Liposomal preparations of calcium- or zinc-DTPA have a high efficacy for removing colloidal ytterbium-169 from rat tissues

Results from this study demonstrate that liposomes increase the effectiveness of chelating agents in removing heavy metals from contaminated tissues in vivo. We compared the ability of free and liposomal preparations of Ca- and zn-diethylenetriaminepentaacetic acid (DTPA) to remove ¹⁶⁹Yb from tissues of rats previously injected intravenously with either soluble or colloidal forms of ¹⁶⁹Yb. Although single injections of liposomal Zn-DTPA were better than the free chelator in reducing the body burden of ¹⁶⁹Yb administered in a soluble form (citrate), the liposomal preparations of Zn-DTPA or Ca-DTPA were even more effective in removing the ¹⁶⁹Yb that had been injected as the colloidal form. However, a second injection of liposomal Zn-DTPA given 8 days after the initial treatment was not as effective in removing ¹⁶⁹Yb as a second injection of the free chelator. Whether injected in the free or liposomal forms, Ca-DTPA was more effective than Zn-DTPA in removing the colloidal ¹⁶⁹Yb. Significantly lower amounts of colloidal ¹⁶⁹Yb remained in the liver, kidney, muscle, bone, and blood of rats after injection of the liposomal preparations of Ca- or Zn-DTPA than in the corresponding organs of the control (P < 0.01). The liposomal preparations were also more efficient in reducing the retention of colloidal ¹⁶⁹Yb in bone and blood than the free chelators (P < 0.01).     

四种络合剂对小鼠体内170^Tm促排效果的比较

应用小鼠对四种络合剂的~(170)Tm内污染促排效果进行了比较性研究。结果表明,~(170)Tm内污染后,立即给促排剂400μM/kg,Ca-DTPA效果最好;在延迟给促排剂情况下,Zn-DTPA与Ca-DTPA等效,且优于811(喹胺酸)和EDTA。     

Subacute inhalation toxicity assessment of fly ash from industrial waste incinerators

Fly ash from industrial waste incinerators has been a significant concern because of their constituent toxic heavy metals and organic compounds. The objective of this study was to identify the subacute inhalation toxicity of fly ash from industrial waste incinerators, using whole body inhalation exposure chambers. Male and female groups of Sprague-Dawley rats were exposed to fly ash by inhalation of concentrations of 0, 50, 100, 200?mg/m(3), for 6?h/day, 5 days/week for 4 weeks. There was no significant difference in body weight, and relative organ weight to body weight, between the exposure groups and the control group. Hematological examinations revealed a significant increase of monocyte counts in fly ash exposed rats and brown pigment laden macrophage was found in the lungs of rats exposed to high concentration of fly ash. A decrease of blood glucose levels and an increase in glutamate oxaloacetate transaminase activity were observed in fly ash treated rats. There was also a significant increase of lactate dehydrogenase levels in rat blood exposed fly ash. A significant dose-dependent increase of DNA damage was found in lymphocytes, spleen, bronchoalveolar lavage, liver, lung, and thymus of rats exposed to fly ash. In addition, the level of lipid peroxidation was increased in the plasma of rats exposed to a high concentration of fly ash. These results suggest that inhalation of fly ash from industrial waste incinerators can induce histopathologic, hematological, and serum biochemical changes and oxidative damage.     

Subacute inhalation toxicity assessment of fly ash from industrial waste incinerators

Fly ash from industrial waste incinerators has been a significant concern because of their constituent toxic heavy metals and organic compounds. The objective of this study was to identify the subacute inhalation toxicity of fly ash from industrial waste incinerators, using whole body inhalation exposure chambers. Male and female groups of Sprague-Dawley rats were exposed to fly ash by inhalation of concentrations of 0, 50, 100, 200?mg/m³, for 6?h/day, 5 days/week for 4 weeks. There was no significant difference in body weight, and relative organ weight to body weight, between the exposure groups and the control group. Hematological examinations revealed a significant increase of monocyte counts in fly ash exposed rats and brown pigment laden macrophage was found in the lungs of rats exposed to high concentration of fly ash. A decrease of blood glucose levels and an increase in glutamate oxaloacetate transaminase activity were observed in fly ash treated rats. There was also a significant increase of lactate dehydrogenase levels in rat blood exposed fly ash. A significant dose-dependent increase of DNA damage was found in lymphocytes, spleen, bronchoalveolar lavage, liver, lung, and thymus of rats exposed to fly ash. In addition, the level of lipid peroxidation was increased in the plasma of rats exposed to a high concentration of fly ash. These results suggest that inhalation of fly ash from industrial waste incinerators can induce histopathologic, hematological, and serum biochemical changes and oxidative damage.     

Biochemical toxicology and disposition of Therminol 66 heat transfer fluid after inhalation or after dietary administration to male Sprague-Dawley rats.

The objectives of this study were to determine the disposition of Therminol 66 in rats and to determine the effects of this heat-transfer fluid on liver and kidney microsomal drug-metabolizing enzymes. Therminol 66 was administered to male Sprague-Dawley rats at various doses as either a single oral administration at 0, 100, or 300 mg/kg, or as a single 6-h inhalation exposure at 0 or 350 mg/m3. Animals were killed 48 h after gavage or after termination of inhalation exposure. Additional groups of animals were exposed to Therminol 66 via the diet at 0, 100, 500, or 5000 ppm for 14 d, or via repeated inhalation exposure at 0, 25, 250, or 1200 mg/m3 for 6 h/d for 14 d. These exposure scenarios represent approximately equivalent doses of Therminol 66 by the different routes of administration. No change in body weight was observed after acute oral or inhalation exposure, and little change in body weight was observed in animals administered Therminol 66 via the diet except at the highest dose. There was no change in kidney weight, and liver weights were increased only at the higher doses of Therminol 66. The body weight gain of animals exposed to Therminol 66 via inhalation decreased in a dose-dependent manner over the 2-wk exposure period. Results from the disposition study indicated that Therminol 66 did not appear to accumulate in the tissues examined and did not appear to be extensively absorbed after a single oral dose of 300 mg/kg. The whole-body elimination half-life was approximately 14 h and occurred primarily via the feces. There was no significant induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity after single oral or inhalation exposures to Therminol 66. Ethoxycoumarin O-deethylase (ECOD) was significantly induced only in animals exposed to 350 mg/m3 via inhalation. Repeated dietary and inhalation exposures resulted in AHH and ECOD induction only at the highest doses, and the kidney appeared to be less sensitive than the liver. Animals exposed via inhalation demonstrated a greater hepatic inductive effect than did animals exposed via the diet, which may be due to absorption differences.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhalation Toxicology of Trimethylamine

Abstract

Trimethylamine (TMA) is a pungent gas that occurs in nature and has many industrial applications, including use as an intermediate in the manufacture of many chemicals. The lowest lethal concentration following a single 4-h inhalation exposure was determined to be 3500 ppm. Croups of 70 male rats each were then exposed by nose-only inhalation 6 h/d, 5 d/wk for 2 wk to either 0 (control), 75, 250, or 750 ppm TMA. Rats were sacrificed either immediately following exposure or following a 14-d recovery period. Parameters investigated included in-life observations and body weights, clinical pathology, and histopathology with organ weights. Exposure to 750 ppm produced a decreased rate of weight gain in rats. Evidence of mild, reversible, polycytnemia was also seen in these rats. Effects of TMA were present in the nose, trachea, and lungs. Degenerative changes in the nose were reversible at 75 ppm, but not at 250 or 750 ppm. Mild emphysematous alveoli were seen in lungs of rats exposed to 750 ppm immediately following the exposures, but not after a recovery period. A no-observed-effect level for TMA under these test conditions was not determined, although the nasal effects seen at 75 ppm were minimal.     

Effects of ozone on lung and somatic growth. Pair fed rats after ozone exposure and recovery periods

Minor differences in lung growth and development during childhood have been considered as a potential cause of rapid decline in pulmonary function in adulthood. Inhalation of ozone commonly causes changes in both body weight and lung volumes, which complicates interpretation of any changes in lung growth. The effects of ozone on lung growth were studied in rats which were pair fed. This technique permitted comparison of ozone-exposed and filtered-air control rats of the same body weight and body size as well as age and sex. Exposure was to filtered air or to 0.64 or 0.96 ppm ozone (UV standard) 8 h/night for 42 nights. A second control group was fed ad libitum and exposed to only filtered air. Half the rats were studied at the end of the 42-night exposures, the rest after a 42-day post-exposure period during which all rats were fed ab libitum and breathed filtered air. Rats examined at the end of the exposure period had larger saline and fixed lung volumes. These larger lungs had greater volumes of parenchyma, alveoli and respiratory bronchioles. Some of these changes persisted throughout a 42-day post-exposure period. Ozone inhalation by young rats alters lung growth and development in ways likely to be detrimental and those changes persist after ozone inhalation stops.     

Radionuclide Decorporation: Matching the Biokinetics of Actinides by Transdermal Delivery of Pro-chelators

The threat of nuclear terrorism by the deliberate detonation of a nuclear weapon or radiological dispersion device (“dirty bomb”) has made emergency response planning a priority. The only FDA-approved treatments for contamination with isotopes of the transuranic elements Am, Pu, and Cm are the Ca and Zn salts of diethylenetriaminepentaacetic acid (DTPA). These injectable products are not well suited for use in a mass contamination scenario as they require skilled professionals for their administration and are rapidly cleared from the circulation. To overcome the mismatch in the pharmacokinetics of the DTPA and the biokinetics of these transuranic elements, which are slowly released from contamination sites, the penta-ethyl ester of DTPA (C2E5) was prepared and formulated in a nonaqueous gel for transdermal administration. When gels comprised of 40% C2E5, 40–45% Miglyol® 840, and 15–20% ethyl cellulose were spiked with [¹⁴C]-C2E5 and applied to rat skin; over 60% of the applied dose was absorbed within a 24-h period. Radioactivity was observed in urinary and fecal excretions for over 3 days after removal of the gel. Using an ²⁴¹Am wound contamination model, transdermal C2E5 gels were able to enhance total body elimination and reduce the liver and skeletal burden of ²⁴¹Am in a dose-dependent manner. The efficacy achieved by a single 1,000 mg/kg dose to contaminated rats was statistically comparable to intravenous Ca-DTPA at 14 mg/kg. The effectiveness of this treatment, favorable sustained release profile of pro-chelators, and ease of administration support its use following radiological emergencies and for its inclusion in the Strategic National Stockpile.     

Biopersistence of inhaled MWCNT in rat lungs in a 4-week well-characterized exposure

It is important to conduct a risk assessment that includes hazard assessment and exposure assessment for the safe production and handling of newly developed nanomaterials. We conducted an inhalation study of a multi-wall carbon nanotube (MWCNT) as a hazard assessment. Male Wistar rats were exposed to well-dispersed MWCNT for 4 weeks by whole body inhalation. The exposure concentration in the chamber was 0.37?±?0.18?mg/m³. About 70% of the MWCNTs in the chamber were single fiber. The geometric mean diameter (geometric standard deviation, GSD) and geometric mean length (GSD) of the aerosolized MWCNTs in the chamber were 63?nm (1.5) and 1.1 μm (2.7), respectively. The amounts of MWCNT deposited in the rat lungs were determined by the X-ray diffraction method and elemental carbon analysis. The average deposited amounts at 3 days after the inhalation were 68 μg/lung by the X-ray diffraction method and 76 μg/lung by elemental carbon analysis. The calculated deposition fractions were 18% and 20% in each analysis. The amount of retained MWCNT in the lungs until 3 months after the inhalation decreased exponentially and the calculated biological half times of MWCNT were 51 days and 54 days, respectively. The clearance was not delayed, but a slight increase in lung weight at 3 days after the inhalation was observed.     

Biopersistence of inhaled MWCNT in rat lungs in a 4-week well-characterized exposure

It is important to conduct a risk assessment that includes hazard assessment and exposure assessment for the safe production and handling of newly developed nanomaterials. We conducted an inhalation study of a multi-wall carbon nanotube (MWCNT) as a hazard assessment. Male Wistar rats were exposed to well-dispersed MWCNT for 4 weeks by whole body inhalation. The exposure concentration in the chamber was 0.37?±?0.18?mg/m3. About 70% of the MWCNTs in the chamber were single fiber. The geometric mean diameter (geometric standard deviation, GSD) and geometric mean length (GSD) of the aerosolized MWCNTs in the chamber were 63?nm (1.5) and 1.1 μm (2.7), respectively. The amounts of MWCNT deposited in the rat lungs were determined by the X-ray diffraction method and elemental carbon analysis. The average deposited amounts at 3 days after the inhalation were 68 μg/lung by the X-ray diffraction method and 76 μg/lung by elemental carbon analysis. The calculated deposition fractions were 18% and 20% in each analysis. The amount of retained MWCNT in the lungs until 3 months after the inhalation decreased exponentially and the calculated biological half times of MWCNT were 51 days and 54 days, respectively. The clearance was not delayed, but a slight increase in lung weight at 3 days after the inhalation was observed.     

Alveolar macrophages suppress non-specific inflammation caused by inhalation challenge with trimellitic anhydride conjugated to albumin

Occupational exposure to low molecular weight chemicals, like trimellitic anhydride (TMA), can result in occupational asthma. Alveolar macrophages (AMs) are among the first cells to encounter these inhaled compounds and were previously shown to affect TMA-induced asthma-like symptoms in the Brown Norway rat (Valstar et al., Toxicol. Appl. Pharmacology 211:20–29, 2006). TMA is a hapten that will bind to endogenous proteins upon entrance of the body. Therefore, in the present study we determined if TMA conjugated to albumin is able to induce asthma-like symptoms and if these are affected by AM depletion. Female Brown Norway rats were sensitized by dermal application of TMA or received vehicle alone on days 0 and 7. One day prior to the inhalation challenge the rats were treated intratracheally with either empty liposomes or liposomes containing clodronate (dichloromethylene diphosphonate) to specifically deplete the lungs of AMs. On day 21, all groups of rats were challenged by inhalation of TMA-BSA. Breathing frequency, tidal volume, and minute ventilation were measured before, during, within 1 h, and 24 h after challenge and the gross respiratory rate score was determined during challenge. Total and TMA-specific IgE levels were determined in serum and lung lavage fluid and parameters of inflammation and tissue damage were assessed in lung lavage fluid and/or lung tissue 24 h after challenge. Sensitization with TMA had no effect on the lung function before challenge, but TMA-BSA challenge resulted in an early asthmatic response as compared to the non-sensitized rats, irrespective of AM depletion. AM depletion had no effect on the sensitization-induced serum and lung lavage fluid IgE levels. TMA-BSA inhalation did not induce airway inflammation and tissue damage irrespective of sensitization, unless AM were depleted. Data indicate that AMs inhibit immunologically non-specific damage and inflammatory cell influx into the lungs as caused by TMA-BSA inhalation. Since effects of inhalation challenge with TMA-BSA are partly different from those of TMA, challenge with the latter is to be preferred for hazard identification.     

The influence of age on the efficiency of delayed therapy with Ca-DTPA for cerium in rats

The influence of age on the effectiveness of chelation therapy starting 24 h after cerium administration was studied in 2- and 6-week-old rats. ¹⁴¹Ce was administered IP, followed after 24 and 48 h by IP administration of trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA). The whole body and organ retention of ¹⁴¹Ce was determined 6 days after its administration. The chelation therapy significantly reduced cerium retention in both age groups but was more efficient in older animals. This age-related effect was, however, less pronounced than after immediate treatment with DTPA observed in our previous experiments, indicating that age as one of the factors which influence the efficacy of chelation treatment is probably more important in conditions of early than in conditions of delayed therapy.     

Application of the EPR spin-trapping technique to the detection of radicals produced in vivo during inhalation exposure of rats to ozone.

Ozone is known to induce lipid peroxidation of lung tissue, although no direct evidence of free radical formation has been reported. We have used the electron paramagnetic resonance (EPR) spin-trapping technique to search for free radicals produced in vivo by ozone exposure. The spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was administered ip to male Sprague-Dawley rats. The rats were then exposed for 2 hr to either 0, 0.5, 1.0, 1.5, or 2.0 ppm ozone with 8% CO2 to increase their respiratory rate. A six-line 4-POBN/radical spin adduct signal (aN = 15.02 G and a beta H = 3.27 G) was detected by EPR spectroscopy in lipid extracts from lungs of rats treated with 4-POBN and then exposed to ozone. Only a weak signal was observed in the corresponding solution from rats exposed to 0 ppm ozone (air with CO2 only). The concentration of the radical adduct increased as a function of ozone concentration. After administration of 4-POBN, rats were exposed for either 0.5, 1.0, 2.0, or 4.0 hr to either 0 or 2.0 ppm ozone (with CO2). The radical adduct concentration of the ozone-exposed groups at exposure times of 2.0 and 4.0 hr was significantly different from that of the corresponding air control groups. A correlation was observed between the radical adduct concentration and the lung weight/body weight ratio. These results demonstrate that ozone induces the production of free radicals in rat lungs during inhalation exposure and that radical production may be involved in the induction of pulmonary toxicity by ozone. This is the first direct evidence for ozone-induced free radical production in vivo.     

Short-term inhalation study of graphene oxide nanoplates

Graphene oxides possess unique physicochemical properties with important potential applications in electronics, pharmaceuticals, and medicine. However, the toxicity following inhalation exposure to graphene oxide has not yet been clarified. Therefore, this study conducted a short-term graphene oxide inhalation toxicity analysis using a nose-only inhalation exposure system and male Sprague–Dawley rats. A total of four groups (15 rats per group) were exposed: (1) control (fresh air), (2) low concentration (0.76?±?0.16?mg/m³), (3) moderate concentration (2.60?±?0.19?mg/m³), and (4) high concentration (9.78?±?0.29?mg/m³). The rats were exposed to graphene oxide for 6?h/day for 5 days, followed by recovery for 1, 3, and 21 days. No significant body or organ weight changes were noted after the short-term exposure or during the recovery period. Similarly, no significant systemic effects of toxicological importance were noted in the hematological assays, bronchoalveolar lavage fluid (BAL) inflammatory markers, BAL fluid cytokines, or blood biochemical assays following the graphene oxide exposure or during the post-exposure observation period. Moreover, no significant differences were observed in the BAL cell differentials, such as lymphocytes, macrophages, or polymorphonuclear cells. Graphene oxide-ingested alveolar macrophages as a spontaneous clearance reaction were observed in the lungs of all the concentration groups from post 1?day to post 21 days. Histopathological examination of the liver and kidneys did not reveal any significant test-article-relevant histopathological lesions. Importantly, similar to previously reported graphene inhalation data, this short-term nose-only inhalation study found only minimal or unnoticeable graphene oxide toxicity in the lungs and other organs.     

Influence of carbon monoxide on lung growth of young rats

Female rats were continuously exposed to 250 ppm carbon monoxide (CO) or to clean air as controls for 21 days. There was a significant increase in wet lung weight in the exposed animals. Since prolonged CO inhalation results in considerable tissue hypoxia, but only slight lowering of arterial pO₂ and no appreciable change in pO₂ in the lungs, tissue hypoxia remote from the lungs stimulates lung growth in addition to other mechanisms discussed in the text.     

Age-related morphometric differences in responses of rat lungs to ozone

The influence of age on morphologic changes in lungs of rats exposed to ozone was studied in female Sprague-Dawley rats, aged 60 and 444 days. Rats of both age groups were exposed continuously for 72 hr to either 0.35 or 0.80 ppm ozone, or to filtered air. Tissues were evaluated using light microscopic morphometry and scanning electron microscopy. The lungs from ozone-exposed 60-day-old rats had larger volume fractions of centriacinar lesions than lungs from exposed 444-day-old rats. Within each age group there was an observed dose response, with rats exposed to 0.80 ppm ozone having larger volume fractions of lesions than those exposed to 0.35 ppm. Only the 444-day-old rats lost body weight during the exposure period. They also had smaller fixed lung volumes than same-aged controls. All 60-day-old rats gained weight during the exposure period, although rats exposed to 0.80 ppm ozone gained less than filtered air controls. Lesions observed in both age groups of female rats were qualitatively similar to those previously described in young adult male rats. We conclude that there are age-related differences in the morphometric responses of rats to ozone exposure. Younger rats had larger proportions of centriacinar lesions and macrophages while older rats had greater body weight and lung volume changes.     

Toxic effects of selenium inhalation: acute damage of the respiratory system of mice

Accidental inhalation of selenium by humans has been associated with damage of respiratory tissues that is lacking a detailed histological definition. We have investigated the natural history of injury to the tracheal epithelium and lungs induced by a single intratracheal instillation of CD-1 mice with two different doses of dimethyl selenide (0.05 and 0.1 mg Se/kg of body weight). The animals were sacrificed 1, 7, 14, and 28 days after the single selenium treatment. Samples of the trachea and lungs were studied by light microscopy. The tracheal epithelium showed loss of cilia and acute necrosis that was followed by metaplastic transformation. Edema and diffuse alveolar damage was observed in the lungs. Our data suggest that: i) severity of respiratory lesions caused by selenium is dose dependent; ii) selenium causes transient metaplastic transformation of the tracheal epithelium; iii) chronic inflammation and increased thickness of alveolar septa occur in the lungs; iv) 4 weeks after selenium treatment, mice recover from the tracheal injury, whereas no amelioration of pulmonary lesions was observed.     

Pharmacokinetics of gentamicin administered intratracheally or as an inhalation aerosol to guinea pigs

The pharmacokinetics of gentamicin were studied after intratracheal, inhalation, and iv administration to guinea pigs. Gentamicin injected intratracheally was almost completely systemically available. The comparison of the gentamicin plasma AUCs after inhalation and iv administration showed that an inhalation exposure lasting 10 min resulted in an absorption of 1.13 mg gentamicin/kg body weight into systemic circulation. This absorbed dose was 40.4 or 67.3% of the amount of gentamicin inhaled, depending on tidal volume assumed, and 1.4% of the amount of gentamicin aerosolized. The postinhalation gentamicin concentration in the lungs decreased with a half-life of 67.3 min. The data differentiate topical pulmonary gentamicin from systemic gentamicin and give a rational basis for study of the mechanism of the therapeutic effect of gentamicin inhalation aerosol in bronchopulmonary infections.     

Beneficial effects of NTP-2000 diet on growth, survival, and kidney and heart diseases of Fischer 344 rats in chronic studies.

Diet is one of the most important environmental factors influencing growth, survival, and appearance of age-associated diseases in rodents. NIH-07 open formula rodent diet was the selected diet for the National Toxicology Program studies from 1980 to 1994. After a number of experimental diets were evaluated, a new one designated as NTP-2000 was selected for rodents in NTP studies beginning in 1994. This report summarizes the results of dosed feed and inhalation studies for differences in growth, survival, and severity of kidney and heart lesions in Fischer 344 rats fed NTP-2000 or NIH-07 diets. In the dosed feed studies, male rats group housed and fed the NTP-2000 diet grew slightly slower, attained maximum body weight later, and lost less body weight by the end of the 2-year studies compared to the groups fed NIH-07. Female rats group housed and fed the NTP-2000 diet in dosed feed studies had significantly slower growth, with lower maximum body weight compared to the groups fed the NIH-07 diet. In the inhalation studies, male rats individually housed and fed the NTP-2000 diet had slightly higher maximum body weight and significantly higher final body weight, with lower loss of weight when compared to similarly housed groups fed the NIH-07 diet. In inhalation studies, female rats fed the NTP-2000 diet and individually housed had significantly slower growth. The NTP-2000 diet significantly increased the survival of male and female rats, with a dramatic increase in survival of males in inhalation studies. This diet also caused significant decreases in severity of nephropathy and cardiomyopathy, and the decrease was marked in males. These observations indicate that diets balanced for nutrients, such as the NTP-2000, could markedly improve the health and increase survival of the rats used in chronic studies.     

Subchronic inhalation toxicity of amorphous silicas and quartz dust in rats.

The inhalation toxicity of three amorphous silicas (Aerosil 200, Aerosil R 974 and Sipernat 22S) was compared with that of quartz dust. Rats were exposed to 1, 6 or 30 mg Aerosil 200/m3, 30 mg Aerosil R 974/m3, 30 mg Sipernat 22S/m3 or 60 mg quartz/m3 for 6 hr/day, 5 days/wk for 13 wk. Some rats were killed at the end of the exposure period and some were killed 13, 26, 39 or 52 wk after the end of exposure. Clinical signs, body weight, haematology, biochemistry, urinalyses, organ weights, retention of test material in the lungs and regional lymph nodes, collagen content of the lungs, and gross and microscopic pathology were determined in order to disclose possible adverse effects and to study the reversibility, stability or progression of the effects. All test materials induced increases in lung weight, and pulmonary lesions such as accumulation of alveolar macrophages, inflammation, alveolar bronchiolization and fibrosis. In addition, rats exposed to Aerosil 200, Aerosil R 974 or quartz developed granulomatous lesions. Silicosis was observed only in quartz-exposed animals. At the end of the exposure period, Aerosil 200 and quartz had induced the most severe changes. Quartz dust was hardly cleared from the lungs and the changes in the lungs progressed during the post-treatment period, and eventually resulted in lesions resembling silicotic nodules and in one squamous cell carcinoma. Although Aerosil 200 was very quickly cleared from the lungs and regional lymph nodes, the changes in these organs were only partly reversed during the post-exposure period in rats exposed to 30 mg/m3. Aerosil R 974 and the lower levels of Aerosil 200 resulted in less severe, and mostly reversible, changes. The slightest changes were found after exposure to Sipernat 22S, notwithstanding the persistence of this silica in the lungs during the major part of the post-treatment period. The results of this study revealed that only quartz induced progressive lesions in the lungs resembling silicotic nodules. Of the amorphous silicas examined Aerosil 200 induced the most severe changes in the lungs, which only partly recovered, whereas Sipernat 22S induced the least severe, completely reversible lung changes.