Abstract
Microbial secondary metabolites include compounds produced during the growth of both fungi and bacteria. These compounds are present in workplaces and indoor environments, although the concentrations of single toxins in the air are typically low. Inhalation is considered to be the most significant route of exposure for microbial secondary metabolites in indoor environments although exposure to microbial toxins may happen also via alimentary or dermal route. Inhalation effects of microbial secondary metabolites have been studied experimentally in vivo in animal models, mainly in rodents. In vitro studies with cells of respiratory system and ex vivo cultured tissues have elucidated the mechanisms of action for the most common toxins. However, there are only few epidemiological studies on health effects of mycotoxin exposure, and often the studies are limited by exposure assessment based on single compounds or surrogates of mycotoxin exposure. We summarize here studies on the inhalation effects of microbial toxins showing a wide variety of adverse health effects which are not limited to the respiratory system, and identify the knowledge gaps where future research efforts should be targeted.
Access provided by CONRICYT-eBooks. Download chapter PDF
Similar content being viewed by others
Keywords
1 Introduction
Mycotoxins, i.e. toxic secondary metabolites of fungi have been recognized as a health concern since early 1960s, after the revelation that aflatoxin-contaminated grain was the reason for mass killings of poultry (Forgacs, 1962). The number of identified mycotoxins (~400 individual compounds) is only a fraction of the total number of toxic metabolites of fungi in our environment (Council for Agricultural Science and Technology, 2003; Täubel and Hyvärinen, 2015). In addition to fungi, also bacteria are able to produce toxic compounds during their growth (Täubel et al., 2011), which increases the number of toxic microbial metabolites possibly relevant to human exposure in the order of thousands. The main exposure route for mycotoxins is alimentary, e.g. eating contaminated foods, which directed the early research efforts into studying the effects of fungi typically present in foods or feeds, and oral exposure as a point of entry. Also dermal or mucosal absorption is possible, but to a lesser extent (Boonen et al., 2012; Pinton and Oswald, 2014). Exposure through respiratory route did not appear to be as relevant, as the majority of mycotoxins are nonvolatile. However, it was soon realized that inhalation is also a major route of exposure to mycotoxins. Not only were mycotoxins found from airborne dust (Croft et al., 1986; Flannigan, 1987), but the spores and fragments of microbial growth were shown to carry mycotoxins along them to the lungs (Brasel et al., 2005).
As a portal of entry for inhaled air, the nasal airway is a primary target for many inhaled toxicants (Harkema et al., 2006). The surface epithelium lining is often the first tissue in the nose to be directly injured, for example, by spores or mycotoxins of Stachybotrys chartarum (Pestka et al., 2008). Also microbial volatile organic compounds (MVOCs) are known to cause eye and upper-airway irritation in experimental exposure studies both in animals and humans (Korpi et al., 2009). Even if the toxins are nonvolatile, the adverse effect of mycotoxins can be carried by spores, as was seen when studying the pulmonary toxicity of intranasal or intrathacheal exposure to spores of S. chartarum in mice and rats (Lichtenstein et al., 2010; Pestka et al., 2008; Yike and Dearborn, 2004; Yike et al., 2005). The effect of inhalation exposure can be further aggravated by the presence and persistence of structural components in the lungs, leading to high concentrations of toxins within spore’s immediate microenvironment (Carey et al., 2012). Comparison of intranasal and oral routes of exposure to mycotoxin deoxynivalenol (DON) in mice showed clearly higher plasma and tissue concentrations, as well as higher mRNA expressions of proinflammatory cytokines in internal organs following intranasal exposure (Amuzie et al., 2008). Accordingly, acute toxicity of the trichothecene mycotoxin T-2 in mice, rats and guinea pigs has been shown to be higher after inhalation exposure than when delivered by other routes (Creasia et al., 1987; Creasia et al., 1990). Considering that the lungs are a likely entry point both for nonvolatile and volatile compounds, inhalation is arguably the most significant route of exposure for microbial secondary metabolites in indoor environments (Fig. 10.1).
First studies on inhalation exposure to mycotoxins appeared in the late 1980s, describing the acute effects of trichothecenes produced by Stachybotrys (Croft et al., 1986). In the early years, the research on inhalation effects focused on mycotoxins that originated from molds thriving in high water activity such as aflatoxin B1 (AFB1) produced by e.g. Aspergillus flavus and satratoxins from Stachybotrys chartarum (Bitnun and Nosal, 1999; Hodgson et al., 1998). Originally the data on mycotoxin concentrations were largely from the workplaces that are routinely monitored for contamination such as factories processing grain, corn, peanut or malt. The most abundant mycotoxins found in the air of these workplaces are AFB1, DON and ochratoxin A (OTA) (Fromme et al., 2016). In addition of AFB1, DON and OTA, fumonisin and zearalenone are also agriculturally important mycotoxins with worldwide distribution (Jarvis and Miller, 2005; Miller and McMullin, 2014). Later, mycotoxins have been detected basically from all workplaces where organic material is handled including greenhouses, pigsties, cowsheds and waste treatment facilities (Degen, 2011; Mayer et al., 2008). In addition to the occupational exposure in industrial settings, the mycotoxin exposure in moisture damaged indoor environments has been a target of interest since 1980s, brought forward by the extensive media attention on cases of proposed intoxications with toxic secondary metabolites of Stachybotrys chartarum (Nevalainen et al., 2015). However, there is still a lack of exposure data, as the airborne mycotoxin concentrations are rarely measured, let alone associated with clinical health data. The challenge of the future studies is a better characterization of exposure to low concentrations of multiple toxins (Miller et al., 2010).
2 Toxicological Models of Respiratory System
Throughout the history of inhalation toxicology, small laboratory animals such as mice, rats, rabbits and guinea pigs have been used as model systems for pulmonary toxicity. In the case of a systemic effect to an inhaled toxicant, animal model is the only available approach for studying the effects in a controlled environment. In experimental conditions the most natural way of introducing mycotoxins into the lungs of laboratory animals is via inhalation (whole body exposure). However, inhalation exposure is restricted by the difficulties in assuring the actual dose in the lungs of each animal as well as the need to use expensive equipment, special expertise and large quantities of the tested materials. For these reasons, intratracheal or intranasal instillation has become widely used for respiratory toxicity studies (Driscoll et al., 2000; Hasegawa-Baba et al., 2014; Islam et al., 2006, 2007). Rodent airways, however, differ from those of human and other primates both structurally and functionally, which has motivated the development of nonhuman primate models in order to better extrapolate the results to humans (Carey et al., 2012).
With an increasing interest and legislation to reduce the use of animals in research (EU, 2003; REACH, 2006), animal models are increasingly being replaced with in vitro models using human cells or tissues. In addition to ethical issues, in vitro toxicity testing appeals with the associated low cost, high throughput and the possibility to target a specific cell type in a defined experimental set-up. The function of the respiratory epithelium as a first contact point for airborne exposure agents makes it an appealing target for toxicological studies aiming to model the effects of inhaled substances. The in vitro respiratory platforms include carcinoma-derived and virus-transformed continuous cell lines, primary cells and ex vivo models. Examples of cell lines typically used in inhalation toxicology are carcinoma-derived lung epithelial or bronchial cells (e.g. A549 and Calu-3) and immortalized human epithelial or bronchial cells (e.g. BEAS-2B and 16HBE140) (Prytherch and BéruBé, 2014). The next step from monolayers of transformed cell lines would be to utilize more complicated cell models, where e.g. macrophages are cultured together with lung epithelia to mimic the components of immune system operational in the lungs. The co-culture models for alimentary exposure to mycotoxins are already in use, as was shown in a study of modulation of inflammatory response by OTA in a co-culture of intestinal and liver cells (González-Arias et al., 2015). However, for inhalation exposure to mycotoxins the studies using co-culture models of transformed cells are still lacking.
Primary cells isolated from nasal and bronchial epithelium or from the alveolar level of the lungs have been used in inhalation toxicology for producing cultures of respiratory tissue with close to realistic morphological and physiological properties (Prytherch et al., 2011). For example the impairment of motile and chemosensory functions due to aflatoxin exposure has been demonstrated with cultures of primary human sinonasal and bronchial cells (Lee et al., 2016). Cultures of primary respiratory cells have shown also the ability of airway epithelium to detoxify both AFB1 and sterigmatocystin (Cabaret et al., 2010; Van Vleet et al., 2001). Generating respiratory tissue by culturing embryonic or induced pluripotent stem cells is possible as well, but achieving accurate characteristics and homogenous bronchial epithelium still needs further development (McIntyre et al., 2015). Alternatively, complete sections of respiratory tissue can be extracted and cultured ex vivo, maintaining the complexity and function of an intact lung. Ex vivo experiments with rat tracheas have elucidated e.g. the vasoconstrictive abilities of OTA (Chatopadhyay et al., 2014) and ciliostatic abilities of several metabolites of indoor fungi (Piecková and Kunová, 2002). However, the life span of current ex vivo models is very limited, and similarly with cultures of primary cells, also cultured tissues are donor specific and thus vary in their responses.
3 Microbial Secondary Metabolites in Indoor Environments
Microbial secondary metabolites have been detected from water-damaged indoor environments both in private residents and public buildings, although the concentrations of single toxins are typically low and the diversity high (Bloom et al., 2009; Cai et al., 2011; Kirjavainen et al., 2015; Peitzsch et al., 2012; Polizzi et al., 2009; Täubel et al., 2011; Tuomi et al., 2000). The most widely studied mycotoxins detected indoors are aflatoxins (sterigmatocystin) (Bloom et al., 2009), OTA (Hope and Hope, 2012) and trichothecene mycotoxins (T2, DON, satratoxins, verrucarin) (Pestka et al., 2008; Straus, 2009).
Aflatoxins, especially AFB1, are known liver carcinogens, but they can also exert their effects on the lungs. The mechanism behind its carcinogenicity in lung is suggested to be oxidative DNA damage (Guindon-Kezis et al., 2014). The high local bioactivation and neuronal transport to the olfactory bulb seen after intranasal administration of AFB1 indicates a risk of tumorigenesis in nasal mucosa after high local exposure (Larsson and Tjälve, 2000). Aerosol exposures of animals to AFB1 have resulted in an increase of lymphatic leukemia in mice (Louria et al., 1974), genotoxic effects in rats (Zarba et al., 1992) and suppression of pulmonary and systemic host defenses in rats and mice (Jakab et al., 1994). Along other mycotoxins, also aflatoxins have been detected in patients with health problems related to exposure to water damaged indoor environment (Trasher et al., 2012; Brewer et al., 2013b). In the industrial setting, the inhalation exposure to aflatoxins has been linked to cancer incidence and pulmonary disorders (Dvorácková and Pichová, 1986; Hayes et al., 1984). Elevated levels of AFB1 were also measured in bronchoalveolar lavage and serum samples of workers in food-grain handling in India, where about 50% of all food-grain workers had chronic respiratory symptoms (Malik et al., 2014). A case-control study by Lai et al., 2014 (Lai et al., 2014) showed an association between the inhalation exposure to AFB1 and the risk of hepatocellular cancer among sugar and papermaking factory workers. Thus, the inhalation of aflatoxins represents an occupational risk factor.
OTA is one of the most important and deleterious mycotoxins contaminating foodstuff, leading to exposure also via inhalation. OTA is thought to be carcinogenic, teratogenic, immunotoxic, hepatotoxic and neurotoxic, but the detailed mechanisms of its toxicity are not known (Hope and Hope, 2012; Kőszegi and Poór, 2016; Malir et al., 2016). Nevertheless, inhibition of protein synthesis and energy production, induction of oxidative stress, DNA adduct formation as well as apoptosis/necrosis and cell cycle arrest are suggested to be involved in its toxic action (Corcuera et al., 2015; Vettorazzi et al., 2013). Elevated levels of OTA have been detected in urine of patients exposed to toxins in water-damaged buildings (Hooper et al., 2009) as well as in workers exposed to airborne dust originating from the processing of contaminated foods (Iavicoli et al., 2002). Inhalation of OTA has been linked to acute renal failure and respiratory distress in workers exposed to Aspergillus-producers of OTA in a granary (Di Paolo et al., 1994). Furthermore, OTA has been found in 22% of sinonasal tissue and mucus of chronic rhinosinusitis patients, and 83% of the urine of patients suffering from chronic fatigue syndrome (CFS) (Brewer et al., 2013b).
Trichothecenes are a group of over 200 structurally related mycotoxins produced by various species of e.g. Fusarium, Myrothecium and Stachybotrys. It has been suggested that the toxicity of trichothecenes might be a reason for many of the adverse effects of Stachybotrys chartarum, an infamous black mold suggested to contribute to damp building related illnesses (Pestka et al., 2008). Macrocyclic trichothecenes have been detected in patients with health problems related to mold contaminated buildings in several studies (Brewer et al., 2013b; Croft et al., 2002; Dennis et al., 2009; Rea et al., 2003, Trasher et al., 2012). The toxic potencies of different inhaled mycotoxins have been compared in hamster lung cells in vitro, listing the T-2 and HT-2 toxins as the most cytotoxic mycotoxins followed by Fusarium toxins DON, beauvericin, and enniatin B (Behm et al., 2012). One possible mechanism for adverse health effects of trichothecenes is the impairment of host defense, as the immune system is extremely sensitive to their effects (Pestka et al., 2008; Pestka, 2010a). The effect may be bipolar, where low concentrations cause immunostimulation and high concentrations result in immunosuppression, which was shown in human immune cells in vitro (Pestka et al., 2004). Both DON and T-2 have been shown to impair host resistance and pulmonary immune responses to enteric reovirus infection in mice (Li et al., 2006; Li et al., 2007).
Ueno (Ueno, 1984) was the first to report on the inhalation toxicity of T-2 in mice. Later, Creasia et al. (1987) demonstrated the acute effects immediately after inhaling aerosolic T-2 in mice: tremors, lethargy, stilted gait, and sometimes prostration. In rats and guinea pigs, respiratory exposure to T-2 revealed that lesions in histopathological examination were similar to those after systemic administration (Creasia et al., 1990). However, even after lethal doses, no histological evidence of acute pulmonary injury was found. The most consistent histological findings in guinea pigs after inhaled T-2 were lymphocytolysis and phagocytosis in the lymphoreticular system, and changes in the gastrointestinal tract (Marrs et al., 1986). Pang et al. (1987, 1988) reported that inhalation exposure of pigs to a sublethal dose of T-2 toxin caused morphological changes, clinical signs of toxicity and effects on hematology, serum biochemistry as well as on pulmonary and systemic immunity.
DON (vomitoxin) is a common trichothecene mycotoxin detected in grain dust. After nasal inhalation in mice, DON rapidly reaches the lungs and other organs, enhancing proinflammatory cytokine expression (Amuzie et al., 2008). Other effects of DON in multiple species are anorexia, diarrhea, growth retardation, neuroendocrine effects, and disruption of the immune system (Pestka, 2010a, 2010b). DON may be an indicator for other trichothecenes as DON, nivalenol and zearalenone have all been detected in the airborne dust from granaries. The occupational exposure to these toxins has been estimated to be below the tolerable daily intake (TDI) values, but activities such as cleaning have been shown to significantly increase the exposure of workers (Mayer et al., 2007; Niculita-Hirzel et al., 2016).
S atratoxins are acutely toxic secondary metabolites of S. chartarum, similarly as T-2 and HT-2 toxins. In mice models, the intranasal exposure to satratoxin G has been reported to evoke apoptosis of olfactory sensory neurons and acute inflammation in the nose and brain (Amuzie et al., 2010; Islam et al., 2006; Jia et al., 2011). Also, the nasal airways of rhesus monkeys were shown to be vulnerable to satratoxin G induced neuronal cell death and inflammation (Carey et al., 2012). Likewise, a single intranasal exposure to roridin A (a trichothecene mycotoxin with a similar chemical structure) has been found to induce rapid apoptosis and loss of olfactory sensory neurons in the nasal airways and the olfactory bulb in mice (Islam et al., 2007), and the effects may be even exacerbated by repeated exposure (Corps et al., 2010). These inflammatory effects have been suggested to account for nasal congestion and runny or itchy nose in people.
In addition to trichothecenes there is another mycotoxin family, atranones, which might contribute to the adverse health effects associated with S. chartarum. Pure atranones have been shown to contribute to inflammatory response by increasing the influx of immunocytes and cytokine responses in mice lungs after intratracheal instillation (Rand et al., 2006). It has been suggested that induction of inflammation by S. chartarum is related to atranones, while cytotoxicity to satratoxin production (Nielsen et al., 2002).
The mycotoxin research has been dominated by toxins of Stachybotrys, but it is good to keep in mind the wide variety of other toxins possibly relevant for human exposure. Less known “emerging toxins” such as sterigmatocystin and mycophenolic acid have been shown to occur frequently in agricultural products and thus could be relevant also for inhalation exposure (Gruber-Dorninger et al., 2016). There are indications that some MVOCs like 1-octen-3-ol might be a risk factor for indoor air related adverse health effects (Sahlberg et al., 2013). Toxins from Penicillium species common on wet building materials (brevianamide A, mycophenolic acid, and roquefortine C) have been shown to stimulate compound-specific inflammatory and cytotoxic responses in a mice model (Rand et al., 2005). Similarly, a study using doses comparable to the estimated doses of possible human exposure showed alterations in the expression of inflammation-associated genes in mice lungs after intratracheal instillation of toxins from fungi common on damp building environment (atranone C, brevianamide, cladosporin, mycophenolic acid, neoechinulin A & B, sterigmatocystin or TMC-120A) (Miller et al., 2010). A mixture of mycotoxins is also suggested to account for the ciliostatic activity of extracts of filamentous fungi isolated from mouldy buildings (Piecková and Kunová, 2002).
In addition to the reported inflammatory and cytotoxic responses, an increase of allergic immune response has also been linked with mycotoxin exposure. In a mice model of allergic asthma, the exposure to gliotoxin and patulin produced by Aspergillus and Penicillium species exacerbated the asthma-like phenotype by modulating the Th1/Th2 balance and by inducing oxidative stress (Schütze et al., 2010). However, in a cohort study measuring a broad set of microbial secondary metabolites no association between the presence of individual toxins and asthma development was observed, indicating that exposure to mycotoxins is not responsible for the increased risk of asthma in homes with moisture damage and mold (Kirjavainen et al., 2015). Overall, the in vivo findings suggest that mycotoxins may play a role in acute inflammation of airways, neurological deficits and impaired host resistance to infections, which are all symptoms associated with damp building exposure. Thus, a prolonged exposure to mycotoxins may provoke some of the adverse health effects associated with damp indoor environments (Miller et al., 2010; Miller and McMullin, 2014; Rand et al., 2011).
4 Exposure Assessment
Adverse health effects of inhalation of microbial toxins are better known from occupational environments such as farms and feed manufacturing plants, where exposure to massive doses of organic dust and resulting pulmonary mycotoxicoses such as organic dust toxic syndrome (ODTS) have been well documented (Seifert et al., 2003; Viegas et al., 2013a). Establishing the link between inhaled microbial toxins in moisture-damaged indoor environments has proven to be more difficult, as the levels of microbial toxins are much lower and only few studies have characterized inhalation exposure accurately. Also the lack of specificity may cause problems, e.g. hundreds of MVOCs can be measured from the air, but none of these compounds are exclusively produced by microbes (Korpi et al., 2009). The exposure assessment is often based on presence of limited number of mycotoxins in indoor dust samples or biological fluids, whereas studies describing airborne concentrations of mycotoxins are virtually nonexistent (Tables 10.1 and 10.2). Determining mycotoxins directly from air is difficult, so usually the inhalation exposure is estimated by multiplying the mycotoxin concentrations in settled dust with either amount of dust measured from the air (Mayer et al., 2008) or derived from exposure limits for dust (Brasel et al., 2005). Even more often the exposure assessment is merely based on assumption that the mycotoxin exposure is taking place because mycotoxin producing fungi were detected from the indoor environment or exposure to molds was reported by the study subjects (Hodgson et al., 1998; Kilburn, 2009; Kilburn et al., 2009). Another shortcoming of mycotoxin exposure assessment is the lack of information about the “normal” level of mycotoxin exposure in indoor environments, although mycotoxins are known to be ubiquitous in built environment and found also from outdoors (Peitzsch et al., 2012; Täubel et al., 2011).
5 Biomonitoring of Mycotoxins
Mycotoxins, specifically trichothecenes, aflatoxins, and ochratoxins, can be detected in human tissue and body fluids in patients who have been exposed to toxin producing molds in their environment (Table 10.2). In fact, in a study of Hooper et al. (2009) trichothecenes were found in 95% of urines, 44% of nasal secretions and 59% of tissue, whereas aflatoxins and ochratoxins were present in lesser cases. Only one study reports an association between levels of OTA in serum and occupational exposure, but AFB1 levels in serum have been consistently associated with working in waste industry, poultry farms and slaughterhouses (Oluwafemi et al., 2012; Viegas et al., 2012, 2013b, 2013c, 2015, 2016). Similarly, levels of macrocyclic trichothecenes as well as hemolysin stachylysin in serum have been associated with exposure to indoor molds (Brasel et al., 2004; Van Emon et al., 2003). Few studies report no association between occupational exposure and levels of mycotoxins in biological fluids (Degen et al., 2007; Föllman et al., 2016), suggesting that exposure levels can be controlled even in workplaces with high risk for mycotoxin contamination.
Some mycotoxins can also form metabolites or protein adducts, which could serve as biomarkers of exposure; e.g. intratracheal exposure to satratoxin G produced adducts with serum albumin in both humans and rats (Yike et al., 2006). Serum AFB1 albumin adducts have been used to assess chronic exposure via both diet (Leong et al., 2012) and inhalation (Autrup et al., 1991; Lai et al., 2014), but detectable levels of adducts were seen only after inhalation exposure to a certain level of AFB1 in an epidemiological study and in an animal model (Mo et al., 2014). Generally, several biomarkers of oral exposure exists for the agriculturally important toxins (Lee and Ryu, 2015), but for the toxins from building associated fungi there is hardly any biomarkers available. The development of biomarkers showing inhalation exposure to broader set of mycotoxins would be an important step for risk assessment.
6 Risk Assessment
A valid risk assessment for inhalation exposure to microbial secondary metabolites is a demanding task for several reasons. Firstly, accurate exposure assessment is needed since mycotoxins can show a wide variety of effects (e.g. immunotoxic, carcinogenic, mutagenic, toxic or teratogenic) depending on the type of toxin. The type of exposure (inhalation, oral, dermal) may also affect the adverse effects seen; the inhalation route seems to be more harmful than ingestion of certain mycotoxins. The dose and duration of exposure are important determinants as well as the toxin fraction absorbed after respiratory intake. Furthermore, the sensitivity to mycotoxins varies between exposed individuals or population groups (Fromme et al., 2016; World Health Organization, 2009). Worryingly, children appear to be at greater risk for inhaled toxicants, as the respiratory deposition of fungal fragments into to lower airways of infants was found to be four to five times higher than in adults (Cho et al., 2005).
In indoor environment toxins never exist individually, but rather are mixed with a variety of fungi and bacteria, their spores, fragments and cell wall components together with allergenic proteins, volatile organic compounds and particulates (Nevalainen et al., 2015). In experimental setups, mycotoxins have been shown to interact synergistically with each other (Vejdovszky et al., 2017), with microbes (Huttunen et al., 2004; Penttinen et al., 2005), with spores (Šegvić Klarić et al., 2015), with microbial structural components (Islam and Pestka, 2006; Islam et al., 2007; Kankkunen et al., 2009, 2014; Korkalainen et al., 2017; Zhou et al., 1999) as well as with particulate matter (PM10) (Capasso et al., 2015). Similarly, there is evidence of strong synergistic or additive effects after simultaneous exposure to multiple foodborne toxins (Stoev, 2015). Synergistic effects of microbial secondary metabolites should be given due consideration, as there is a possibility of underestimating the effects of microbial exposures if the risk assessment is based on information on individual exposure agents.
Several regulatory agencies and organizations, such as World Health Organisation (WHO), Joint FAO/WHO Expert Committee on Food Additives (JECFA), EU Scientific Committee for Food (SCF) and European Food Safety Authority (EFSA) have set maximum permissible levels and produced TDIs for agriculturally important mycotoxins worldwide. International Agency for Research of Cancer (IARC) has also evaluated the carcinogenic risks of some naturally occurring toxins to humans. However, these limit values are merely directed to regulate the exposure via food. Since only limited toxicological data from inhalation exposure are available, the extended threshold of toxicological concern (TTC) concept (concentration of no toxicologic concern, CoNTC) has been introduced for safety assessment purposes (Drew and Frangos, 2007; Munro et al., 2008). The resulting airborne concentration, 30 ng/m3, is expected not to pose hazard to humans through lifetime. Although exposures in the most extreme working conditions may exceed this concentration, measured airborne mycotoxin levels in the built indoor environment have been repeatedly found to be too low to pose a credible health risk, as the doses of both nonvolatile and volatile microbial metabolites are consistently below the CoNTC (Hardin et al., 2003; Hardin et al., 2009; Kelman et al., 2004; Robbins et al., 2000, Korpi et al., 2009) (Fig. 10.2). However, the presence of mycotoxins in materials or products handled in a workplace should be considered as a potential hazard to health, even though the causal connection between mycotoxin exposure and adverse health effects is not established and risk assessment requires more detailed information about the quality and quantity of the inhaled substance (Degen, 2011).
7 Conclusions
Microbial secondary metabolites can be found from indoor environments and particularly in workplaces where organic material is handled or moisture damage supports excessive microbial growth. Exposure to microbial toxins is possible and even likely, as the spores and fragments of microbes can act as carriers. Among microbial secondary metabolites there are numerous compounds which have been shown to be toxic to mammals. However, the concentrations of microbial toxins indoors are typically low, and same microbial secondary metabolites can be found also from outdoor air as well as microbiologically “normal” indoor environments. In order to pose a health risk the amount of toxin in the air (or retained in the body) should exceed the threshold of toxicological concern, and at least for single toxins, this is typically not the case.
Future efforts should concentrate on the studies of multiple exposures, comorbidities of microbial toxicoses and effects of low-level chronic exposures. Epidemiological studies are needed to establish causality, but they need better measures of exposure to a wider selection of microbial secondary metabolites. There is a lack of toxicokinetic data on humans, clinical studies measuring both exposure and health outcome as well as biomonitoring studies assessing internal exposure after respiratory intake in residential settings. In addition, more experimental studies with advanced models of respiratory system are needed to elucidate the complex relationships between toxin exposure and health outcome.
References
Amuzie CJ, Harkema JR, Pestka JJ (2008) Tissue distribution and proinflammatory cytokine induction by the trichothecene deoxynivalenol in the mouse: comparison of nasal vs. oral exposure. Toxicology 248:39–44. doi:10.1016/j.tox.2008.03.005
Amuzie CJ, Islam Z, Kim JK et al. (2010) Kinetics of satratoxin G tissue distribution and excretion following intranasal exposure in the mouse. Toxicol Sci 116:433–440. doi:10.1093/toxsci/kfq142
Autrup JL, Schmidt J, Seremet T et al. (1991) Determination of exposure to aflatoxins among Danish workers in animal-feed production through the analysis of aflatoxin B1 adducts to serum albumin. Scand J Work Environ Health 17:436–440
Behm C, Föllmann W, Degen GH (2012) Cytotoxic potency of mycotoxins in cultures of V79 lung fibroblast cells. J Toxicol Environ Health A 75:1226–1231. doi:10.1080/15287394.2012.709170
Bitnun A, Nosal RM (1999) Stachybotrys chartarum (atra) contamination of the indoor environment: health implications. Paediatr Child Health 4:125–129
Bloom E, Nyman E, Must A et al. (2009) Molds and mycotoxins in indoor environments – a survey in water-damaged buildings. J Occup Environ Hyg 6:671–678. doi:10.1080/15459620903252053
Boonen J, Malysheva SV, Taevernier L et al. (2012) Human skin penetration of selected model mycotoxins. Toxicology 301:21–32. doi:10.1016/j.tox.2012.06.012
Brasel TL, Campbell AW, Demers RE et al. (2004) Detection of trichothecene mycotoxins in sera from individuals exposed to Stachybotrys chartarum in indoor environments. Arch Environ Health 59:317–323
Brasel TL, Martin JM, Carriker CG et al. (2005) Detection of airborne Stachybotrys chartarum macrocyclic trichothecene mycotoxins in the indoor environment. Appl Environ Microbiol 71:7376–7388
Brewer JH, Thrasher JD, Hooper D (2013a) Chronic illness associated with mold and mycotoxins: is naso-sinus fungal biofilm the culprit? Toxins (Basel) 6:66–80. doi:10.3390/toxins6010066
Brewer JH, Thrasher JD, Straus DC et al. (2013b) Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins (Basel) 5:605–617. doi:10.3390/toxins5040605
Burg WA, Shotwell OL, Saltzman BE (1981) Measurements of airborne aflatoxins during the handling of contaminated corn. Am Ind Hyg Assoc J 42:1–11. doi:10.1080/15298668191419271
Burg WR, Shotwell OL, Saltzman BE (1982) Measurement of airborne aflatoxins during the handling of 1979 contaminated corn. Am Ind Hyg Assoc J 43:580–586
Cabaret O, Puel O, Botterel F et al. (2010) Metabolic detoxication pathways for sterigmatocystin in primary tracheal epithelial cells. Chem Res Toxicol 23:1673–1681. doi:10.1021/tx100127b
Cai GH, Malarstig B, Kumlin A et al. (2011) Fungal DNA and plergen levels in Swedish day care centers and associations with building characteristics. J Environ Monit 13:2018–2024. doi:10.1039/c0em00553c
Capasso L, Longhin E, Caloni F et al. (2015) Synergistic inflammatory effect of PM10 with mycotoxin deoxynivalenol on human lung epithelial cells. Toxicon 104:65–72. doi:10.1016/j.toxicon.2015.08.008
Carey SA, Plopper CG, Hyde DM et al. (2012) Satratoxin-G from the black mold Stachybotrys chartarum induces rhinitis and apoptosis of olfactory sensory neurons in the nasal airways of rhesus monkeys. Toxicol Pathol 40:887–898. doi:10.1177/0192623312444028
Chatopadhyay P, Tariang B, Agnihotri A et al. (2014) Synergism of ochratoxin B and calcium-channel antagonist verapamil caused mitochondrial dysfunction. Toxicol Mech Methods 24:428–432. doi:10.3109/15376516.2014.936543
Cho S, Seo S, Schmechel D et al. (2005) Aerodynamic characteristics and respiratory deposition of fungal fragments. Atmos Environ 39:5454–5465
Corcuera LA, Vettorazzi A, Arbillaga L et al. (2015) Genotoxicity of aflatoxin B1 and ochratoxin A after simultaneous application of the in vivo micronucleus and comet assay. Food Chem Toxicol 76:116–124. doi:10.1016/j.fct.2014.12.003
Corps KN, Islam Z, Pestka JJ et al. (2010) Neurotoxic, inflammatory, and mucosecretory responses in the nasal airways of mice repeatedly exposed to the macrocyclic trichothecene mycotoxin roridin A: dose-response and persistence of injury. Toxicol Pathol 38:429–451. doi:10.1177/0192623310364026
Council for Agricultural Science and Technology (2003) Mycotoxins: risk in plant, animal, and human systems. Task force report 139, Ames, Iowa
Creasia DA, Thurman JD, Jones 3rd LJ et al. (1987) Acute inhalation toxicity of T-2 mycotoxin in mice. Fundam Appl Toxicol 8:230–235
Creasia DA, Thurman JD, Wannemacher Jr RW et al. (1990) Acute inhalation toxicity of T-2 mycotoxin in the rat and guinea pig. Fundam Appl Toxicol 14:54–59
Croft WA, Jarvis BB, Yatatwara CS (1986) Airborne outbreak of trichothecene toxicosis. Atmos Environ 20:549–552
Croft WA, Jastromski BM, Croft AL et al. (2002) Clinical confirmation of trichothecene mycotoxicosis in patient urine. J Environ Biol 23:301–320
Degen G (2011) Tools for investigating workplace-related risks from mycotoxin exposure. World Mycotoxin J 4:315–327
Degen GH, Mayer S, Blaszkewicz M (2007) Biomonitoring of ochratoxin A in grain workers. Mycotoxin Res 23:88–93. doi:10.1007/BF02946032
Dennis D, Robertson D, Curtis L et al. (2009) Fungal exposure endocrinopathy in sinusitis with growth hormone deficiency: Dennis-Robertson syndrome. Toxicol Ind Health 25:669–680. doi:10.1177/0748233709348266
Di Paolo N, Guarnieri A, Garosi G et al. (1994) Inhaled mycotoxins lead to acute renal failure. Nephrol Dial Transplant 9(Suppl 4):116–120
Drew R, Frangos J (2007) The concentration of no toxicological concern (CoNTC): a risk assessment screening tool for air toxics. J Toxicol Environ Health A 70:1584–1593. 781628584 [pii]
Driscoll KE, Costa DL, Hatch G et al. (2000) Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations. Toxicol Sci 55:24–35
Dvorácková I, Pichová V (1986) Pulmonary interstitial fibrosis with evidence of aflatoxin B1 in lung tissue. J Toxicol Environ Health 18:153–157. doi:10.1080/15287398609530856
EU (2003) EU Directive 76/768/EEC, Directive 2003/15/EC of the European Parliament and of the Council. Off J Eur Union L66:26–35
Flannigan B (1987) Mycotoxins in the air. Int Biodeterior 23:73–78
Föllmann W, Ali N, Blaszkewicz M et al. (2016) Biomonitoring of mycotoxins in urine: pilot study in mill workers. J Toxicol Environ Health A 79:1015–1025
Forgacs J (1962) Mycotoxicoses – the neglected disease. Feedstuffs 34:124–134
Fromme H, Gareis M, Völkel W et al. (2016) Overall internal exposure to mycotoxins and their occurrence in occupational and residential settings – an overview. Int J Hyg Environ Health 219:143–165. doi:10.1016/j.ijheh.2015.11.004
González-Arias CA, Crespo-Sempere A, Marin S et al. (2015) Modulation of the xenobiotic transformation system and inflammatory response by ochratoxin A exposure using a co-culture system of Caco-2 and HepG2 cells. Food Chem Toxicol 86:245–252. doi:10.1016/j.fct.2015.10.007
Gottschalk C, Bauer J, Meyer K (2008) Detection of satratoxin g and h in indoor air from a water-damaged building. Mycopathologia 166:103–107. doi:10.1007/s11046-008-9126-z
Gruber-Dorninger C, Novak B, Nagl V, et al. (2016) Emerging mycotoxins: beyond traditionally determined food contaminants. J Agric Food Chem. doi:10.1021/acs.jafc.6b03413
Guindon-Kezis KA, Mulder JE, Massey TE (2014) In vivo treatment with aflatoxin B1 increases DNA oxidation, base excision repair activity and 8-oxoguanine DNA glycosylase 1 levels in mouse lung. Toxicology 321:21–26. doi:10.1016/j.tox.2014.03.004
Hardin BD, Kelman BJ, Saxon A (2003) Adverse human health effects associated with molds in the indoor environment. J Occup Environ Med 45:470–478
Hardin BD, Robbins CA, Fallah P et al. (2009) The concentration of no toxicologic concern (CoNTC) and airborne mycotoxins. J Toxicol Environ Health A 72:585–598. doi:10.1080/15287390802706389
Harkema JR, Carey SA, Wagner JG (2006) The nose revisited: a brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicol Pathol 34:252–269. H1080432VQ59X328 [pii]
Hasegawa-Baba Y, Kubota H, Takata A et al. (2014) Intratracheal instillation methods and the distribution of administered material in the lung of the rat. J Toxicol Pathol 27:197–204. doi:10.1293/tox.2014-0022
Hayes RB, van Nieuwenhuize JP, Raatgever JW et al. (1984) Aflatoxin exposures in the industrial setting: an epidemiological study of mortality. Food Chem Toxicol 22:39–43
Hodgson MJ, Morey P, Leung WY et al. (1998) Building-associated pulmonary disease from exposure to Stachybotrys chartarum and Aspergillus versicolor. J Occup Environ Med 40:241–249
Hooper DG, Bolton VE, Guilford FT et al. (2009) Mycotoxin detection in human samples from patients exposed to environmental molds. Int J Mol Sci 10:1465–1475. doi:10.3390/ijms10041465
Hope JH, Hope BE (2012) A review of the diagnosis and treatment of ochratoxin A inhalational exposure associated with human illness and kidney disease including focal segmental glomerulosclerosis. J Environ Public Health 2012:835059. doi:10.1155/2012/835059
Huttunen K, Pelkonen J, Nielsen KF et al. (2004) Synergistic interaction in simultaneous exposure to Streptomyces californicus and Stachybotrys chartarum. Environ Health Perspect 112:659–665
Iavicoli I, Brera C, Carelli G et al. (2002) External and internal dose in subjects occupationally exposed to ochratoxin A. Int Arch Occup Environ Health 75:381–386. doi:10.1007/s00420-002-0319-3
Islam Z, Amuzie CJ, Harkema JR et al. (2007) Neurotoxicity and inflammation in the nasal airways of mice exposed to the macrocyclic trichothecene mycotoxin roridin a: kinetics and potentiation by bacterial lipopolysaccharide coexposure. Toxicol Sci 98:526–541.
Islam Z, Harkema JR, Pestka JJ (2006) Satratoxin G from the black mold Stachybotrys chartarum evokes olfactory sensory neuron loss and inflammation in the murine nose and brain. Environ Health Perspect 114:1099–1107
Islam Z, Pestka JJ (2006) LPS priming potentiates and prolongs proinflammatory cytokine response to the trichothecene deoxynivalenol in the mouse. Toxicol Appl Pharmacol 211:53–63. S0041-008X(05)00223-1 [pii]
Jakab GJ, Hmieleski RR, Zarba A et al. (1994) Respiratory aflatoxicosis: suppression of pulmonary and systemic host defenses in rats and mice. Toxicol Appl Pharmacol 125:198–205. S0041-008X(84)71065-9 [pii]
Jarvis BB, Miller JD (2005) Mycotoxins as harmful indoor air contaminants. Appl Microbiol Biotechnol 66:367–372. doi:10.1007/s00253-004-1753-9
Jia C, Sangsiri S, Belock B et al. (2011) ATP mediates neuroprotective and neuroproliferative effects in mouse olfactory epithelium following exposure to satratoxin G in vitro and in vivo. Toxicol Sci 124:169–178. doi:10.1093/toxsci/kfr213
Kankkunen P, Rintahaka J, Aalto A et al. (2009) Trichothecene mycotoxins activate inflammatory response in human macrophages. J Immunol 182:6418–6425. doi:10.4049/jimmunol.0803309
Kankkunen P, Välimäki E, Rintahaka J et al. (2014) Trichothecene mycotoxins activate NLRP3 inflammasome through a P2X7 receptor and Src tyrosine kinase dependent pathway. Hum Immunol 75:134–140. doi:10.1016/j.humimm.2013.11.010
Kelman BJ, Robbins CA, Swenson LJ et al. (2004) Risk from inhaled mycotoxins in indoor office and residential environments. Int J Toxicol 23:3–10. doi:10.1080/10915810490265423
Kilburn KH (2009) Neurobehavioral and pulmonary impairment in 105 adults with indoor exposure to molds compared to 100 exposed to chemicals. Toxicol Ind Health 25:681–92. doi:10.1177/0748233709348390
Kilburn KH, Thrasher JD, Immers NB (2009) Do terbutaline- and mold-associated impairments of the brain and lung relate to autism? Toxicol Ind Health 25:703–10. doi:10.1177/0748233709348391
Kirjavainen PV, Täubel M, Karvonen AM et al. (2015) Microbial secondary metabolites in homes in association with moisture damage and asthma. Indoor Air 3:448–456. doi:10.1111/ina.12213
Korkalainen M, Täubel M, Naarala J et al. (2017) Synergistic proinflammatory interactions of microbial toxins and structural components characteristic to moisture-damaged buildings. Indoor Air 27:13–23. doi:10.1111/ina.12282
Korpi A, Järnberg J, Pasanen AL (2009) Microbial volatile organic compounds. Crit Rev Toxicol 39:139–93. doi:10.1080/10408440802291497
Kőszegi T, Poór M (2016) Ochratoxin A: molecular interactions, mechanisms of toxicity and prevention at the molecular level. Toxins 8:111. doi:10.3390/toxins8040111
Lai H, Mo X, Yang Y et al. (2014) Association between aflatoxin B1 occupational airway exposure and risk of hepatocellular carcinoma: a case-control study. Tumour Biol 35:9577–9584. doi:10.1007/s13277-014-2231-3
Larsson P, Tjälve H (2000) Intranasal instillation of aflatoxin B(1) in rats: bioactivation in the nasal mucosa and neuronal transport to the olfactory bulb. Toxicol Sci 55:383–391
Lee HJ, Ryu D (2015) Advances in mycotoxin research: public health perspectives. J Food Sci 80:T2970–83. doi:10.1111/1750-3841.13156
Lee RJ, Workman AD, Carey RM et al. (2016) Fungal aflatoxins reduce respiratory mucosal ciliary function. Sci Rep 6:33221. doi:10.1038/srep33221
Leong YH, Rosma A, Latiff AA et al. (2012) Associations of serum aflatoxin B1-lysine adduct level with socio-demographic factors and aflatoxins intake from nuts and related nut products in Malaysia. Int J Hyg Environ Health 215:368–372. doi:10.1016/j.ijheh.2011.12.005
Li M, Harkema JR, Cuff CF et al. (2007) Deoxynivalenol exacerbates viral bronchopneumonia induced by respiratory reovirus infection. Toxicol Sci 95:412–426
Li M, Harkema JR, Islam Z et al. (2006) T-2 toxin impairs murine immune response to respiratory reovirus and exacerbates viral bronchiolitis. Toxicol Appl Pharmacol 217:76–85. S0041-008X(06)00265-1 [pii]
Lichtenstein JH, Molina RM, Donaghey TC et al. (2010) Pulmonary responses to Stachybotrys chartarum and its toxins: mouse strain affects clearance and macrophage cytotoxicity. Toxicol Sci 116:113–121. doi:10.1093/toxsci/kfq104
Lieberman SM, Jacobs JB, Lebowitz RA et al. (2011) Measurement of mycotoxins in patients with chronic rhinosinusitis. Otolaryngol Head Neck Surg 145:327–329. doi:10.1177/0194599811403891
Louria DB, Finkel G, Smith JK et al. (1974) Aflatoxin-induced tumors in mice. Sabouraudia 12:371–375
Malik A, Ali S, Shahid M et al. (2014) Occupational exposure to Aspergillus and aflatoxins among food-grain workers in India. Int J Occup Environ Health 20:189–193. doi:10.1179/2049396714Y.0000000055
Malir F, Ostry V, Pfohl-Leszkowicz A et al. (2016) Ochratoxin A: 50 years of research. Toxins 8:191. doi:10.3390/toxins8070191
Marrs TC, Edginton JA, Price PN et al. (1986) Acute toxicity of T2 mycotoxin to the guinea-pig by inhalation and subcutaneous routes. Br J Exp Pathol 67:259–268
Mayer S, Curtui V, Usleber E et al. (2007) Airborne mycotoxins in dust from grain elevators. Mycotoxin Res 23:94–100. doi:10.1007/BF02946033
Mayer S, Engelhart S, Kolk A et al. (2008) The significance of mycotoxins in the framework of assessing workplace related risks. Mycotoxin Res 24:151–164. doi:10.1007/BF03032342
McIntyre BA, Kushwah R, Mechael R et al. (2015) Innate immune response of human pluripotent stem cell-derived airway epithelium. Innate Immun 21:504–511. doi:10.1177/1753425914551074
Miller JD, McMullin DR (2014) Fungal secondary metabolites as harmful indoor air contaminants: 10 years on. Appl Microbiol Biotechnol 98:9953–9966. doi:10.1007/s00253-014-6178-5
Miller JD, Sun M, Gilyan A et al. (2010) Inflammation-associated gene transcription and expression in mouse lungs induced by low molecular weight compounds from fungi from the built environment. Chem Biol Interact 183:113–124. doi:10.1016/j.cbi.2009.09.023
Mo X, Lai H, Yang Y et al. (2014) How does airway exposure of aflatoxin B1 affect serum albumin adduct concentrations? Evidence based on epidemiological study and animal experimentation. J Toxicol Sci 39:645–653. DN/JST.JSTAGE/jts/39.645 [pii]
Munro IC, Renwick AG, Danielewska-Nikiel B (2008) The Threshold of Toxicological Concern (TTC) in risk assessment. Toxicol Lett 180:151–156. doi:10.1016/j.toxlet.2008.05.006
Nevalainen A, Täubel M, Hyvärinen A (2015) Indoor fungi: companions and contaminants. Indoor Air 25:125–156. doi:10.1111/ina.12182
Niculita-Hirzel H, Hantier G, Storti F et al. (2016) Frequent occupational exposure to Fusarium mycotoxins of workers in the Swiss Grain Industry. Toxins (Basel). 8(12). doi:10.3390/toxins8120370
Nielsen KF, Huttunen K, Hyvärinen A et al. (2002) Metabolite profiles of Stachybotrys isolates from water-damaged buildings and their induction of inflammatory mediators and cytotoxicity in macrophages. Mycopathologia 154:201–205
Norbäck D, Hashim JH, Cai GH et al. (2016) Rhinitis, ocular, throat and dermal symptoms, headache and tiredness among students in schools from Johor Bahru, Malaysia: associations with fungal DNA and mycotoxins in classroom dust. PLoS One 11:e0147996. doi:10.1371/journal.pone.0147996
Oluwafemi F, Odebiyi T, Kolapo A (2012) Occupational aflatoxin exposure among feed mill workers in Nigeria. World Mycotoxin J 5:385–389
Pang VF, Lambert RJ, Felsburg PJ et al. (1987) Experimental T-2 toxicosis in swine following inhalation exposure: effects on pulmonary and systemic immunity, and morphologic changes. Toxicol Pathol 15:308–319
Pang VF, Lambert RJ, Felsburg PJ et al. (1988) Experimental T-2 toxicosis in swine following inhalation exposure: clinical signs and effects on hematology, serum biochemistry, and immune response. Fundam Appl Toxicol 11:100–109
Peitzsch M, Sulyok M, Täubel M et al. (2012) Microbial secondary metabolites in school buildings inspected for moisture damage in Finland, The Netherlands and Spain. J Environ Monit 14:2044–2053. doi:10.1039/c2em30195d
Penttinen P, Pelkonen J, Huttunen K et al. (2005) Interactions between Streptomyces californicus and Stachybotrys chartarum can induce apoptosis and cell cycle arrest in mouse RAW264.7 macrophages. Toxicol Appl Pharmacol 202:278–288. S0041-008X(04)00347-3 [pii]
Pestka JJ (2010a) Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance. Arch Toxicol 84:663–679. doi:10.1007/s00204-010-0579-8
Pestka JJ (2010b) Deoxynivalenol-induced proinflammatory gene expression: mechanisms and pathological sequelae. Toxins 2:1300–1317. doi:10.3390/toxins2061300
Pestka JJ, Yike I, Dearborn DG et al. (2008) Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: new insights into a public health enigma. Toxicol Sci 104:4–26. doi:10.1093/toxsci/kfm284
Pestka JJ, Zhou HR, Moon Y et al. (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153:61–73. doi:10.1016/j.toxlet.2004.04.023
Piecková E, Kunová Z (2002) Indoor fungi and their ciliostatic metabolites. Ann Agric Environ Med 9:59–63
Pinton P, Oswald IP (2014) Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins 6:1615–1643. doi:10.3390/toxins6051615
Polizzi V, Delmulle B, Adams A et al. (2009) JEM Spotlight: fungi, mycotoxins and microbial volatile organic compounds in mouldy interiors from water-damaged buildings. J Environ Monit 11:1849–1858. doi:10.1039/b906856b
Prytherch Z, Job C, Marshall H et al. (2011) Tissue-specific stem cell differentiation in an in vitro airway model. Macromol Biosci 11:1467–1477. doi:10.1002/mabi.201100181
Prytherch ZC, BéruBé KA (2014) A normal and biotransforming model of the human bronchial epithelium for the toxicity testing of aerosols and solubilised substances. Altern Lab Anim 42:377–381
Rand TG, Dipenta J, Robbins C et al. (2011) Effects of low molecular weight fungal compounds on inflammatory gene transcription and expression in mouse alveolar macrophages. Chem Biol Interact 190:139–147. doi:10.1016/j.cbi.2011.02.017
Rand TG, Flemming J, David Miller J et al. (2006) Comparison of inflammatory responses in mouse lungs exposed to atranones A and C from Stachybotrys chartarum. J Toxicol Environ Health A 69:1239–1251. R5048J37649XT10X [pii]
Rand TG, Giles S, Flemming J et al. (2005) Inflammatory and cytotoxic responses in mouse lungs exposed to purified toxins from building isolated Penicillium brevicompactum Dierckx and P. chrysogenum Thom. Toxicol Sci 87:213–222. doi: kfi223 [pii]
Rea WJ, Didriksen N, Simon TR et al. (2003) Effects of toxic exposure to molds and mycotoxins in building-related illnesses. Arch Environ Health 58:399–405
REACH (2006) Regulation (EC) no 1907/2006 of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). Off J Eur Union L396:1–849
Robbins CA, Swenson LJ, Nealley ML et al. (2000) Health effects of mycotoxins in indoor air: a critical review. Appl Occup Environ Hyg 15:773–784. doi:10.1080/10473220050129419
Sahlberg B, Gunnbjörnsdottir M, Soon A et al. (2013) Airborne molds and bacteria, microbial volatile organic compounds (MVOC), plasticizers and formaldehyde in dwellings in three North European cities in relation to sick building syndrome (SBS). Sci Total Environ 444:433–40. doi:10.1016/j.scitotenv.2012.10.114
Schütze N, Lehmann I, Bönisch U et al. (2010) Exposure to mycotoxins increases the allergic immune response in a murine asthma model. Am J Respir Crit Care Med 181:1188–1199. doi:10.1164/rccm.200909-1350OC
Šegvić Klarić M, Jakšić Despot D, Kopjar N et al. (2015) Cytotoxic and genotoxic potencies of single and combined spore extracts of airborne OTA-producing and OTA-non-producing Aspergilli in human lung A549 cells. Ecotoxicol Environ Saf 120:206–214. doi:10.1016/j.ecoenv.2015.06.002
Seifert SA, Von Essen S, Jacobitz K et al. (2003) Organic dust toxic syndrome: a review. J Toxicol Clin Toxicol 41:185–193
Selim MI, Juchems AM, Popendorf W (1998) Assessing airborne aflatoxin B1 during on-farm grain handling activities. Am Ind Hyg Assoc J 59:252–256. doi:10.1080/15428119891010514
Skaug MA, Eduard W, Stormer FC (2001) Ochratoxin A in airborne dust and fungal conidia. Mycopathologia 151:93–98
Sorenson WG, Jones W, Simpson J et al. (1984) Aflatoxin in respirable airborne peanut dust. J Toxicol Environ Health 14:525–533. doi:10.1080/15287398409530603
Stoev SD (2015) Foodborne mycotoxicoses, risk assessment and underestimated hazard of masked mycotoxins and joint mycotoxin effects or interaction. Environ Toxicol Pharmacol 39:794–809. doi:10.1016/j.etap.2015.01.022
Straus DC (2009) Molds, mycotoxins, and sick building syndrome. Toxicol Ind Health 25:617–635. doi:10.1177/0748233709348287
Täubel M, Hyvärinen A (2015) Occurrence of mycotoxins in indoor environments. In: Viegas C, Pinheiro A, Sabino R, et al (eds) Environmental mycology in public health, Amsterdam, Elsevier Academic Press pp 299–319
Täubel M, Sulyok M, Vishwanath V et al. (2011) Co-occurrence of toxic bacterial and fungal secondary metabolites in moisture-damaged indoor environments. Indoor Air 21:368–375. doi:10.1111/j.1600-0668.2011.00721.x
Thrasher JD, Gray MR, Kilburn KH et al. (2012) A water-damaged home and health of occupants: a case study. J Environ Public Health 2012:312836. doi:10.1155/2012/312836
Trout D, Bernstein J, Martinez K et al. (2001) Bioaerosol lung damage in a worker with repeated exposure to fungi in a water-damaged building. Environ Health Perspect 109:641–644. sc271_5_1835 [pii]
Tuomi T, Reijula K, Johnsson T et al. (2000) Mycotoxins in crude building materials from water-damaged buildings. Appl Environ Microbiol 66:1899–1904
Ueno Y (1984) Toxicological features of T-2 toxin and related trichothecenes. Fundam Appl Toxicol 4:S124–32
Van Emon JM, Reed AW, Yike I et al. (2003) ELISA measurement of stachylysin in serum to quantify human exposures to the indoor mold Stachybotrys chartarum. J Occup Environ Med 45:582–591. doi:10.1097/01.jom.0000071503.96740.65
Van Vleet TR, Klein PJ, Coulombe Jr RA (2001) Metabolism of aflatoxin B1 by normal human bronchial epithelial cells. J Toxicol Environ Health A 63:525–540. doi:10.1080/15287390152410156
Vejdovszky K, Hahn K, Braun D, et al. (2017) Synergistic estrogenic effects of Fusarium and Alternaria mycotoxins in vitro. Arch Toxicol 91:1147–1460. doi:10.1007/s00204-016-1795-7
Vettorazzi A, van Delft J, López de Cerain A (2013) A review on ochratoxin A transcriptomic studies. Food Chem Toxicol 59:766–783. doi:10.1016/j.fct.2013.05.043
Viegas S, Veiga L, Almeida A et al. (2016) Occupational exposure to aflatoxin B1 in a Portuguese poultry slaughterhouse. Ann Occup Hyg 60:176–183. doi:10.1093/annhyg/mev077
Viegas S, Veiga L, Figueiredo P et al. (2015) Assessment of workers’ exposure to aflatoxin B1 in a Portuguese waste industry. Ann Occup Hyg 59:173–181. doi:10.1093/annhyg/meu082
Viegas S, Faisca VM, Dias H et al. (2013a) Occupational exposure to poultry dust and effects on the respiratory system in workers. J Toxicol Environ Health A 76:230–239. doi:10.1080/15287394.2013.757199
Viegas S, Veiga L, Figueredo P et al. (2013b) Occupational exposure to aflatoxin B1 in swine production and possible contamination sources. J Toxicol Environ Health A 76:944–951. doi:10.1080/15287394.2013.826569
Viegas S, Veiga L, Figueredo P et al. (2013c) Occupational exposure of aflatoxin B1: the case of poultry and swine production. World Mycotoxin J 6:309–315
Viegas S, Veiga L, Malta-Vacas J et al. (2012) Occupational exposure to aflatoxin (AFB(1)) in poultry production. J Toxicol Environ Health A 75:1330–1340. doi:10.1080/15287394.2012.721164
Wang Y, Chai T, Lu G et al. (2008) Simultaneous detection of airborne aflatoxin, ochratoxin and zearalenone in a poultry house by immunoaffinity clean-up and high-performance liquid chromatography. Environ Res 107:139–144. doi:10.1016/j.envres.2008.01.008
World Health Organization (2009) WHO guidelines for indoor air quality: dampness and mould. WHO Regional Office for Europe, Copenhagen.
Yike I, Dearborn DG (2004) Pulmonary effects of Stachybotrys chartarum in animal studies. Adv Appl Microbiol 55:241–273. doi:10.1016/S0065-2164(04)55009-8
Yike I, Distler AM, Ziady AG et al. (2006) Mycotoxin adducts on human serum albumin: biomarkers of exposure to Stachybotrys chartarum. Environ Health Perspect 114:1221–1226
Yike I, Rand TG, Dearborn DG (2005) Acute inflammatory responses to Stachybotrys chartarum in the lungs of infant rats: time course and possible mechanisms. Toxicol Sci 84:408–417
Zarba A, Hmieleski R, Hemenway DR et al. (1992) Aflatoxin B1 – DNA adduct formation in rat liver following exposure by aerosol inhalation. Carcinogenesis 13:1031–1033
Zhou HR, Harkema JR, Yan D et al. (1999) Amplified proinflammatory cytokine expression and toxicity in mice coexposed to lipopolysaccharide and the trichothecene vomitoxin (deoxynivalenol). J Toxicol Environ Health A 57:115–136
Zock JP, Borras-Santos A, Jacobs J, et al (2014) Dampness and microbial secondary metabolites in schools and respiratory symptoms in teachers. European Respiratory Society 2014 International Congress. Abstract 2161
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this chapter
Cite this chapter
Huttunen, K., Korkalainen, M. (2017). Microbial Secondary Metabolites and Knowledge on Inhalation Effects. In: Viegas, C., Viegas, S., Gomes, A., Täubel, M., Sabino, R. (eds) Exposure to Microbiological Agents in Indoor and Occupational Environments. Springer, Cham. https://doi.org/10.1007/978-3-319-61688-9_10
Download citation
DOI: https://doi.org/10.1007/978-3-319-61688-9_10
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-61686-5
Online ISBN: 978-3-319-61688-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)