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1.
Toxicol Pathol ; 42(7): 1130-42, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24705883

ABSTRACT

The interaction between exposure to nanomaterials and existing inflammatory conditions has not been fully established. Multiwalled carbon nanotubes (MWCNT; Nanocyl NC 7000 CAS no. 7782-42-5; count median diameter in atmosphere 61 ± 5 nm) were tested by inhalation in high Immunoglobulin E (IgE)-responding Brown Norway (BN) rats with trimellitic anhydride (TMA)-induced respiratory allergy. The rats were exposed 2 days/week over a 3.5-week period to a low (11 mg/m(3)) or a high (22 mg/m(3)) concentration of MWCNT. Nonallergic animals exposed to MWCNT and unexposed allergic and nonallergic rats served as controls. At the end of the exposure period, the allergic animals were rechallenged with TMA. Histopathological examination of the respiratory tract showed agglomerated/aggregated MWCNT in the lungs and in the lung-draining lymph nodes. Frustrated phagocytosis was observed as incomplete uptake of MWCNT by the alveolar macrophages and clustering of cells around MWCNT. Large MWCNT agglomerates/aggregates were found in granulomas in the allergic rats, suggesting decreased macrophage clearance in allergic rats. In allergic rats, MWCNT exposure decreased serum IgE levels and the number of lymphocytes in bronchoalveolar lavage. In conclusion, MWCNT did not aggravate the acute allergic reaction but modulated the allergy-associated immune response.


Subject(s)
Nanotubes, Carbon/chemistry , Phthalic Anhydrides/adverse effects , Phthalic Anhydrides/immunology , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/pathology , Administration, Inhalation , Allergens/administration & dosage , Allergens/adverse effects , Animals , Female , Immunoglobulin E/blood , Lung/cytology , Lung/immunology , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymphocytes/cytology , Lymphocytes/immunology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/immunology , Phagocytosis , Phthalic Anhydrides/administration & dosage , Rats , Rats, Inbred BN , Respiratory Hypersensitivity/chemically induced
2.
Nanotoxicology ; 8(6): 643-53, 2014 Sep.
Article in English | MEDLINE | ID: mdl-23768316

ABSTRACT

There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects.


Subject(s)
Cerium/toxicity , Lung/drug effects , Nanoparticles/toxicity , Administration, Inhalation , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Cerium/administration & dosage , Cerium/chemistry , Female , Inhalation Exposure , Lung/pathology , Male , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Neutrophils/drug effects , Particle Size , Pneumonia/chemically induced , Rats
3.
Drug Chem Toxicol ; 37(1): 83-92, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23869688

ABSTRACT

Trans-1-chloro,3,3,3-trifluoropropene (HCFO-1233zd(E)) is being developed as a foam blowing agent, refrigerant and solvent because it has a very low global warming potential (<10), as contrasted to the hydrofluorocarbons (>500). The toxicology profile is described. The acute 4-hour 50% lethal concentration value in rats receiving HCFO-1233zd(E) was 120 000 ppm. The no observed effect level (NOEL) in cardiac sensitization studies in dogs was 25 000 ppm. In a 2-week range-finding study, rats were exposed to HCFO-1233zd(E) at levels of 0, 2000, 7500 and 20 000 ppm 6 hours/day for 5 days/week. Histopathological changes in the heart described as multifocal mononuclear infiltrates were observed in males (mid- and high-exposure group) and females (high-exposure group), suggesting this organ was the target for HCFO-1233zd(E) toxicity. In a 4-week study, rats were exposed to 0, 2000, 4500, 7500 and 10 000 ppm. The only finding was an increase in potassium (mid- and high-exposure males). No increase was observed after a 2-week recovery period, nor in a subsequent 13-week toxicity study. In a 13-week study, rats were exposed to 4000, 10 000 and 15 000 ppm 6 hours/day for 5 days/week. Findings consisted of multifocal mononuclear cell infiltrates in the heart with a NOEL/lowest observed adverse effect level of 4000 ppm. No genetic toxicity was observed in a battery of genetic toxicity studies. In a rat prenatal developmental toxicity study, dilated bladders were observed in the high-exposure group fetuses (15 000 ppm), a finding of unclear significance. HCFO-1233zd(E) was not a developmental toxin in rabbits, even at exposure levels up to 15 000 ppm.


Subject(s)
Chlorofluorocarbons/toxicity , Chromosome Aberrations/drug effects , Heart/drug effects , Administration, Inhalation , Animals , Chlorofluorocarbons/administration & dosage , Dogs , Dose-Response Relationship, Drug , Female , Lethal Dose 50 , Male , No-Observed-Adverse-Effect Level , Rabbits , Rats , Rats, Wistar , Urinary Bladder/drug effects
4.
Drug Chem Toxicol ; 36(4): 412-20, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23742174

ABSTRACT

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is being developed as a refrigerant because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons, which is intended to replace with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 101,850 or 405,800 ppm, respectively. Additionally, there was no mortality or clinical signs of toxicity when rabbits were exposed to 100,000 ppm for 1 hour. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin in dogs. Rats were exposed to HFO-1234yf at levels of 5000, 20,000 and 50,000 ppm 6 hours/day 5 days/week for 2 weeks and at levels of 5000, 15,000 and 50,000 ppm for 4 weeks and for 90 days. No treatment-related adverse effects were noted in these studies. HFO-1234yf was not genotoxic in a mouse and a rat micronucleus assay, and unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. HFO-1234yf was mutagenic to Salmonella typhimurium TA 100 and Escherichia coli (WP2 uvrA) at concentrations of 20% and higher in the presence of metabolic activation only. There were no biologically significant effects in a rat developmental toxicity study with exposures up to 50,000 ppm.


Subject(s)
Chromosome Aberrations/chemically induced , Escherichia coli/drug effects , Fluorocarbons/toxicity , Salmonella typhimurium/drug effects , Animals , Bronchial Provocation Tests , DNA Replication/drug effects , Dogs , Dose-Response Relationship, Drug , Female , Humans , Male , Mice , Micronucleus Tests , Rabbits , Rats , Rats, Sprague-Dawley , Refrigeration/methods , Time Factors , Toxicology/methods
5.
Drug Chem Toxicol ; 36(2): 170-80, 2013 Apr.
Article in English | MEDLINE | ID: mdl-22486185

ABSTRACT

HFO-1234ze is being developed as a refrigerant, propellant, and foam-blowing agent because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 103,300 or 207,000 ppm, respectively. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin. Rats were exposed to HFO-1234ze at levels of 5,000, 20,000, and 50,000 ppm 6 hours/day 5 days/week for 2 weeks. Predominate findings of increased liver and kidney weights and histopathological changes in the liver and heart suggested that these organs were the targets for HFO-1234ze toxicity. In a 4-week study at 1000, 5000, 10,000, and 15,000 ppm, the only organ showing treatment-related effects was the heart. In a 90-day study with exposures of 1500, 5000, and 15,000 ppm 6 hours/day 5 days/week, again, the heart was the only target organ. The findings consisted of focal and multifocal mononuclear cell infiltrates in the heart. There was no evidence of fibrosis, and, when compared to the 2- and 4-week studies, there did not appear to be an increase in severity with length of exposure. HFO-1234ze was inactive in a mouse and rat micronucleus assay, an Ames assay, and an unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. It was also not a developmental toxin in either the rat or rabbit, even at exposure levels up to15,000 ppm.


Subject(s)
Aerosol Propellants/toxicity , Fluorocarbons/toxicity , Toxicity Tests/methods , Administration, Inhalation , Aerosol Propellants/administration & dosage , Animals , Dose-Response Relationship, Drug , Female , Fluorocarbons/administration & dosage , Global Warming , Heart/drug effects , Humans , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/pathology , Lymphocytes/drug effects , Lymphocytes/metabolism , Male , Mice , Organ Size/drug effects , Rabbits , Rats , Rats, Sprague-Dawley , Species Specificity , Time Factors
6.
Crit Rev Toxicol ; 41(3): 213-29, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21244219

ABSTRACT

Advances of nanoscale science have produced nanomaterials with unique physical and chemical properties at commercial levels which are now incorporated into over 1000 products. Nanoscale cerium (di) oxide (CeO(2)) has recently gained a wide range of applications which includes coatings, electronics, biomedical, energy and fuel additives. Many applications of engineered CeO(2) nanoparticles are dispersive in nature increasing the risk of exposure and interactions with a variety of environmental media with unknown health, safety and environmental implications. As evident from a risk assessment perspective, the health effects of CeO(2) nanoparticles are not only dependent on their intrinsic toxicity but also on the level of exposure to these novel materials. Although this may seem logical, numerous studies have assessed the health effects of nanoparticles without this simple but critical risk assessment perspective. This review extends previous exposure and toxicological assessments for CeO(2) particles by summarizing the current state of micro and nano-scale cerium exposure and health risks derived from epidemiology, air quality monitoring, fuel combustion and toxicological studies to serve as a contemporary comprehensive and integrated toxicological assessment. Based on the new information presented in this review there is an ongoing exposure to a large population to new diesel emissions generated using fuel additives containing CeO2 nanoparticles for which the environmental (air quality and climate change) and public health impacts of this new technology are not known. Therefore, there is an absolute critical need for integrated exposure and toxicological studies in order to accurately assess the environmental, ecological and health implications of nanotechnology enabled diesel fuel additives with existing as well as new engine designs and fuel formulations.


Subject(s)
Air Pollutants/toxicity , Cerium/toxicity , Metal Nanoparticles/toxicity , Air Pollutants/chemistry , Cerium/chemistry , Environmental Exposure/analysis , Environmental Exposure/statistics & numerical data , Gasoline/toxicity , Humans , Metal Nanoparticles/chemistry , Metal Nanoparticles/ultrastructure , Particle Size , Risk Assessment , Vehicle Emissions/toxicity
7.
Toxicology ; 279(1-3): 115-22, 2011 Jan 11.
Article in English | MEDLINE | ID: mdl-20933045

ABSTRACT

Previously, a selection of low molecular weight contact and respiratory allergens had tested positive in both a skin and a respiratory local lymph node assay (LLNA), but formaldehyde was negative for sensitization by inhalation. To investigate whether this was due to intrinsic properties of aldehyde sensitizers, the structurally related allergen glutaraldehyde (GA) was tested. BALB/c mice were exposed by inhalation to 6 or 18ppm GA (respiratory LLNA), both generated as a vapor and as an aerosol. Other groups received 0.25% or 2.5% GA on the skin of the ears (skin LLNA). Lymphocyte proliferation and cytokine production were measured in the draining lymph nodes. GA was positive in the skin LLNA and its cytokine profile (IL-4/IFN-γ) skewed towards a Th2-type immune response with increasing dose. Inhalation exposure did not result in increased lymphocyte proliferation or increased cytokine levels, despite comparable tissue damage (irritation) in the skin and respiratory tract. We hypothesize that the highly reactive and hydrophilic GA oligomerizes in the protein-rich mucous layer of the respiratory tract, which impedes sensitization but still facilitates local irritation. Within the context of risk assessment in respiratory allergy, our results stress the importance of prevention of skin--besides inhalation-- exposure to aldehydes like GA.


Subject(s)
Allergens/immunology , Glutaral/immunology , Lymph Nodes/drug effects , Respiratory Hypersensitivity/chemically induced , Administration, Cutaneous , Aerosols , Allergens/administration & dosage , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Glutaral/administration & dosage , Inhalation Exposure , Interferon-gamma/metabolism , Interleukin-4/metabolism , Local Lymph Node Assay , Lymph Nodes/immunology , Lymphocytes/drug effects , Male , Mice , Mice, Inbred BALB C , Respiratory Hypersensitivity/immunology , Th2 Cells/immunology
8.
Toxicology ; 269(1): 73-80, 2010 Feb 28.
Article in English | MEDLINE | ID: mdl-20096324

ABSTRACT

Previously, the contact allergen dinitrochlorobenzene (DNCB) was identified as a sensitizer by inhalation in BALB/c mice; in addition, DNCB induced a lymphocytic infiltrate in the larynx of dermally sensitized Th1-prone Wistar rats upon a single inhalation challenge. In the present study, repeated inhalation exposures to DNCB were investigated using the same protocol as the single-challenge study: female Wistar rats were dermally sensitized with DNCB and subsequently challenged by inhalation exposure to 7 or 15 mg/m(3) DNCB twice a week for 4 weeks. Allergy-related apnoeic breathing was not observed. DNCB-specific IgG antibodies were found in the serum and--predominantly lymphocytic--inflammations were found in the nasal tissues and larynx. Similar effects were observed in animals repeatedly exposed by inhalation without previous dermal contact, indicating sensitization by inhalation. The inflammation may be the upper respiratory tract analogue of hypersensitivity pneumonitis/allergic alveolitis. Possible progression of the airway inflammation upon long-term exposure should be investigated to support or dismiss discrimination between contact and respiratory allergens in relation to respiratory allergy.


Subject(s)
Allergens/toxicity , Dinitrochlorobenzene/toxicity , Inflammation Mediators/toxicity , Inhalation Exposure/adverse effects , Respiratory System/drug effects , Administration, Inhalation , Allergens/administration & dosage , Animals , Dermatitis, Allergic Contact/immunology , Dermatitis, Allergic Contact/pathology , Dinitrochlorobenzene/administration & dosage , Dinitrochlorobenzene/immunology , Female , Inflammation Mediators/administration & dosage , Inflammation Mediators/immunology , Rats , Rats, Wistar , Respiratory Mechanics/drug effects , Respiratory Mechanics/immunology , Respiratory System/pathology , Respiratory System/physiopathology
9.
Regul Toxicol Pharmacol ; 52(2): 189-94, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18786592

ABSTRACT

The paper aims to evaluate the indoor air limit of 1 microg/m(3) (0.8 ppb) formaldehyde as advised by the European Commission [the INDEX project; Kotzias, D., Koistinen, K., Kephalopoulos, S., Schlitt, C., Carrer, P., Maroni, M., Jantunen, M., Cochet, C., Kirchner, S., Lindvall, T., McLaughlin, J., Mølhave, L., de Oliveira Fernandes, E., Seifert, B., 2005. Critical appraisal of the setting and implementation of indoor exposure limits in the EU. European Commission, Institute for Health and Consumer Protection, Physical and Chemical Exposure Unit, Ispra, Italy, pp. 1-50]. The limit has been based on a nose and throat irritation threshold of 0.1mg/m(3) (0.08 ppm; LOAEL), a NOAEL of 0.03 mg/m(3) (0.025 ppm) and an assessment factor of 30, including a factor of 3 for the higher sensitivity of children. Nose and throat irritation, at concentrations below which hyperplasia/metaplasia occurs, are most likely the manifestation of trigeminal nerve stimulation (sensory irritation). The threshold for sensory irritation in human volunteers is 1 ppm, much higher than the 0.1mg/m(3) indicated above. Eye irritation is the most sensitive effect reported in human volunteers but has been mentioned only occasionally in the studies used by the European Commission. Moreover, sensory irritation is a local reaction that requires a low assessment factor, if any. It is difficult to judge the sensitivity for sensory irritation in children because of the potential confounding factors in the evaluated studies. It is concluded that an indoor air level of 0.1 ppm (0.12 mg/m(3)) formaldehyde, as indicated by Appel et al. (2006) [Appel, K.E., Bernauer, U., Herbst, U., Madle, S., Schulte, A., Richter-Reichhelm, H.B., Gundert-Remy, U. 2006. Kann für Formaldehyd eine "sichere" Konzentration abgeleitet werden?--Analyse der Daten zur krebserzeugenden Wirkung (Can a "safe" concentration be established for formaldehyde?--Analysis of carcinogenicity data)? Umweltmed. Forsch. Prax. 11, 347-361], can be considered a safe and appropriate level.


Subject(s)
Air Pollutants/toxicity , Formaldehyde/toxicity , Inhalation Exposure/adverse effects , Irritants/toxicity , Administration, Inhalation , Carcinogens/administration & dosage , Carcinogens/toxicity , Child , European Union , Eye/drug effects , Eye/pathology , Formaldehyde/administration & dosage , Humans , Irritants/administration & dosage , No-Observed-Adverse-Effect Level , Nose/drug effects , Nose/pathology , Occupational Exposure/adverse effects , Pharynx/drug effects , Pharynx/pathology , Trigeminal Nerve/drug effects , Trigeminal Nerve/metabolism
10.
Inhal Toxicol ; 20(7): 665-70, 2008 May.
Article in English | MEDLINE | ID: mdl-18464054

ABSTRACT

The objectives of this study were to examine the respiratory irritancy of boron trifluoride (BF(3)) and fluorosulfonic acid (FSA) following acute inhalation exposure. Testing was conducted using groups of 10 male and 10 female rats (BF(3)) or groups of 6 male rats (FSA). Rats were exposed for a single 4-h period (BF(3)) or a single 1-h period (FSA) and necropsied 1 or 14 days after exposure (BF(3)) or 14 days after exposure (FSA). Measurements consisted of clinical signs, body weight, kidney and lung weight, histopathology (BF(3)), and breathing parameters (FSA) and were used to evaluate the possible irritating effects of these compounds. The results indicated treatment-related findings in the larynx and trachea in the rats exposed to 74.4 mg/m(3) BF(3), consisting of ventral cartilage necrosis, hemorrhage, and an increase in ventral epithelial hyperplasia and ventral inflammatory cell inflammation 24 h postexposure. In the animals sacrificed 14 days postexposure, the only notable observation was ventral cartilage necrosis, present in 2 animals. The next lower level tested, 24.6 mg/m(3) BF, was considered a no-observed-adverse-effects level (NOAEL). A concentration of 4125 mg/m(3) FSA resulted in a clearly decreased breathing rate during and shortly after exposure with 67% (4/6) mortality on days 5-9 after exposure. A concentration of 845 mg/m(3) FSA resulted in only minor signs of irritation, consisting of slight changes in breathing pattern shorlty after exposure. The results of the present 4-h inhalation study with BF(3) indicated that respiratory irritation was present at a level of 74.4 mg/m(3) whereas 24.6 mg/m(3) was a NOAEL. A single 1-h exposure to 845 mg/m(3) FSA resulted in only minor signs of respiratory irritation, indicating that on a mass basis FSA is no more toxic or irritating than hydrogen fluoride (HF) or sulfuric acid.


Subject(s)
Boranes/toxicity , Fluorides/toxicity , Irritants/toxicity , Respiratory Tract Diseases/chemically induced , Sulfuric Acids/toxicity , Animals , Female , Male , Rats , Rats, Sprague-Dawley , Respiratory Mechanics/drug effects , Respiratory Tract Diseases/pathology , Toxicity Tests, Acute
11.
Toxicol Pathol ; 36(7): 985-98, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19126793

ABSTRACT

To contribute to the hazard identification of low molecular weight (LMW) respiratory allergens, respiratory allergy induced by trimellitic anhydride (TMA) was characterized by whole genome analysis of lung tissue and blood proteomics in Brown Norway rats. Dermal sensitization (50% and 25% w/v) with TMA and an inhalation challenge of 15 mg/m(3) TMA-induced apneas, laryngeal inflammation, increased numbers of eosinophils, neutrophils and macrophages in bronchoalveolar lavage (BAL), and increased immunoglobulin E levels in serum and lung tissue. Whole genome analysis of lung, sampled 24 hours after challenge, showed expression changes of not only genes belonging to several Gene Ontology groups with up-regulation of inflammatory-associated genes and those associated with lung remodeling but also genes involved in downsizing these processes. Blood proteomics reflected activation of inflammation-inhibiting pathways. Unsensitized animals challenged with TMA exhibited also an increased number of macrophages in BAL, but gene expression in the above-mentioned gene pathways was unchanged or down-regulated. The authors conclude that parameters for lung remodeling can be a valuable tool in hazard identification of LMW respiratory allergens.


Subject(s)
Allergens/toxicity , Phthalic Anhydrides/toxicity , Respiratory Hypersensitivity/genetics , Respiratory Hypersensitivity/metabolism , Allergens/administration & dosage , Analysis of Variance , Animals , Bronchoalveolar Lavage , Cluster Analysis , Female , Gene Expression Profiling , Immunoglobulin E/metabolism , Immunohistochemistry , Lung/metabolism , Lung/pathology , Oligonucleotide Array Sequence Analysis , Phthalic Anhydrides/administration & dosage , Principal Component Analysis , Proteomics , Rats , Rats, Inbred BN , Respiratory Hypersensitivity/blood , Signal Transduction/drug effects , Statistics, Nonparametric , Toll-Like Receptors/metabolism
12.
Food Chem Toxicol ; 45(10): 1856-67, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17524541

ABSTRACT

Evidence suggests that short-term animal exposures to synthetic amorphous silicas (SAS) and crystalline silica can provide comparable prediction of toxicity to those of 90-day studies, therefore providing the opportunity to screen these types of substances using short-term rather than 90-day studies. To investigate this hypothesis, the inhalation toxicity of three SAS, precipitated silica Zeosil 45, silica gel Syloid 74, and pyrogenic silica Cab-O-Sil M5 was studied in Wistar rats. Rats were exposed nose-only to concentrations of 1, 5 or 25mg/m(3) of one of the SAS 6h a day for five consecutive days. Positive controls were exposed to 25mg/m(3) crystalline silica (quartz dust), negative controls to clean air. Animals were necropsied the day after the last exposure or 1 or 3 months later. All exposures were tolerated without serious clinical effects, changes in body weight or food intake. Differences in the effects associated with exposure to the three types of SAS were limited and almost exclusively confined to the 1-day post-exposure time point. Silicon levels in tracheobronchial lymph nodes were below the detection limit in all groups at all time points. Silicon was found in the lungs of all high concentration SAS groups 1-day post-exposure, and was cleared 3 months later. Exposure to all three SAS at 25mg/m(3) induced elevations in biomarkers of cytotoxicity in bronchoalveolar lavage fluid (BALf), increases in lung and tracheobronchial lymph node weight and histopathological lung changes 1-day post-exposure. Exposure to all three SAS at 5mg/m(3) induced histopathological changes and changes in BALf only. With all three SAS these effects were transient and, with the exception of slight histopathological lung changes at the higher exposure levels, were reversible during the 3-month recovery period. No adverse changes were observed in animals exposed to any of the SAS at 1mg/m(3). In contrast, with quartz-exposed animals the presence of silicon in the lungs was persistent and toxicological effects differed from those seen with SAS both with regard to the type and severity as well as in the time-response profile. In quartz-exposed animals silicon in the tracheobronchial lymph nodes was below the detection limit but silicon was found in the lungs at comparable levels 0-, 1- and 3-months post-exposure. One-day post-exposure to quartz, elevations in biomarkers of cytotoxicity in BALf, increases in lung and tracheobronchial lymph node weight and histopathological lung changes were minimal. These effects were present at 1-month post-exposure and progressively more severe at 3-months post-exposure. Overall, the results of the current study are similar to those of other published studies that had a 90-day exposure period and both types of studies indicate that the lack of lung clearance is a key factor in the development of silicosis.


Subject(s)
Silicon Dioxide/toxicity , Aerosols , Animals , Body Weight/drug effects , Bronchoalveolar Lavage Fluid/cytology , Eating/drug effects , Female , Hydroxyproline/metabolism , Inhalation Exposure/adverse effects , Leukocyte Count , Lung/drug effects , Lung/metabolism , Male , Organ Size/drug effects , Particle Size , Quartz/toxicity , Rats , Rats, Wistar , Silicon/toxicity , Silicon Dioxide/administration & dosage , Silicon Dioxide/analysis
13.
Environ Toxicol Pharmacol ; 20(3): 431-42, 2005 Nov.
Article in English | MEDLINE | ID: mdl-21783623

ABSTRACT

The health risks of inhalation exposure to volatile organic solvents may not only depend on the total external dose, but also on the pattern of exposure. It has been suggested that exposure to regularly occurring peak concentrations may have a stronger impact on the brain than constant exposure at the same average level. Recent animal experimental studies conducted in our laboratory using relatively high concentrations of toluene have shown different effects on discrimination performance and motor activity during and after exposure, depending on the exposure scenario. Relevance of these findings for man was evaluated in a volunteer study in which 11 healthy men (age 20-49 years) were exposed by inhalation for 4h to either a constant concentration of 40ppm toluene or to three 30-min exposure peaks at 110ppm during this 4h period. Selected tests from the Neurobehavioural Evaluation System (NES) were performed repeatedly during and after exposure. Blood concentrations of toluene as well as urinary o-cresol excretion were measured at relevant time points. The results show that toluene concentration in blood increased during constant exposure and fluctuated during occupationally relevant peak exposures. Presumably, brain concentrations showed similar qualitative patterns. No clear changes were observed on neurobehavioural measures of motor performance, attention, perceptual coding and memory, or on measures of mood and affect. The exposure conditions do not seem to induce significant acute changes in central nervous system function similar to those observed at much higher concentrations in animals, although a statistical correlation was found between one motor performance test (Finger Tapping Test with alternating hands) and blood toluene concentrations. Urinary o-cresol excretion appeared to be significantly higher during the first 2h after exposure.

14.
Food Chem Toxicol ; 42(9): 1389-99, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15234069

ABSTRACT

The subacute oral and inhalation toxicity of furfural vapour was studied in Fischer 344 rats to investigate whether route-to-route extrapolation could be employed to derive the limit value for inhalation exposure from oral toxicity data. Groups of 5 rats per sex were treated by gavage daily for 28 days at dose levels of 6-192 mg/kg bw/day, or exposed by inhalation to concentrations of 20-1280 mg/m3 (6 h/day, 5 days/week) or 160-1280 mg/m3 (3 h/day, 5 days/week) for 28 days. Controls received vehicle (corn oil) or were exposed to clean air. Daily oral treatment with the highest dose of furfural (initially 192 mg/kg bw/day, later reduced to 144 mg/kg bw/day and finally to 120 mg/kg bw/day) resulted in mortality, and in increases in absolute and relative kidney and liver weight in surviving females of this group. Exposure of rats by inhalation for 6 h/day, 5 days/week for 28 days induced mortality at concentrations of 640 mg/m3 and above within 1-8 days. At 640 mg/m3 (3 h/day) and at 320 mg/m3 (3 and 6 h/day) and below, however, exposure was tolerated without serious clinical effects. In contrast, histopathological nasal changes were seen even at the lowest concentration of 20 mg/m3. With increasing exposure concentration, the nasal effects increased in incidence and severity and also expanded from the anterior part to the posterior part, including the olfactory epithelium. It was concluded that the no-observed-adverse-effect level (NOAEL) for oral toxicity was 96 mg/kg bw/day. The NOAEL for systemic inhalation toxicity was comparable, i.e. 92 mg/kg bw/day (corresponding to 320 mg/m3 (6 h/day) or 640 mg/m3 (3 h/day)) assuming 100% absorption. The presence of the histopathological nasal changes at the lowest tested concentration of 20 mg/m3 (corresponding to 6 mg/kg bw/day) proves that for locally acting substances like furfural extrapolation from the oral to the inhalation route is not valid.


Subject(s)
Furaldehyde/toxicity , Administration, Inhalation , Administration, Oral , Animals , Dose-Response Relationship, Drug , Female , Furaldehyde/administration & dosage , Kidney/drug effects , Kidney/pathology , Liver/drug effects , Liver/pathology , Longevity/drug effects , Male , No-Observed-Adverse-Effect Level , Olfactory Mucosa/drug effects , Olfactory Mucosa/pathology , Organ Size/drug effects , Rats , Rats, Inbred F344
15.
Arch Toxicol ; 76(5-6): 277-86, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12107645

ABSTRACT

The relative importance of the three particulate matter (PM) size fractions in ambient air, i.e. coarse (2.5-10 microm), fine (0.1-2.5 microm) and ultrafine (<0.1 microm) fractions, on the induction of adverse health effects is still unknown. Moreover, there is no straightforward relationship between ambient concentration levels, exposure (external dose) and the dose delivered to the target site (internal dose). Recently, a human and a rat airway PM deposition model (MPPDep V1.1) have been developed by CIIT Centers for Health Research and the National Institute of Public Health and the Environment (RIVM), based on the work of O.G. Raabe et al. (1977, In: W.H. Walton, editor, Inhaled Particles IV/2; Pergamon, Oxford) and S. Anjilvel and B. Asgharian (1995, Fundam Appl Toxicol 28:41-50). This paper describes studies using cadmium chloride (CdCl(2)) as a model for toxic aerosol particles to (1) investigate the role of particle size in the development of pulmonary effects, and (2) evaluate the MPPDep model, by comparing predicted deposition with measured deposition of CdCl(2)in the respiratory tract. Rats (ten per group) were exposed for a single 4-h period to CdCl(2)particles at various sizes, i.e. 33, 170, 637 and 1495 nm, all at a target concentration of 1 mg/m(3). Immediately after exposure, four of ten rats per group were killed and trachea, lung lobes, heart, liver and kidneys were collected and preserved to determine the amount of CdCl(2) present in each of these organs. CdCl(2)-induced toxicity, as measured by lactate dehydrogenase (LDH), N-acetyl glucosaminidase (NAG) and protein levels in bronchoalveolar lavage fluid, was determined in the remaining six rats per group the day after exposure. Animals exposed to 33 nm particles showed the highest level of respiratory toxicity, followed by animals exposed to 637 nm particles, then to 170 nm particles and finally by those exposed to 1495 nm particles. Pulmonary cadmium levels showed a similar relationship. The results from the present study suggest that the induction of pulmonary toxicity following inhalation exposure to soluble CdCl(2)particles in the range 30-1500 nm depends on the amount of deposited material, which in its turn depends on the initial (aerodynamic) particle size. In addition, the MPPDep model accurately predicted the measured CdCl(2) deposition. Conclusively, for soluble particles the deposited pulmonary mass (dose) of particles is important for toxicity and is dependent of particle size. These findings may have serious impact on the evaluation of the role of various particle sizes in PM10-associated health effects.


Subject(s)
Cadmium Chloride/pharmacokinetics , Cadmium Chloride/toxicity , Lung/metabolism , Aerosols , Animals , Bronchoalveolar Lavage Fluid/chemistry , Cadmium Chloride/administration & dosage , Dose-Response Relationship, Drug , Inhalation Exposure , Male , Models, Biological , Particle Size , Rats , Rats, Wistar , Tissue Distribution
16.
Neurotoxicol Teratol ; 24(4): 503-10, 2002.
Article in English | MEDLINE | ID: mdl-12127896

ABSTRACT

The present study was designed to compare the ototoxic effects of volatile ethyl benzene in guinea pigs and rats. Rats showed deteriorated auditory thresholds in the mid-frequency range, based on electrocochleography, after 550-ppm ethyl benzene (8 h/day, 5 days). Outer hair cell (OHC) loss was found in the corresponding cochlear regions. In contrast, guinea pigs showed no threshold shifts and no OHC loss after exposure to much higher ethyl benzene levels (2500 ppm, 6 h/day, 5 days). Subsequently, a limited study (four rats and four guinea pigs) was performed in an attempt to understand these differences in susceptibility. Ethyl benzene concentration in blood was determined in both species after exposure to 500-ppm ethyl benzene (8 h/day, 3 days). At the end of the first day, blood of the rats contained 23.2+/-0.8-microg/ml ethyl benzene, whereas the concentration in guinea pig blood was 2.8+/-0.1 microg/ml. After 3 days, the concentration in both species decreased with respect to the first day, but the ethyl benzene concentration in rat blood was still 4.3 times higher than that in guinea pig blood. Thus, the difference in susceptibility between the species may be related to the ethyl benzene concentration in blood.


Subject(s)
Benzene Derivatives/toxicity , Cochlea/pathology , Evoked Potentials, Auditory/drug effects , Genetic Predisposition to Disease , Acoustic Stimulation , Animals , Audiometry, Evoked Response , Benzene Derivatives/blood , Chromatography, Gas , Evoked Potentials, Auditory/genetics , Female , Guinea Pigs , Rats , Rats, Inbred Strains , Species Specificity
17.
Noise Health ; 3(9): 23-32, 2000.
Article in English | MEDLINE | ID: mdl-12689440

ABSTRACT

The effect of noise exposure on the auditory system is well known from animal studies. However, most of the studies concern short-term exposure conditions. The purpose of the present research was to find the dose-effect curve for hearing loss in rats following 5 days of noise exposure. Three groups of eight Wag/Rij rats were exposed to broad band noise at levels of 90, 100 and 110 dB SPL for 8 hours/day and 5 consecutive days. An additional group of eight rats served as the control group. Between three and seven weeks after the exposure, hearing was tested by electrocochleography (CAP) and distortion product otoacoustic emissions (DPOAE). Subsequently, the cochleas were morphologically examined. Only the highest two exposure levels affected hearing. The DPOAE growth curves at 4, 8 and 16 kHz and the CAP growth curves at 4, 8, 12, 16 and 24 kHz were affected after the 110 dB SPL broad band noise. After the 100 dB SPL noise, only the 12 kHz CAP growth curve was affected. At the light-microscopic level, OHC damage was not detected in this study.

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