Whole-body Inhalation Chamber Research Articles

Particulate matter (PM10) exacerbates on MK-801-induced schizophrenia-like behaviors through the inhibition of ERK-CREB-BDNF signaling pathway

Particulate matter (PM), released into the air by a variety of natural and human activities, is a key indicator of air pollution. Although PM is known as the extensive health hazard to affect a variety of illness, few studies have specifically investigated the effects of PM10 exposure on schizophrenic development. In the present study, we aimed to investigate the impact of PM10 on MK-801, N-methyl-D-aspartate (NMDA) receptor antagonist, induced schizophrenia-like behaviors in C57BL/6 mouse. Preadolescent mice were exposed PM10 to 3.2 mg/m3 concentration for 4 h/day for 2 weeks through a compartmentalized whole-body inhalation chamber. After PM10 exposure, we conducted behavioral tests during adolescence and adulthood to investigate longitudinal development of schizophrenia. We found that PM10 exacerbated schizophrenia-like behavior, such as psychomotor agitation, social interaction deficits and cognitive deficits at adulthood in MK-801-induced schizophrenia animal model. Furthermore, the reduced expression levels of brain-derived neurotrophic factor (BDNF) and the phosphorylation of BDNF related signaling molecules, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), were exacerbated by PM10 exposure in the adult hippocampus of MK-801-treated mice. Thus, our present study demonstrates that exposure to PM10 in preadolescence exacerbates the cognitive impairment in animal model of schizophrenia, which are considered to be facilitated by the decreased level of BDNF through reduced ERK-CREB expression.

Transcriptomic alterations in the olfactory bulb induced by exposure to air pollution: Identification of potential biomarkers and insights into olfactory system function

This study evaluated how exposure to the ubiquitous air pollution component, ultrafine particles (UFPs), alters the olfactory bulb (OB) transcriptome. The study utilised a whole-body inhalation chamber to simulate real-life conditions and focused on UFPs due to their high translocation and deposition ability in OBs as well as their prevalence in ambient air. Female C57BL/6J mice were exposed to clean air or to freshly generated combustion derived UFPs for two weeks, after which OBs were dissected and mRNA transcripts were investigated using RNA sequencing analysis. For the first time, transcriptomics was applied to determine changes in mRNA expression levels occurring after subacute exposure to UFPs in the OBs. We found forty-five newly described mRNAs to be involved in air pollution-induced responses, including genes involved in odorant binding, synaptic regulation, and myelination signalling pathway, providing new gene candidates for future research. This study provides new insights for the environmental science and neuroscience fields and nominates future research directions.

Low-dose inhalation exposure to trichloroethylene induces dopaminergic neurodegeneration in rodents.

Trichloroethylene (TCE) is one of the most pervasive environmental contaminants in the world and is associated with Parkinson disease (PD) risk. Experimental models in rodents show that TCE is selectively toxic to dopaminergic neurons at high doses of ingestion, however, TCE is a highly volatile toxicant, and the primary pathway of human exposure is inhalation. As TCE is a highly lipophilic, volatile organic compound (VOC), inhalation exposure results in rapid diffusion throughout the brain, avoiding first-pass hepatic metabolism that necessitated high doses to recapitulate exposure conditions observed in human populations. We hypothesized that inhalation of TCE would induce significantly more potent neurodegeneration than ingestion and better recapitulate environmental conditions of vapor intrusion or off gassing from liquid TCE. To this end, we developed a novel, whole-body passive exposure inhalation chamber in which we exposed 10-month-old male and female Lewis rats to 50 ppm TCE (time weighted average, TWA) or filtered room air (control) over 8 weeks. In addition, we exposed 12-month-old male and female C57Bl/6 mice to 100 ppm TCE (TWA) or control over 12 weeks. Both rats and mice exposed to chronic TCE inhalation showed significant degeneration of nigrostriatal dopaminergic neurons as well as motor and gait impairments. TCE exposure also induced accumulation of pSer129-αSyn in dopaminergic neurons as well as microglial activation within the substantia nigra of rats. Collectively, these data indicate that TCE inhalation causes highly potent dopaminergic neurodegeneration and recapitulates some of the observed neuropathology associated with PD, providing a future platform for insight into the mechanisms and environmental conditions that influence PD risk from TCE exposure.

Acute inhalation of tungsten particles results in early signs of cardiac injury

Epidemiological studies have established that exposure to tungsten increases the risk of developing cardiovascular diseases. However, no studies have investigated how tungsten affects cardiac function or the development of cardiovascular disease. Inhalation of tungsten particulates is relevant in occupational settings, and inhalation of particulate matter has a known causative role in driving cardiovascular disease. This study examined if acute inhalation to tungsten particulates affects cardiac function and leads to heart tissue alterations. Female BALB/c mice were exposed to Filtered Air or 1.5 ± 0.23 mg/m3 tungsten particles, using a whole-body inhalation chamber, 4 times over the course of two weeks. Inhalation exposure resulted in mild pulmonary inflammation characterized by an increased percentage and number of macrophages and metabolomic changes in the lungs. Cardiac output was significantly decreased in the tungsten-exposed group. Additionally, A′, an indicator of the amount of work required by the atria to fill the heart was elevated. Cardiac gene expression analysis revealed, tungsten exposure increased expression of pro-inflammatory cytokines, markers of remodeling and fibrosis, and oxidative stress genes. These data strongly suggest exposure to tungsten results in cardiac injury characterized by early signs of diastolic dysfunction. Functional findings are in parallel, demonstrating cardiac oxidative stress, inflammation, and early fibrotic changes. Tungsten accumulation data would suggest these cardiac changes are driven by systemic consequences of pulmonary damage.

Titanium Dioxide Nanoparticles Modulate Systemic Immune Response and Increase Levels of Reduced Glutathione in Mice after Seven-Week Inhalation

Titanium dioxide nanoparticles (TiO2 NPs) are used in a wide range of applications. Although inhalation of NPs is one of the most important toxicologically relevant routes, experimental studies on potential harmful effects of TiO2 NPs using a whole-body inhalation chamber model are rare. In this study, the profile of lymphocyte markers, functional immunoassays, and antioxidant defense markers were analyzed to evaluate the potential adverse effects of seven-week inhalation exposure to two different concentrations of TiO2 NPs (0.00167 and 0.1308 mg TiO2/m3) in mice. A dose-dependent effect of TiO2 NPs on innate immunity was evident in the form of stimulated phagocytic activity of monocytes in low-dose mice and suppressed secretory function of monocytes (IL-18) in high-dose animals. The effect of TiO2 NPs on adaptive immunity, manifested in the spleen by a decrease in the percentage of T-cells, a reduction in T-helper cells, and a dose-dependent decrease in lymphocyte cytokine production, may indicate immunosuppression in exposed mice. The dose-dependent increase in GSH concentration and GSH/GSSG ratio in whole blood demonstrated stimulated antioxidant defense against oxidative stress induced by TiO2 NP exposure.

Carcinogenicity and chronic toxicity of butyl methacrylate in rats and mice by a two-year inhalation study.

We conducted a two-year inhalation study of butyl methacrylate using F344/DuCrlCrlj rats and B6D2F1/Crl mice. Rats were exposed to 0, 30, 125 and 500 ppm (v/v) and mice were exposed to 0, 8, 30 and 125 ppm (v/v) using whole-body inhalation chambers. Non-neoplastic lesions developed in the nasal cavities of both rats and mice, but neoplastic lesions were not found. There was also a positive trend in the incidence of large granular lymphocytic (LGL) leukemia in the spleen of male rats. No changes were observed in female rats. Overall, there is some evidence of carcinogenicity in male rats, but there is no evidence of carcinogenicity in female rats. In male mice, there was a positive trend by Peto's test in the incidence of hepatocellular adenomas, and the incidence of hepatocellular adenomas and hepatocellular carcinomas combined was significantly increased compared to the controls by Fisher's exact test in the 30 ppm exposed male group. In female mice, the incidence of hemangiosarcoma in all organs combined showed a positive trend by Peto's test. Therefore, there is some evidence of carcinogenicity in male mice, and there is equivocal evidence of carcinogenicity in female mice.

Folic acid targets splenic extramedullary hemopoiesis to attenuate carbon black-induced coagulation-thrombosis potential

Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.

Adverse postnatal developmental effects in offspring from humidifier disinfectant biocide inhaled pregnant rats

Inhalation exposure to polyhexamethylene guanidine phosphate (PHMG-P), one of the primary biocides used in humidifier disinfectants, caused a fatal pulmonary disease in Korea. Pregnant women were also exposed to PHMG-P, and subsequent studies showed that PHMG-P inhalation during pregnancy adversely affects their health and embryo-fetal development. However, the postnatal developmental effects after birth on prenatally PHMG-P-exposed offspring have not yet been investigated. Therefore, in this study, we aimed to examine the postnatal development of prenatally PHMG-P-exposed offspring. Pregnant rats (22 or 24 females per group) were exposed to PHMG-P during pregnancy in a whole-body inhalation chamber at the target concentrations of 0, 0.14, 1.60, and 3.20 mg/m3. After parturition, the prenatally exposed offspring were transferred to non-exposed surrogate mothers to minimize the secondary effects of severe maternal toxicities. Postnatal development of offspring was then examined with a modified extended one-generation reproductive toxicity study design. At 3.20 mg/m3 PHMG-P, increased perinatal death rates and decreased viability index (postnatal survival of offspring between birth and postnatal day 4) were observed. In addition, F1 offspring had lower body weight at birth that persisted throughout the study. PHMG-P-exposed pregnant rats also had severe systemic toxicities and increased gestation period. At 1.60 mg/m3 PHMG-P, a decreased viability index was also observed with systemic toxicities of PHMG-P-exposed pregnant rats. These results indicate that prenatal PHMG-P exposure adversely affects the offspring's future health and could be used for human risk assessment.

Design and development of whole-body rodent inhalation chamber for exposure to Aroclor 1232 in Swiss albino mice

Design and development of whole-body rodent inhalation chamber for exposure to Aroclor 1232 in Swiss albino mice

Thirteen-week inhalation toxicity study of 1-propanol in F344 rats

1-Propanol is a colorless volatile liquid at room temperature and is an important industrial alcohol. Workers are potentially exposed to it through inhalation during industrial activities, including manufacturing, sampling, filling, and mixing processes, as well as during cleaning, maintenance, and repair. Consequently, further information and/or testing for inhalation-related toxicological data is required to assess occupational risk. In this study, 80 (40 male and 40 female) F344 rats were exposed to 1-propanol vapors for 13 weeks (6 h a day, 5 days per week) at target concentrations of 0, 500, 1,600, and 5200 ppm in a whole-body inhalation chamber system. Clinical signs, mean body weight changes, food consumption, hematology, blood biochemistry, necropsy, organ weight, and histopathological findings were observed. The exposure concentrations in chambers were 501.30 ± 9.54 ppm, 1605.43 ± 66.55 ppm, and 5202.19 ± 102.74 ppm for the low, middle, and high dose groups, respectively. No changes related to 1-propanol were observed, including histopathological findings, except for mean body weight changes. The significant decrease in mean body weight at a high dose was not considered to be an adverse effect. Based on these results, the no observed adverse effect concentration of 1-propanol was estimated to be 5202.19 ppm.

Paraquat Inhalation, a Translationally Relevant Route of Exposure: Disposition to the Brain and Male-Specific Olfactory Impairment in Mice.

Epidemiological and experimental studies have associated oral and systemic exposures to the herbicide paraquat (PQ) with Parkinson's disease. Despite recognition that airborne particles and solutes can be directly translocated to the brain via olfactory neurons, the potential for inhaled PQ to cause olfactory impairment has not been investigated. This study sought to determine if prolonged low-dose inhalation exposure to PQ would lead to disposition to the brain and olfactory impairment, a prodromal feature of Parkinson's disease. Adult male and female C57BL/6J mice were exposed to PQ aerosols in a whole-body inhalation chamber for 4 h/day, 5 days/week for 4 weeks. Subsets of mice were sacrificed during and after exposure and PQ concentrations in various brain regions (olfactory bulb, striatum, midbrain, and cerebellum) lung, and kidney were quantified via mass spectrometry. Alterations in olfaction were examined using an olfactory discrimination paradigm. PQ inhalation resulted in an appreciable burden in all examined brain regions, with the highest burden observed in the olfactory bulb, consistent with nasal olfactory uptake. PQ was also detected in the lung and kidney, yet PQ levels in all tissues returned to control values within 4 weeks post exposure. PQ inhalation caused persistent male-specific deficits in olfactory discrimination. No effects were observed in females. These data support the importance of route of exposure in determination of safety estimates for neurotoxic pesticides, such as PQ. Accurate estimation of the relationship between exposure and internal dose is critical for risk assessment and public health protection.

Luminescent Marker for GSR: Evaluation of the Acute Oral and Inhalation Toxicity of the MOF [Eu(DPA)(HDPA)

The metal-organic framework (MOF) [Eu(DPA)(HDPA)] (where DPA is dipicolinic acid) has been previously reported as an efficient marker for gunshot residues (GSRs). Since this marker will be in contact with various shooters, industrial workers, and the environment, however, it is important to identify its toxicity. In this work, the oral and the inhalation acute toxicities of the MOF [Eu(DPA)(HDPA)] (also called R-Marker) were evaluated in young Wistar rats using Guidelines 423 (oral) and 436 (inhalation) from the Organisation for Economic Co-operation and Development (OECD). Animal behavior; body weight, water, and food intake; and organ weight, as well as biochemical parameters were evaluated in both evaluations. For the inhalation test, a concentration of 1 mg·Lair-1·(4 h-1) was reached in a whole-body inhalation chamber. When the respiratory tract was analyzed, it was observed that part of the marker had been swallowed instead of inhaled by the animal. For the oral test, the highest administrated dose was 2000 mg/kg with no sign of toxicity. This marker has been classified in the least toxic category of the Globally Harmonized System (GHS; category 5), with an oral median lethal dose (LD50) of 5000 mg/kg. After the oral administration, the feces of the animals were collected using a metabolic cage. Luminescent feces were present up to 24 h after administration, indicating that the marker had been excreted by the organism without causing intoxication. This study has opened perspectives for drug delivery and toxicity studies, since it enables visual detection of the marker.

Variability in the Clearance of Lead Oxide Nanoparticles Is Associated with Alteration of Specific Membrane Transporters.

Lead oxide nanoparticles (PbONPs), upon their entry into the lungs via inhalation, induce structural changes in primary and secondary target organs. The fate and ultrastructural localization of PbONPs in organs is known to be dependent on the specific organ. Here, we focused on the differences in the ability to clear the inhaled PbONPs from secondary target organs and on molecular and cellular mechanisms contributing to nanoparticle removal. Mice were exposed to PbONPs in whole-body inhalation chambers. Clearance of ionic lead and PbONPs (Pb/PbONPs) from the lungs and liver was very effective, with the lead being almost completely eliminated from the lungs and the physiological state of the lung tissue conspicuously restored. Kidneys exposed to nanoparticles did not exhibit serious signs of damage; however, LA-ICP-MS uncovered a certain amount of lead located preferentially in the kidney cortex even after a clearance period. The concentration of lead in femurs, as representatives of the axial skeleton, was the highest among studied organs at all designated time points after PbONP exposure, and the clearance ability of lead from the femurs was very low in contrast to other organs. The organ-specific increase of ABC transporters expression (ABCG2 in lungs and ABCC3 in the liver) was observed in exposed animals, suggesting their involvement in removing Pb/PbONPs from tissues. Moreover, the expression of caveolins and clathrin displayed a tissue-specific response to lead exposure. Our results uncovered high variability among the organs in their ability to clear Pb/PbONPs and in the transporters involved in this process.

Four-week inhalation toxicity study of 1-propanol in F344 rats.

1-Propanol is used as a solvent for waxes, vegetable oils, resins, cellulose esters, and ethers, and is not considered harmful to humans by food and non-occupational exposures. However, workers are potentially exposed to 1-propanol by inhalation when it is used in the workplace. Thus, inhalation toxicity data are needed to assess the hazard of 1-propanol for workers safety. Five male and five female F344 rats were exposed to 1-propanol vapor for 4-weeks (6h/day, 5days/week) at concentrations of 0, 100, 400, and 1600ppm in a whole-body inhalation chamber system. The actual exposure concentrations were 100.11 ± 5.10, 403.19 ± 12.31, and 1598.08 ± 139.58ppm for the low, middle, and high dose groups, respectively. No clinical signs, significant mean body weight changes, significant changes of hematology or blood biochemistry results, or histopathological abnormalities were seen related to exposure to the test substance. Under the conditions of this study, the no-observed-adverse-effect level of 1-propanol was over 1600ppm.

Effects of bentonite nanoparticles inhalation on lung tissue and blood antioxidant indices in a rat model.

Bentonite is an inorganic clay material that is often easily dispersed as fine particles by air and water circulation, and most people are exposed to different concentrations of bentonite particles. Therefore, the inhaled effects of bentonite nanoparticles (BNPs) were studied in Wistar rats. Seventy-five rats were divided into five groups of 15: four exposure groups (0.1, 0.5, 2, and 10 mg/m3 of BNPs) and one control group. The rats were exposed for 30, 60, and 90 days to BNPs for 5 days a week (6 h/day) in whole-body inhalation chambers. Blood samples were collected to measure the levels of antioxidant activity of the contents such as total antioxidant capacity (TAC) and malondialdehyde (MDA). X-ray diffraction and scanning electron microscopy were used to identify nanoparticles. The results showed no significant difference in the effect of nanoparticles on levels of TAC and MDA in the studied groups based on the concentrations of nanoparticles. However, the level of MDA increased significantly with extending exposure time; there was a significant increase in the level of MDA content 90 days postexposure compared to 30 days postexposure at concentrations of 0.5, 2, and 10 mg/m3. Histopathological examination showed that inhalation exposure of rats to BNPs led to different histopathologic responses in the lung tissue, such as inflammatory infiltration, granulomatous inflammation, acute neutrophilic reaction in the early stages, and lung fibrosis. At the lowest concentration, BNPs have low or no toxicity, and inhalation of these nanoparticles at low concentrations does not affect the levels of MDA and TAC content. However, increased concentration and exposure time caused correspondingly greater increases in MDA and more damage to lung tissue.

Thirteen-week inhalation toxicity study of 1-methylnaphthalene in F344 rats.

1-Methylnaphthalene is generally utilized in solvents, as an intermediate in organic synthesis, a dye carrier, in resins, and others. There are some toxicological studies of 1-methylnaphthalene; however, inhalation toxicity studies are rare. Each of 10 male and female F344 rats was exposed to vapors of 1-methylnaphthalene for 13weeks (6h a day, 5days per week) at concentrations of 0, 0.5, 4, and 30ppm in a whole-body inhalation chamber system. The exposure concentrations were 0.52 ± 0.05, 4.08 ± 0.25, and 30.83 ± 1.28ppm for the low-, middle-, and high-dose group, respectively. Body weight changes were not affected by exposure to 1-methylnaphthalene. Blood prothrombin time was delayed at 30ppm in male and female groups, and activated partial thromboplastin time was also delayed at 30ppm in the male group. Values of alanine aminotransferase in the serum were decreased and those of albumin were increased at 30ppm in the male group. Differential cell counts and levels of lactate dehydrogenase in the bronchoalveolar lavage fluid were not affected. However, mucous cell hyperplasia in the nasopharyngeal tissues was found and the severity was correlated to exposure concentrations. In conclusion, 1-methylnaphthalene mainly affects the upper respiratory system and the no-observed-adverse-effect levelis suggested to be 4ppm on the basis of histopathological findings.

Inhalation toxicity of benzalkonium chloride and triethylene glycol mixture in rats

Benzalkonium chloride (BAC), a disinfectant, and triethylene glycol (TEG), an organic solvent/sanitizer, are frequently combined in commercially available household sprays. To assess the respiratory effect of this combination, Sprague-Dawley rats were exposed to an aerosol containing BAC (0.5%, w/v) and TEG (10%, w/v) for up to 2 weeks in a whole-body inhalation chamber. BAC (4.1–4.5 mg/m3, sprayed from 0.5% solution) promoted pulmonary cell damage and inflammation as depicted by the increase in total protein, lactate dehydrogenase, polymorphonuclear leukocytes, and macrophage inflammatory protein-2 in the bronchoalveolar lavage fluid, whereas TEG (85.3–94.5 mg/m3, sprayed from 10% solution) did not affect the lung. Rats exposed to the BAC/TEG mixture for 2 weeks showed severe respiratory symptoms (sneezing, wheezing, breath shortness, and chest tightness), but no lung damage or inflammation was observed. However, significant ulceration and degenerative necrosis were observed in the nasal cavities of rats repeatedly exposed to the BAC/TEG mixture. The mass median aerodynamic diameters of the aqueous, BAC, TEG and BAC/TEG aerosols were 1.24, 1.27, 3.11 and 3.24 μm, respectively, indicating that TEG-containing aerosols have larger particles than those of the aqueous and BAC alone aerosols. These results suggest that the toxic effects of BAC and BAC/TEG aerosols on the different respiratory organs may be associated with the difference in particle diameter, since particle size is important in determining the deposition site of inhaled materials.

Excipient-free isoniazid aerosol administration in mice: Evaporation-nucleation particle generation, pulmonary delivery and body distribution

Excipient-free isoniazid aerosol formation and pulmonary delivery in mice are studied. An evaporation-nucleation route is used for the generation of isoniazid aerosol. Particle diameters and number concentrations are measured with an aerosol spectrometer consisting of a diffusion battery, condensation chamber, and photoelectric counter. The pulmonary delivery of isoniazid particles is studied in both nose-only (NO) and whole-body (WB) inhalation chambers for the particle mean diameter and number concentration to be 600 nm and 6 × 106 cm−3, respectively. It is found that the rate of drug systemic absorption in the WB chamber is 27% higher than that for the NO one because of an additional consumption of drug orally from the fur in the WB chamber. The particle deposition efficiency ε in the mouse respiratory tract is measured as a function of mean diameter. The quantity ε is equal to 0.7 for the particle diameter d = 10 nm and decreases to 0.2 with the diameter increasing to 300 nm, and then, at d > 300 nm the deposition efficiency increases with diameter to 0.5 at d = 2000 nm. The bioavailability of the aerosol form of isoniazid (72 ± 10%) is very close to that for the per-oral form (61 ± 10%).

Inhalation exposure of nano diamond induced oxidative stress in lung, heart and brain

1. Today, diamond nanoparticles have several industrial applications. Nano diamond (ND) as a carbon allotrope diffuses in the air easily during producing and processing procedures.2. In this study, we investigated sub-acute exposed to ND at the exposure chamber in mice. The animals were divided into two groups (control and exposed group to ND at the concentration of 3 µg/m3 for 3 h/day, 5 days/week for 30 days) in a whole-body inhalation chamber.3. Our results showed that exposure to ND induced the hematological and biochemical changes. The target organs for ND were the lungs, brain and heart in the mice, respectively. Also, ND increased reactive oxygen species (ROS) generation, lipid peroxidation (LPO), the collapse of mitochondrial membrane potential (MMP), decreased a level of reduced glutathione (GSH) and finally increased a level of glutathione disulfide (GSSG) in lung, brain and heart tissues. Our results suggest that exposure to ND can induce oxidative stress in the tissue mentioned.4. These results suggest that exposure of researchers and workers with diamond nanoparticles probably increase a risk of respiratory, cardiovascular and cerebral disorders through oxidative stress. However, good ventilation, appropriate personal protective equipment and using of anti-oxidant compounds in daily diet of worker are suggested.

Chronic toxicity and oncogenicity of octamethylcyclotetrasiloxane (D4) in the Fischer 344 rat

Octamethylcyclotetrasiloxane (D4) is a cyclic volatile methylsiloxane primarily used in the synthesis of silicon-based materials used in a variety of consumer products. This paper details the chronic toxicity and oncogenicity evaluation of D4 in the Fischer 344 rat. Animals were exposed to 0, 10, 30, 150, or 700ppm D4 vapor for 6h/day, 5days/week for up to 104 weeks in whole-body inhalation chambers. Effects of two year chronic exposure included increased liver, kidney, testes, and uterine weight with correlating microscopic findings of hepatocellular hypertrophy (males only), chronic nephropathy (both sexes), interstitial cell hyperplasia, and cystic endometrial hyperplasia and endometrial adenoma, respectively. Upper respiratory tract irritation and lymphocytic leukocytosis were evident in both sexes. Increased neoplasia was demonstrated only in the uterus. Uterine endometrial adenomas were present in four of sixty animals exposed to 700ppm D4 for 24 months. None were present in the other treatment groups. In contrast, in 700ppm D4 group males the incidence of pituitary and pancreatic neoplasia was reduced as was thyroid c-cell adenoma/carcinoma in 700ppm females. This study has identified that D4 is a mild respiratory irritant and increases liver and kidney weight without inducing neoplasia in these tissues. The increased incidence of uterine adenoma was the only treatment-related neoplastic finding associated with chronic exposure to D4.