Fundamental and Applied Toxicology (Fund Appl Toxicol )

Publisher: Society of Toxicology (U.S.)

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This journal is no longer published by Academic Press

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  • Website
    Fundamental and Applied Toxicology website
  • Other titles
    Fundamental and applied toxicology (Online), Fundamental and applied toxicology
  • ISSN
    0272-0590
  • OCLC
    36980446
  • Material type
    Document, Periodical, Internet resource
  • Document type
    Internet Resource, Computer File, Journal / Magazine / Newspaper

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: This symposium focused on the research which documents benefit and toxicity in beta-carotene supplementation. Reflecting on past and current studies, the panel of experts discussed: (1) the potential harm of a high intake of beta-carotene on selected populations, (2) biochemical antioxidant/prooxidant mechanisms of beta-carotene at the cellular level, (3) potential benefits of other carotenoids and antioxidants, and (4) future directions for research in beta-carotene and other antioxidants.
    Fundamental and Applied Toxicology 01/1998; 40(2):163-74.
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    ABSTRACT: Methyl tert -butyl ether (MTBE) is a widely used gasoline oxygenate. Two other ethers, ethyl tert -butyl ether (ETBE) and tert -amyl methyl ether (TAME), are also used in reformulated gasoline. Inhalation is a major route for human exposure to MTBE and other gasoline ethers. The possible adverse effects of MTBE in humans are a public concern and some of the reported symptoms attributed to MTBE exposure appear to be related to olfactory sensation. In the present study, we have demonstrated that the olfactory mucosa of the male Sprague-Dawley rat possesses the highest microsomal activities, among the tissues examined, in metabolizing MTBE, ETBE, and TAME. The metabolic activity of the olfactory mucosa was 46-fold higher than that of the liver in metabolizing MTBE, and 37- and 25-fold higher, respectively, in metabolizing ETBE and TAME. No detectable activities were found in the microsomes prepared from the lungs, kidneys, and olfactory bulbs of the brain. The observations that the metabolic activity was localized exclusively in the microsomal fraction, depended on the presence of NADPH, and was inhibitable by carbon monoxide are consistent with our recent report on MTBE metabolism in human and mouse livers (Hong et al., 1997) and further confirm that cytochrome P450 enzymes play a critical role in the metabolism of MTBE, ETBE, and TAME. The apparent K m and V max values for the metabolism of MTBE, ETBE, and TAME in rat olfactory microsomes were very similar, ranging from 87 to 125 μM and 9.8 to 11.7 nmol/min/mg protein, respectively. Addition of TAMIE (0.1 to 0.5 mM) into the incubation mixture caused a concentration-dependent inhibition of the metabolism of MTBE and ETBE. Coumarin (50 μM) inhibited the metabolism of these ethers by approximately 87%. Further comparative studies with human nasal tissues on the metabolism of these ethers are needed in order to assess the human relevance of our present findings.
    Fundamental and Applied Toxicology 01/1998;
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    ABSTRACT: Nitroaromatic musks, including musk ketone (MK; 2,6-dimethyl-3,5-dinitro-4-t-butylacetophenone), are chemicals used as perfume ingredients in household products, cosmetics, and toiletries. Musk xylene (MX; 1,3,5-trinitro-2-t-butylxylene), another nitromusk, is not genotoxic but has been reported to produce mouse liver tumors in a chronic bioassay. In addition, MX has been shown to both induce and inhibit mouse liver cytochrome P450 2B (CYP2B) isozymes. The ability of MX to inhibit CYP2B enzyme activity is attributable to inactivation of the enzyme by a specific amine metabolite. MK is structurally similar to MX, but lacks the nitro substitution that is reduced to the inactivating amine metabolite. Therefore, we hypothesized that MK would induce, but not inhibit, CYP2B isozymes. To test this hypothesis, and to evaluate the effects of MK on mouse liver cytochrome P450 enzymes, two sets of experiments were performed. To evaluate the ability of MK to induce cytochromes P450, mice were dosed daily by oral gavage at dosages ranging from 5 to 500 mg/ kg MK for 7 days. This treatment resulted in a pleiotropic response in mouse liver, including increased liver weight, increased total microsomal protein, and centrilobular hepatocellular hypertrophy. At the highest dose tested, MK caused a 28-fold increase in CYP2B enzyme activity and a small (approximately 2-fold) increase in both cytochromes P450 1A and 3A (CYP1A and CYP3A) enzyme activities over control levels. Protein and mRNA analyses confirmed the relative levels of induction for CYP2B, CYP1A, and CYP3A. In addition, the no-observable-effect level (NOEL) for CYP2B induction by MK was 20 mg/kg. To evaluate the ability of MK to inhibit phenobarbital-induced CYP2B activity, mice were given 500 ppm phenobarbital (PB) in the drinking water for 5 days to induce CYP2B isozymes, followed by a single equimolar (0.67 mmol/kg) oral gavage dose of either MK (198 mg/kg) or MX (200 mg/kg), and microsomes were prepared 18 h later. While MX inhibited more than 90% of the PB-induced CYP2B activity in the microsomes, MK caused only a small (about 20%) reduction in PB-induced CYP2B enzyme activity. These results indicate that, like MX. MK is a PB-type inducer of mouse liver CYP2B isozymes, but unlike MX, MK does not effectively inhibit PB-induced CYP2B enzyme activity.
    Fundamental and Applied Toxicology 01/1998; 40(2):264-71.
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    ABSTRACT: Triglyceride-containing lipid emulsions have been designed as caloric sources that can be administered intravenously to patients that cannot meet their nutritional needs by conventional parenteral therapies. In their study, we evaluate the developmental toxicity of a 20% lipid emulsion that contains a 3:1 ratio of medium chain triglyceride (MCT) to one long chain containing lipid emulsion (LCT). This emulsion was administered by intravenous infusion to rats and rabbits at dosages of 1 and 4.28 g lipid/kg body weight (g lipid/kg) at dose volumes of 5 and 21.4 mL/kg, respectively, once daily during organogenesis to assess the potential developmental toxicity of the test article. The control group received 0.9% saline at a dose volume of 21.4 mL/kg. Animals were observed for clinical signs of toxicity and adverse effects on body weights and feed consumption. On Day 20 (rats) or Day 29 (rabbits), females were necropsied and examined for maternal and embryo/fetal toxicity. Fetuses were removed, weighed, and examined for external, soft tissue, and skeletal abnormalities. Dosages of 4.28 g lipid/kg resulted in lower feed consumption for rats and rabbits, an expected finding based on the high-caloric nature of the test article. Potentially test article-related gross necropsy findings, including enlarged lymph nodes and spleen, small thymus, and enlarged renal pelvis, for rats given 4.28 g lipid/kg were present at a low incidence. There were no adverse effects on fetal parameters for rats even in the presence of some maternal toxicity. However, embryo and fetal toxicity (i.e., resorptions) and skeletal abnormalities were present for rabbits given 4.28 g lipid/kg. Under the conditions of this study, the no-observable-effect level for developmental toxicity was greater than or equal to 4.28 g lipid/kg for rats and greater than or equal to 1 g lipid/kg but less than 4.28 g lipid/kg for rabbits.
    Fundamental and Applied Toxicology 01/1998; 40(2):185-90.
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    ABSTRACT: The proposed Neurotoxicity Risk Assessment Guidelines (U.S. EPA, 1995c Fed Reg. 60(192), 52032–52056) of the U.S. Environmental Protection Agency (EPA) were the subject of a workshop at the 1997 Meeting of the Society of Toxicology. The workshop considered the role of guidelines in the risk assessment process, the primary features, scientific basis, and implications of the guidelines for EPA program offices, as well as for industrial neurotoxicologists from the perspectives of both pesticides and toxic substances regulation. The U.S. National Academy of Sciences (NAS, 1983, Risk Assessment in the Federal Government: Managing the Process) established a framework for distinguishing risk management from risk assessment, the latter being the result of integrating hazard identification, hazard characterization, and exposure assessment data. The guidelines are intended to establish operating principles that will be used when examining data in a risk assessment context. The proposed neurotoxicity risk assessment guidelines provide a conceptual framework for deciding whether or not a chemically induced effect can be considered to be evidence of neurotoxicity. Topics in the proposed guidelines include structural and functional effects, dose-response and duration considerations, and relationships between effects. Among the issues that must be considered are the multiplicity of chemical effects, the levels of biological organization in the nervous system, and the tests, measurements, and protocols used. Judgment of the adversity of an effect depends heavily on the amount and types of data available. The attribution of a chemically induced effect to an action on the nervous system depends on several factors such as the quality of the study, the nature of the outcome, dose-response and time-response relationships, and the possible involvement of nonneural factors. The guidelines will also serve as a reference for those conducting neurotoxicity testing, as well as establish a consistent approach to neurotoxicity risk assessment by regulators. Extending this approach through international harmonization would be advantageous to the development of products for a worldwide market. Thus, both risk assessors and regulated industries have a large stake in the guidelines to provide a framework that will lead to accurate risk assessment decisions.
    Fundamental and Applied Toxicology 01/1998;
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    ABSTRACT: Tributyl phosphate (TBP) produces tumors of the bladder urothelium in rats at high doses (700 and 3000 ppm), with greater effects in males than in females. TBP does not produce tumors in mice and it is nongenotoxic. The dose response of TBP effects on urine and urothelium was evaluated in male Sprague-Dawley rats at 0, 200, 700, and 3000 ppm of the diet, 10 rats per group, for 10 weeks. Another group received 3000 ppm TBP plus 12,300 ppm NH4Cl to evaluate the effect of urinary acidification. An additional group of 10 rats received 12,300 ppm NH4Cl. A high-dose recovery group (10 weeks 3000 ppm TBP, then 10 weeks control diet) was included to evaluate reversibility. Urine chemistries for control and TBP-treated animals were similar except for a slight decrease in osmolality and creatinine at the highest dose. Scanning electron microscopic examination of the urine of TBP-treated rats showed no increased or abnormal crystalluria, urinary precipitate, or calculi. The urothelial effects were seen at the two highest doses, but were most severe at 3000 ppm TBP, with ulceration and hemorrhage into the bladder lumen and consequent diffuse papillary and nodular hyperplasia. Dietary NH4Cl acidified the urine but did not prevent the urothelial toxicity and regeneration. The bladder epithelial changes were reversible, but the ulcer repair process was accompanied by submucosal fibrosis. TBP at high doses appears to produce urothelial cytotoxicity with marked regenerative hyperplasia which is reversible upon withdrawal of treatment. The cytotoxicity is likely due to the direct effect of TBP or its metabolites rather than an indirect consequence of urinary changes.
    Fundamental and Applied Toxicology 01/1998; 40(2):247-55.
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    ABSTRACT: Our laboratory has developed a method of intratracheal inhalation whereby rats can be exposed to high aerosol concentrations, resulting in high lung particle burdens in a short time period with deposition occurring directly in the lower respiratory tract, thus avoiding many drawbacks of larger nose-only or whole body inhalation systems. In this report, we compare the response of rats exposed by intratracheal inhalation to "fine" (approximately 250 nm) and "ultrafine" (approximately 21 nm) titanium dioxide particles with rats exposed to similar doses by intratracheal instillation. Animals receiving particles through inhalation showed a decreased pulmonary response, measured by bronchoalveolar lavage parameters, in both severity and persistence, when compared with those receiving particles through instillation. These results demonstrate a difference in pulmonary response to an inhaled vs an instilled dose, which may be due to differences in dose rate, particle distribution, or altered clearance between the two methods.
    Fundamental and Applied Toxicology 01/1998; 40(2):220-7.
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    ABSTRACT: Primary hepatocyte cultures prepared from male beagle dog liver were used to determine susceptibility of the canine liver to tetracycline-induced steatosis. The effects of the drug on mitochondrial lipid metabolism and intracellular triglyceride accumulation were monitored at the same time that steatosis was detected by light microscopy and quantitated using lipid-specific stains. Exposure of primary canine hepatocyte cultures to tetracycline for 24-48 h resulted in concentration-dependent, significant increases in the Oil Red O-stained lipid inclusions. Microscopic examination of the total stained areas suggested that increases over control levels were due primarily to the increase in the size of the lipid inclusions rather than in the number. Biochemical analyses for triglyceride content and histological staining with Nile red, another neutral lipid-specific dye, confirmed a specific increase in intracellular triglyceride following a 24-h exposure to noncytotoxic levels of tetracycline beta-oxidation studies based on the oxidation of [14C]palmitic acid or [14C]palmitoyl carnitine demonstrated a concentration-dependent inhibition of mitochondrial but not peroxisomal beta-oxidation in hepatocytes after a 24-h exposure to tetracycline. In vitro incubation of tetracycline with mitochondria isolated from dog liver showed similar concentration-dependent inhibition. This study clearly indicates that the canine hepatocyte is susceptible to tetracycline-induced steatosis. Triglyceride accumulation was concomitant with the inhibition of mitochondrial lipid metabolism, indicating that this is a primary mechanism leading to steatosis in dog hepatocytes following tetracycline exposure.
    Fundamental and Applied Toxicology 01/1998; 40(2):256-63.
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    ABSTRACT: Tributyl phosphate (TBP) was tested for reproductive toxicity in rats. Thirty weanlings/sex (F0) were exposed to TBP in the diet ad libitum at 0, 200, 700, or 3000 ppm for 10 weeks and then randomly mated within groups for 3 weeks with continued exposure. F0 parents and 10 F1 weanlings/sex/dose were necropsied, and adult reproductive organs, urinary bladders (both sexes), kidneys (males), and livers (females) were evaluated histologically. Thirty F1 weanlings/sex/dose continued exposure for 11 weeks and were bred as described above. F1 parents and F2 weanlings, 10/sex/dose, were then necropsied as described above. Adult toxicity was observed in both sexes and generations at 700 and 3000 ppm; observations included reduced body weights, weight gain and feed consumption, urinary bladder epithelial hyperplasia (both sexes), renal pelvis epithelial hyperplasia only at 3000 ppm (male kidneys), and centrilobular hypertrophy (female livers). At 200 ppm, transient reductions in body weight were observed in F0 and F1 females, with urinary bladder epithelial hyperplasia in F0 males and females and in F1 males. There was no evidence of reproductive toxicity, of reproductive organ pathology, or of effects on gestation or lactation at any dose tested. Postnatal toxicity was evidenced by consistent reductions in F1 and F2 pup body weights at 3000 ppm and by occasional weight reductions in F2 litters at 700 ppm, and was associated with maternal toxicity observed at these doses and times. Under the conditions of this study, a NOAEL was not determined for adult toxicity; the NOAEL for reproductive toxicity was at least 3000 ppm and the NOAEL for postnatal toxicity was approximately 200 ppm.
    Fundamental and Applied Toxicology 12/1997; 40(1):90-100.
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    ABSTRACT: While considerable research has focused on the neurotoxicity of developmental exposures to polychlorinated biphenyls, including Aroclor 1254, relatively little is known about exposures in adult animals. This study investigated the behavioral effects of acute and repeated Aroclor 1254 exposures to adult rats on motor activity and flavor aversion conditioning. Male Long-Evans rats (60 days old) were tested for motor activity in a photocell device after acute (0, 100, 300, or 1000 mg/kg, po) or repeated (0, 1, 3, 10, 30 or 100 mg/kg/day, po, 5 days/week for 4 to 6 weeks) exposure to Aroclor 1254. Motor activity was decreased dose-dependently at doses of 300 mg/kg or more after acute exposure. Severe body weight loss and deaths occurred at 1000 mg/kg. Recovery of activity occurred over 9 weeks but was incomplete. After repeated exposure, motor activity was decreased dose-dependently at doses of 30 mg/kg or more, and severe weight loss and deaths occurred at 100 mg/kg. In contrast to acute exposure, complete recovery of activity occurred 3 weeks after exposure. Additional rats were water deprived (30 mm/day) and received acute po administration of Aroclor 1254 (0, 10, 15, 25, 30, 100, or 300 mg/kg) shortly after consuming a saccharin solution. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. Saccharin preference was decreased at doses of 25 mg/kg or more. Additional experiments determined the effect of repeated saccharin-Aroclor 1254 pairings (0, 3.75, 7.5, or 15 mg/kg/day, 14 days) followed by a choice test 1 day after the last dose. Repeated exposure to 15 mg/kg produced robust flavor aversion conditioning. Repeated exposure to 7.5 mg/kg produced flavor aversion conditioning in four of 12 rats. These results demonstrate that Aroclor 1254 causes hypoactivlty and flavor aversions in adult rats; the no observable effect level (NOEL) for motor activity was 100 mg/kg for acute exposure and 10 mg/kg for repeated exposure for a period of up to 6 weeks. The acute NOEL for flavor aversion conditioning was 15 mg/kg while the repeated NOEL was 7.5 mg/kg.
    Fundamental and Applied Toxicology 12/1997;
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    ABSTRACT: Bromodichloromethane (BDCM) and chloroform (CHCl3) are by-products of drinking water chlorination and are the two most prevalent trihalomethanes (THMs) in finished drinking water. To date, no comprehensive comparison of the acute renal and hepatic effects of BDCM and CHCl3 following oral gavage in an aqueous dosing vehicle has been conducted. To characterize BDCM- and CHCl3-induced nephro- and hepatotoxicity following aqueous gavage and compare directly the responses between these THMs, 95-day-old male F-344 rats were given single oral doses of 0.0, 0.75, 1.0, 1.5, 2.0, or 3.0 mmol BDCM or CHCl3/kg body wt in an aqueous 10% Emulphor solution. Compound-related hepatic and renal damage was evaluated by quantitating clinical toxicity markers in the serum and urine, respectively. Both THMs appear to be equally hepatotoxic after 24 h, but BDCM caused significantly greater elevations in serum hepatotoxicity markers than CHCl3 at 48 h following exposure to 2.0 and 3.0 mmol/kg. In addition to causing more persistent liver toxicity than CHCl3, BDCM also appears to be slightly more toxic to the kidney at lower doses. Potency differences between the two THMs may be due to pharmacokinetic dissimilarities such as greater metabolism of BDCM to reactive metabolites or more extensive partitioning of BDCM into kidneys and fat depots, resulting in prolonged target tissue exposure.
    Fundamental and Applied Toxicology 12/1997; 40(1):101-10.
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    ABSTRACT: Pregnant Wistar rats (40/group) were administered monoethanolamine (MEA) as an aqueous solution by gavage at dose levels of 0, 40, 120, and 450 mg/kg/day on days 6 through 15 of gestation. On day 20 of gestation, 25 dams/group were euthanized and the fetuses were delivered by cesarean section, weighted, sexed, and examined for external, visceral, and skeletal alterations. The remaining dams (15/group) were allowed to litter and rear their pups to day 21 postpartum. The dams and pups were then euthanized and examined for gross pathologic changes. Gavage administration of 450 mg MEA/kg/day to pregnant rats resulted in maternal toxicity as evidenced by statistically significant (alpha = 0.05) decreases in feed consumption on gestation days 6-8 and 17-20 and on postpartum days 0-4. Additionally, statistically significant decreases in mean maternal body weights were observed on gestation days 15, 17, and 20 and on lactation days 0, 4, 7, and 21. Body weight gains of the 450 mg/kg/day dams were also significantly decreased (13% relative to controls) on gestation days 15-20. There was no evidence of maternal toxicity at 40 or 120 mg/kg/day of MEA. Despite the maternal effects observed at 450 mg/kg/day, no significant fetal effects were observed at this or any dose level tested, nor were there any indications of a treatment-related effect on postnatal growth or on the viability of offspring. Thus, it was concluded that MEA was not developmentally toxic to Wistar rats following repeated oral administration, even at maternally toxic dose levels as high as 450 mg/kg/day.
    Fundamental and Applied Toxicology 12/1997; 40(1):158-62.
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    ABSTRACT: Domoic acid (DA) is an environmental neurotoxin to humans. This work examines whether repeated exposure to subsymptomatic or symptomatic nonlethal doses of domoic acid leads to enhanced symptomatic toxicity in ICR outbred and DBA inbred strains of laboratory mice. A multiple independent exposure paradigm was designed in which doses were administered intraperito neally every other day for 7 days to achieve four separate exposures to domoic acid. We first examined the effect of repeated exposure on serum clearance of domoic acid. Serum domoic acid levels did not differ following a single or repeated exposure. We next examined the effect of repeated exposure on symptomatic toxicity. The mean toxicity scores did not show a significant difference between single and repeated exposures of either subsymptomatic (0.5 mg/ kg) or symptomatic sublethal (2.0 mg/kg) doses of domoic acid. We then examined the effects of repeated domoic acid exposure on a second strain of mouse. DBA mice were chosen based upon their sensitivity to kainic acid-induced seizures; however, the ICR mice were more sensitive to low-dose domoic acid toxicity, particularly in terms of onset and duration of stereotypic scratching behavior. Our results indicate that both strains of mice have comparable concentration-dependent toxic responses to domoic acid; however, differences exist in the magnitude of the response and in specific symptoms. The mean toxicity scores did not show a significant difference when a single exposure (1.0 and 2.0 mg/kg domoic acid) and repeated exposure of the same dose were com pared in the DBA mice. This study provides no evidence that short-term repeated exposure to domoic acid in laboratory mice alters domoic acid clearance from the serum, or leads to a more sensitive or a greater neurotoxic response.
    Fundamental and Applied Toxicology 12/1997;
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    ABSTRACT: Rats were administered hexamethylphosphoramide (HMPA) at dosages of 10, 100, 300, and 1000 ppm in drinking water or at 15, 40, or 120 mg/kg/day by gavage for approximately 90 days. Another group of rats was implanted subcutaneously with HMPA-filled osmotic minipumps, designed to deliver a dosage of 40 mg/kg/day to prevent the possibility of direct contact of HMPA with the nasal epithelium. After 90 days at 10 ppm in the drinking water, some rats had tracheas lined with regenerated epithelium, but no HMPA-related lesions were present in any other organs and tissues. At 100 ppm, nasal lesions (epithelial denudation, regeneration, and squamous metaplasia) were mostly in the maxilloturbinates, tips of nasoturbinates, and the adjacent septum in the anterior nasal cavity (level I), but the lesions were confined to the ventral region of the mid-anterior nasal cavity (level II) and to recesses of the posterior nasal cavity (levels III and IV). At 300 ppm, nasal turbinates in level I were partially adhered to the nasal septum by fibrous tissue. In level II the lesions were mainly confined to the ventral medial meatus, but were scattered diffusely in levels III and IV. Denuded turbinates showed minimal bone proliferation. At 1000 ppm, the anterior nasal cavity was partially occluded by extensive adhesion of the turbinates to the nasal septum by granulation tissue and proliferating turbinate bone. The general architecture of the posterior nasal cavity was obliterated by the marked proliferation of turbinate bone and fibrous tissue in the interturbinate spaces. Tracheas showed regenerated epithelium and bronchi had focal epithelial denudation at 100, 300, and 1000 ppm. Foamy alveolar macrophages (histiocytosis) were increased in the lungs at 300 and 1000 ppm. Testicular atrophy occurred at 1000 ppm. No other tissues were affected by HMPA treatment. Nasal lesions in rats given HMPA by gavage were identical in nature to, but sometimes slightly more severe than, the lesions in rats given HMPA in the drinking water. Rats given 40 mg/kg/day HMPA via an osmotic minipump had slightly less severe nasal lesions than did the rats given the same dosage of HMPA by gavage. Testicular atrophy was present in the rats given 120 mg/kg/day by gavage. The results of this study show that, with the exception of bone proliferation, systemic delivery of HMPA or its metabolites to the nasal tissue following oral administration causes tissue damage similar to that caused by direct exposure of the nasal tissue via inhalation. Oral administration of HMPA is a less potent route for producing nasal lesions than is inhalation.
    Fundamental and Applied Toxicology 12/1997; 40(1):15-29.