Proliferative glomerulonephritis in mice induced by sea snake (Aipysurus laevis) venom.

Aipysurus laevis venom has been shown to have a direct nephrotoxic effect in mice. A single subcutaneous injection (0.075 mg/kg body wt.) of the whole venom caused acute renal tubular degeneration and proliferative glomerulonephritis. The tubular changes appeared within 1 hour and remained for at least 14 days. Mesangial proliferative glomerulonephritis developed within 3-10 days, and is characterised by mild mesangial proliferation, mesangial and glomerular basement membrane deposits. This is followed by a partial resolution and subsequent mesangial sclerosis. The exact pathogenesis of venom-induced glomerulonephritis is not clear although it may have an immunological basis similar to that seen in human poststreptococcal glomerulonephritis. It was not possible to clarify the nature of the deposits by conventional immunohistochemical stains.     

Evaluation of Genotoxicity and Reproductive Toxicity of Silicon Nanocrystals

Silicon crystal 2-5 nm nanoparticles in the form of 1-5-μ granules in water suspension were injected intraperitoneally in a single dose to male F(1)(CBA×C57Bl/6) mice or to outbred albino rats on days 1, 7, and 14 of gestation. Silicon crystal nanoparticles in doses of 5, 25, and 50 mg/kg exhibited no cytogenetic activity in mouse bone marrow cells after 24-h exposure and in doses of 5 and 25 mg/kg after 7 and 14-day exposure. A 24-h exposure to silicon nanoparticles in a dose of 5 mg/kg significantly increased DNA damage (detected by DNA comet assay) in bone marrow cells. In a dose of 50 mg/kg they considerably increased DNA damage in bone marrow and brain cells after exposure of the same duration. Silicon nanoparticles in doses of 5 and 50 mg/kg caused no genotoxic effects in the same cells after 3-h and in a dose of 5 mg/kg after 7-day exposure. Silicon crystal nanoparticles in a dose of 50 mg/kg caused death of 60-80% mice after exposure <24 h. Injected in a dose of 50 mg/kg on days 1, 7, and 14 of gestation, silicon crystal nanoparticles reduced body weight gain in pregnant rats and newborn rats at different stages of the experiment, but had no effect on other parameters of physical development of rat progeny and caused no teratogenic effects.     

Cyclosporin A-induced nephrotoxicity in the rat: Relationship to increased plasma renin activity

Cyclosporin A (CsA; 50, 100 or 150 mg/kg) was administered by gavage, daily for 4 days, to groups of normotensive rats. An additional group of animals received the drug vehicle. CsA-induced nephrotoxicity, characterized by reduced glomerular filtration rate (GFR) and urinary sodium flow, enzymuria and proximal tubular cell damage was accompanied by elevated plasma renin activity (PRA).These changes were dose-related at 50 and 100 mg/kg CsA, but were not increased by administration of 150 mg/kg. Circulating trough drug levels were related to dosage.Four days after CsA withdrawal in animals given 50 mg/kg, there was reduced nephrotoxicity and PRA had returned to normal, even though circulating CsA levels had not diminished. Rats given 100 and 150 mg/kg, however, showed no reduction in nephrotoxicity or in PRA. Hyperglycaemia was evident at 4 days in animals given 100 and 150 mg/kg CsA and persisted 4 days after drug withdrawal.There were no accompanying abnormalities in islet cell structure.Continuous administration of CsA (50 mg/kg) to rats for 14 days caused elevated PRA on day 4 but a return to normal levels by day 7. In contrast, significant GFR impairment was evident by day 7 whilst enzymuria was significantly increased from day 4 onwards.CsA nephrotoxicity in the rat is clearly associated with activation of the renin-angiotensin-aldosterone system. Possible mechanisms leading to increased renin release are discussed.     

Effects of vitamin A on doxorubicin-induced chromosomal aberrations in bone marrow cells of rats

The present study was carried out to evaluate the role of vitamin A (VA) on the induction of chromosomal aberrations (CA) in rat bone marrow cells and to investigate its modulating effect on chromosomal damage induced by doxorubicin (DXR). Wistar rats were treated with VA (7.5, 15 and 30 microg/kg body wt) once a day for 2 days by gavage before injecting DXR (90 mg/kg body wt). Rats in the control group were treated with corresponding doses of water and olive oil. Animals treated with the medium dose of VA (15 microg/kg body wt) plus single dose of DXR presented a statistically significant reduction in total number of CA and in number of abnormal metaphases (P < 0.05). However, when compared with control and DXR groups, the low and high VA doses (7.5 and 30 microg/kg body wt) were found to be less efficient than the medium dose VA (15 microg/kg body wt) in terms of parameters analyzed. Furthermore, the high dose of VA group (30 microg/kg body wt) was found to be clastogenic (P < 0.05). This study concludes that the protective effect of VA against chromosome damage is dose dependent.     

Anticonvulsant Activity of Extracts of Diospyros Fischeri Stem Bark

Evaluation of extracts of Diospyros fischeri Gurke (Ebenaceae), which is used traditionally for the treatment of epilepsy shows that the aqueous extract of the tem bark has no effect againstpicrotoxin induced convulsions in mice. However, an 80% ethanol extract of the bark caused dose-dependent suppression of convulsions induced by 10 mg/kg body wt picrotoxin, at doses between 100–3200 mg/kg body wt. Petroleum ether, 1:1 dichloromethane:methanol, and methanol extracts also suppressed picrotoxin-induced convulsions, but had a slightly lower inhibitory effect. The petroleum ether extract was the most active, but all were less active than the ethanol extract. Unlike phenobarbitone, which at 50 mg/kg body wt completely suppressed convulsions induced by 10 mg/kg body wt picrotoxin, none of the plant extracts completely suppressed convulsions in the mice. These results support the traditional uses of D.fischeri for the treatment of epilepsy. Given the seemingly innocuous nature of the extracts more work is suggested to ascertain their clinical application.     

Tobramycin-induced changes in renal histology of fetal and newborn Sprague-Dawley rats.

Effects on renal development were studied using tobramycin (TBM) as a model compound. Pregnant Sprague-Dawley rats were injected i.p. with TBM at 30 or 60 mg/kg body weight/day on gestational days (GD) 10-19. Kidneys from dams and conceptuses were examined on GD 20 and on postnatal day (PD) 9. The dosing regimen caused in dams moderate proximal tubular alterations and increased concentrations in serum creatinine. Fetal kidneys showed granularity and swelling of proximal tubule cells at the 30 mg/kg dose, poor glomerular differentiation at the 60 mg/kg dose, increased glomerular density at both doses, and no changes on macroscopic examination at either dose. In newborns were observed a moderate developmental delay and tubular lesions at the higher dose, and dose-related increases of glomerular density and relative medullary area at both doses. All findings were more pronounced in males. A maturational disruption of the tubular structures possibly leading to increased glomerular density was attributed to TBM exposure during renal organogenesis in the rat.     

Effect of prolonged saline loading on HgCl2-induced renal tubular damage

Male Porton-Wistar rats, 32 weeks old, were given i.p. one of the following doses of HgCl2; 0.5, 1.0 or 1.5 mg Hg/kg. In the preceding 4-week period and throughout the experiment the animals had free access to either tap water or 1.0% saline. The urinary excretion of alkaline phosphatase measured in urine samples, collected during the first 24 h after treatment with mercury, indicated that chronic saline loading significantly attenuated tubular damage caused by 0.5 mg or 1.0 mg Hg/kg, but not by 1.5 mg Hg/kg. Tubular necrosis 12 and 24 h after mercury was also less severe and extensive in saline than in tap water-drinking rats. This difference was still noticeable 4 days after mercury treatment in rats dosed with 0.5 mg Hg/kg, but death in the two higher dose groups prevented further pair-to-pair histological comparison. At the selected dose levels chronic saline loading did not decrease renal mercury content at 12 or 24 h and therefore protection was not associated with decrease in renal mercury uptake. The experiment indicates that chronic saline drinking, which at higher doses attenuates HgCl2-induced acute renal failure but not tubular necrosis, is able to moderate the severity of tubular necrosis when the dose of HgCl2 is as low as 0.5 mg Hg/kg. This protective effect diminishes as the dose is increased.     

Analgesic nephropathy in Fischer 344 rats: comparative effects of chronic treatment with either aspirin or paracetamol.

This study has compared the relative nephrotoxicity of chronic treatment with aspirin or paracetamol in an animal model. Changes in renal structure and urinary concentrating ability were examined in female Fischer 344 rats after continuous treatment with either aspirin (120-230 mg/kg body wt/day), or paracetamol (140-210 mg/kg body wt/day), and were compared with age-matched untreated control rats. Renal morphological changes were examined after 40-83 weeks of analgesic treatment, using light and electron microscopy. Aspirin caused renal papillary necrosis and a decrease in urinary concentrating ability, whereas paracetamol alone did not cause significant renal damage. Aspirin produced damage to the interstitial cells and matrix, particularly in the mid-papillary region, followed by changes to the thin limbs of the loop of Henle and medullary capillary endothelium. These structural changes were similar to those described previously, when continuous treatment with combined aspirin and paracetamol was studied in the same animal model.     

Effect of prolonged saline loading on HgCl2-induced renal tubular damage.

Male Porton-Wistar rats, 32 weeks old, were given i.p. one of the following doses of HgCl2; 0.5, 1.0 or 1.5 mg Hg/kg. In the preceding 4-week period and throughout the experiment the animals had free access to either tap water or 1.0% saline. The urinary excretion of alkaline phosphatase measured in urine samples, collected during the first 24 h after treatment with mercury, indicated that chronic saline loading significantly attenuated tubular damage caused by 0.5 mg or 1.0 mg Hg/kg, but not by 1.5 mg Hg/kg. Tubular necrosis 12 and 24 h after mercury was also less severe and extensive in saline than in tap water-drinking rats. This difference was still noticeable 4 days after mercury treatment in rats dosed with 0.5 mg Hg/kg, but death in the two higher dose groups prevented further pair-to-pair histological comparison. At the selected dose levels chronic saline loading did not decrease renal mercury content at 12 or 24 h and therefore protection was not associated with decrease in renal mercury uptake. The experiment indicates that chronic saline drinking, which at higher doses attenuates HgCl2-induced acute renal failure but not tubular necrosis, is able to moderate the severity of tubular necrosis when the dose of HgCl2 is as low as 0.5 mg Hg/kg. This protective effect diminishes as the dose is increased.     

Testis response to low doses of cadmium in Wistar rats

Although it is well known that cadmium (Cd) causes adverse effects on male rat reproductive organs, few studies have quantified alterations caused by its low doses. Quantification of these alterations, especially in the testis, was measured using morphometry. A single dose of cadmium chloride (1 or 1.2 mg/kg BW) was injected i.p. in adult rats, killed after 7 or 56 days. The lower dose caused slight alterations as measured by morphometrical analysis. The higher dose caused significant reduction in testis and epididymis weight, gonadossomatic index and length of seminiferous tubule (ST) after 7 and 56 days. Cadmium significantly reduced the ST diameter after 56 days. Decreased volume density of ST, after 7 and 56 days, was accompanied by an increase in interstitium volume density. The damage caused by the dose of 1.2 mg/kg can be clearly observed with light microscope. After 7 days, the tubule lumens were filled with degenerated germ cells and multinucleated spermatid aggregates. Vacuolization of the seminiferous epithelium was also observed. After 56 days, increased damage resulted in vacuolated ST, consisting only of Sertoli cells. Scanning electron microscopy examination of the testis showed that, in the group cadmium treated (1.2 mg/kg) and killed after 56 days, the interstitial tissue presents a compact and fibrous appearance with absence of fenestrae. The seminiferous epithelium height diminished and the absence of spermatozoa can be noted. The results show that a very small difference of Cd dose causes a sudden increase in testicular damage, apparently overpowering this tissue’s natural defences.     

Therapeutic effects of estradiol benzoate on development of collagen-induced arthritis (CIA) in the Lewis rat are mediated via suppression of the humoral response against denatured collagen type II (CII)

The effects of estradiol benzoate (EB) on the development of anti-CII antibodies and their pathogenic potential were studied during the progress of established CIA in the rat. CIA was induced in mature female Lewis rats by two subcutaneous inoculations containing bovine native CII (BCIIn), emulsified in Freund's incomplete adjuvant. Clinical arthritis fully developed by day 18 and then EB (1 mg/kg body wt per day, diluted in corn oil (CO)) was administered intramuscularly every second day thereafter. Antibodies binding four different CIIs (bovine or rat, either native or heat-denatured) were detected in sera and joint tissue extracts by means of solid-phase ELISA. Pharmacological doses of EB (>0·2 mg/kg body wt per day) caused significant remission of established CIA 5-7 days after treatment, and selectively suppressed the production of antibodies specific for denatured CII. To evaluate the arthritogenic potential of circulating anti-CIId IgG, transfer experiments were performed. IgG anti-CIIn, purified from EB-treated CIA rats, was not arthritogenic, whereas IgG anti-denatured (CIId), purified from CO-treated CIA rats, caused severe passive arthritis. Furthermore, pretreatment with rat CIId protected against subsequent induction of CIA, and this protection was associated with suppressed antibody production against CIId. Collectively, our results indicate that antibodies specific for CIId are involved in the pathogenesis of CIA, and that oestrogen-related remission of clinical arthritis may be caused by a selective suppression of antibodies produced against degraded/denatured CII.     

Cisplatin-induced nephrotoxicity causes altered renal hemodynamics in Wistar Kyoto and spontaneously hypertensive rats: Role of augmented renal alpha-adrenergic responsiveness

The pathogenesis of cisplatin-induced renal failure is related to reduced renal blood flow due to severe tubular damage and enhanced renovascular resistance. It is also known that alpha(1)-adrenoceptors, the major subtype of alpha-adrenoceptors in renal vasculature play the pivotal role in regulating renal hemodynamics. With this background, we have hypothesized that the altered renal hemodynamics and enhanced renovascular resistance in cisplatin-induced renal failure might be caused by the altered alpha-adrenergic responsiveness with a possible involvement of alpha(1)-adrenoceptors in the renal vasculature. In a unique experimental approach with anesthetized rats, this study has therefore examined if there is any shift in the renovascular responsiveness to renal nerve stimulation and a series of alpha-adrenergic agonists in Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats with cisplatin-induced renal failure in comparison with their body weight-matched normal controls. Thirty-two male rats of both WKY (n=16) and SHR (n=16) origin with body weight 236+/-7.9 g received cisplatin (5mg/kg i.p.). The renal failure was confirmed in terms of significantly reduced renal blood flow, reduced creatinine clearance, increased fractional excretion of sodium, increased kidney index (all P<0.05) and tubular damage. After 7 days of cisplatin, the overnight fasted rats were anesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and renal vasoconstrictor experiments were done. The changes in the vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by electrical renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine and methoxamine. It was observed that in the cisplatin-treated renal failure WKY and SHR rats there were significant (all P<0.05) reductions in the renal blood flow along with significantly (P<0.05) higher renal adrenergic responsiveness as compared with their non-renal failure controls. The data showed that in the renal failure WKY and SHR rats, the altered renal hemodynamics might be caused by an augmented renal adrenergic responsiveness. The results obtained further led us to suggest that the augmented renal adrenergic responsiveness in the cisplatin-induced renal failure rats were possibly mediated by the alpha(1)-adrenoceptors.     

Tubular kidney damage and centrilobular liver injury after intratracheal instillation of dimethyl selenide

Accidental inhalation of selenium (Se) derivatives, such as dimethyl selenide (DMSe), has been associated with damage of respiratory tissues. However, systemic effects of inhaled Se have not been thoroughly established. We have investigated whether mouse kidney and liver show cellular pathology as a result of a single intratracheal instillation of two different doses of DMSe (0.05 and 0.1 mg Se/kg BW). The animals were sacrificed 1, 7, 14, and 28 days after either 1 of the 2 DMSe treatments; samples were studied by light microscopy. Instillation of the low DMSe dose resulted in acute and transient tubular disease of the kidney expressed by swelling and vacuolation of epithelial cells of proximal tubules; in some mice, tubular necrosis was observed. After 14 days of the DMSe treatment, these lesions were ameliorated and, by day 28, the kidney tubular epithelium depicted a normal morphology. The same low dose of DMSe caused sustained damage to centrilobular hepatocytes characterized by swollen and vacuolized liver cells. After the instillation of the high DMSe dose, the mice presented sustained liver and kidney focal necrosis. Our data suggest that inhalation of DMSe results in: (i) acute tubular injury of the kidney and damage to centrilobular liver cells and (ii) this systemic pathology induced by DMSe is a dose-dependent phenomenon.     

Chlorpyrifos-induced DNA damage in rat liver and brain

Chlorpyrifos (O,O'-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothionate, CPF) is a broad spectrum organophosphate pesticide used to control a variety of pests. The present study was undertaken to test the in vivo genotoxic potential of CPF in rats, using the single cell gel electrophoresis (or comet) assay. The rats were administered 50 mg and 100 mg CPF/kg body weight daily for 1, 2, and 3 days as well as 1.12 mg and 2.24 mg CPF/kg body weight for 90 days. The level of DNA damage was estimated by scoring 100 cells per animal, dividing into five types: types 0, I, II, III, and IV. The results clearly indicate that exposure to CPF, acutely or chronically, caused a dose-dependent increase in DNA damage in the liver and brain of rats. From the present study, it can be concluded that CPF exhibits genotoxic potential in vivo.     

The effects of 11-deoxycorticosterone and antidiuretic hormone (pitressin) on fluid exchange and electrolyte excretion by normal and starved polyuric-polydipsic rabbits

Summary The effects of 11-deoxycorticosterone (DOC) and antidiuretic hormone (pitressin) (ADH) on fluid exchange and Na⁺ excretion have been studied in normal rabbits and in rabbits showing a typical polyuric-polydipsic response to 4 days starvation. DOC (0.5 mg/kg body wt/day i.m. during 4 days starvation) significantly reduced total Na⁺ excretion to 48% (mean) of the level observed over 4 days starvation alone, while water intake and urine output volumes fell to 71% and 73% of their previous values respectively. ADH (0.1 units/kg body wt/day i.m. during 4 days starvation) caused water intake and urine output to fall to 55% and 44% of the levels observed during starvation alone, whithout significantly affecting Na⁺ output. These occurrences were correlated with the gradients of [Na⁺], [K]⁺, [urea] and hydration in renal tissue at the end of 4 day periods. Similar observations were made on groups of rabbits which failed to show a polyuric-polydipsic response. The findings are interprected in terms of metabolic, endocrine and physical factors likely to affect tubular function and Na⁺ output during starvation and polyuria-polydipsia.     

Tissue injury and repair in the rat kidney after exposure to cisplatin or carboplatin

Cisplatin (cis-diamminedichloroplatinum II) has emerged as an anticancer drug of considerable value for the chemotherapy of several human neoplasms. However, this agent often causes renal toxicity, which appears to be the dose-limiting untoward effect. The present animal study was undertaken to compare, with regard to kidney injury and renal tissue repair, cisplatin and carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II), a platinum derivative more recently introduced in clinics. Female Sprague-Dawley rats (four animals per group) were treated ip with cisplatin (4 or 8 mg/kg, delivered in four consecutive daily injections) or carboplatin (40 mg/kg given in one injection) and terminated 4, 7, and 21 days after drug administration. One hour prior to sacrifice, each animal received ip 200 microCi of [3H]thymidine for the measurement of DNA synthesis and cell proliferation (frequency of S-phase cells in renal tissue, determined by histoautoradiography). Cisplatin, particularly at 8 mg/kg, caused severe tubular injury (acute tubular necrosis) culminating in a long-lasting cystic tubular dilatation in the outer stripe of outer medulla. Tubular damage was followed by a sharp proliferative response, indicative of tubular regeneration. However, the proliferative activity was still above basal level at the end of the observation period, suggesting that the tissue repair process had not reached completeness 3 weeks after cisplatin administration. In contrast, carboplatin only induced focal tubular necrosis in proximal tubules. Distal and collecting tubules also showed ultrastructural evidence of hydropic degeneration after exposure to the latter drug. Renal tubular injury associated with carboplatin was followed by a mild proliferative response. From this study, we can infer that carboplatin is less nephrotoxic than cisplatin, but still causes histopathological alterations in renal tissue. Furthermore, the lesser nephrotoxicity of carboplatin has a primary origin and is not due to a more efficient tissue repair reaction.     

Dexamethasone’s influence on tyrosine hydroxylase activity in the chemoreflex pathway and on the hypoxic ventilatory response

 Catecholamines have been implicated in neuromodulation of peripheral chemosensitivity and central respiratory mechanisms. Because glucocorticoids can affect catecholamine metabolism in the carotid body and brainstem, this study explored the possibility that, in rats, dexamethasone or adrenalectomy affects catecholamine biosynthesis in carotid body chemoreceptors and the medullary areas (A2C2, A5, A6, A7) involved in the chemoreflex pathway and the hypoxic ventilatory response (HVR). One dexamethasone injection (1 mg/kg body wt.) stimulated tyrosine hydroxylase activity in the carotid body and had no effect in brainstem catecholamine areas, while HVR was reduced. Chronic dexamethasone (1 mg/kg body wt. daily for 10 days) had a stimulatory influence on tyrosine hydroxylase activity in the carotid body and an inhibitory effect on A2C2, A5 and A7 cell groups. Breathing pattern, but not HVR, was altered. Adrenalectomy elicited an increase in tyrosine hydroxylase activity in A2C2, which was accompanied by a decreased respiratory frequency in hypoxia. The data show that glucocorticoids have differential effects on catecholamine biosynthesis in peripheral and central structures involved in the chemoreflex pathway. Depending on the treatment, the neurochemical changes were accompanied by alterations of HVR or the breathing pattern, which are consistent with a neuromodulating influence of catecholamines on peripheral chemosensory inputs or the central respiratory network. Received: 25 September 1997 / Received after revision: 9 December 1997 / Accepted: 16 December 1997     

Ameliorating effect of vitamin C on murine sperm toxicity induced by three pesticides (endosulfan, phosphamidon and mancozeb)

The ameliorating effect of vitamin C (injected intraperitoneally)was evaluated against changes in sperm count and sperm headmorphology in mice fed either 3, 6 or 1000 mg/kg body wt/dayendosulfan, phosphamidon or mancozeb, respectively. The animalsreceived aqueous preparations of the pesticides and/or vitaminC once daily for 35 consecutive days. All three pesticides,irrespective of their chemical nature, significantly decreasedthe sperm count, as well as increased the frequency of spermwith aberrant head morphology. Out of the three doses of vitaminC used the middle and higher ones (20 and 40 mg/kg body wt/day,respectively) afforded comparatively more significant amelioration.The lower dose (10 mg/kg body wt/day) of this vitamin (quantitativelyequivalent to the human therapeutic dose according to body weight)was least efficacious in both the tests. However, ameliorationwas never up to the control level in any case. Vitamin C doses,when administered alone, did not produce any adverse effecton sperm count and sperm head morphology. ¹To whom correspondence should be addressed     

The Enhancement of Paraquat Toxicity in Rats by 85% Oxygen: Lethality and Cell-Specific Lung Damage

When rats were dosed s.c. with paraquat or diquat and then exposed to air or 85% oxygen, the lethality of paraquat was enhanced approximately 10-fold by 85% oxygen exposure, whereas the lethality of diquat was enhanced only 2-fold. This increase in toxicity was not caused by an increase in the lung concentration of either bipyridyl.The lungs of rats which had been dosed with paraquat (2·5 and 20 mg/kg) or diquat (10 and 20 mg/kg) and exposed to air or 85% oxygen were examined morphologically at various times up to 24 h after dosing. By 24 h after dosing, the extent of damage appeared to be generally similar for those doses of paraquat that killed the same proportion of animals when combined with air or 85% oxygen. The combination of 20 mg paraquat/kg and air exposure caused alveolar epithelial Type I and Type II cell damage. Following 2·5 mg paraquat/kg and 85% oxygen exposure or 20 mg diquat/kg and 85% oxygen exposure the Type II alveolar epithelial cells were more severely damaged than the Type I epithelial and endothelial cells. In contrast, there was no cell damage after 1 or 2 days of exposure to 85% oxygen alone, and when lung damage did develop after 4 days of exposure, it was the capillary endothelial cells which were primarily affected. Thus the toxic effects of paraquat to the Type II alveolar epithelial cells are enhanced by exposure to oxygen.The ability of the lung to accumulate paraquat was measured in lung slices that had been taken from rats dosed with paraquat or diquat and exposed to air or 85% oxygen for 2, 8 or 24 h. Paraquat accumulation was inhibited at times after dosing when the alveolar epithelial cells appeared to be damaged. This is consistent with the hypothesis that paraquat is primarily accumulated by the alveolar epithelial cells.We have concluded that (i) the toxic effects of paraquat to the alveolar epithelial cells of the lung are markedly enhanced when paraquat-treated rats are exposed to 85% oxygen, and (ii) the combination of low concentrations of paraquat (2·5 mg/kg) and 85% oxygen or high concentrations of diquat (20 mg/kg) and 85% oxygen damages the Type II alveolar epithelial cells.