Toxicological effects of the fungal volatile compound 1-octen-3-ol against the red flour beetle, Tribolium castaneum (Herbst).

Tribolium castaneum (Herbst) is an important pest of stored grain, and benzoquinones secreted by this pest are harmful to humans. T. castaneum has developed strong resistance to fumigants, and an ecofriendly alternative for managing T. castaneum is urgently needed. 1-Octen-3-ol is a major volatile compound present in many mushrooms and fungi. In the current study, the direct toxicity and sublethal and transgenerational effects of 1-octen-3-ol on T. castaneum were investigated. Our results showed that 1-octen-3-ol had strong insecticidal activity against all developmental stages of T. castaneum and repelled T. castaneum adults. 1-Octen-3-ol showed negative effects on the development and reproduction of parental T. castaneum and the subsequent generation: LC30 and LC50 treatments significantly decreased the pupa and adult weights, pupation and emergence rates and fecundity of the parental generation. In addition, LC50 treatment shortened the larval and pupal periods. In the unexposed progeny (F1) of 1-octen-3-ol-exposed parents, decreased survival and pupation rates as well as reduced pupa and adult weights were observed under LC30 and LC50 treatments. In addition, a model food-system experiment showed that 1-octen-3-ol at 98 µL/L exhibited an efficacy of 100% after 7 days of fumigation and completely eliminated T. castaneum offspring. Although a higher concentration of 1-octen-3-ol was needed to achieve an efficacy equal to that of the positive control, dichlorvos (DDVP), 1-octen-3-ol promoted the seedling growth of wheat seeds, suggesting that the concentration used was not only acceptable but also beneficial for wheat seeds. Overall, 1-octen-3-ol seems to be a promising candidate for use as a fumigant and repellent against T. castaneum as well as a seed protectant.

RIFM fragrance ingredient safety assessment, 3-octanol, CAS Registry Number 589-98-0.

The existing information supports the use of this material as described in this safety assessment. 3-Octanol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog 3-hexanol (CAS # 623-37-0) show that 3-octanol is not expected to be genotoxic. Data on 3-octanol provide a calculated margin of exposure (MOE) > 100 for the repeated dose toxicity endpoint. Data on read-across analog 2-octanol (CAS # 123-96-6) provide a calculated MOE >100 for the reproductive toxicity endpoint and show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on ultraviolet (UV) spectra; 3-octanol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the Threshold of Toxicological Concern (TTC) for a Cramer Class I material; exposure is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; 3-octanol was found not to be Persistent, Bioaccumulative, and Toxic (PBT) as per the International Fragrance Association (IFRA) Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., Predicted Environmental Concentration/Predicted No Effect Concentration [PEC/PNEC]), are <1.

Fungal compound 1-octen-3-ol induces mitochondrial morphological alterations and respiration dysfunctions in Drosophila melanogaster.

Fungal volatile organic compounds (VOCs) comprise a group of compounds commonly found in damp or water-damaged indoor places affecting air quality. Indoor fungal pollution is a severe threat to human health, contributing to the onset of allergic diseases. The compound 1-octen-3-ol, known as "mushroom alcohol", is the most abundant VOC and confers the characteristic mold odor. Exposure to 1-octen-3-ol induces inflammatory markers and episodes of allergic rhinitis and conjunctivitis; however, the effects of this compound towards mitochondria are fairly known. The present study aimed to evaluate the effects of 1-octen-3-ol on inflammatory targets and on mitochondrial morphology and bioenergetic rate in D. melanogaster. Drosophilas were exposed by inhalation to 2.5 µL/L and 5 µL/L of 1-octen-3-ol for 24 h. Observation showed a decreasing in the survival and locomotor ability of flies. Superoxide dismutase (SOD) activity was induced whereas Catalase (CAT) activity was inhibited. Analysis of the mitochondria respiration, detected inhibition of complex I and II in the electron transport chain and a decreased bioenergetic rate. Electronic microscopy provided morphological insights of the mitochondrial status in which a disarrangement in mitochondrial cristae profile was observed. 1-Octen-3-ol induced increased activity of caspase 3/7 and ERK phosphorylation. The mRNA relative steady-state levels of p38MAPK and JNK were down-regulated, whereas NF-κB and p53 were up-regulated. In parallel, nitrite levels were induced in relation to the non-exposed group. These findings point to the mitochondria as a crucial target for the toxicity of 1-octen-3-ol in parallel with activation of pro-inflammatory factors and apoptotic signaling pathway cascade.

RIFM fragrance ingredient safety assessment, hydroxycitronellal dimethyl acetal, CAS Registry Number 141-92-4.

Hydroxycitronellal dimethyl acetal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that hydroxycitronellal dimethyl acetal is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material and the exposure to hydroxycitronellal dimethyl acetal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from hydroxycitronellal dimethyl acetal and from read-across material hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hydroxycitronellal dimethyl acetal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hydroxycitronellal dimethyl acetal was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

Estimation of physicochemical properties of 2-ethylhexyl-4-methoxycinnamate (EHMC) degradation products and their toxicological evaluation.

The organic UV filters, commonly used in personal protection products, are of concern because of their potential risk to aquatic ecosystems and living organisms. One of UV filters is ethylhexyl-4-methoxycinnamate (EHMC) acid. Studies have shown that, in the presence of oxidizing and chlorinating factors, EHMC forms a series of products with different properties than the substrate. In this study, the toxicities of EHMC and its transformation/degradation products formed under the influence of NaOCl/UV and H2O2/UV systems in the water medium were tested using Microtox® bioassay and by observation of mortality of juvenile crustaceans Daphnia magna and Artemia Salina. We have observed that oxidation and chlorination products of EHMC show significantly higher toxicity than EHMC alone. The toxicity of chemicals is related to their physicochemical characteristic such as lipophilicity and substituent groups. With the increase in lipophilicity of products, expressed as log KOW, the toxicity (EC50) increases. On the basis of physicochemical properties such as vapour pressure (VP), solubility (S), octanol-water partition coefficient (KOW), bioconcentration factor (BCF) and half-lives, the overall persistence (POV) and long-range transport potential (LRTP) of all the products and EHMC were calculated. It was shown that the most persistent and traveling on the long distances in environment are methoxyphenol chloroderivatives, then methoxybenzene chloroderivatives, EHMC chloroderivatives, methoxybenzaldehyde chloroderivatives and methoxycinnamate acid chloroderivatives. These compounds are also characterised by high toxicity.

The effects of fungal volatile organic compounds on bone marrow stromal cells.

Evidence has shown that individuals exposed to indoor toxic molds for extended periods of time have elevated risk of developing numerous respiratory illnesses. It is not clear at the cellular level what impact mold exposure has on the immune system. Herein, we show that 2 fungal volatiles (E)-2-octenal and oct-1-en-3-ol have cytotoxic effects on murine bone marrow stromal cells. To further analyze alterations to the cell, we evaluated the impact these volatile organic compounds have on membrane composition and hence fluidity. Both (E)-2-octenal and oct-1-en-3-ol exposure caused a shift to unsaturated fatty acids and lower cholesterol levels in the membrane. This indicates that the volatile organic compounds under investigation increased membrane fluidity. These vast changes to the cell membrane are known to contribute to the breakdown of normal cell function and possibly lead to death. Since bone marrow stromal cells are vital for the appropriate development and activation of immune cells, this study provides the foundation for understanding the mechanism at a cellular level for how mold exposure can lead to immune-related disease conditions.

Evaluation of the reproductive and developmental toxicity of 6:2 fluorotelomer alcohol in rats.

6:2 Fluorotelomer alcohol (6:2 FTOH) was evaluated for potential developmental and reproductive toxicity. 6:2 FTOH was administered by oral gavage to Sprague-Dawley rats as a suspension in 0.5% aqueous methylcellulose at dosages of 5, 25, 125, or 250 mg/kg/day. The developmental toxicity study was performed in accordance with the Organization for Economic Development (OECD) Test Guideline 414, and the one-generation reproductive toxicity study was performed in accordance with the OECD Test Guideline 415. For the developmental toxicity study, adverse maternal toxicity observed at 250 mg/kg/day included reductions in body weight parameters and food consumption. Evidence of developmental toxicity was limited to increases in skeletal variations (ossification delays in the skull and rib alterations) at 250 mg/kg/day. There were no adverse maternal or developmental effects observed at 5, 25, or 125 mg/kg/day and there were no effects on reproductive outcome or quantitative litter data at any dose level. For the one-generation reproduction toxicity study, systemic parental and developmental toxicity were observed at 125 and 250 mg/kg/day. At 250 mg/kg/day, there was increased mortality among male and female parental rats, effects on body weight parameters, food consumption, and clinical signs, and there were effects on offspring survival indices and body weights. At 125 mg/kg/day, there was an increase in mortality in parental males only, and parental toxicity was limited to effects on body weight gain, food consumption (lactation), and clinical signs. Uterine weights were decreased at 125 and 250 mg/kg/day, although there were no corroborative histopathological changes. At 125 mg/kg/day, pup mortality was increased on lactation day 1, and body weights of the offspring were decreased during the second half of lactation. There was no evidence of either parental or developmental toxicity at 5 or 25mg/kg/day, and there were no effects on reproductive outcome at any dose level. Based on these data, 6:2 FTOH is not a selective reproductive or developmental toxicant at dosages that induce clear maternal/parental toxicity. Therefore, 6:2 FTOH would not be classified for reproductive/developmental toxicity under the United Nations' Globally Harmonized System of Classification and Labeling of Chemicals.

Signaling pathways involved in 1-octen-3-ol-mediated neurotoxicity in Drosophila melanogaster: implication in Parkinson's disease.

Previously, we have pioneered Drosophila melanogaster as a reductionist model to show that 1-octen-3-ol, a musty-smelling volatile compound emitted by fungi and other organisms, causes loss of dopaminergic neurons and Parkinson's disease-like symptoms in flies. Using our in vivo Drosophila system, the modulatory roles of important signaling pathways­JNK, Akt and the caspase-3-dependent apoptotic pathway were investigated in the context of 1-octen-3-ol-induced dopamine neurotoxicity. When heterozygous flies carrying mutant alleles for these proteins were exposed to 0.5 ppm of 1-octen-3-ol, they had shorter survival times than wild-type Drosophila. The overexpressed levels of wild-type JNK and Akt, (UAS-bsk and UAS-Akt) with TH-GAL4 and elav-GAL4 drivers improved the survival duration of exposed flies compared with controls. Thus, we found that Akt and JNK both protect against loss of dopamine activity associated with 1-octen-3-ol exposure, indicating the pro-survival role of these signaling pathways. Further, 1-octen-3-ol exposure was associated with activation of caspase 3, a hallmark for apoptosis.

Disruption of Phthorimaea operculella (Lepidoptera: Gelechiidae) oviposition by the application of host plant volatiles.

BACKGROUND: Phthorimaea operculella is a key pest of potato. The authors characterised the P. operculella olfactory system, selected the most bioactive host plant volatiles and evaluated their potential application in pest management. The electrophysiological responses of olfactory receptor neurons (ORNs) housed in long sensilla trichodea of P. operculella to plant volatiles and the two main sex pheromone components were evaluated by the single-cell recording (SCR) technique. The four most SCR-active volatiles were tested in a laboratory oviposition bioassay and under storage warehouse conditions. RESULTS: The sensitivity of sensilla trichodea to short-chained aldehydes and alcohols and the existence of ORNs tuned to pheromones in females were characterised. Male recordings revealed at least two types of ORN, each of which typically responded to one of the two pheromone components. Hexanal, octanal, nonanal and 1-octen-3-ol significantly disrupted the egg-laying behaviour in a dose-dependent manner. Octanal reduced the P. operculella infestation rate when used under storage conditions. CONCLUSIONS: This work provides new information on the perception of plant volatiles and sex pheromones by P. operculella. Laboratory and warehouse experiments show that the use of hexanal, octanal, nonanal and 1-octen-3-ol as host recognition disruptants and/or oviposition deterrents for P. operculella control appears to be a promising strategy.

Drosophila melanogaster as a model to characterize fungal volatile organic compounds.

Fungi are implicated in poor indoor air quality and may pose a potential risk factor for building/mold related illnesses. Fungi emit numerous volatile organic compounds (VOCs) as alcohols, esters, ethers, ketones, aldehydes, terpenoids, thiols, and their derivatives. The toxicity profile of these VOCs has never been explored in a model organism, which could enable the performance of high throughput toxicological assays and lead to a better understanding of the mechanism of toxicity. We have established a reductionist Drosophila melanogaster model to evaluate the toxicity of fungal VOCs. In this report, we assessed the toxicity of fungal VOCs emitted from living cultures of species in the genera, Trichoderma, Aspergillus, and Penicillium and observed a detrimental effect on larval survival. We then used chemical standards of selected fungal VOCs to assess their toxicity on larval and adult Drosophila. We compared the survival of adult flies exposed to these fungal VOCs with known industrial toxic chemicals (formaldehyde [37%], xylene, benzene, and toluene). Among the tested fungal VOC standards, the compounds with eight carbons (C8) caused greater truncation of fly lifespan than tested non-C8 fungal VOCs and industrial toxins. Our data validate the use of Drosophila melanogaster as a model with the potential to elucidate the mechanistic attributes of different toxic VOCs emitted by fungi and also to explore the potential link between reported human illnesses/symptoms and exposure to water damaged and mold contaminated buildings.

Cytotoxic and immunomodulatory effects of polyhydroxyoctane isolated from Lentinus polychrous mycelia.

A polyhydroxyoctane, 6-methylheptane-1,2,3,4,5-pentaol (MHP), was first isolated from mycelia of the Thai edible mushroom Lentinus polychrous. MHP was evaluated for its cytotoxic and immunomodulatory effects in vitro. MHP was slightly cytotoxic to murine splenocytes but not to RAW264.7 cells or peripheral blood mononuclear cells. MHP decreased nitric oxide and intracellular O2 (-) production from lipopolysaccharide- and phorbol-12-myristate-13-acetate-activated RAW264.7 cells at levels of 78.98 ± 4.72 and 78.48 ± 2.41 % of controls, respectively. The mRNA expression of pro-inflammatory mediators, including iNOS, TNF-α, IL-1ß, IL-6, COX-1 and COX-2, were significantly suppressed by MHP. In addition, MHP significantly increased the proliferation of phytohemagglutinin and pokeweed mitogen-induced splenocytes. These results indicate that MHP is able to modulate inflammatory responses and the proliferation of both T- and B-lymphocyte cells, suggesting that MHP may be a good natural immunomodulator.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration.

Parkinson disease (PD) is the most common movement disorder and, although the exact causes are unknown, recent epidemiological and experimental studies indicate that several environmental agents may be significant risk factors. To date, these suspected environmental risk factors have been man-made chemicals. In this report, we demonstrate via genetic, biochemical, and immunological studies that the common volatile fungal semiochemical 1-octen-3-ol reduces dopamine levels and causes dopamine neuron degeneration in Drosophila melanogaster. Overexpression of the vesicular monoamine transporter (VMAT) rescued the dopamine toxicity and neurodegeneration, whereas mutations decreasing VMAT and tyrosine hydroxylase exacerbated toxicity. Furthermore, 1-octen-3-ol also inhibited uptake of dopamine in human cell lines expressing the human plasma membrane dopamine transporter (DAT) and human VMAT ortholog, VMAT2. These data demonstrate that 1-octen-3-ol exerts toxicity via disruption of dopamine homeostasis and may represent a naturally occurring environmental agent involved in parkinsonism.

Test concentration setting for fish in vivo endocrine screening assays.

Fish in vivo screening methods to detect endocrine active substances, specifically interacting with the hypothalamic-pituitary-gonadal axis, have been developed by both the Organization for Economic Co-operation and Development (OECD) and United States Environmental Protection Agency (US-EPA). In application of these methods, i.e. regulatory testing, this paper provides a proposal on the setting of test concentrations using all available acute and chronic data and also discusses the importance of avoiding the confounding effects of systemic toxicity on endocrine endpoints. This guidance is aimed at reducing the number of false positives and subsequently the number of inappropriate definitive vertebrate studies potentially triggered by effects consequent to systemic, rather than endocrine, toxicity. At the same time it provides a pragmatic approach that maximizes the probability of detecting an effect, if it exists, thus limiting the potential for false negative outcomes.

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).

There are few studies on associations between airborne microbial exposure, formaldehyde, plasticizers in dwellings and the symptoms compatible with the sick building syndrome (SBS). As a follow-up of the European Community Respiratory Health Survey (ECRHS II), indoor measurements were performed in homes in three North European cities. The aim was to examine whether volatile organic compounds of possible microbial origin (MVOCs), and airborne levels of bacteria, molds, formaldehyde, and two plasticizers in dwellings were associated with the prevalence of SBS, and to study associations between MVOCs and reports on dampness and mold. The study included homes from three centers included in ECRHS II. A total of 159 adults (57% females) participated (19% from Reykjavik, 40% from Uppsala, and 41% from Tartu). A random sample and additional homes with a history of dampness were included. Exposure measurements were performed in the 159 homes of the participants. MVOCs were analyzed by GCMS with selective ion monitoring (SIM). Symptoms were reported in a standardized questionnaire. Associations were analyzed by multiple logistic regression. In total 30.8% reported any SBS (20% mucosal, 10% general, and 8% dermal symptoms) and 41% of the homes had a history of dampness and molds There were positive associations between any SBS and levels of 2-pentanol (P=0.002), 2-hexanone (P=0.0002), 2-pentylfuran (P=0.009), 1-octen-3-ol (P=0.002), formaldehyde (P=0.05), and 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate (Texanol) (P=0.05). 1-octen-3-ol (P=0.009) and 3-methylfuran (P=0.002) were associated with mucosal symptoms. In dwellings with dampness and molds, the levels of total bacteria (P=0.02), total mold (P=0.04), viable mold (P=0.02), 3-methylfuran (P=0.008) and ethyl-isobutyrate (P=0.02) were higher. In conclusion, some MVOCs like 1-octen-3-ol, formaldehyde and the plasticizer Texanol, may be a risk factor for sick building syndrome. Moreover, concentrations of airborne molds, bacteria and some other MVOCs were slightly higher in homes with reported dampness and mold.