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Toxicology Jun 2009Naphthalene and close structural analogues have been shown to cause necrosis of bronchiolar epithelial cells in mice by both inhalation exposure and by systemic... (Comparative Study)
Comparative Study Review
Naphthalene and close structural analogues have been shown to cause necrosis of bronchiolar epithelial cells in mice by both inhalation exposure and by systemic administration. Cancer bioassays of naphthalene in mice have demonstrated a slight increase in bronchiolar/alveolar adenomas in female mice, and in inflammation and metaplasia of the olfactory epithelium in the nasal cavity. Similar work in rats demonstrated a significant, and concentration-dependent increase in the incidence of respiratory epithelial adenomas and neuroblastomas in the nasal epithelium of both male and female rats. Although the studies on the acute toxicity of the methylnaphthalene derivatives are more limited, it appears that the species selective toxicity associated with naphthalene administration also is observed with methylnaphthalenes. Chronic administration of the methylnaphthalenes, however, failed to demonstrate the same oncogenic potential as that observed with naphthalene. The information available on the isopropylnaphthalene derivatives suggests that they are not cytotoxic. Like the methylnaphthalenes, 1-nitronaphthalene causes lesions in both Clara and ciliated cells. However, the species selective lung toxicity observed in the mouse with both naphthalene and the methylnaphthalenes is not seen with 1-nitronaphthalene. With 1-nitronaphthalene, the rat is far more susceptible to parenteral administration of the compound than mice. The wide-spread distribution of these compounds in the environment and the high potential for low level exposure to humans supports a need for further work on the mechanisms of toxicity in animal models with attention to whether these processes are applicable to humans. Although it is tempting to suppose that the toxicity and mechanisms of toxicity of the alkylnaphthalenes and nitronaphthalenes are similar to naphthalene, there is sufficient published literature to suggest that this may not be the case. Certainly the enzymes involved in the metabolic activation of each of these substrates are likely to differ. The available data showing extensive oxidation of the aromatic nucleus of naphthalene, nitronaphthalene and the methylnaphthalenes (with some oxidation of the methyl group) contrast with the isopropylnaphthalene derivatives, where the major metabolites involve side chain oxidation. Overall, these data support the view that ring epoxidation is a key step in the process involved in cytotoxicity. Whether the epoxide itself or a downstream metabolite mediates the toxic effects is still not clear even with naphthalene, the best studied of this group of compounds. Additional work is needed in several areas to further assess the potential human health consequences of exposure to these agents. These studies should involve the definition of the extent and severity of methylnaphthalene toxicity after single dose exposures with attention to both the nasal and respiratory epithelia. The cytochromes P450 responsible for the initial activation of these agents in rodents with subsequent complimentary studies in primate models should help determine whether key metabolic processes responsible for toxicity occur also in primates. Finally, the precise involvement of reactive metabolite formation and adduction of cellular proteins in toxicity will be important in not only assessing the potential for human toxicity, but also in developing an understanding of the genetic and environmental factors which could alter the toxicity of these agents.
Topics: Animals; Environmental Exposure; Humans; Lung Diseases; Naphthalenes
PubMed: 19464565
DOI: 10.1016/j.tox.2009.03.002 -
Critical Reviews in Toxicology 2016Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available... (Review)
Review
Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available human data have not identified an association between naphthalene exposure and increased respiratory cancer risk. Assessing naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of naphthalene to the epoxide, followed by GSH depletion, cytotoxicity, chronic inflammation, regenerative hyperplasia, and tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose-response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for naphthalene-induced rat nasal tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions.
Topics: Administration, Inhalation; Animals; Carcinogenesis; DNA Damage; Dose-Response Relationship, Drug; Environmental Exposure; Humans; Lung Neoplasms; Models, Animal; Naphthalenes; Risk Assessment
PubMed: 26202831
DOI: 10.3109/10408444.2015.1061477 -
International Journal of Environmental... Jul 2010Both the recent classification of naphthalene as a possible human carcinogen and its ubiquitous presence motivate this critical review of naphthalene's sources and... (Review)
Review
Both the recent classification of naphthalene as a possible human carcinogen and its ubiquitous presence motivate this critical review of naphthalene's sources and exposures. We evaluate the environmental literature on naphthalene published since 1990, drawing on nearly 150 studies that report emissions and concentrations in indoor, outdoor and personal air. While naphthalene is both a volatile organic compound and a polycyclic aromatic hydrocarbon, concentrations and exposures are poorly characterized relative to many other pollutants. Most airborne emissions result from combustion, and key sources include industry, open burning, tailpipe emissions, and cigarettes. The second largest source is off-gassing, specifically from naphthalene's use as a deodorizer, repellent and fumigant. In the U.S., naphthalene's use as a moth repellant has been reduced in favor of para-dichlorobenzene, but extensive use continues in mothballs, which appears responsible for some of the highest indoor exposures, along with off-label uses. Among the studies judged to be representative, average concentrations ranged from 0.18 to 1.7 microg m(-3) in non-smoker's homes, and from 0.02 to 0.31 microg m(-3) outdoors in urban areas. Personal exposures have been reported in only three European studies. Indoor sources are the major contributor to (non-occupational) exposure. While its central tendencies fall well below guideline levels relevant to acute health impacts, several studies have reported maximum concentrations exceeding 100 microg m(-3), far above guideline levels. Using current but draft estimates of cancer risks, naphthalene is a major environmental risk driver, with typical individual risk levels in the 10(-4) range, which is high and notable given that millions of individuals are exposed. Several factors influence indoor and outdoor concentrations, but the literature is inconsistent on their effects. Further investigation is needed to better characterize naphthalene's sources and exposures, especially for indoor and personal measurements.
Topics: Air Pollutants; Air Pollution, Indoor; Environmental Exposure; Humans; Naphthalenes
PubMed: 20717549
DOI: 10.3390/ijerph7072903 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Carcinogenicity Tests; Carcinogens, Environmental; Environmental Exposure; Humans; Mice; Molecular Structure; Naphthalenes; Occupational Exposure
PubMed: 21860488
DOI: No ID Found -
International Journal of Environmental... Jun 2017Naphthalene and benzene are widely-used volatile organic compounds. The aim of this research was to examine the toxicological effects of naphthalene and benzene against...
Naphthalene and benzene are widely-used volatile organic compounds. The aim of this research was to examine the toxicological effects of naphthalene and benzene against as an animal model. Adult insects were exposed to these aromatic compounds to assess mortality after 4-48 h of exposure. The lethal concentration 50 (LC) for naphthalene, naphthalin, and benzene were 63.6 µL/L, 20.0 µL/L, and 115.9 µL/L in air, respectively. Real-time polymerase chain reaction (PCR) analysis revealed expression changes in genes related to oxidative stress and metabolism [Glutathione S-Transferase (Gst), and Cytochrome P450 6BQ8 (Cyp6bq8)]; reproduction and metamorphosis [Hormone receptor in 39-like protein (Hr39), Ecdysone receptor: (Ecr), and Chitin synthase 2 (Chs2)]; and neurotransmission [Histamine-gated chloride channel 2 (Hiscl2)] in insects exposed for 4 h to 70.2 µL/L naphthalene. Adults exposed to benzene (80 µL/L; 4 h) overexpressed genes related to neurotransmission [GABA-gated anion channel (Rdl), Hiscl2, and GABA-gated ion channel (Grd)]; reproduction and metamorphosis [Ultraspiracle nuclear receptor (USP), Ecr; and Hr39]; and development (Chs2). The data presented here provides evidence that naphthalene and benzene inhalation are able to induce alterations on reproduction, development, metamorphosis, oxidative stress, metabolism, neurotransmission, and death of the insect.
Topics: Animals; Benzene; Environmental Pollutants; Gene Expression Regulation; Glutathione Transferase; Lethal Dose 50; Naphthalenes; Real-Time Polymerase Chain Reaction; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Tribolium
PubMed: 28635673
DOI: 10.3390/ijerph14060667 -
Chemico-biological Interactions Jan 2020Mineral oils are widely applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils...
Mineral oils are widely applied in food production and processing and may contain polycyclic aromatic hydrocarbons (PAHs). The PAHs that may be present in mineral oils are typically alkylated, and have been barely studied. Metabolic oxidation of the aromatic ring is a key step to form DNA-reactive PAH metabolites, but may be less prominent for alkylated PAHs since alkyl substituents would facilitate side chain oxidation as an alternative. The current study investigates this hypothesis of preferential side chain oxidation at the cost of aromatic oxidation using naphthalene and a series of its alkyl substituted analogues as model compounds. The metabolism was assessed by measuring metabolite formation in rat and human liver microsomal incubations using UPLC and GC-MS/MS. The presence of an alkyl side chain markedly reduced aromatic oxidation for all alkyl-substituted naphthalenes that were converted. 1-n-Dodecyl-naphthalene was not metabolized under the experimental conditions applied. With rat liver microsomes for 1-methyl-, 2-methyl-, 1-ethyl-, and 2-ethyl- naphthalene, alkyl side chain oxidation was preferred over aromatic oxidation. With human liver microsomes this was the case for 2-methyl-, and 2-ethyl-naphthalene. It is concluded that addition of an alkyl substituent in naphthalene shifts metabolism in favor of alkyl side chain oxidation at the cost of aromatic ring oxidation. Furthermore, alkyl side chains of 6 or more carbon atoms appeared to seriously hamper and reduce overall metabolism, metabolic conversion being no longer observed with the C12 alkyl side chain. In summary, alkylation of PAHs likely reduces their chances of aromatic oxidation and bioactivation.
Topics: Alkylating Agents; Alkylation; Animals; Chromatography, Gas; Chromatography, High Pressure Liquid; Humans; Microsomes, Liver; Naphthalenes; Oxidation-Reduction; Polycyclic Aromatic Hydrocarbons; Rats; Tandem Mass Spectrometry
PubMed: 31765606
DOI: 10.1016/j.cbi.2019.108905 -
International Journal of Molecular... Apr 2023Polycyclic aromatic hydrocarbons are a class of chemicals that occur naturally. They generally demonstrate a high degree of critical toxicity towards humans....
Polycyclic aromatic hydrocarbons are a class of chemicals that occur naturally. They generally demonstrate a high degree of critical toxicity towards humans. Acenaphthene and naphthalene contain compounds that are commonly found in the environment as compared to other PAHs. Consequently, a reliable method of detecting PAHs is crucial for the monitoring of water quality. A colorimetric method based on sodium nitrite-functionalized gold nanoparticles was developed in this study for acenaphthene and naphthalene detection. Different functionalized parameters are determined for the optimization of assay conditions. A linear relationship was found in the analyte concentration range of 0.1-10 ppm with the limit of detection for acenaphthene and naphthalene being 0.046 ppm and 0.0015 ppm, respectively, under the optimized assay conditions. The method's recovery rate for actual samples falls within the range of 98.4-103.0%. In selective and anti-interference tests, the presence of cations and anions has minimal impact on the detection of the analyte. The colorimetric detection method proposed in this study effectively determines the presence of the analyte in real water samples and has a high recovery rate.
Topics: Humans; Acenaphthenes; Gold; Colorimetry; Metal Nanoparticles; Naphthalenes; Polycyclic Aromatic Hydrocarbons
PubMed: 37047607
DOI: 10.3390/ijms24076635 -
Toxicological Sciences : An Official... Aug 2019Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are...
Human exposure to naphthalene (NA), an acute lung toxicant and possible human carcinogen, is primarily through inhalation. Acute lung toxicity and carcinogenesis are thought to be related because the target sites for both are similar. To understand susceptibility of the developing lung to cytotoxicity of inhaled NA, we exposed neonatal (7 days), juvenile (3 weeks), and adult mice to 5 or 10 ppm NA vapor for 4 h. We measured vacuolated airway epithelium morphometrically, quantified NA and NA-glutathione levels in plasma and lung, and quantified gene expression in microdissected airways. NA inhalation caused airway epithelial cytotoxicity at all ages, in both sexes. Contrary to a previous study that showed the greatest airway epithelial cytotoxicity in neonatal mice following intraperitoneal NA injection, we observed the most extensive airway epithelial toxicity in older, juvenile, animals exposed to NA by inhalation. Juvenile female animals were the most susceptible. Furthermore, NA inhalation in juvenile animals resulted in damage to conducting airway Club cells that was greater in proximal versus distal airways. We also found NA tissue burden and metabolism differed by age. Gene expression pathway analysis was consistent with the premise that female juvenile mice are more predisposed to damage; DNA damage and cancer pathways were upregulated. Our data demonstrate special susceptibility of young, juvenile mice to NA inhalation-induced cytotoxicity, highlight the importance of route of exposure and airway location in toxicity of chemicals in the developing lung, and provide metabolic and molecular insights for further identification of mechanisms underlying age and sex differences in NA toxicity.
Topics: Administration, Inhalation; Age Factors; Animals; Animals, Newborn; Female; Glutathione; Lung; Male; Mice; Mice, Inbred C57BL; Naphthalenes; Sex Characteristics
PubMed: 31020322
DOI: 10.1093/toxsci/kfz100 -
Molecules (Basel, Switzerland) Feb 2023Naproxen (6-methoxy-α-methyl-2-naphthaleneacetic acid), 1-naphthylacetic acid, 2-naphthylacetic acid and 1-pyreneacetic acid are derivatives of acetic acid bearing a... (Review)
Review
Naproxen (6-methoxy-α-methyl-2-naphthaleneacetic acid), 1-naphthylacetic acid, 2-naphthylacetic acid and 1-pyreneacetic acid are derivatives of acetic acid bearing a naphthalene-based ring. In the present review, the coordination compounds of naproxen, 1- or 2-naphthylacetato and 1-pyreneacetato ligands are discussed in regard to their structural features (nature and nuclearity of metal ions and coordination mode of ligands), their spectroscopic and physicochemical properties and their biological activities.
Topics: Coordination Complexes; Naproxen; Ligands; Naphthalenes; Acetates
PubMed: 36903416
DOI: 10.3390/molecules28052171 -
Chemosphere Nov 2017A new naphthalene bioreporter was designed and constructed in this work. A new vector, pWH1274_Nah, was constructed by the Gibson isothermal assembly fused with a 9 kb...
A new naphthalene bioreporter was designed and constructed in this work. A new vector, pWH1274_Nah, was constructed by the Gibson isothermal assembly fused with a 9 kb naphthalene-degrading gene nahAD (nahAa nahAb nahAc nahAd nahB nahF nahC nahQ nahE nahD) and cloned into Acinetobacter ADPWH_lux as the host, capable of responding to salicylate (the central metabolite of naphthalene). The ADPWH_Nah bioreporter could effectively metabolize naphthalene and evaluate the naphthalene in natural water and soil samples. This whole-cell bioreporter did not respond to other polycyclic aromatic hydrocarbons (PAHs; pyrene, anthracene, and phenanthrene) and demonstrated a positive response in the presence of 0.01 μM naphthalene, showing high specificity and sensitivity. The bioluminescent response was quantitatively measured after a 4 h exposure to naphthalene, and the model simulation further proved the naphthalene metabolism dynamics and the salicylate-activation mechanisms. The ADPWH_Nah bioreporter also achieved a rapid evaluation of the naphthalene in the PAH-contaminated site after chemical spill accidents, showing high consistency with chemical analysis. The engineered Acinetobacter variant had significant advantages in rapid naphthalene detection in the laboratory and potential in situ detection. The state-of-the-art concept of cloning PAHs-degrading pathway in salicylate bioreporter hosts led to the construction and assembly of high-throughput PAH bioreporter array, capable of crude oil contamination assessment and risk management.
Topics: Acinetobacter; Cloning, Molecular; Environmental Monitoring; Genes, Bacterial; Groundwater; Naphthalenes; Plasmids; Polycyclic Aromatic Hydrocarbons; Sodium Salicylate; Soil
PubMed: 28810221
DOI: 10.1016/j.chemosphere.2017.08.027