptanoctane-2- 470 1,8- Monoterpenoi l-2- C10H18 76- 176.4 Campho Monoterpenoi lbicyclo[1,7,7one - C10H16 -82- 205.7 154.25 C, I D ** Cineole d ethers oxabicyc O 22- °C 152.23 ** Int. J.r Environ. Res.d ketones Public Healthtrimethy2.2.1]he 203,720- , 17, x O 6 °C 10 of 37 lo[2.2.2] 762 - Campho Monoterpenoi dimethylbicyclo[ptan-2- C10H16 78- 205.7 Monoterpenoi octane C10H18 22- 197.5 152.23 ** Linaloolr d ketones 2.2.1]helocta1,3,3one - O 70- °C 154.25 C, L D ** +/++ d alcohol 1,7,7- O 2 °C Int. J. Environ. Res. Public Health1,6trimethyptan 203,7-dien20-2, -1-7, x 6 10 of 37 trimethy 470 1,8- Monoterpenoi dimethy3onel-2ol- C10H18 7678- 176.4 Campho Monoterpenoi lbicyclo[ C10H16C10H18 -82- 205.7197.5 154.25 C, I D ** LinaloolCineole d ethers oxabicyclocta1,3,33,71---- O 2270- °C 152.23154.25 C, L D ** +/++ r d ketonesalcohol 2.2.1]he O 6 °C trimethy1,6dimethy-dien- 7826 - Monoterpenoi methyllo[2.2.2]ptan-2-- C10H18 470 197.5 Linalool1,8- MonoterpenoiAromatic octanelocta3l-4-2ol-- - C10H18 9970-- 176.4 154.25 C, L D ** +/++ p- d alcohol one O -82- °C 154.25 C, I D ** Cineole monoterpened ethers oxabicyc1,6propan1,7,7-1dien- - -- C10H14O 876 - 177°C °C 134.22 C D ** Cymene 3,7- 6 hydrocarbons trimethylo[2.2.2]methyl32-ol- - 6 dimethy 7876- Campho MonoterpenoiAromatic lbicyclo[ylbenzeoctane41- C10H18C10H16 99- 197.5205.7 Linaloolp- locta- 7022- 154.25152.23 C, L D ** +/++ r monoterpened ketonesalcohol propanmethyl2.2.1]he1,7,7ne - - C10H14O 87- 177°C °C 134.22 C D ** Cymene 1,6-dien- 62 hydrocarbonsAromatic trimethy24- 996 - p- ptan34-ol--2 - 76- Campho Monoterpenoimonoterpene lbicyclo[propanylbenze- C10H16C10H14 87- 177205.7 °C 134.22 C D ** Int. J. Environ. Res. Public Health 2020, 17, 6506 Cymene methylione1- 22- 152.23 ** 10 of 36 r hydrocarbonsd ketones 2.2.1]hedene3,7ne2-- 1- O 3386 °C methyl- 2 Sabinen Monoterpene dimethypropanylbenzeptan4--2-- 787-- MonoterpenoiAromatic 4- C10H16C10H18 99- 164197.5 °C 136.23 C D ** Linaloolpe- hydrocarbons methyliloctaonene2- - 4170- 154.25 C, L D ** +/++ monoterpened alcohol propan- C10H14O 87- 177°C °C 134.22 C D ** Cymene dene3,74--1- 338 hydrocarbons 1,6ylbicycl-Table2dien- - 2. Cont. 65 Sabinen Monoterpene o[3.1.0]hdimethypropanmethyli3-ol - 787-- Monoterpenoi ylbenze C10H18C10H16 164197.5 °C 136.23 C D ** Linaloole hydrocarbons denelocta2--1- - 3387041- 154.25 C, L D ** +/++ d alcohol exanene1- O °C Boiling Chemical Sabinen Monoterpene 1,6propanylbicycl-dien-- 765- CAS Molar Mass Molecule IUPAC(1R,4E,9methyl4- - FormulaC10H16 Structure 164 °C 136.23Point (atC 760 D ** I/C 1 C/D 2 E 3 P 4 Family e hydrocarbonsAromatic o[3.1.0]h3S)42-ol-- 9941- number (g/mol) p- methyli mmHg) monoterpene propan4,11,11ylbicyclexane1- -- C10H14 875 - 177 °C 134.22 C D ** Cymene dene-1- 338 hydrocarbons trimethyo[3.1.0]h(1R,4E,9methyl2- - 6 Sabinenβ- Monoterpene propan- 877-- Aromatic SesquiterpeneAromatic ylbenzeexanelS)-48--- C10H16 99- 164 °C 136.23 C D ** Caryophpe- hydrocarbons 2- C15H24 4144- NA 204.35 C, I D ** +/++ p-Cymene monoterpene 1-methyl-4-propan-2-ylbenzenehydrocarbonsmonoterpene propan(1R,4E,9methyli4,11,11ne -- C10H14C10H14 87- 99-87-6177 °C 134.22 177 ◦CC D 134.22** C D ** Cymeneyllene ylbicycl 5 hydrocarbons hydrocarbons trimethydenebicS)24-- 6 β- o[3.1.0]h 87- Sesquiterpene yclo[7.2.ylbenzemethyli4,11,11l-8- - Caryoph exane C15H24 44- NA 204.35 C, I D ** +/++ hydrocarbons 0]undectrimethymethylidenene -1-- 338 ylleneβ- (1R,4E,9 875 - Sabinen SesquiterpeneMonoterpene propandenebic4-l4-ene8-- - 7- Monoterpene Caryoph S)- C10H16C15H24 44- 164NA °C 136.23204.35 C,C I D ** +/++ Sabinene 4-methylidene-1-propan-2-ylbicyclo[3.1.0]hexanehydrocarbons yclo[7.2.methyli C10H16 3387-41-5 164 ◦C 136.23 C D ** hydrocarbons yllenee hydrocarbons 4,11,1172- - 415 - 0]undecdenedenebic-1-- 338 trimethymethylylbicycl- 5 Sabinenβ- Monoterpene o[3.1.0]hpropanyclo[7.2.4-3ene- - 123877-- Sesquiterpene (1R,4E,9S)-4,11,11-trimethyl-β- SesquiterpeneMonoterpene l-8- C10H16 164 °C 136.23 C D ** β-Caryophyllene Caryophe hydrocarbons 0]undecmethyliexane27- -C15H24C15H24C10H16 -414435-- 87-44-5167NA °C 204.35136.23 NAC,C I D 204.35** +/++ C, I D ** +/++ hydrocarbons 8-methylidenebicyclo[7.2.0]undec-4-eneMyrcene hydrocarbons methyli yllene ylbicyclmethyl4-ene - 5 deneocta(1R,4E,9denebic 3 o[3.1.0]h-1,6S)37--- 123 β- Monoterpene yclo[7.2. methylimethyl4,11,11exanediene -- C10H16 -35- 167 °C 136.23 C D ** Myrcene hydrocarbons 0]undec- deneoctatrimethy(1R,4E,96,63-- 1233 Monoterpene Int.β J.- Environ.Monoterpene Res. Public Health 420-ene20, 17, x 87- 11 of 37 β-Myrcene 7-methyl-3-methylideneocta-1,6-dieneSesquiterpene dimethymethyli-l1,6S)-8--- C10H16C10H16 -35-123-35-3167 °C 136.23 167 ◦CC D 136.23** C D ** hydrocarbons CaryophMyrcene hydrocarbons 7- C15H24 44- NA 204.35 C, I D ** +/++ hydrocarbons deneocta4,11,11methylidienel-2- - 3 yllene methyl2- - 1275 Monoterpene trimethymethylidenebic-6,61,6-- 166.0 βInt.-Pineneβ J.- Environ. Res. Public Health[(2S,5S) 20320- , 1-7, x C10H16 -1238791-- 136.234 C, I D ** 11 of 37 β- SesquiterpenehydrocarbonsMonoterpene dimethyyclo[7.2.denebicdienel-8- °C Caryoph methyli5- C15H24C10H16 -44353 -- 167NA °C 204.35136.23 C,C I D ** +/++ Myrcene hydrocarbons 0]undecyclo[3.1.methyli6,6l-2-- - 110 Int.yllene(E) J. -Environ. Res. Public Healthdeneoctaethenyl 20220- , 1-7, x 12753 11 of 37 Monoterpene MonoterpenoiMonoterpene 1]heptandimethydenebicmethyli4-ene C10H18 63- 166.0 β-Pinene 6,6-dimethyl-2-methylidenebicyclo[3.1.1]heptaneβLinalool-Pinene [(2S,5S)-1,65-- - C10H16C10H16 -91-127-91-3NA 136.234170.25 166.0 C,C I D 136.234*** C, I D ** hydrocarbons hydrocarbonsd oxide yclo[7.2.denebicl7-e2- - O2 78- °C ◦ -oxide methylodiene5- 1273 Int. J. Environ.Monoterpene Res. Public Health 0]undecyclo[3.1.methylmethyli 3,7,720220- -, 1--7, x 1108 166.0 11 of 37 β-Pinene(E)- ethenylxolan6,6--2- C10H16 -74891- 136.234 C, I D ** Monoterpenoihydrocarbons 1]heptantrimethy[(2S,5S)denebic4-3ene- - C10H18 12363- °C Monoterpene Linaloolββ 3-- Monoterpene dimethyyl]propa5- 063 - 171.4NA 170.25 C D * yclo[3.1.75e- β 3-Carene 3,7,7-trimethylbicyclo[4.1.0]hept-3-ened oxide lbicyclo[methylil2-2-- C10H16C10H16O2 -110783574806-04-5-- 167 °C 136.234136.23 171.4 ◦C D 136.234** C D ** hydrocarbons MyrceneCarene-oxide(E)- hydrocarbons 1]heptanethenylmethylon-2-ol - 04- °C Monoterpenoi deneocta[(2S,5S)methyl4.1.0]he3,7,7- - C10H18 1276383 - Monoterpene xolanmethyli2-(5--2- 7485 166.0 βLinalool-Pinene trimethypt-1,6335e--ene - C10H16 -12391- NA 136.234170.25 C,C I D *** ββ 3-- hydrocarbonsMonoterpened oxide yl]propaethenyldenebic5- - O2 7806- 171.4°C -oxide methylomethyli3,7,7- C10H16 -110353 - 167 °C 136.23 C D ** (E)- lbicyclo[ethenyldiene - C10H16 7481408 136.234 C D ** MyrceneCarene(Z)- Monoterpenoihydrocarbons yclo[3.1.xolann-25-ol-2 - C10H18 6304- °C Monoterpenoid Linalool Monoterpenoi deneoctatrimethy4.1.0]he6,65-- C10H18 493 - 224.2NA 170.25 C D * (E)-Linalool-oxide 2-[(2S,5S)-5-ethenyl-5-methyloxolan-2-yl]propan-2-olLinaloolβ 3- Monoterpened oxide 1]heptanmethylo2-(5- C10H18O2O2 78065 -11063-78-8- 171.4 170.25 NAC D 170.25* C D * oxide d oxide yl]propadimethylbicyclo[pt--1,63-ene- C10H16O2 11- °C 136.234 C D ** Carene--oxideoxide hydrocarbons methyloethenylxolane -2- 04- °C 4.1.0]hendiene-2-ol 8 xolanl-2--2- 14057 (Z)- yl)propa3,7,72-5(5- -- 127 MonoterpenoiMonoterpene yl]propaptmethyli-6,63-ene- C10H18 74849- 224.2166.0 βLinalool-Pinene trimethyethenylmethylon-2-ol - C10H16 -91- 136.234170.25 C,C I D *** β 3- hydrocarbonsMonoterpened oxide dimethydenebicn-2-ol O2 1400611- 171.4°C -oxide(Z)- lbicyclo[xolan1,7,75- --2- C10H16 3 136.234 C D ** Carene hydrocarbons yclo[3.1.l-2- 047 - °C Monoterpenoid Monoterpenoi yl)propatrimethy4.1.0]he2-(5- C10H18 12746449- 224.2 (Z)-Linalool-oxide 2-(5-ethenyl-5-methyloxolan-2-yl)propan-2-ol Linalool Monoterpene 1]heptanmethylomethyli C10H18O2 5 14049-11-7166.0 170.25 224.2 ◦C D 170.25* C D * oxide β-Pinene Monoterpenoid oxide ethenylptlbicyclo[n--32--eneol - C10H16C10H18O2 --119145--- 212.0°C 136.234 C, I D ** -oxide hydrocarbons xolandenebic-2- 140 °C Borneol(Z)- 5e- 7 154.25 C * Monoterpenoid alcohol yl)propa2.2.1]he1,7,7- C10H18O 4939 - 224.2°C Linalool methyloyclo[3.1.3,7,7- 170.25 C D * d oxide trimethyptan-2- O2 46474811 - °C 1]heptantrimethyn-2-ol -oxide Monoterpenoi lbicyclo[xolanol -2- C10H18 -45- 212.0 Monoterpenoid β 3- Monoterpene 1,7,7e - 067 - 171.4 Borneol 1,7,7-trimethylbicyclo[2.2.1]heptan-2-olBorneol yl)propalbicyclo[ C10H18OC10H16 464-45-9136.234154.25 212.0 ◦C D 154.25*** C * alcohol Carene hydrocarbonsd alcohol trimethy2.2.1]he(1,7,7- O 464049 - °C 4.1.0]hen3,7,7-2-ol- trimethyptan-2- 7485 Monoterpenoi trimethylbicyclo[pt-3-ene C10H18 -20345- 212.0 Borneolβ 3- Monoterpene 1,7,7lol-2 -- 06- 171.4 154.25 C * d alcohol lbicyclo[2.2.1]he C10H16O 9 °C 136.234 C D ** Monoteropene-derived Bornyl Monoteropene trimethy C12H20 46447- 223.5 Bornyl acetate (1,7,7-trimethyl-2-bicyclo[2.2.1]heptanyl)Carene hydrocarbons acetate bicyclo[2ptan(1,7,7-2- C12H20O2- 04 -20347-65-3°C 196.286 223.5 ◦C 196.286* C * ester acetate Monoterpenoi-derived ester lbicyclo[4.1.0]he C10H18O2 -6545- 212.0°C Borneol trimethy.2.1]heptol 5 154.25 C * d alcohol pt2.2.1]he-3-ene O 20393 °C (1,7,7anyl)l-2- - Bornyl Monoteropene ptan-2- C12H20 47 - 223.5 bicyclo[2trimethyacetate 196.286 C * acetate -derived ester ol O2 20365- °C .2.1]heptl2,2-2-- Bornyl Monoteropene (1,7,7- C12H20 473 - 223.5 bicyclo[2dimethyanyl) 196.286 C * acetate -derived ester trimethy O2 65- °C .2.1]heptacetatel-3- 203 l-2- 793 - CampheBornyl MonoteropeneMonoterpene methylianyl)2,2- C12H20 47- 223.5157.5 bicyclo[2 C10H16 92- 196.286136.234 C D ** acetatene -hydrocarbonsderived ester dimethydenebicacetate O2 65- °C°C .2.1]hept 5 yclo[2.2.2,2l-3- 3 anyl) 79- Camphe Monoterpene 1]heptandimethymethyli 157.5 acetate C10H16 92- 136.234 C D * ne hydrocarbons denebicl-e3 - °C 2,2- 795 - Camphe Monoterpene yclo[2.2.methyli4- 157.5 dimethy C10H16 92- 136.234 C D * ne hydrocarbons 1]heptandenebicmethyl- °C l-3- 5 yclo[2.2.1e- 79- Camphe Monoterpene methyli 562 157.5 Terpine Monoterpenoi 1]heptanpropan4- - C10H16C10H18 92- 209.0 136.234 C D * ne hydrocarbons denebic -74- °C 154.25 C * n-4-ol d alcohol methyl2e- - O 5 °C yclo[2.2. 3 ylcycloh41- 1]heptan 562 Terpine Monoterpenoi propanmethylex-3-en-- C10H18 209.0 e -74- 154.25 C * n-4-ol d alcohol 112-ol- O °C 4- 5623 Terpine Monoterpenoi ylcycloh(1R)propan-1,3-- C10H18 209.0 methyl- -74- 154.25 C * n-4-ol d alcohol dimethyex-32-en- O °C 1- 3 ylcycloh1l-8ol- 562 Terpine Monoterpenoi propan- C10H18 385 209.0 (1R)expropan-3--1,3en-- -74- 154.25 C * n-4α--ol Sesquiterpened alcohol 2- O 6- 248.5°C dimethy12-ol- C15H24 3 204.35 I * Copaene hydrocarbons ylcycloh 25- °C (1R)yltricycll-8-1,3- - ex-3-en- 3855 dimethypropano[4.4.0.0- α- Sesquiterpene 1-ol 6- 248.5 2,7]decl-28-- - C15H24 204.35 I * Copaene hydrocarbons (1R)-1,3- 38525- °C propanyltricycl3-ene - α- Sesquiterpene dimethy 65- 248.5 o[4.4.0.0(1E,4E,82- C15H24 204.35 I * Copaene hydrocarbons l-8- 25- °C yltricycl2,7]decE)- - 385 propan- 5 α- Sesquiterpene o[4.4.0.02,6,6,93-ene - 6756- 248.5 α- 2- C15H24 204.35 I * Copaene hydrocarbonsSesquiterpene tetramet(1E,4E,82,7]dec- 253-- 166°C - Humule yltricycl C15H24 204.35 C D * hydrocarbons hylcyclo3-E)ene- 985 - 168 °C ne o[4.4.0.0 (1E,4E,8undeca2,6,6,9-- 6756 α- 2,7]dec- Sesquiterpene tetramet1,4,8E)- - 3- 166- Humule 3-ene C15H24 204.35 C D * hydrocarbons hylcyclo2,6,6,9triene- 67598- 168 °C neα- (1E,4E,8 Sesquiterpene tetrametundeca- 36- 166- Humule E)- C15H24 204.35 C D * hydrocarbons hylcyclo1,4,8- 98- 168 °C ne 2,6,6,9- 675 α- undecatriene - 6 Sesquiterpene tetramet 3- 166- Humule 1,4,8- C15H24 204.35 C D * hydrocarbons hylcyclo 98- 168 °C ne triene undeca- 6 1,4,8- triene

Int. J. Environ. Res. Public Health 2020, 17, x 11 of 37

2- [(2S,5S)- 5- Int. J. Environ. Res. Public Health 2020, 17, x 110 11 of 37 (E)- ethenyl- Monoterpenoi C10H18 63- Linalool 5- NA 170.25 C D * d oxide 2- O2 78- -oxide methylo [(2S,5S)- 8 Int. J. Environ. Res. Public Healthxolan 2020-2, -17, x 11 of 37 5- yl]propa 110 (E)- ethenyl- Monoterpenoi n-2-ol C10H18 63- Linalool 5- NA 170.25 C D * Int. J. Environ. Res.d oxide Public Health[(2S,5S) 202-(520-, 1-7, x O2 78- 11 of 37 -oxide methylo ethenyl5- - 8 xolan-2- 140110 (Z)(E)- ethenyl52- - Monoterpenoi yl]propa C10H18 4963-- 224.2 Linalool methylo[(2S,5S)5- - NA 170.25 C D * d oxide n-2-ol O2 1178-- °C --oxide xolanmethylo5- -2- 2-(5- 11078 (E)- yl)propaethenylxolan-2- Monoterpenoi ethenyl- C10H18 63- Linalool yl]propan-52-ol 140 NA 170.25 C D * (Z)- d oxide 5- O2 78- -oxide Monoterpenoi methylon1,7,7-2-ol- C10H18 49- 224.2 Linalool methylo 8 170.25 C D * d oxide trimethyxolan2-(5--2- O2 46411- °C -oxide xolan-2- Monoterpenoi yl]propalbicyclo[ethenyl- C10H18 -457 - 212.0 Borneol yl)propa 140 154.25 C * (Z)- d alcohol 2.2.1]hen-25-ol O 9 °C Monoterpenoi n-2-ol C10H18 49- 224.2 Linalool methyloptan2-(5--2- 170.25 C D * d oxide 1,7,7- O2 11- °C -oxide ethenylxolanol -2- trimethy 4641407 (Z)- yl)propa(1,7,75- - Monoterpenoi lbicyclo[ C10H18 -4945-- 212.0224.2 LinaloolBorneol trimethymethylon-2-ol 154.25170.25 C D * dd alcohol oxide 2.2.1]he O2O 203119 - °C -oxide xolan1,7,7l-2---2- Bornyl Monoteropene ptan-2- C12H20 477 - 223.5 bicyclo[2yl)propatrimethy 464 196.286 C * acetate -derived ester ol O2 65- °C Monoterpenoi .2.1]heptlbicyclo[n-2-ol C10H18 -45- 212.0 Borneol (1,7,7- 3 154.25 C * d alcohol 2.2.1]he1,7,7anyl)- O 9 °C trimethy trimethyacetateptan-2- 203464 l-2- Bornyl MonoteropeneMonoterpenoi lbicyclo[2,2ol- C12H20C10H18 -4745-- 223.5212.0 Borneol bicyclo[2 196.286154.25 C * acetate -derivedd alcohol ester dimethy2.2.1]he(1,7,7- O2O 659 - °C .2.1]hept trimethyptanl-3-2- 3 anyl) 20379- Camphe Monoterpene methylilol-2 - 157.5 Bornyl Monoteropene acetate C10H16C12H20 9247-- 223.5 136.234 C D * Int. J. Environ. Res. Public Health 2020, 17, 6506 ne hydrocarbons bicyclo[2denebic(1,7,7- °C 196.286 C * 11 of 36 acetate -derived ester 2,2- O2 655 - °C trimethyyclo[2.2..2.1]hept dimethy 2033 1]heptananyl)l-2- Bornyl Monoteropene l-3- C12H20 47- 223.5 bicyclo[2acetatee 79- 196.286 C * Campheacetate -Monoterpenederived ester methyli O2 65- 157.5°C .2.1]hept2,2Table4-- 2.C10H16Cont. 92- 136.234 C D * ne hydrocarbons denebic 3 °C dimethymethylanyl) - 5 yclo[2.2. acetatel1-3-- Boiling Chemical 1]heptan 56279- CAS Molar Mass Molecule IUPACCampheTerpine MonoterpenoiMonoterpene propanmethyli2,2- - FormulaC10H18 Structure 209.0157.5 Point (at 760 I/C 1 C/D 2 E 3 P 4 Family e C10H16 -9274--number 136.234154.25 C D (g/mol)* n-ne4-ol hydrocarbonsd alcohol dimethydenebic2- O °C mmHg) 4- 35 ylcyclohyclo[2.2.l-3- methyl- 79- Monoterpene Camphe Monoterpene 1]heptanexmethyli-3-en- 157.5 Camphene 2,2-dimethyl-3-methylidenebicyclo[2.2.1]heptane1- C10H16C10H16 92- 79-92-5136.234 157.5 C D 136.234* C D * hydrocarbons ne hydrocarbons denebic1-eol 562 °C ◦ Terpine Monoterpenoi propan- C10H18 5 209.0 (1R)yclo[2.2.4--1,3- -74- 154.25 C * n-4-ol d alcohol 2- O °C 1]heptandimethymethyl- 3 ylcycloh l-1e8- - ex-3-en- 385562 Monoterpenoid Terpine Monoterpenoi propan4- -- C10H18 209.0 Terpinen-4-ol 4-methyl-1-propan-2-ylcyclohex-3-en-1-olα- Sesquiterpene 1-ol C10H18O -746- -562-74-3248.5 154.25 209.0 C 154.25* C * alcohol n-4-ol d alcohol methyl2-- - C15H24O °C 204.35 ◦ I * Copaene hydrocarbons (1R)-1,3- 253 - °C yltricyclylcycloh1- dimethy 5625 Terpine Monoterpenoi o[4.4.0.0propanex-3-en- C10H18 209.0 l-8- -74- 154.25 C * Int.n- J.4- Environ.ol Res.d alcohol Public Health2,7]dec 2012-20ol- , 1-7, x O 385 °C 12 of 37 propan- 3 Sesquiterpene Int. αJ.- Environ.Sesquiterpene Res. Public Health ylcycloh(1R) 320-ene20-1,3, 1-7, x 6- 248.5 12 of 37 α-Copaene (1R)-1,3-dimethyl-8-propan-2-yltricyclo[4.4.0.02,7]dec-3-ene2- C15H24C15H24 3856-25-5204.35 248.5 CI 204.35* I * Copaene hydrocarbons dimethy(1E,4E,8ex-23--en- 25- °C ◦ hydrocarbons Int. J. Environ. Res. Public Healthyltricycl 2020, 17, x 12 of 37 methyl1lE)-8ol-- - 5 o[4.4.0.02- 385 (1R)methylpropan2,6,6,95-1,3--- 675 Int.α αJ.--- Environ.Sesquiterpene Res. Public Health 2,7]dec 20220- , 1-7, x 996- 248.5 12 of 37 Sesquiterpene MonoterpeneSesquiterpene propantetrametdimethy52-- - C15H24 3- 171.5166- 204.35 I * α-Humulene (1E,4E,8E)-2,6,6,9-tetramethylcycloundeca-1,4,8-trienePhellandCopaeneHumuleα- hydrocarbons methyl3-ene - C15H24C10H16C15H24 839925---6753-98-6°C 136.234204.35 166-168 CC◦ C D 204.35** C D * hydrocarbons hydrocarbonshydrocarbonsMonoterpene hylcyclopropanyltricycll2-8- - - 98- 168171.5°C °C renene (1E,4E,85- 38525 Phelland ylcyclohundeca2- - C10H16 836 - 136.234 C * α- hydrocarbons propano[4.4.0.02- - 99- °C reneα- SesquiterpeneMonoterpene propanmethylE)- - 62- 171.5248.5 Phelland ylcyclohexa2,7]dec1,4,82-1,3- --- C10H16C15H24 83- 136.234204.35 CI ** Copaene hydrocarbonshydrocarbons 2,6,6,92- - 67525- °C°C reneα- yltricycldienetriene3-5ene- 2 α- Sesquiterpene ylcyclohtetrametexa-1,3- 9935-- 166- Monoterpene Humule Monoterpene propano[4.4.0.0(1E,4E,81- - C15H24 171.5 204.35 C D * α-Phellandrene 2-methyl-5-propan-2-ylcyclohexa-1,3-dienePhelland hydrocarbons hylcycloexadiene-1,3 - C10H16C10H16 8398-- 99-83-2168 °C 136.234 171.5 ◦C 136.234* C * hydrocarbons ne hydrocarbons methyl2,7]decE)2-- -- °C rene undecadiene1- - 26 ylcycloh2,6,6,93-4ene- - 675 αα-- methyl1,4,81- - - 99- MonoterpeneSesquiterpene propanexatetramet(1E,4E,8-1,3- 3- 174.1166- TerpineHumule methyltriene4- - C10H16C15H24 86- 136.234204.35 CC DD ** α- hydrocarbonshydrocarbons hylcyclodieneE)2-- 9998-- 168°C °C nene Monoterpene propan4- - 5 174.1 Terpine ylcycloh1- C10H16 86- 136.234 C D * α- hydrocarbons undeca2,6,6,92- -- 996756- °C Monoterpene neα- Monoterpene propanmethyl- 5 174.1 α-Terpinene 1-methyl-4-propan-2-ylcyclohexa-1,3-dieneTerpine Sesquiterpene ylcyclohexatetramet1,4,8-1,3-- C10H16C10H16 863-- 99-86-5166- 136.234 174.1 ◦C D 136.234* C D * hydrocarbons Humule hydrocarbons 2- C15H24 °C 204.35 C D * ne hydrocarbons hylcyclodienetriene4- 985 - 168 °C αne- ylcyclohexa-1,3- 99- Monoterpene propanundeca2-(4- -- 6 174.1 Terpine exadiene-1,3 - C10H16 86- 136.234 C D * hydrocarbons methylc1,4,82- - 104 °C αne- diene2-(4- 5 Monoterpenoi yclohexylcyclohtriene - C10H18 82- 217.5 Terpine methylc2-(4- 104 154.249 C * α- d alcohol exa3-en-1,3-1-- O 56- °C Monoterpenoid ol Monoterpenoi yclohexmethylc- C10H18 10482- 217.5 α-Terpineol 2-(4-methylcyclohex-3-en-1-yl)propan-2-olTerpineα- yl)propadiene C10H18O 1 10482-56-1154.249 217.5 ◦C 154.249* C * alcohol Monoterpenoid alcohol yclohex3-en-1-- C10H18O 8256-- 217.5°C Terpineol n2--2(4-ol- 154.249 C * d alcohol yl)propa3-en-1- O 561 - °C ol methylc1- 104 α- yl)propan-2-ol 1 Monoterpenoi yclohexmethyl-- C10H18 82- 217.5 Terpine n-21-ol 154.249 C * d alcohol 3-en4--1- O 11256- °C αol- methyl1- - Monoterpene Monoterpene yl)propapropan- 41- 186.0 α-Terpinolene 1-methyl-4-propan-2-ylidenecyclohexeneTerpinol methyl4- - C10H16C10H16 1121124-27-2138.25 186.0 C D 138.25* C D * hydrocarbons α- hydrocarbons n-22--ol 27- °C ◦ ene Monoterpene propan4- - 1124- 186.0 Terpinol ylidenec1- C10H16 2 138.25 C D * α- hydrocarbons 2- 27- °C ene Monoterpene propanmethyl- 4- 186.0 Terpinol yclohexeylidenec C10H16 2 138.25 C D * hydrocarbons 2- 27- °C ene ne4- 112 α- yclohexeylidenec 2 Monoterpene propan3- - 4- 186.0 Terpinol yclohexene C10H16 138.25 C D * hydrocarbons methyli2- 27- °C ene ne3- β- ylidenecdene-6- 5552 Monoterpene methyli3- +/++ Phelland yclohexepropan- C10H16 -10- 175 °C 136.234 C, I * β- hydrocarbons methylidene-6- 555 + rene Monoterpene ne2- 2 +/++ Phellandβ- propandene-6-- C10H16 -55510- 175 °C 136.234 C, I * hydrocarbonsMonoterpene ylcycloh3- +/+++ Phellandrene propan2- - C10H16 -102 - 175 °C 136.234 C, I * hydrocarbons methyliexene + rene ylcycloh2- 2 β- dene1- -6- 555 Monoterpene ylcyclohexene +/++ Phelland methylpropan-- C10H16 -10- 175 °C 136.234 C, I * hydrocarbons exene1- + rene 42-- 2 β- methyl1- - 99- Monoterpene ylcyclohpropan- 183.0 Terpine methyl4- - C10H16 85- 136.234 C, I D * β- hydrocarbons exene2- 99- °C ne Monoterpene propan4- - 4 183.0 Terpine ylcycloh1- C10H16 85- 136.234 C, I D * β- hydrocarbons 2- 99- °C ne Monoterpene propanmethyl- 4 183.0 Terpine ylcyclohexa-1,4- C10H16 85- 136.234 C, I D * hydrocarbons 2- °C ne diene4- 4 β- ylcyclohexa-1,4- 99- Monoterpene (3Z)propan-3,7- 183.0 Terpine exadiene-1,4 - C10H16 13885- 136.234 C, I D * hydrocarbons dimethy2- °C (Z)ne-β - Monoterpene (3Z)diene-3,7 - 774 - 175.2 ylcyclohlocta- C10H16 138 136.234 C, I D +/++ Ocimene hydrocarbons (3Z)dimethy-3,7- 91- °C (Z)-β- Monoterpene exa1,3,6-1,4- - 13877- 175.2 dimethylocta- C10H16 3 136.234 C, I D +/++ Ocimene(Z)-β- hydrocarbonsMonoterpene trienediene 7791-- 175.2°C locta1,3,6- C10H16 136.234 C, I D +/++ Ocimene hydrocarbons (3Z)6-3,7- 913 - °C triene1,3,6- 138 dimethymethyl- 3 (Z)-β- Monoterpene triene6- 77- 175.2 locta2- - C10H16 136.234 C, I D +/++ Ocimene hydrocarbons methyl6- - 91- °C methyli1,3,6- methyl2- - 3 denetriene-6- 766 methyli2- Bergam Sesquiterpene (46-- 3- methylidene-6- C15H24 766 NA 208.38 I otene hydrocarbons methylpmethyl- 66- Bergam Sesquiterpene dene(4--6- 7663- ent2-3- C15H24 3 NA 208.38 I Bergamotene Sesquiterpenehydrocarbons methylp(4- 663-- enyl)bicmethyli C15H24 NA 208.38 I otene hydrocarbons methylpent-3- 663 - yclo[3.1.dene-6- 766 enyl)bicent-3- 3 Bergam Sesquiterpene 1]heptan(4- 3- yclo[3.1. C15H24 NA 208.38 I otene hydrocarbons methylpenyl)bic 66- 1]heptane yclo[3.1.ent-3- 3 e 1]heptanenyl)bic yclo[3.1.e 1]heptan e

Int. J. Environ. Res. Public Health 2020, 17, x 12 of 37

2- Int. J. Environ. Res. Public Healthmethyl 2020, -17, x 12 of 37 5- α- 99- Monoterpene propan- 171.5 Int.Phelland J. Environ. Res. Public Health 20220- , 17, x C10H16 83- 136.234 C * 12 of 37 hydrocarbons 2- °C rene methyl- 2 ylcycloh Int. J. Environ. Res. Public Health 20520- , 17, x 12 of 37 α- exa2--1,3- 99- Monoterpene propan- 171.5 Phelland methyldiene - C10H16 83- 136.234 C * hydrocarbons 252-- °C reneα- 1- 992- Monoterpene propanmethylylcycloh-- 171.5 Phelland methyl- C10H16 83- 136.234 C * hydrocarbons exa52--1,3- °C reneα- 4- 992 - α- Monoterpene ylcyclohpropandiene - 99- 171.5 Phelland Monoterpene propan- C10H16 83- 174.1 136.234 C * Terpine hydrocarbons 21-- C10H16 86- °C 136.234 C D * rene hydrocarbons exa2-1,3- - 2 °C ne ylcyclohmethyl- 5 ylcyclohdiene exa4-1,3- - α- exa1--1,3- 99- Monoterpene propandiene - 174.1 Terpine methyldiene - C10H16 86- 136.234 C D * hydrocarbons 142-- °C αne- 2-(4- 995- Monoterpene propanmethylylcycloh-- 174.1 Terpine methylc C10H16 86104- 136.234 C D * α- hydrocarbons exa42--1,3- °C neα- Monoterpenoi yclohex- C10H18 99825 -- 217.5 Terpine Monoterpene ylcyclohpropandiene - 174.1 154.249 C * Terpine d alcohol 3-en-1- C10H16O 8656-- °C 136.234 C D * ol hydrocarbons 22-(4- - °C ne yl)propaexa-1,3- 51 ylcyclohmethylc 104 α- dienen-2-ol Monoterpenoi yclohexexa-1,3-- C10H18 82- 217.5 Terpine 2-1(4-- 154.249 C * d alcohol methylc3diene-en-1 - O 10456- °C αol- methyl- Monoterpenoi yclohexyl)propa2-(4- - C10H18 821- 217.5 Terpine 4- 112 154.249 C * α- d alcohol methylc3n-en-2--ol1- O 10456- °C αol- Monoterpene propan- 4- 186.0 Terpinol Monoterpenoi yl)propayclohex1- - C10H18C10H16 821 - 217.5 138.25 C D * Terpine hydrocarbons 2- 27- °C 154.249 C * ene d alcohol methyl3-en-1-- O 56- °C ol ylidenecn-2-ol 2 yl)propa4- 1121 α- yclohexe1- Monoterpene propann-2-ol - 4- 186.0 Int. J. Environ. Res. Public Health 2020, 17, 6506 Terpinol methylne - C10H16 138.25 C D * 12 of 36 hydrocarbons 142-- 11227- °C eneα- 3- Monoterpene propanmethylylidenec-- 42- 186.0 Terpinol methyli C10H16 138.25 C D * hydrocarbons yclohexe42- 11227- °C eneαβ-- dene-6- 555 MonoterpeneMonoterpene ylidenecpropanne - 42- 186.0 +/++ TerpinolPhelland propanTable- 2.C10H16C10H16Cont. -10- 175 °C 136.234138.25 C,C I D ** hydrocarbonshydrocarbons 23-- 27- °C + reneene yclohexe2- 2 ylidenecmethyli 2 ylcyclohne Boiling Chemical β- yclohexedene-6- 555 CAS Molar Mass Molecule IUPACMonoterpene exene3- Formula Structure Point (at 760 +/++ I/C 1 C/D 2 E 3 P 4 Family Phelland propanne - C10H16 -10-number175 °C 136.234 C, I (g/mol)* hydrocarbons methyli1- mmHg) + rene 32-- 2 β- denemethyl-6-- 555 Monoterpene methyliylcycloh +/++ Phelland propan4- - C10H16 -10- 175 °C 136.234 C, I * ββ-- hydrocarbons deneexene-6- 55599- + Monoterpene rene MonoterpeneMonoterpene propan2- - 2 183.0 +/++ β-Phellandrene 3-methylidene-6-propan-2-ylcyclohexenePhellandTerpine propan1- - C10H16C10H16C10H16 -1085- 555-10-2175 °C 136.234136.234 175 C,CC, II D 136.234** C, I * +/+++ hydrocarbons hydrocarbonshydrocarbons ylcycloh2- °C ◦ + renene methyl2- - 24 ylcyclohexene ylcycloh4- β- exa1--1,4- 99- Monoterpene propanexene - 183.0 Terpine methyldiene - C10H16 85- 136.234 C, I D * hydrocarbons 142-- °C βne- (3Z)-3,7- 994- Monoterpene Monoterpene propanmethylylcycloh-- 138 183.0 β-Terpinene 1-methyl-4-propan-2-ylcyclohexa-1,4-dieneTerpine dimethy C10H16C10H16 85- 99-85-4136.234 183.0 C,C I D 136.234* C, I D * hydrocarbons (Z)-β- hydrocarbonsMonoterpene exa42--1,4- 77- 175.2°C ◦ neβ- locta- C10H16 994 - 136.234 C, I D +/++ Ocimene Monoterpenehydrocarbons ylcyclohpropandiene - 91- 183.0°C Terpine 1,3,6- C10H16 85- 136.234 C, I D * hydrocarbons (3Z)2-3,7- 3 °C ne exatriene-1,4- 1384 ylcyclohdimethy Monoterpene (Z)-β- Monoterpene diene6- 77- 175.2 (Z)-β-Ocimene (3Z)-3,7-dimethylocta-1,3,6-triene(3Z)exalocta--1,43,7--- C10H16C10H16 13877-91-3136.234 175.2 ◦C,C I D 136.234 +/++ C, I D +/++ hydrocarbons Int.Ocimene J. Environ. hydrocarbons Res. Public Health methyl 2020, 17- , x 13891- °C 13 of 37 dimethydiene1,3,6- (Z)-β- Monoterpene 2- 773- 175.2 (3Z)loctatriene-3,7- - C10H16 136.234 C, I D +/++ Int.Ocimene J. Environ. hydrocarbons Res. Public Health methyli 2020, 17, x 13891- °C 13 of 37 dimethy1,3,66- - (Z)-β- Monoterpene dene4,8--6- 777663 - 175.2 methyltrienelocta- - C10H16 199 136.234 C, I D +/++ Sesquiterpene 6-methyl-2-methylidene-6-(4-methylpent-OcimeneBergam hydrocarbonsSesquiterpene dimethy(4- 913-- °C Bergamotene Homoterpene 1,3,64,862---- C15H24C15H24 45-7663-66-3195.6NA 208.38 NAI 208.38 I hydrocarbons 3-enyl)bicyclo[3.1.1]heptaneDMNTotene hydrocarbons methylplnona- C11H18 199663 - 150.26 I +/++ Int. J. Environ.hydrocarbons Res. Public Health dimethymethylmethylitriene 2020, - 17, x 61- °C 13 of 37 Homoterpene ent1,3,7-3-- 453- 195.6 DMNT denelnona62- -6-- C11H18 7660 150.26 I +/++ Int. J. Environ.hydrocarbons Res. Public Health enyl)bic triene2020, 17, x 61- °C 13 of 37 Bergam Sesquiterpene methylmethyli1,3,7(4-- - 3- yclo[3.1. C15H24 0 NA 208.38 I otene hydrocarbons methylpdenetriene3,3,74,82---6- - 76666- 1]heptan 199 Bergam Sesquiterpene trimethymethylidimethyent4,8(4--3- 33- Homoterpene 3,3,7e - C15H24 19945- 195.6NA 208.38 I DMNTotene hydrocarbons methylpdimethydeneenyl)biclnonal-8-6- C11H18 76666- 150.26 I +/++ Homoterpene Homoterpenehydrocarbons trimethy 4754561-- 195.6°C DMNT 4,8-dimethylnona-1,3,7-trieneLongifolBergamDMNT SesquiterpeneSesquiterpene yclo[3.1.methylilnonaent1,3,7(4--3-- C11H18C11H18 33- 19945-61-0252.2 150.26 195.6 CI 150.26+/++ I +/++ hydrocarbons hydrocarbons l-8- C15H24 -61200- - NA°C 208.38204.35 ◦CI D oteneene hydrocarbons methylp1]heptanenyl)bicdenetric1,3,7triene- 47566- °C Longifol Sesquiterpene methyli 07 252.2 yclo[3.1.yclo[5.4.enttrienee- 3- C15H24 -203 - 204.35 C D ene hydrocarbons denetric3,3,7- °C 1]heptanenyl)bic0.02,9]u 7 trimethy yclo[5.4.yclo[3.1.ndecane3,3,7e - 0.02,9]ul-8- 1]heptantrimethymethyl 475 Sesquiterpene Longifol Sesquiterpene ndecanemethylil-e8 - 252.2 Longifolene 3,3,7-trimethyl-8-methylidenetricyclo[5.4.0.02,9]undecane2- C15H24C15H24 475-20-475-20-7204.35 252.2 ◦C D 204.35 C D hydrocarbons Longifolene Sesquiterpenehydrocarbons methylimethyldenetric 252.2°C [(1R,2R)- C15H24 -207- 204.35 C D ene hydrocarbons denetricyclo[5.4.2- 399 °C Methyl 3-oxo-2- 7 Jasmonate [(1R,2R)yclo[5.4.0.02,9]u- C13H20 24- 302.9 jasmona [(Z)- 399 224.296 I Methyl ester 30.02,9]undecane-oxo-2- O3 52- °C Methyl Jasmonate methylte Jasmonate pent-2- C13H20 24- 302.9 jasmona ndecanemethyl[(Z)- C13H20O3 2 39924-52-2224.296 302.9 IC 224.296 I jasmonate ester 2-[(1R,2R)-3-oxo-2-[(Z)-pent-2-enyl]cyclopentyl]acetate ester enyl]cyc O3 52- °C ◦ te pentmethyl2-2- lopentyl 2 enyl]cyc[(1R,2R)- ]acetate2- 399 Methyl [(1R,2R)lopentyl3-oxo-2- Jasmonate methyl C13H20 39924- 302.9 jasmonaMethyl 3]acetate-oxo[(Z)--2- 119 224.296 I Jasmonateester 2- C13H20O3 2452-- 302.9222.0°C Methyl salicylate Benzoate ester methyl 2-hydroxybenzoatejasmonasalicylatte Benzoate ester methylpent[(Z)--2- C8H8O3C8H8O3 -36-119-36-8224.296152.147 222.0 ◦CI 152.147++++ I ++++ Methyl ester hydroxy O3 119522- °C tee enyl]cycpent2--2- 8 222.0 salicylat Benzoate ester benzoate C8H8O3 -362 - 152.147 I ++++ hydroxyenyl]cyclopentyl °C e (3E,7Z)- 8 ]acetate benzoatelopentyl4,8,12- 622 (3methylE,7Z)- Methyl Homoterpene trimethy]acetate 35119- 293.2 TMTT methyl4,8,122- - C16H26 622 222.0 218.38 I +/++ salicylatMethyl hydrocarbonsBenzoate ester ltrideca- C8H8O3 119-0636-- °C 152.147 I ++++ Homoterpene trimethyhydroxy2- 35- 293.2222.0°C TMTTe 1,3,7,11- C16H26 78 218.38 I +/++ salicylat Benzoate ester benzoate C8H8O3 -36- 152.147 I ++++ hydrocarbons ltridecahydroxytetraene- 06- °°CC e (3E,7Z)- 8 benzoate1,3,7,112- - 7 4,8,12- 622 tetraene(3methylE,7Z)- Homoterpene trimethy2- 35- 293.2 TMTT 4,8,125- - C16H26 622286 218.38 I +/++ hydrocarbons ltrideca- 06- °C α- HomoterpeneMonoterpene trimethymethylpropan-- 357-- 293.2 TMTT 1,3,7,11- C16H26C10H16 7 152 °C 218.38136.23 CI +/++ Thujene hydrocarbons ltrideca52-- - 2860605- °C α- Monoterpene propan1,3,7,11tetraene-- 77- ylbicycl C10H16 2 152 °C 136.23 C 2- Thujene hydrocarbons o[3.1.0]htetraene2- 05- methyl- ylbicyclex-22--en 2 5- 286 o[3.1.0]hmethyl7,11- - α- Monoterpene expropan-2-en - 7- dimethy5- C10H16 286 152 °C 136.23 C Thujene hydrocarbons 2- 05- α- Monoterpene propan7,11l-3-- - 1877- β- ylbicycl C10H16 2 152 °C 136.23 C Thujene hydrocarbonsSesquiterpene dimethymethyli2- 0594- 279.6 Farnese o[3.1.0]hylbicycll-3- C15H24 1872 204.35 I ++ β- hydrocarbons denedod 84- °C ne Sesquiterpene o[3.1.0]hmethyliex-2-en 94- 279.6 Farnese eca- C15H24 8 204.35 I ++ hydrocarbons denedodex7,11-2-en- 84- °C ne 1,6,10- dimethy triene7,11eca-- 8 dimethy1,6,10l-3-- 187 β- 1 I/C = Inducible/constitutive: forest VOC types. 2 C/D = Conifers/deciduous: tree types. 3 E = Emissions Sesquiterpene methylitrienel-3- 18794- 279.6 Farneseβ- C15H24 204.35 I ++ 1[3,8,42]:Sesquiterpenehydrocarbons highly abundant denedodmethyli emissions: ****; abundant2 emissions:9484-- ***;279.6°C moderately abundant3 emissions: Farnesene I/C = Inducible/constitutive: forestC15H24 VOC types. C/D = Conifers/deciduous:204.35 tree types.I E = Emissions ++ **; commonhydrocarbons emissions: denedod *.eca 4 -P = Persistence [3,8,42]: less than848- 10 min:°C +; 10–60 min: ++; 1 h–24 h: +++; ne [3,8,42]: highly abundant emissions: ****; abundant emissions: ***; moderately abundant emissions: more than 24 h: ++++. 1,6,10eca- - 8 **; common emissions: *. 4 P = Persistence [3,8,42]: less than 10 min: +; 10–60 min: ++; 1 h–24 h: +++; 1,6,10triene- more1 than 24 h: ++++. 2 3 3.3. BVOCs I/C = Inducible/constitutive: and Plant-Derivedtriene Essential forest VOC Oils types. C/D = Conifers/deciduous: tree types. E = Emissions 1[3,8,42]: I/C = Inducible/constitutive: highly abundant emissions: forest VOC ****; types. abundant 2 C/D emissions:= Conifers/deciduous: ***; moderately tree types.abundant 3 E = Emissionsemissions: 3.3. BVOCs[3,8,42]:Apart**; common andfrom highly Plant emissions: being abundant-Derived plant-emitted *. emissions:4 EssentialP = Persistence Oilscomponents****; abundant [3,8,42]: of lessemissions: the than atmosphere, 10 ***;min: moderately +; 10 forest–60 min: abundantVOCs ++; 1 can h emissions:–24 be h: found +++; in plant-derivedApart**;more common than from products24 emissions: beingh: ++++. plant-emitted and, *. 4 P in = particular,Persistence components [3,8,42]: in distilled ofless the than essential atmosphere, 10 min: oils, +; 10 theforest–60 lipophilicmin: VOCs ++; 1 can h result–24 be h: found of+++; steam in plant-deriveddistillationmore than of products24aromatic h: ++++. and,plants in [52]. particular, Although in distilled essential essential oils do contain oils, the BVOCs, lipophilic not result all BVOCs of steam are distillationpresent3.3. BVOCs in essentialofand aromatic Plant oils,-Derived plants and Essential some [52]. Although molecules Oils essential included oils in essentialdo contain oils BVOCs, are not not part all of BVOCs the BVOC are 3.3.molecular BVOCs suite and Plantbut are-Derived rather Essential artefacts Oils of distillation. Essential oils are dominated by volatile terpenes presentApart in essentialfrom being oils, plant-emitted and some molecules components included of the in atmosphere, essential oils forest are notVOCs part can of be the found BVOC in and terpenoids (C10 and C15) and, in specific cases, they contain phenylpropanoids, oxylipins, and, molecularplant-derivedApart suite from productsbut being are ratherplant-emitted and, artefacts in particular, componentsof distillation. in distilled of Essential the essential atmosphere, oils oils,are dominated theforest lipophilic VOCs by volatilecan result be foundterpenes of steam in more rarely, N- and S-containing molecules. They do not contain appreciable quantities of isoprene, andplant-deriveddistillation terpenoids of productsaromatic (C10 and and,plantsC15) inand, [52]. particular, in Although specific in cases, distilled essential they essential oilscontain do contain oils,phenylpropanoids, the BVOCs, lipophilic not result oxylipins, all BVOCs of steam and, are moredistillationpresent rarely, in essentialof N- aromatic and S-containing oils, plants and some [52]. molecules. Although molecules They essential included do not oils incontain essentialdo contain appreciable oils BVOCs, are quantities not not part all of of BVOCs theisoprene, BVOC are presentmolecular in suite essential but are oils, rather and artefacts some molecules of distillation. included Essential in essential oils are oilsdominated are not by part volatile of the terpenes BVOC molecularand terpenoids suite but(C10 are and rather C15) artefacts and, in ofspecific distillation. cases, Essentialthey contain oils arephenylpropanoids, dominated by volatile oxylipins, terpenes and, andmore terpenoids rarely, N- (C10 and S-containingand C15) and, molecules. in specific They cases, do they not containcontain phenylpropanoids,appreciable quantities oxylipins, of isoprene, and, more rarely, N- and S-containing molecules. They do not contain appreciable quantities of isoprene, Int. J. Environ. Res. Public Health 2020, 17, x 13 of 37 Int. J. Environ. Res. Public Health 2020, 17, x 13 of 37

4,8- 199 Int. J. Environ. Res. Public Healthdimethy 2020, 17, x 13 of 37 Homoterpene 4,8- 45- 195.6 DMNT lnona- C11H18 199 150.26 I +/++ hydrocarbons dimethy 61- °C Homoterpene 1,3,7- 45- 195.6 DMNT lnona4,8- - C11H18 0 150.26 I +/++ hydrocarbons triene 61199- °C dimethy1,3,7- Homoterpene 450 - 195.6 DMNT lnonatriene3,3,7-- C11H18 150.26 I +/++ hydrocarbons 61- °C trimethy1,3,7- 3,3,7- 0 trienel-8- trimethy 475 Longifol Sesquiterpene methyli 252.2 3,3,7l-8- - C15H24 -20- 204.35 C D ene hydrocarbons denetric 475 °C Longifol Sesquiterpene trimethymethyli 7 252.2 yclo[5.4. C15H24 -20- 204.35 C D ene hydrocarbons denetricl-8- °C 0.02,9]u 4757 Longifol Sesquiterpene yclo[5.4.methyli 252.2 ndecane C15H24 -20- 204.35 C D ene hydrocarbons 0.02,9]udenetric °C methyl 7 ndecaneyclo[5.4. 2- 0.02,9]umethyl [(1R,2R)- ndecane2- 399 Methyl 3-oxo-2- Jasmonate [(1R,2R)methyl- C13H20 24- 302.9 jasmona [(Z)- 399 224.296 I Methyl ester 3-oxo2- -2- O3 52- °C te Jasmonate pent-2- C13H20 24- 302.9 jasmona [(1R,2R)[(Z)- - 2 224.296 I ester enyl]cyc O3 52399- °C Methylte 3pent-oxo--22-- Jasmonate lopentyl C13H20 242 - 302.9 jasmona enyl]cyc[(Z)- 224.296 I Int. J. Environ. Res. Public Health 2020, 17, 6506 ester ]acetate O3 52- °C 13 of 36 te lopentylpent-2- methyl 2 Methyl enyl]cyc]acetate 119 2- 222.0 salicylat Benzoate ester lopentylmethyl C8H8O3 -36- 152.147 I ++++ Methyl hydroxy 119 °C e ]acetate2- 8 222.0 salicylat Benzoate ester benzoateTable 2.C8H8O3Cont. -36- 152.147 I ++++ hydroxymethyl °C Methyle (3E,7Z)- 1198 benzoate2- 222.0 salicylat Benzoate ester 4,8,12- C8H8O3 622-36- 152.147Boiling I ++++ Chemical hydroxy(3E,7Z)- CAS°C Molar Mass Molecule IUPACe Homoterpene trimethy Formula Structure 358- 293.2 Point (at 760 I/C 1 C/D 2 E 3 P 4 Family TMTT benzoate4,8,12- C16H26 622number 218.38 I (g/mol) +/++ hydrocarbons ltrideca- 06- °C mmHg) Homoterpene trimethy(3E,7Z)- 35- 293.2 TMTT 1,3,7,11- C16H26 7 218.38 I +/++ hydrocarbons ltrideca4,8,12-- 06622- °C tetraene Homoterpene Homoterpene trimethy1,3,7,11- 357 - 293.2 TMTT (3E,7Z)-4,8,12-trimethyltrideca-1,3,7,11-tetraeneTMTT 2- C16H26C16H26 62235-06-7218.38 293.2 CI 218.38+/++ I +/++ hydrocarbons tetraeneltrideca- 06- °C ◦ hydrocarbons methyl- 1,3,7,112- - 7 5- 286 methyltetraene- α- Monoterpene propan- 7- 52-- C10H16 286 152 °C 136.23 C Thujene hydrocarbons 2- 05- Monoterpene α- Monoterpene propanmethyl- 7- α-Thujene 2-methyl-5-propan-2-ylbicyclo[3.1.0]hex-2-enylbicycl C10H16C10H16 2 2867-05-2152 °C 136.23 152 ◦CC 136.23 C hydrocarbons Thujene hydrocarbons 25-- 05286- o[3.1.0]h α- Monoterpene ylbicyclpropan- 72- ex-2-en C10H16 152 °C 136.23 C Thujene hydrocarbons o[3.1.0]h2- 05- 7,11- ylbicyclex-2-en 2 dimethy o[3.1.0]h7,11- l-3- 187 β- dimethyex-2-en Sesquiterpene Sesquiterpene methyli 94- 279.6 β-Farnesene 7,11-dimethyl-3-methylidenedodeca-1,6,10-trieneFarnese 7,11l-3-- C15H24C15H24 18718794-84-8204.35 279.6 CI 204.35++ I ++ hydrocarbons β- hydrocarbons denedod 84- °C ◦ ne Sesquiterpene dimethymethyli 94- 279.6 Farnese eca- C15H24 8 204.35 I ++ hydrocarbons denedodl-3- 84187- °C neβ- 1,6,10- Sesquiterpene methylieca- 948 - 279.6 Farnese triene C15H24 204.35 I ++ hydrocarbons denedod1,6,10- 84- °C ne 1 2 3 1 I/C = Inducible/constitutive: forest VOC types. 2 C/D = Conifers I/C/ deciduous:= Inducible/constitutive: tree types.trieneeca- forest3 E = VOCEmissions types. [ C/D3,8,42 = Conifers/deciduous:]: highly8 abundant tree emissions: types. E ****;= Emissions abundant emissions: ***; moderately abundant emissions: **; common emissions: *. 4 P = Persistence[3,8,42]:1 I/C[3 ,=8 ,Inducible/constitutive:42 highly]: less abundant than 101,6,10 min: emissions:- forest+; 10–60 VOC ****; min:types. abundant++ 2 C/D; 1 emissions: = h–24 Conifers/deciduous: h: +++ ***; ;moderately more than tree types.abundant 24 h: 3++++ E = emissions:Emissions. **;[3,8,42]: common highly emissions: abundant triene*. 4emissions: P = Persistence ****; abundant [3,8,42]: less emissions: than 10 ***;min: moderately +; 10–60 min: abundant ++; 1 h –emissions:24 h: +++; more**;1 I/C common = than Inducible/constitutive: 24 emissions: h: ++++. *. 4 P =forest Persistence VOC types. [3,8,42]: 2 C/D less = Conifers/deciduous: than 10 min: +; 10– 60tree min: types. ++; 3 1E h=– Emissions24 h: +++; more[3,8,42]: than highly 24 h: abundant++++. emissions: ****; abundant emissions: ***; moderately abundant emissions: 3.3. BVOCs**; common and Plant emissions:-Derived *. 4 EssentialP = Persistence Oils [3,8,42]: less than 10 min: +; 10–60 min: ++; 1 h–24 h: +++; 3.3. BVOCsmore than and 24 Plant h: ++++.-Derived Essential Oils Apart from being plant-emitted components of the atmosphere, forest VOCs can be found in plant-derivedApart from products being plant-emitted and, in particular, components in distilled of the essential atmosphere, oils, theforest lipophilic VOCs can result be offound steam in 3.3. BVOCs and Plant-Derived Essential Oils distillationplant-derived of aromaticproducts plants and, in [52]. particular, Although in distilledessential essential oils do contain oils, the BVOCs, lipophilic not result all BVOCs of steam are presentdistillationApart in essentialfrom of aromatic being oils, plant-emitted plants and some [52]. moleculesAlthough components essentialincluded of the oils inatmosphere, essentialdo contain oils forest BVOCs,are VOCs not not part can all of be BVOCs the found BVOC are in molecularpresentplant-derived in suite essential products but are oils, rather and,and artefacts in some particular, molecules of distillation. in distilled included Essential essential in essential oils oils,are dominated oils the are lipophilic not by part volatile result of the ofterpenes BVOC steam andmoleculardistillation terpenoids suite of aromatic (C10but are and rather plants C15) artefacts and, [52]. in Although specificof distillation. cases, essential theyEssential oils contain do oils contain phenylpropanoids,are dominated BVOCs, by not volatile oxylipins, all BVOCs terpenes and, are moreandpresent terpenoids rarely, in essential N- (C10and S-containing oils,and C15)and someand, molecules. in molecules specific They cases, included do they not incontain essential appreciablephenylpropanoids, oils are quantities not part oxylipins, of of the isoprene, BVOC and, moremolecular rarely, suite N- butand are S-containing rather artefacts molecules. of distillation. They do Essential not contain oils appreciableare dominated quantities by volatile of isoprene, terpenes and terpenoids (C10 and C15) and, in specific cases, they contain phenylpropanoids, oxylipins, and, more rarely, N- and S-containing molecules. They do not contain appreciable quantities of isoprene, Int. J. Environ. Res. Public Health 2020, 17, 6506 14 of 36

3.3. BVOCs and Plant-Derived Essential Oils Apart from being plant-emitted components of the atmosphere, forest VOCs can be found in plant-derived products and, in particular, in distilled essential oils, the lipophilic result of steam distillation of aromatic plants [52]. Although essential oils do contain BVOCs, not all BVOCs are present in essential oils, and some molecules included in essential oils are not part of the BVOC molecular suite but are rather artefacts of distillation. Essential oils are dominated by volatile terpenes and terpenoids (C10 and C15) and, in specific cases, they contain phenylpropanoids, oxylipins, and, more rarely, N- and S-containing molecules. They do not contain appreciable quantities of isoprene, highly reactive chemical species such as GLVs (although occasionally found in essential oils from Camellia sinensis, Viola odorata, Carpinus betulus, Fragaria vesca, Rubus idaeus), or any of the volatile but hydrophilic compounds found in hydrosols [53]. Essential oils have a higher percentage of heavier compounds (sesquiterpenes and sesquiterpenoids) compared to atmospheric BVOCs, due to higher temperatures involved in distillation that allow vaporization of the less volatile compounds (the high-boiling ones), and are mainly obtained from plant species with storage structures (glandular trichomes, resiniferous ducts, etc.). Many essential oils seem capable of exerting interesting pharmacological activities, even if not all essential oils are active and no single essential oil exerts all these activities. Moreover, given that essential oils are inherently perceptively salient, they can have mood-altering effects, which are mediated not by classical pharmacological mechanisms but by olfactory images. A simplified list of the most common and noteworthy activities of essential oils upon inhalation includes general antimicrobial ones and specific effects [54–57]: antimicrobial effects on antibiotic-resistant bacterial strains; • antitussive, mucoactive, bronchodilation, and antispasmodic activities on the respiratory system; • non-olfactory-mediated psychopharmacological effects on arousal, activation, memory loss, • dementia, cognitive performance, anxiety, quality of life, quality of sleep; antioxidant effect; • antinociceptive, anti-inflammatory, and cytotoxic activity; • anti-nausea and spasmolytic effects on the intestine. • 3.4. Evidence about the General Effects of Forest VOCs on Health From a pharmacokinetic point of view, when visiting a forest, monoterpene VOCs such as limonene and pinene are mainly absorbed through inhalation, their blood levels rapidly rise after exposure, and they are mostly eliminated unchanged both in exhaled air and in the urine [58]. Accumulation in the adipose tissue has been demonstrated for some BVOCs like limonene [59], as well as some degree of metabolization for terpenes like pinene [60]. Their general activity on inflammation, stress, sleep, and psychological behavior is described below. In particular, among monoterpenes, limonene and pinene are important for their biological activities even on human subjects [36,58] and, therefore, their health properties have been described in dedicated paragraphs.

3.4.1. Immune System and Inflammation A recent review synthesized available evidence on the immune function enhancing effects of essential oils and, in particular, results of studies about forest bathing were discussed, thus suggesting that even 2-h-long forest walks can be associated with a significant increase in Natural Killer (NK) cell count and activity and can augment the number of cytolytic molecules expressing cells, with such variations lasting for many days after the experience, both in healthy subjects and in individuals with cancer-related pain [61]. Some studies included in this review also showed an effect of forest bathing on serum levels of IL-8, IL-6, and TNFα [61]. These findings confirmed the main results of preclinical laboratory experiments [62]. As with all studies about forest bathing, the suggestion that the mechanism for the observed health benefits is due to the inhalation of forest BVOCs must be balanced by the possible role of mediators like other sensory or non-sensory stimulators [63]. Int. J. Environ. Res. Public Health 2020, 17, 6506 15 of 36

A review of preclinical studies analyzed available evidence regarding the effects of the most common volatile terpenoids found among BVOCs on inflammation and concluded that these compounds might act as inhibitors of pro-inflammatory mediators such as NO, TNF-α, and PGE2, thus modulating signal transduction pathways involving transcription factors like NF-κB and the mitogen-activated protein kinase (MAPK) [4]. Moreover, some terpenoids can directly interact with TRP receptors (implicated in nociception and inflammatory responses), reduce oxidative stress, and stimulate cell autophagy. The authors reported that, although these activities are not limited to forest bathing and can be exploited through skin applications or oral intake of essential oils, the contact during forest bathing may be safer, although less beneficial [4]. In any case, only a small number of preclinical studies have investigated the role of total extracts of forest BVOCs: volatile compounds extracted from hinoki wood essential oil have been reported to increase in vitro the natural killer (NK) cell activity by enhancing the expression of cytolytic enzymes [64]; also, an extract obtained from pinecones has been found to protect bovine mammary epithelial cells, stimulated with lipopolysaccharide (LPS), from oxidative stress after downregulating cyclooxygenase-2 (COX-2) expression [65]. On the other hand, single terpenes (α-phellandrene, 1,8 cineole, linalool, and β-caryophyllene) have been successfully used as pre-treatment to reduce the levels of interleukins, TNF-α, and iNOS in cellular and animal inflammatory-induced models [66–69]. Furthermore, mitogen-activated protein kinase (MAPK) signal transduction pathways (e.g., JNK and p38) can be inhibited by myrcene, limonene, and borneol [70,71]. Interestingly, β-caryophyllene has been shown to bind the peripheral receptor for cannabinoids (CB2R) and modulate the immune function [72,73]. Additionally, terpene treatment is able to reduce nucleus translocation, phosphorylation, and expression levels of NF-kB [4] and Nrf2 [74–76], the main transcriptional factors regulating levels of pro-inflammatory mediators. Moreover, many studies have demonstrated some BVOCs’ (i.e., myrcene, linalool, 1,8 cineole, α- and γ-terpinene) antioxidant properties such as the decrease of Reactive Oxygen Species (ROS), Matrix Metallo-Proteinase (MMP), and Nitric Oxide (NO) production [77–80]. Finally, inhibition of neuro-inflammation has been shown in vitro for 1,8-cineole [81] and β-caryophyllene [82,83] and in in vivo animal models for d-limonene [84] and linalool [85].

3.4.2. Nervous System and Psychological Behavior A systematic review on the general effects of forest bathing found that this meditative practice can be associated with positive health benefits, like a reduction in heart rate and blood pressure, increased relaxation, ameliorated general wellbeing, and improvement of depression scores [86], although available evidence is still limited and observed effects are likely to be multifactorial, thus probably depending not only on the presence of BVOCs in the atmosphere but also on the whole natural, green context [87]. These results are in line with preclinical studies on animal behavioral models investigating BVOCs’ neurological role in central nervous system (CNS) depression. In fact, BVOCs have been able to reduce locomotor activity and increase muscle relaxation, with consequent improvement of sleep, pain, and anxiety in mice [88–90]. Recently, it has been reported that substances derived from pine trees, such as α-pinene and 3-carene, can enhance sleep by acting as a positive modulator for GABA-A-BZD receptors [91]. Similar effects are reported for borneol, verbenol, isopulegol, and pinocarveol [92,93]. Moreover, inhaled linalool and β-pinene have shown anxiolytic [94,95] and antidepressive [96,97] properties in different animal models.

3.4.3. Endocrine System and Stress A systematic review concluded that forest bathing can induce a state of physiological relaxation, with a concomitant reduction in stress hormone levels, and it can also exert beneficial effects on general stress-related health outcomes, such as short-term improvements of cardiovascular and metabolic parameters, including reduced glucose levels [98]. A very recent systematic review of 22 clinical studies analyzing the effects of forest bathing on stress discovered that salivary cortisol levels were significantly lower in forest groups compared to control groups both before and after the intervention Int. J. Environ. Res. Public Health 2020, 17, 6506 16 of 36 and pointed out that, although further research is needed, forest bathing can significantly influence cortisol levels in the short term in such a way as to reduce stress, with anticipated placebo effects playing an important role in this [99]. In animal models, forest VOCs have shown a positive effect on stress response [100,101], whilst levels of stress hormones (i.e., plasma corticosterone and adrenaline) have not been influenced by limonene and α-pinene [102,103]. On the other hand, limonene may protect PC12 cells against corticosterone-induced neurotoxicity via the modulation of AMP-activated protein kinase cascade [104].

3.5. Limonene Limonene (1-methyl-4-prop-1-en-2-ylcyclohexene) is a monocyclic monoterpene hydrocarbon, a cyclohex-1-ene substituted by a methyl group at position 1 and a prop-1-en-2-yl group at position 4, respectively. Given that limonene has a carbon chiral center at position 4, it occurs as two optical isomers: D-limonene or [R-(+)-isomer] and L-limonene or [S-(+)-isomer]. Of the two, D-limonene (also called “citrene” or “carvene”) is the most abundant in plants and it is typical of Rutaceae such as orange, lemon, mandarin, etc. On the other hand, L-limonene is far less common and it can be found in essential oils obtained from Pinus spp., Illicium verum, and Mentha spp., while the D-L mixture (dipentene) is even less common [53,105]. Table3 reports average contents in D-limonene of some essential oils derived from trees [106].

Table 3. Average content of D-limonene in some tree-derived essential oils [106].

Part of the Plant Plant Source Botanical Family Content (%) * Used Boswellia rivae Engl. Burseraceae Oleoresin 28.0–45.0 Boswellia sacra Flueck Burseraceae Oleoresin 6.0–21.9 Bursera graveolens Burseraceae Oleoresin 58.6–63.3 (Kunth) Triana et Planch Canarium luzonicum (Blume) A. Gray, C. Burseraceae Oleoresin 26.9–65.0 vulgare Leenh. Ravensara aromatica Lauraceae Leaves 13.9–22.5 Sonnerat Abies alba Mill. Pinaceae Leaves and branches 28.5–54.7 Abies spectabilis (D. Don) Pinaceae Leaves and branches 29.6 Spach Pinus mugo Turra Pinaceae Leaves and branches 6.1–37.1 Citrus spp. Rutaceae Fruit peel 27.0–95.0 * Content (%) = the relative quantity, expressed as a range of percentages, of D-limonene included in tree-derived essential oils.

3.5.1. Anti-Inflammatory Activity In a systematic review investigating the anti-inflammatory potential of forest BVOCs, D-limonene was shown to be able to modulate many pro-inflammatory mediators such as TNF-α, NO, IL-1β, IL-6, enzymes involved in the inflammatory response (5-LOX, COX-2, iNOS), transcription factors (NF-κB), and signal transduction kinases (p38, JNK, ERK) [4]. In particular, the modulation of inflammatory substances and transcription factors was demonstrated in various animal models (Wistar rats, BALB/c mice, fruit flies) and in some cell cultures (raw 264.7 cell lines, human chondrocytes) [4]. These activities seemed responsible both for preventative action and for a direct effect on inflammation [24]. It was also noted that the (l)-(+)-limonene enantiomer was approximately three-fold less active than the (S)-(–)-limonene one in 5-lipoxygenase inhibitory activity [107]. On the specific role of limonene in respiratory tract inflammation, the review by Santana and colleagues concluded that the monoterpene has effective anti-inflammatory activity in both preventing Int. J. Environ. Res. Public Health 2020, 17, 6506 17 of 36 and controlling respiratory system injuries [108], and this points towards a possible role for limonene in the management of allergic airway diseases and asthma [24]. In a clinical trial on “inflamm-ageing” and oxidative stress in healthy elderly subjects, the intake of 10 mg/kg of limonene as a food supplement in the context of a specific diet resulted in a decrease in fibrinogen, glucose, and insulin levels and in an amelioration of the HOMA-IR index, a homeostatic model assessment used to quantify insulin resistance and beta-cell function [109].

3.5.2. Antioxidant Activity In a review conducted by Vieira and colleagues, limonene was described as an antioxidant compound with free radical scavenging properties, capable of reducing oxidative stress in diabetic rats and of attenuating oxidative stress not only in murine lymphocytes but also in human epithelial cells and fibroblasts, with cell proliferating, anti-apoptotic, and DNA-protecting effects [24]. Specifically, limonene may act by inhibiting caspase-3/caspase-9 activation, p38 MAPK phosphorylation, and LOX activity and by increasing the activities of cell antioxidant enzymes and the Bcl-2/Bax ratio [4].

3.5.3. Antiproliferative Activity D-Limonene has been studied as an antiproliferative agent, and in vitro experiments have suggested a series of possible mechanisms, such as the induction of phase II carcinogen-metabolizing enzymes (a); the reduction of cancer cell proliferation via prenyl-transferase inhibiting activity (possibly diminishing the addition of FPP to the tail of RAS proteins) (b); increased tumor cell apoptosis, autophagy (via the mitochondrial death pathway, the PI3k/Akt pathway, and the caspase-3 and -9 activity), and differentiation (c); growth suppression (through a reduction in cyclin-D1 and an increase in TGF-β signaling leading to a more benign phenotype) (d); decreased tumor-induced immunosuppression, tumor-promoting inflammation, angiogenesis, and metastasis (through a reduction in circulating VEGF and a blockage of the receptor VEGFR1) (e); improved genome stability (increased DNA damage repair and PARP cleavage) (f) [4,17,24,110,111]. In spite of the many mechanistic studies, there is a dearth of preclinical studies with proper animal models and of human clinical trials. The most relevant ones are summarized in Table4 and mostly involve the oral administration of limonene.

Table 4. Summary of findings of clinical studies and preclinical experiments with animal models about anti-proliferative effects of D-limonene.

Type Doses Results Ref. 25 mg orally Limonene reduces mice Animal model—mice [112] administered stomach/lung tumors by 3% Breast cancer regression in 89% Animal model—rats 7.5–10% diet [113] of animals Partial response in breast cancer patients Phase I—humans 0.5–12 g/m2 [114] Absence of progression in subjects with colorectal cancer No responses in patients with Phase II—humans 8 g/m2 [114] solid tumors 22% reduction in cyclin D1 in Open-label—humans 2 g/die [115] early-stage breast cancer

3.5.4. Antinociceptive Activity Data about the activity of D-limonene on nociception are scant. Available evidence with laboratory animals points towards a bimodal action of this monoterpene, which, when administered orally, appears to inhibit nociception and to prevent artificially-induced hyperalgesia (probably by Int. J. Environ. Res. Public Health 2020, 17, 6506 18 of 36 reducing the synthesis of cytokines), while, when topically applied, it seems capable of eliciting pain, probably after an interaction with TRPA1 ion channels [24,116].

3.5.5. Other Pharmacological Activities According to a review by Vieira and colleagues analyzing data from experiments with animal models, limonene may be a potential metabolic agent, capable of improving hyperglycemia, pancreatic β-cell mass, lipid blood levels, and liver fat accumulation [24]. Limonene could also be a solvent for cholesterol, and it has been used to dissolve gallstones after direct infusion into the gallbladder [117]. Limonene may even exert protective and healing effects in experimental models of gastric ulcer and colitis, possibly by promoting mucus secretion and PGE2 production [24]. In in vitro settings with Rolf B1.T cells, limonene can decrease levels of neuropeptide Y, the most important appetite regulator [118]. It finally shows moderate antifungal and antibacterial activities, more pronounced in Gram-positive strains [116]. A summary of preclinical evidence of limonene biological activity has been reported in Table5.

Table 5. Preclinical evidence of limonene biological activity.

Molecules/Mechanisms Functional Response Model Ref. Involved in Targeted Pathways Murine raw 264.7 cell line TNF-α, IL-1, IL-6 [119] Human chondrocytes NF-kB, NO, iNOS, p38, JNK [70] Human lens epithelial cells ROS, CASP, MAPK, Bcl-2/Bax [120] Human neuroblastoma cells LC3, clonogenic capacity [121] Fruit fly NO [84] BALB/c mice NO [122]

Anti-inflammatory BALB/c mice Catalase, peroxidase [123] Antioxidant BALB/c mice IL-5, IL-13, MCP-1, TGF-β [124] BALB/c mice NF-kB, p38, JNK, ERK [125] Wistar rats NF-kB, COX-2, iNOS [126] Swiss mice IL-1β [127] COX2, ERK, iNOS, MMP-2, Sprague–Dawley rats [128] MMP-9, PGE, TGF-β BALB/c mice Apoptosis-related genes [129] Swiss mice Oxidative stress [130] ICR mice Elevated plus maze test [90] Anxiolytic Mice Sleeping time [88] Antidepressant Swiss mice MBT assay, anxiolytic effect [131] Sedative Rats Locomotion, dopamine level [132] Rats Immobility in forced swim test [133] Body weight, sucrose preference, CUMS mice [134] mobility Mus musculus albino mice Elevated Plus Maze (EPM) test [135] Int. J. Environ. Res. Public Health 2020, 17, 6506 19 of 36

Table 5. Cont.

Molecules/Mechanisms Functional Response Model Ref. Involved in Targeted Pathways Swiss mice Induced nociception [136] ICR mice Writhing test [90] Analgesic Rats Mechanical hyperalgesia [133] Swiss mice Writhing test [127] Mechanical hyperalgesia, IL-1β, Swiss mice [137] TNF-α Abbreviations: CASP, caspase; COX-2, cyclooxygenase-2; ERK, extracellular signal-regulated kinase; ICR, imprinted control region; IL, interleukin; iNOS, inducible NO synthase; JNK, c-jun N-terminal kinase; LC3, microtubule-associated protein light chain 3; MAPK, mitogen-activated protein kinase; MBT, marble burying test; MCP, monocyte chemoattractant protein; NF-kB, nuclear factor-B; NO, nitric oxide; p38, protein 38; PGE, prostaglandin E; ROS, reactive oxygen species; TGF, tumor growth factor; TNF, tumor necrosis factor.

3.6. Pinenes Pinene is a bicyclic monoterpene hydrocarbon with two structural isoforms, α- and β-pinenes. Both L- and/or D-forms, as well as racemic forms, may occur. These two isoforms are important constituents of conifer oleoresins and are widely distributed in plants, although α-pinene is generally more abundant. α-pinene (2,6,6-trimethylbicyclo[3.1.1]hept-2-ene) is a bicyclo[3.1.1]hept-2-ene substituted by methyl groups at positions 2, 6, and 6, respectively. Both optical forms are present in conifer essential oils [138]. Table6 reports the most common tree species whose total essential oil contains a quantity of α-pinene at a percentage of more than 20% [70].

Table 6. Tree species whose total essential oil contains more than 20% of α-pinene [106].

Part of the Plant Plant Source Botanical Family Content (%) * Used Boswellia frereana Burseraceae Oleoresin 41.7–80.0 Birdwood Boswellia sacra Flueck Burseraceae Oleoresin 10.3–51.3 Cupressus sempervirens L. Cupressaceae Leaves 20.4–52.7 Juniperus communis L. Cupressaceae Fruit 24.1–55.4 Juniperus phoenicea L. Cupressaceae Leaves and branches 41.8–53.5 Dryobalanops aromatica Dipterocarpaceae Wood 54.3 Gaertn Abies alba Mill. Pinaceae Cones 18.0–31.7 Larix laricina Du Roi Pinaceae Leaves and branches 38.5 Picea abies (Mill.) Britton Pinaceae Leaves 14.2–21.5 Pinus divaricata Aiton Pinaceae Leaves and branches 23.1–32.1 Pinus mugo Turra Pinaceae Leaves 4.1–31.5 Pinus nigra J. F. X Arnold Pinaceae Leaves 11.5–35.1 Pinus resinosa Ait. Pinaceae Leaves and branches 47.7–52.8 Pinus strobus L Pinaceae Leaves 30.8–36.8 Pinus sylvestris L Pinaceae Leaves 20.3–45.8 * Content (%) = the relative quantity, expressed as a range of percentages, of α-pinene included in tree-derived essential oils.

β-pinene (6,6-dimethyl-2-methylidenebicyclo[3.1.1]heptane) is a bicyclo[3.1.1]heptane substituted by methyl groups at positions 6 and 6, respectively, and an exocyclic double bond [139]. It usually accompanies α-pinene in turpentine and other essential oils and is present with both optical forms. It is Int. J. Environ. Res. Public Health 2020, 17, 6506 20 of 36 the main compound of essential oil derived from Piper capense [53]. Table7 reports the most common tree species whose total essential oil contains a quantity of β-pinene at a percentage of more than 20% [70].

Table 7. Tree species whose total essential oil contains more than 20% of β-pinene [106].

Plant Source Botanical Family Part of the Plant Used Content (%) * Abies alba Mill. Pinaceae Cones 3.0–22.5 Abies balsamea L. Pinaceae Leaves and twigs 28.1–56.1 Picea abies (Mill.) Britton Pinaceae Leaves and twigs 4.8–31.9 Picea glauca (Moench) Voss Pinaceae Leaves and twigs 23.0 Pinus mugo Turra Pinaceae Leaves and twigs 1.3–20.7 Pinus ponderosa Douglas ex P. Pinaceae Leaves and twigs 28.9 Lawson & C. Lawson Pinus resinosa Ait. Pinaceae Leaves and twigs 29.4–29.9 Pinus strobus L. Pinaceae Leaves and twigs 31.1–33.3 Pinus sylvestris L. Pinaceae Leaves and twigs 1.9–33.3 Tsuga canadensis (L.) Carriere Pinaceae Leaves and twigs 20.8 Citrus x aurantifolia Christm. Rutaceae Fruit peel 21.1 * Content (%) = the relative quantity, expressed as a range of percentages, of β-pinene included in tree-derived essential oils.

Pharmacological and Clinical Activities of Pinenes In a recent review of the scientific literature, it has been reported that, although many in vitro studies exist about the pharmacological activities of pinene and pinene-containing essential oils, few in vivo studies and even less clinical trials on the topic have been conducted so far [23]. In fact, none of the reviewed clinical studies tested isolated pinene, but mixtures of different molecules or whole essential oils have been often tested. A clinical trial involving patients with bronchitis tested a product containing α-pinene, D-limonene, and 1,8-cineole, and, although study results were positive [140], if we consider the clinically recognized effects of 1,8-cineole on bronchitis, it is impossible to discern whether α-pinene was important for the results. A single-blind clinical trial on pediculosis tested two essential oils, one of Eucalyptus globulus and one of Cinnamomum zeylanicum, both containing α-pinene, and found eucalyptus oil to be superior to permethrin [141], while a second study evaluated the effects of essential oil obtained from the leaves of Lippia multiflora and found it to be superior to benzyl benzoate [142]. In both cases, however, given the recognized significant activity of 1,8-cineole and terpineol, respectively, on pediculosis, it is impossible to declare pinene as an active and useful compound per se. The reviewed trials on memory and Alzheimer’s disease tested only whole essential oils belonging to the genus Salvia (Salvia officinalis and Salvia lavandulaefolia) for their inhibitory activity on cholinesterases [143–145]. Again, as previously noted, these essential oils contain, apart from pinene, several compounds, and, in fact, 1,8-cineole is likely to be the most active molecule, although a synergistic interaction with other monoterpenes has been suggested. Amongst pharmacological effects of pinenes demonstrated on the basis of preclinical evidence, authors of the previously mentioned review specifically analyzed those relevant to cancer growth, allergies, inflammation, infections, and anxiety [23]. Data about cancer cells suggest that α-pinene might have effects on NF-κB and IκBα, and, therefore, on inflammation, mitochondrial functions, ROS production, caspase-3 activity, and DNA fragmentation [146], but also on efflux pumps responsible for multidrug-resistant tumors [147], as well as on cell cycle arrest via the cyclin-B protein [148]. Int. J. Environ. Res. Public Health 2020, 17, 6506 21 of 36

A pre-treatment of allergic rhinitis models with α-pinene resulted in a significant reduction in clinical symptoms and inflammatory cytokine levels [149]. α-pinene also appears to exert moderate antimicrobial [150,151] and immune-modulating effects [61,62]. Finally, it has been shown that α-pinene binds to the GABA-A receptor, at the benzodiazepine binding site, thus prolonging GABAergic inhibitory signaling and suggesting an anxiolytic and sleep-enhancing effect [91]. A summary of preclinical evidence of α-pinene biological activity has been reported in Table8.

Table 8. Preclinical evidence of α-pinene biological activity.

Model Target Reference NF-kB, Murine macrophages [152] ERK, JNK Human U373-MG cells ROS, peroxidase [80] NF-kB, Human chondrocytes IL-1β, JNK, iNOS, MMP-1, [153] Anti-inflammatory MMP-13 Antioxidant Human lymphocytes Total antioxidant capacity [154] Mouse Ig-E, IL-4 [149] Superoxide dismutase, Wistar rats catalase, peroxidase, NO, [155] IL-6 C57BL/6 mice CD4, CD8 and NK cells [102] Wistar rats COX2 [156] Sprague–Dawley rats Sleep rhythm [157] Mice BDNF, TH, EPM test [158] GABA BZD receptor, Anxiolytic ICR and C57BL/6N mice [159] Antidepressant sleep behavior Forced swim test, oxidative Sedative Wistar–Kyoto mice [160] phosphorylation expression Wistar rats Sensorimotor severity score [155] C57BL/6 mice Schizophrenia-like behavior [161] BALB/c mice Tail-flick test [162] Analgesic Mice Neuropathic pain [163] Wistar rats Nociception [156] Abbreviations: BDNF, brain-derived neurotrophic factor; BZD, benzodiazepine; EPM, elevated plus maze; ERK, extracellular signal-regulated kinase; GABA, γ-aminobutyric acid; Ig-E, immunoglobulin E; JNK, c-jun N-terminal kinase; MMP-1, metalloproteinase 1; MMP-13, metalloproteinase 13; NF-kB, nuclear factor-B; ROS, reactive oxygen species; TH, tyrosine hydroxylase.

4. Discussion

4.1. Implications for Individual Health Inhaling forest VOCs can result in useful antioxidant and anti-inflammatory effects on the airways, and the pharmacological activity of some terpenes absorbed through inhalation may be also beneficial to promote brain function by decreasing mental fatigue, inducing relaxation, and improving cognitive performance and mood [164,165]. The effect of these volatile compounds found in forest air is not limited to an action on the respiratory system, but, after absorption through inhalation, they are supposed to exert systemic effects, such as those on the nervous system (relaxing, anxiolytic, and antidepressant action). Evidence from laboratory studies seems to confirm these effects, thus underscoring that, in particular, limonene and pinene can modulate the release of various cytokines (for example, TNF-α, IL-1, IL-6), inflammatory mediators (for example, NF-κB signal transduction pathway, MAPK, COX-2 Int. J. Environ. Res. Public Health 2020, 17, 6506 22 of 36 activity), and neurotransmitters (for example, dopamine levels, action on GABA receptors) in such a way as to reduce inflammation and pain and to improve anxiety, mood, and sleep quality (Table5, Table8, and Table9). Although the magnitude of some of these pharmacological effects may be limited when inhaling such compounds during a short forest trip due to their relative atmospheric concentration (generally lower than that one prepared in experimental settings) and pharmacokinetics, even a mild action associated with psychophysical relaxation may be already beneficial for individual wellbeing. In fact, large studies aimed at thoroughly assessing pharmacokinetic and pharmacodynamic characteristics of forest VOCs in real-life situations are, to date, actually lacking, and it is only possible to formulate some plausible hypotheses. For example, with regard to limonene, human studies discussed in this review mostly investigated pharmacological effects of its oral intake when taken in relatively high quantities, up to several grams a day (Table4). In a pharmacokinetic study coupled with a phase-I trial, the administration of limonene to cancer patients was observed to be followed within a few hours by a peak in limonene plasma concentrations of 10.8 µM (mean Cmax) when the oral daily dose amounted 2 2 to 8 g/m and of 20.5 µM (mean Cmax) when the dose was 12 g/m [114]. However, inhaling limonene in a forest setting can be quite different, since many environmental and individual characteristics along with inhalation-related pharmacokinetic mechanisms can introduce a high degree of variability, which makes it hard (to date) to fully predict the exact short- and long-term health effects of a natural and real-life exposure to specific BVOCs. In fact, as reported in a review, measured concentrations of limonene in the air of different forest areas can largely vary, ranging from as little as 0.9 ng/m3 to as much as 12.2 g/m3 [45]. In a toxicokinetic study with healthy volunteers, participants were exposed for 2 h in a chamber with different concentrations of limonene (10, 225, and 450 mg/m3) and the pulmonary uptake was estimated to be up to 70% of the amount supplied, with plasma concentrations of this substance rapidly rising within 2 h after exposure and peaking at different levels (ranging, on average, from less than 2 to almost 25 µM), depending on the quantity of limonene diffused in the air [166]. No major short-term clinically symptomatic or toxic/irritative effects were observed, and only minor changes in respiratory function were reported when limonene concentration in the chamber was set at the highest experimental level (450 mg/m3)[166]. However, the pulmonary absorption of terpenes may be even less efficient, since more recent studies state that it could be 54–76% of the dose supplied with inhaled air [167]. In an interesting study involving a small cohort of healthy subjects, blood concentrations of some conifer-derived monoterpenes were measured before and after a 60-min trip in a Japanese forest [58]. The authors noticed that blood concentrations of some BVOCs exhibited a marked increase after visiting the forest, and, in particular, average plasma levels of α-pinene changed from 2.6 (baseline) to 19.4 nM (post-intervention) [58]. A pharmacokinetic study about metabolites of α-pinene showed that their blood levels tend to markedly and rapidly peak after the administration of a single oral dose of 10 mg to four volunteers, with trans-verbenol (one of the most relevant pinene metabolites) Cmax quickly reaching a mean value of 26 nM and α-pinene being already undetectable 1 h after the exposure [60]. In brief, blood concentrations of BVOCs after indoor and, even more, outdoor inhalation show a higher degree of variability than after their oral intake in more controlled experimental settings. With available data, we can only affirm that plasma concentrations of BVOCs tend to rise whenever a subject is exposed to a forest, but, to date, due to limitations of existing studies, it is not possible to exactly quantify the actual magnitude of their specific beneficial effects for human health, especially with regard to their action at a systemic level. Taking into account all these findings, potential moderators of the effect and confounding factors to be considered by researchers when planning future studies can include the following:

the exact concentration of any BVOC in the forest air when exposure occurs; • the duration of exposure; • the intensity of physical activities performed in the green environment; • specific modalities of biological sample collection, transport, and analysis; • Int. J. Environ. Res. Public Health 2020, 17, 6506 23 of 36

individual health-related characteristics, which can influence the uptake, metabolism, • accumulation, and excretion of inhaled BVOCs; lifestyle habits, which can determine baseline blood levels of compounds like limonene and pinene • absorbed from food, medicines, and perfumes [58].

Further rigorous pharmacokinetic studies ought to be performed to thoroughly estimate the actual absorbed quantity of BVOCs during a forest trip. Then, it would be possible to precisely assess short- and long-term effects on health of the inhalation of specific BVOCs and to correlate such effects with specific thresholds of BVOCs concentrations in the forest air. It is known that forest VOCs like limonene and, even more, pinene, are mostly released by conifers (pines, fir trees, cypresses) (Table3, Table6, and Table7), and, therefore, the exposure to these volatile substances (with more documented effects on health) can be maximized by visiting a forest whose composition is rich in these trees. In general, beyond differences in tree composition, levels of BVOCs in the forest air exhibit diurnal quali-quantitative variations, with two daily peaks (early in the morning and in the afternoon) [31,32], and these cyclic changes may influence the magnitude and type of potential beneficial effects of their inhalation depending on the time of the day when the exposure occurs. For this reason, it would be useful to carry out additional environmental studies aimed at quantifying all concentration changes in forest VOCs in order to maximize the visitors’ exposure and, therefore, the impact of such compounds on health after inhalation. Moreover, beneficial psychological and physiological effects of visiting a forest (such as in the meditative practice called “forest bathing”) cannot be solely attributed to VOC inhalation but are due to a global and integrated stimulation of the five senses [63], induced by all specific characteristics of the natural environment, with the visual component probably playing a fundamental role in the overall effect [99]. Therefore, even if inhaling BVOCs can exert useful effects on health while visiting a forest, absorbing these volatile compounds does not cover all benefits of forest bathing, which, to date, cannot be artificially replaced with a virtual experience and actually requires a full real-life interaction with the natural environment. However, further investigating all medicinal properties of specific forest VOCs with properly designed clinical studies can be useful to discover their potential uses in medical practice as drugs for some health conditions and to possibly discover new therapeutic agents derived from them.

Table 9. Summary of preclinical evidence relative to biological activities of the five most common forest VOCs [3,30,34–37].

Molecule Effects Mechanisms References It inhibits the synthesis or release of pro-inflammatory mediators (TNF-α, NO, IL-1β, IL-6, IL-5, IL-13, TGF-β), enzymes Anti-inflammatory [4,70,71,124] (5-LOX, COX-2, iNOS), transcription factors (NF-κB), and mitogen-activated protein (MAP) kinase family members (p38, JNK, ERK). It inhibits caspase-3/caspase-9 activation, increases the activities of cell antioxidant Antioxidant [4,70,123] enzymes (catalase, peroxidase) and the Bcl-2/Bax ratio. It induces phase II carcinogen-metabolizing D-Limonene enzymes, inhibits prenyl-transferase activity, increases cell autophagy (via MAP1LC3B, mitochondrial death pathway, the PI3k/Akt pathway, and caspase-3 and -9 activity) and differentiation, reduces cyclin-D1 and increases TGF-β signaling, decreases tumor-induced [4,17,24,110,111,121,124, Antiproliferative immunosuppression, reduces circulating 128,129] Vascular Endothelial Growth Factor (VEGF) and blocks the receptor VEGF-R1, increases DNA damage repair and PARP cleavage. It modulates the expression of the chemotactic protein MCP-1 and of the proteolytic enzymes MMP-2, MMP-9. Int. J. Environ. Res. Public Health 2020, 17, 6506 24 of 36

Table 9. Cont.

Molecule Effects Mechanisms References Bimodal activity: topically applied, it seems capable of eliciting pain, via interaction with [24,90,116,127,133,136, Antinociceptive TRPA1 ion channels, while in other modes of 137] administration, it has shown antinociceptive effects in different experimental models. It shows some degree of efficacy in mice and Anxiolytic [90,127,135] rat models. It shows some degree of efficacy in mice and Antidepressant [132–134] rat models. In several animal models, it enhances sleep by acting as a positive modulator for Anxiolytic, sedative [91,155,157–161] GABA-A-BZD receptors, prolonging GABAergic inhibitory signaling. It modulates NF-κB and IκBα, ERK, JNK, IL-1β, Anti-inflammatory IL-6, iNOS (and NO secretions), MMP-1, [146,152,153,155,156] MMP-13, COX-2. α-Pinene It reduces ROS production, caspase-3 activity, Antioxidant modulates superoxide dismutase, catalase, [146,155,168] peroxidase activity, NO and IL-6 secretions. It acts on efflux pumps responsible for Antiproliferative multidrug-resistant tumors and on cell cycle [147,148] arrest via the cyclin-B protein. It shows some degree of efficacy in Analgesic [156,162,163] animal models. It binds to the GABA-A receptor, prolonging Anxiolytic, GABAergic inhibitory signaling. It showed [91,94–97] antidepressant efficacy in animal models. Anti-inflammatory It modulates NF-κB and IκBα.[146] β-Pinene It reduces ROS production, caspase-3 activity, Antioxidant [77–80,146] MMP and NO activities. It acts on efflux pumps responsible for Antiproliferative multidrug-resistant tumors and on cell cycle [147,148] arrest via the cyclin-B protein. It modulates MAP kinases such as JNK, p38, Anti-inflammatory and it inhibits the synthesis and release [70,71,169] of PGE-2. It blocks hepatic carcinogenesis caused Antiproliferative [170] by aflatoxin. It is analgesic in mice, and its action is blocked β-Myrcene Analgesic by naloxone, perhaps via the α-2 [171] adrenoreceptor. It is a muscle relaxant in mice, and it Sedative, myorelaxant [88] potentiates barbiturate sleep time at high doses. It contributes to the integrity of the gastric mucosa, decreasing ulcerative lesions, Gastroprotective [172] attenuating lipid peroxidative damage, and preventing depletion of GSH, GR, and GPx. As a food supplement, it reduces animal models’ body weight and increases adiponectin Metabolism [173] levels and receptor mRNA expression in the liver. It induces apoptosis in cancer cell lines (B16F10-Nex2 melanoma), chromatin Antiproliferative condensation, cell shrinkage, apoptotic body [174] formation, fragmentation of nucleus, and caspase-3 activation. Camphene It prevents AAPH-induced lipoperoxidation Antioxidant [175] and inhibits the superoxide radical. Weak effects on acetic acid-induced writhing in Antinociceptive [175] mice models. It reduces total and LDL-cholesterol and triglycerides in hyperlipidemic rats and in HepG2 cells, not by inhibiting HMG-CoA Antihyperlipidemic [176] reductase but by increasing apolipoprotein AI expression, possibly via SREBP-1 upregulation and MTP inhibition. Int. J. Environ. Res. Public Health 2020, 17, 6506 25 of 36

4.2. Implications for Preventive Medicine and Public Health Useful effects of forests and green areas on psychophysical wellbeing have been underscored by several studies, with all sensory components, ranging from visual to olfactory stimulations, playing an integrated role in the overall beneficial action on individual health [63,86,99,177]. This may also explain the tight link between shamanism and wild environments, and why folkloristic and ritual practices have spread worldwide from the Amazon to the Siberian forest [178,179]. Evidence from research works analyzed in this review suggests that forest bathing can be beneficial for general health, thus exerting a general anti-stress and immune boosting activity. At a public health level, epidemiological studies have highlighted that there is evidence for a significant association between the extension of green areas within a given community and specific health outcomes like perceived mental and general health, as well as all-cause mortality [177]. Similar research works have confirmed a positive association between living closer to green areas and improvements in physician-assessed morbidity determined by various cardiovascular, muskuloskeletal, respiratory, mental, neurological, digestive, and other health conditions [180]. Indeed, the type of activities performed outside, possibly ranging from static relaxation to intense physical exercises, along with the subjective perception of safety and connectedness to nature while visiting the natural environment, can influence the magnitude of beneficial effects exerted by the exposure to green areas [181]. In particular, forests can be perceived as dangerous for several reasons (wild and unknown environment, potentially aggressive fauna, parasites, poisonous plants, limited supporting facilities, human activities like hunting, cutting trees, practicing extreme sports, etc.), and all necessary precautions have to be taken to prevent any risk of being harmed in order to fully and safely benefit from forest exposure. Additionally, when subjects suffer from specific diseases, a medical consultation is advised before planning to visit a forest. Recently, research efforts of many expert scientists from different countries all around the world have converged into the definition of new concepts like “forest therapy” and “forest medicine”, which both refer to the scientific study and evidence-based applications of visiting a forest for therapeutic or preventive purposes [182]. In particular, from the foundation of the International Society of Nature and Forest Medicine (INFOM), researchers of this field have advocated for studying the topic in more depth, as well as to disseminate relevant findings worldwide in order to “establish Forest Therapy as an effective, evidence-based and low-cost public health treatment for selected lifestyle-related diseases” [182,183]. Beneficial effects of this practice are (although not exclusively) determined by the inhalation of forest VOCs, which are responsible for the olfactory perception of pleasing fragrances from trees and flowers [182]. Beyond these chemical factors, useful health effects of visiting a forest can be also attributed to physical (such as environmental characteristics, climate conditions, visual impressions, sounds) and psychological factors (to what extent the environment is perceived as pleasant, relaxing, and safe by an individual, i.e., placebo effects) [182]. Visiting forests on a relatively regular basis can be a good health-promoting practice, since, by reducing stress levels and boosting immune function, it seems capable of diminishing the incidence of stress-related and lifestyle-induced illnesses, varying from cardiovascular, respiratory, or metabolic diseases to neuropsychiatric conditions and, possibly, even cancer [86]. Some practical recommendations to optimally benefit from forest bathing for preventive purposes include performing only light physical activity in the natural environment (like walking at a regular pace without getting tired), stay well hydrated, avoiding the use of technological devices for recreation (thus preferring meditative contemplation as a relaxing practice during the forest visit and a bath in hot spring waters after the trip), spending in the forest 2 to 4 h and walking 2.5 to 5 km in a day along clean paths with some stopovers [182]. In general, on the basis of retrieved evidence and experts’ proposals, visiting a forest can be a useful practice, with the olfactory component playing a role in it, and it can be a sustainable public health practice to promote both individual wellbeing and community health, thus contributing to the prevention of many stress- and lifestyle-related diseases. Int. J. Environ. Res. Public Health 2020, 17, 6506 26 of 36

4.3. Forest VOCs and Natural Landscape Design Today, around half of the world’s population lives in metropolitan areas and, over the years, technology, commuting, working, and some leisure activities have made us more and more inhabitants of an “indoor society”, in which natural light has been almost completely supplanted by artificial light, and the sounds and smells of nature are often a distant memory. Even if we do not notice it immediately, this can keep us under constant stress, not only because of the constant exposure to urban environments and their stressful stimuli but also because of the lack of contact with natural environments, which can promote health and wellbeing. Another equally important aspect is that green areas, even within an urban space, offer the possibility to organize open-air recreational activities, thus increasing socialization and residents’ quality of life [184–186]. In the last few decades, the concept of “biophilic design” has been introduced to indicate any sustainable design aimed at better connecting people with the natural world and with vital processes [187]. In particular, the attention of some outdoor designers has been focused on “healing gardens”, namely green areas purportedly planned to induce a psycho-physical state of wellbeing in their visitors/users [188]. Elements involved in the design of a healing garden are closely related to the therapy of the senses: perfumes (aromatherapy), colors (chromotherapy), sounds (music therapy), sometimes tactile or gustatory experiences, and symbols. Provided that, today, the relationship between man and architecture is mainly governed by sight, but, as underscored in this review, some natural volatile compounds can influence health, designing outdoor environments that have an impact on both sight and smell should be the next step. In particular, it is deemed necessary to create green areas and paths surrounded by fragrant shrubs, where it is possible to talk or relax, while walking immersed in nature with positive olfactory stimulations to guarantee an inclusive experience for all, both sighted and visually impaired or blind people. From this point of view, a precaution to take in order not to create confusion in passers-by is to group aromatic plants by species and arrange them at a certain distance, thus avoiding creating chaotic green spots. In fact, the relationship between space and smell is complex and depends on many factors, including the type of building materials, specific activities that take place in a given environment, the time of the day, air humidity, but also plants, animals, and people who pass through it. All these factors should be taken into account by landscape and outdoor designers, who must be encouraged to cooperate with a multidisciplinary team in order to achieve the best results. A virtuous example of how to harness beneficial properties of forests in order to promote health is the landscape project involving the natural park of the Oasi Zegna, in Alta Val Sessera (Piedmont region, Italy). A study carried out in 2012 has scientifically shown that the beech wood of the Oasi Zegna can release volatile substances from the foliage, like monoterpenes, capable of bringing benefits to the organism and of stimulating the immune system in a positive way [189]. For this reason, three freely accessible paths were created from June to September, which corresponds to the period of maximum foliation of beech trees. Another project designed by the CERFIT team (Research and Innovation Center in Phytotherapy and Integrated Medicine, Careggi University Hospital) is the so called “Giardino della Salute”, a healing garden which will be located in an outdoor green area (a pine forest) within the Careggi Hospital district in Florence (Italy) [190]. The ultimate aim of the project is to revitalize and redevelop a public park, as well as to improve the wellbeing and quality of life of all its users, with keen attention to healthcare personnel, hospital patients, and their relatives or visitors. In order to offer a personalized experience which is expected to meet individual needs, some specific footpaths will be laid: the “nutrition” path, where there will be plants used for food; the path of “the five senses”, characterized by an immersive sensory experience with various impressions; the “mind” path, for relaxing or stimulating the nervous system; the path of “natural hazards”, in which poisonous plants will be described for educational purposes; a path for generic users, another one dedicated to patients, and the last one to students. Specific characteristics of plants and flowers displayed along each path, including their appearance, colors, and phytochemical substances released into the surrounding environment, have been chosen to Int. J. Environ. Res. Public Health 2020, 17, 6506 27 of 36

be synergically harnessed for beneficial purposes. The project also involves a herbalist and an educator who can guide visitors along their journey across the healing garden and help them to understand the most important uses and properties of medicinal plants. This project is a valuable example of how to make the most of beneficial properties of an ad hoc designed urban green area, taking into consideration various aspects of the effects of plants on human health, including the activity of biogenic VOCs released in the air.

5. Conclusions Inhaling forest VOCs like limonene and pinene can result in useful antioxidant and anti-inflammatory effects on the airways, and the pharmacological activity of some terpenes absorbed through inhalation may be also beneficial to promote brain function by decreasing mental fatigue, inducing relaxation, and improving cognitive performance and mood. The tree composition can markedly influence the concentration of specific VOCs in the forest air. Moreover, beneficial psychological and physiological effects of visiting a forest (such as in the meditative practice called “forest bathing”) cannot be solely attributed to VOC inhalation but are due to a global and integrated stimulation of the five senses, induced by all specific characteristics of the natural environment, with the visual component probably playing a fundamental role in the overall effect. Globally, these findings can have useful implications for individual wellbeing, public health, and landscape design. Further clinical and environmental studies are advised, since the majority of the existing evidence is derived from laboratory findings.

Author Contributions: Conceptualization, M.A. and D.D.; Methodology, M.A., D.D., G.B., M.V., V.M., and F.F.; Validation, M.A., D.D., G.B., M.V., V.M., and F.F.; Investigation, M.A., D.D., G.B., M.V., V.M., and F.F.; Resources, M.A., D.D., G.B., M.V., V.M., and F.F.; Data Curation, M.A., D.D., G.B., M.V., V.M., and F.F.; Writing—Original Draft Preparation, M.A., D.D., G.B., M.V., V.M., and F.F.; Writing—Review and Editing, M.A., D.D., G.B., M.V., V.M., and F.F.; Visualization, M.A., D.D., G.B., M.V., V.M., and F.F.; Supervision, M.A., D.D., and F.F.; Project Administration, M.A. All authors have read and agreed to the published version of the manuscript. Funding: This research work was not funded. Conflicts of Interest: The authors declare no conflict of interest.

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