# Forest Volatile Organic Compounds and Their Effects on Human Health: A State-of-the-Art Review
## 4 Discussion
### Implications for Individual Health
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 (Table 4). 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 \(\upmu\)M (mean C\({}_{\text{max}}\)) when the oral daily dose amounted to 8 g/m\({}^{2}\) and of 20.5 \(\upmu\)M (mean C\({}_{\text{max}}\)) when the dose was 12 g/m\({}^{2}\)[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/m\({}^{3}\) to as much as 12.2 g/m\({}^{3}\)[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/m\({}^{3}\)) 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 \(\upmu\)M), 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/m\({}^{3}\)) [166]. However, the pulmonary absorption of terpen 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 confer-derived monoterenes 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 \(\upalpha\)-pinene changed from 2.6 (baseline) to 19.4 nM (post-intervention) [58]. A pharmacokinetic study about metabolites of \(\upalpha\)-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) C\({}_{\text{max}}\) quickly reaching a mean value of 26 nM and \(\upalpha\)-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.