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Biomedical subjects

B I Ghanayem

Publications and source records attributed to B I Ghanayem.

At least 55 records · Page 3Linked to original sources
PubMed1993

Assessment of the haemolytic activity of 2-butoxyethanol and its major metabolite, butoxyacetic acid, in various mammals including humans.

2-Butoxyethanol (BE) is a glycol ether produced in volumes exceeding 335 million pounds/year for industrial and domestic uses. BE causes acute haemolytic anaemia in rats and some other mammals. While BE is inactive in vitro, 2-butoxyacetic acid (BAA) is a potent haemolytic agent in vivo and in vitro. This finding suggests that metabolic activation of BE to BAA is required for haemolysis of erythrocytes to occur in vivo. Haemolysis of red blood cells (RBC) by BAA is preceded by swelling (increased mean cell volume [MCV] and haematocrit [HCT]). In an attempt to assess the potential risk to humans exposed to BE, studies were designed to determine the in vitro effect of BAA on RBCs from 10 mammalian species including humans. Blood samples from each mammalian species (n = 3-5) were incubated with BAA at a final concentration of 0 (vehicle), 1 or 2 mM and kept at 37 degrees C in a gently shaking water bath. Complete blood counts (CBCs) were measured at 0, 1, 2 and 4 h, BAA caused a time- and concentration-dependent increase in MCV and HCT of blood from rats, mice and hamsters (rodents), rabbits (lagomorphs), and baboons (primates). In contrast, blood from pigs (artiodactyls), dogs and cats (carnivores), guinea pigs (rodents/marsupials), and humans (primates), was minimally affected by BAA. These results were confirmed in guinea pigs and rats in vivo. Gavage administration of BE (250 mg kg-1) to rats resulted in increased MCV and HCT followed by haemolysis (decreased RBCs). Identical treatment with BE resulted in no significant change in these parameters in guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Hemolytic↗
PubMed1993

Relationship between the time of sustained ethyl acrylate forestomach hyperplasia and carcinogenicity.

Chronic administration of ethyl acrylate (EA) by gavage at 100 or 200 mg/kg/day resulted in a significant dose-dependent increase in the incidence of forestomach (FS) squamous cell papillomas and carcinomas in both sexes of F344 rats and B6C3F1 mice. Subsequent work in this laboratory was designed to investigate the relationship between EA-induced FS hyperplasia and carcinogenicity. Current studies have focused on determining the time required for sustained FS hyperplasia to produce neoplastic transformation. Results of these studies demonstrated that gavage administration of EA to male F344 rats at 200 mg/kg/day for 6 or 12 months caused a sustained increase in FS epithelial hyperplasia for as long as exposure to EA continued. However, FS hyperplasia regressed, and no neoplasms developed when animals receiving EA for 6 months were allowed to recover until they were sacrificed at 24 months of age. In contrast, rats treated for 12 months and allowed 9 months recovery developed FS squamous cell carcinomas (3/13) and papillomas (1/13) for a combined incidence of 4/13. No gross lesions were detected in the liver of any of the rats treated with EA or corn oil vehicle, confirming the tissue specificity in the relationship between EA-induced FS hyperplasia and carcinogenesis. In conclusion, the present work has demonstrated that FS hyperplasia is selectively sustained at the site of EA-induced carcinogenicity for as long as EA is administered and has also demonstrated a temporal relationship between FS mucosal hyperplasia and the development of FS neoplasia by EA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylates↗
PubMed1992

Determination of methacrylonitrile in serum using gas chromatography and flame ionization detection.

A gas chromatographic method is described for the quantitation of methacrylonitrile in serum. Methacrylonitrile was extracted from rat serum with diethyl ether and then quantified using a gas chromatograph equipped with a flame ionization detector and a 60-m megabore column coated with polyethylene glycol polymer. The recoveries obtained following a one-step extraction with diethyl ether varied from 60% at 3.2 micrograms/ml to 70% at 80 micrograms/ml. The coefficient of variation for the analysis ranged from 2.5% at 400 micrograms/ml to 15.0% at 3.2 micrograms/ml.

Animals↗
PubMed1992

Development of tolerance to 2-butoxyethanol-induced hemolytic anemia and studies to elucidate the underlying mechanisms.

Early work demonstrated that a single administration of 2-butoxyethanol (BE) causes acute hemolytic anemia in rats. Current studies were undertaken to investigate the effect of repetitive daily dosing of BE on the hematologic parameters of male F344 rats. Treatment of rats with BE daily (125 mg/kg/day) for 1 to 3 consecutive days resulted in a time-dependent increase in the hemolysis of erythrocytes. However, when daily treatment with BE continued beyond 3 days, the number of erythrocytes began to rebound and approached pretreatment levels within 12 days despite continued daily exposure, suggesting development of tolerance to the hemolytic effect of BE. In vivo and in vitro studies were designed to investigate the underlying mechanism(s) of tolerance to the hematotoxicity of BE. Rats were treated with 125 mg BE/kg/day for 3 days followed by a 7-day recovery. At the end of this recovery period, rats were challenged with a single 125 or 250 mg BE/kg dose and the hematologic profiles were assessed at 2, 8, and 24 hr later. A significant decline in the sensitivity of BE-pretreated/recovered rats compared to vehicle-pretreated rats was observed. Further, in vitro incubation of blood obtained from BE-pretreated/recovered with the hematotoxic metabolite of BE, 2-butoxyacetic acid (BAA), revealed that erythrocytes obtained from these rats were significantly less sensitive to BAA than those obtained from normal rats. These studies suggested that tolerance is due, at least in part, to the lesser sensitivity of young erythrocytes formed during the regeneration process. In another study, rats were rendered anemic by bleeding followed by a 7-day recovery. BE administration to bled/recovered rats demonstrated that these rats were less sensitive than rats which were not subjected to bleeding. In vitro incubation of blood obtained from the bled/recovered animals with BAA demonstrated that erythrocytes were significantly less sensitive to BAA than those obtained from control rats. This further confirmed that young erythrocytes, formed during the regeneration process, were less sensitive to BAA than older erythrocytes. Current data also suggested that it is unlikely that tolerance is caused by modification of BE metabolism in rats repetitively exposed to this chemical. In conclusion, chronic exposure to BE would be expected to result in tolerance to BE-induced hemolytic anemia. The mechanisms responsible are likely related to the fact that older cells are more susceptible to BE and BAA and that hemolysis of these cells during the initial exposure followed by their replacement with less susceptible younger cells may account for tolerance development.

Adenosine Triphosphate↗
PubMed1991

The urotoxic effects of N,N'-dimethylaminopropionitrile. 2. In vivo and in vitro metabolism.

The urotoxicity and metabolism of N,N'-dimethylaminopropionitrile (DMAPN) were investigated in male Sprague-Dawley rats. Animals treated with 525 mg DMAPN/kg or equimolar doses of commercially available potential DMAPN metabolites showed varying levels of urinary retention. About 44% of the administered dose of DMAPN was excreted unchanged in 5 days. beta-Aminopropionitrile and cyanoacetic acid were identified as urinary metabolites. The urinary excretion of cyanoacetic acid was nonlinearly proportional to the volume of urine retained in the bladders. In vitro, the metabolism of DMAPN to cyanide, formaldehyde, and cyanoacetic acid was localized mostly in the microsomal fraction of liver, kidney, and urinary bladders. This reaction required NADPH and oxygen for maximal activity. Metabolism of DMAPN was increased in hepatic microsomes obtained from phenobarbital-treated rats (220% of control) and decreased following CoCl1 treatments (73% of controls). Addition of SKF 525-A to the incubation mixtures inhibited the metabolism of DMAPN to formaldehyde (47-64% of controls). Addition of sulfhydryl compounds (glutathione and cysteine) to the incubation mixtures did not affect the rate of these reactions. These findings indicate that DMAPN is primarily metabolized via a cytochrome P450-dependent mixed-function oxidase system and that the urotoxic effects of DMAPN may be related to this metabolism.

Acetates↗
PubMed1991

Effects of sulfhydryl modulation on ethyl acrylate-induced forestomach toxicity.

Acute administration of a single dose of ethyl acrylate (EA) to F344 rats by gavage caused time- and dose-dependent forestomach edema. Evidence from our laboratory and others suggested that EA is hydrolyzed to acrylic acid (AA) and ethanol both in vivo and in vitro. The major metabolites detected in teh urine of rats treated with EA were derivatives of the glutathione conjugates of EA and AA. The current work was undertaken to investigate the effects of sulfhydryl-depleting agents (diethylmaleate and fasting) and sulfhydryl-containing agents (cysteine and cysteamine) on EA-induced forestomach edema. Results presented in this report revealed that pretreatment of rats with sulfhydryl-containing chemicals such as cysteine or cysteamine has potentiated EA-induced forestomach edema. In contrast, depletion of indigenous sulfhydryls by fasting of rats or pretreatment with diethylmaleate (DEM) protected against EA-induced forestomach edema. Furthermore, repetitive daily administration of EA by gavage induced mucosal forestomach hyperplasia. Co-administration of cysteamine and EA resulted in a significant enhancement of the severity of EA-induced forestomach mucosal hyperplasia. In conclusion, current data suggest that modulation of indigenous sulfhydryls play a role in EA-induced forestomach toxicity; however, the exact mechanism underlying this role remains to be characterized.

Acrylates↗
PubMed1991

Studies on the mechanism of urotoxic effects of N,N'-dimethylaminopropionitrile in rats and mice. 1. Biochemical and morphologic characterization of the injury and its relationship to metabolism.

N,N'-Dimethylaminopropionitrile (DMAPN), a major component of the NIAX catalyst ESN, is known to cause urinary bladder dysfunction in exposed workers. In order to investigate the mechanism of DMAPN toxicity, we carried out time-course (0-72 h) and dose-response (175-700 mg/kg) studies on the effects of DMAPN in rats and mice. Treated animals exhibited several signs of toxicity including loss of body weight, reduced water consumption, and bladder urine retention, as well as bladder injury. DMAPN-induced bladder injury was characterized by distended bladders with marked diffuse submucosal and subserosal edema, petechial hemorrhage, and multifocal perivascular inflammatory infiltrates. The qualitative and quantitative analysis of urine indicated hypoosmolality, aciduria, hematuria, proteinuria, and oliguria. Elevated levels of creatinine and urea levels in plasma were indicative of renal dysfunction. Within hours following DMAPN administration, the animals exhibited a significant increase in urinary retention that resolved between 60 and 72 h. Rats excreted about 44% of the administered DMAPN dose unchanged in the urine, while mice excreted only about 6% of the dose. Commercially available DMAPN metabolites, administered by gavage, produced toxic effects less adverse than DMAPN. The biochemical effects of DMAPN included depletion of glutathione and increased lipid peroxidation in target organs, including urinary bladder and kidney. These studies indicate that there are species differences in DMAPN toxicity. The differences may be due to differences in the formation of reactive metabolic intermediates of DMAPN.

Aminopropionitrile↗
PubMed1991

Sustainability of forestomach hyperplasia in rats treated with ethyl acrylate for 13 weeks and regression after cessation of dosing.

In a chronic study conducted by the National Toxicology Program (NTP), gavage administration of 100 or 200 mg ethyl acrylate (EA)/kg/day, 5 days/week, to F344 rats and B6C3F1 mice resulted in a significant dose-dependent increase in the incidence of squamous cell papillomas and carcinomas of the forestomach of both sexes of rats and mice. No increase in the incidence of tumors was observed at any other site in these rats. Chemically-induced cell proliferation is currently thought to play a role in the development and progression of chemically-induced neoplasia. Therefore, a stop-study was initiated where 100 or 200 mg EA/kg (in corn oil) was administered daily, 5 days/week, for 13 weeks. Rats sacrificed at the end of the treatment regimen had severe epithelial hyperplasia of the forestomach. No lesions were observed in the glandular stomach or liver of EA-treated rats. Forestomach hyperplasia induced by EA included upward and downward cell proliferation. However, forestomachs of rats treated for 13 weeks and sacrificed 8 weeks after the last EA dose exhibited a significant decline in the incidence and severity of forestomach mucosal hyperplasia. Histopathologic evaluation of forestomachs of EA-treated rats (13 weeks) which were allowed a 19-month-recovery (with no exposure to EA) showed further decline in the incidence and severity of mucosal cell hyperplasia. These results indicate that gavage administration of EA to rats results in extensive and sustained forestomach mucosal hyperplasia. The sustainability of forestomach hyperplasia is apparently dependent on the continued exposure of rats to ethyl acrylate, and regressed after cessation of dosing. Furthermore, although enough post-treatment time was allowed for tumors to develop after cessation of EA administration, forestomachs exhibited a nearly complete recovery with no increased incidence of papillomas or carcinomas. It, therefore, remains to be determined what duration of exposure or other factors are critical for reversibility or progression of EA-induced forestomach mucosal hyperplasia to neoplasia.

Acrylates↗
PubMed1990

Hemoglobin degradation, lipid peroxidation, and inhibition of Na+/K(+)-ATPase in rat erythrocytes exposed to acrylonitrile.

The effect of acrylonitrile (VCN) on erythrocyte lipid metabolism was investigated in vitro in metabolically active red cells from male Sprague-Dawley rats containing three types of hemoglobins: oxyhemoglobin, methemoglobin, and carbon monoxyhemoglobin. VCN at the concentration of 10 mM rapidly depleted erythrocyte glutathione (GSH) (75% of control) and induced lipid peroxidation (274% of control). Degradation of oxy- and methemoglobin was directly proportional to the extent of lipid peroxidation (r = 0.89). Addition of glucose to the incubation medium decreased hemoglobin degradation while it slightly increased VCN-induced lipid peroxidation. The highest amount of lipid peroxidation occurred in erythrocytes containing carbon monoxyhemoglobin and glucose. In the isolated red cell membranes incubated with 10 mM VCN, the lipid peroxidation was 400% of controls. VCN (25 mM) noncompetitively inhibited erythrocyte membrane Na+/K(+)-ATPase activity and the degree of inhibition was inversely proportional to the reaction temperature (r = -0.88). These findings indicate that the VCN induced hemoglobin degradation and lipid peroxidation are two extremes of a spectrum of oxidative damage in red cells leading to a change in physical state of membrane structure causing inhibition of adenosine triphosphate (ATPase) activity.

Acrylonitrile↗
PubMed1990

Calcium channel blockers protect against ethylene glycol monomethyl ether (2-methoxyethanol)-induced testicular toxicity.

Disruption of normal calcium homeostasis has been implicated in the development of cell injury by certain chemicals. Furthermore, calcium channel blockers, which may prevent such a disruption, were shown to protect against this type of cellular damage in some excitable and nonexcitable tissues. Therefore, the present work was designed to address the role of calcium in the pachytene cell death caused by ethylene glycol monomethyl ether (EGME) by investigating the effect of the calcium channel blockers, verapamil and diltiazem, on the pathogenesis of such lesions. Male F344 rats were treated with a single gavage dose of 200 or 300 mg EGME/kg. Other groups of rats were treated with the same doses of EGME in combination with one, two, three, or four doses of verapamil or diltiazem. Twenty-four hours after administration of EGME, the animals were sacrificed, and the left testis and epididymis were excised, fixed in Bouin's solution, embedded in paraffin, sectioned, and stained with PAS-H. The sections were evaluated "blind" and scored for the number of lesioned stage XIV tubules. At 200 mg/kg, EGME produced a moderately severe lesion as characterized by pachytene spermatocyte cell death in stage XIV semniferous tubules. Verapamil was protective against this lesion with the protection being directly proportional to the number of verapamil doses administered and was maximum in rats treated with three doses. At 300 mg/kg, EGME caused a severe lesion in the testis, and verapamil was not as effective in protecting against this lesion as against the low dose of EGME. In contrast, diltiazem was not as effective as verapamil at either dose of EGME. These studies show, for the first time, that verapamil protects rats against EGME-induced testicular toxicity.

Animals↗
PubMed1990

Comparison of the hematologic effects of 2-butoxyethanol using two types of hematology analyzers.

Earlier reports from this laboratory indicated that 2-butoxyethanol (BE) causes acute hemolytic anemia in rats as evidenced by a time- and dose-dependent decrease in the number of red blood cells, in hemoglobin concentrations, and in hematocrits (HCT). Subsequent studies showed that treatment with BE causes an early increase in HCT and mean cell volume (MCV). Since this effect went undetected in our early work and resulted in the publication of inaccurate information, present studies were designed to reinvestigate the hematologic effects of BE using the laser-based hematology analyzer which was used in the early studies and an impedance-based hematology analyzer, simultaneously. Packed cell volumes (PCV; spun HCT) were also performed on all blood samples. Male F344 rats were treated with 0, 125, 250, or 500 mg BE/kg (po) and blood was collected from the retro-orbital venous plexus at 1, 2, 4, 8, and 24 hr after dosing. Hematology profiles of BE-treated rats obtained from the impedance-based analyzer showed an early dose- and time-dependent increase in HCTs and MCVs. In contrast, analysis of the same blood samples using the laser-based analyzer showed a dose- and time-dependent decrease in HCTs with little or no change in MCVs. Changes observed in PCVs were consistent with results obtained from the impedance-based analyzer. Therefore, under the experimental conditions of this and previous studies, the laser-based analyzer was unable to detect early increases in HCTs and MCVs in rats treated with BE. Finally, these data explain the different principles utilized to measure cell size by both instruments as they relate to the hematologic effects of BE. Moreover, present data show that BE-induced hemolysis of erythrocytes is preceded by a quantitatively unique and massive swelling suggesting the erythrocyte membrane as the target.

Animals↗
PubMed1990

Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites.

Acute exposure to 2-butoxyethanol (BE) causes dose- and age-dependent hemolytic anemia in rats. Recently, we have shown that butoxyacetic acid (BAA) is the proximate hemolytic agent and that inhibition of alcohol or aldehyde dehydrogenases protected rats against BE-induced hemolytic anemia. In the present investigations, the kinetics of 14C-BE metabolism and clearance were studied in control adult (3-4 months old) and old (12-13 months old) male F344 rats and in adult male F344 rats treated with pyrazole, cyanamide or probenecid. Our results showed that the area under the curve (AUC), maximum plasma concentration (Cmax) and systemic clearance (Cls) of BE were dose-dependent. In contrast, there was no effect of dose on half-life (T1/2) or volume of distribution (Vd) of BE. These results also showed that there was no age effect on T1/2, Vd or Cls of BE. However, Cmax and AUC of BE increased as a function of age. Also, analysis of variance indicated no significant interactions (P less than or equal to .05) between dose and age in relation to BE kinetics. As expected, inhibition of BE metabolism by pretreatment of rats with pyrazole or cyanamide resulted in a significant increase in the T1/2 and AUC of BE, whereas it caused a significant decrease in the Cls. Furthermore, pyrazole had no effect, whereas cyanamide had decreased Vd of BE. Analysis of the toxicokinetic parameters of BAA revealed that T1/2, AUC and Cmax of BAA were directly related to the age of the rats and the dose of BE administered.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1989

Metabolic and cellular basis of 2-butoxyethanol-induced hemolytic anemia in rats and assessment of human risk in vitro.

Recent work in this laboratory indicated that 2-butoxyethanol (BE) causes acute hemolytic anemia in rats, and activation of BE to butoxyacetic acid (BAA), presumably through the intermediate 2-butoxyacetaldehyde (BAL), is a prerequisite for development of hematotoxicity. In the present studies, the effects of BE and its metabolites, BAL and BAA, on erythrocytes from rats and humans were investigated in vitro. Incubation of BE (up to 10 mM) with blood from male F344 rats caused no hemolysis and resulted in no metabolic alteration of BE. Further, addition of alcohol and aldehyde dehydrogenases, with their co-factors, to the incubation mixture failed to alter BE or its effect. At 20 mM, BE caused significant (P less than or equal to 0.05) hemolysis of rat erythrocytes accompanied by a significant (P less than or equal to 0.05) decrease in hematocrit (HCT). In contrast, incubation of BAL or BAA with rat blood caused time- and concentration-dependent swelling of red blood cells followed by hemolysis; however, BAA was significantly more efficacious than BAL. Addition of aldehyde dehydrogenase and its co-factors significantly (P less than or equal to 0.05) potentiated the effect of BAL on rat erythrocytes. Further in vitro investigation of the cellular mechanisms involved in the hemolytic effect revealed that incubation of rat blood with BAA or BAL caused a time- and concentration-dependent decrease in blood ATP concentration. As observed with the hemolytic effects, the decrease in blood ATP was significantly (P less than or equal to 0.05) greater with BAA than with BAl and was not induced by BE. Further, BAA caused no significant changes in the concentration of reduced glutathione and glucose-6-phosphate dehydrogenase in rat erythrocytes. Assessment of human sensitivity by incubation of human blood with BAA showed minimal swelling or hemolysis of erythrocytes with minimal decline in blood ATP levels at BAA concentrations several-fold higher than required to cause complete hemolysis of rat erythrocytes. In summary, the current studies confirm that the hemolytic effect of BE can be attributed primarily to its metabolite BAA, that hemolysis of rat erythrocytes by BAA or BAL is preceded by swelling and ATP depletion, suggesting that the erythrocyte membrane is the most likely target, and, finally, that human erythrocytes are comparatively insensitive to the hemolytic effects of BAA in vitro.

Acetaldehyde↗
PubMed1989

Structure-activity relationships for the in vitro hematotoxicity of N-alkoxyacetic acids, the toxic metabolites of glycol ethers.

Ethylene glycol mono-n-alkyl ethers are a major class of industrial chemicals which cause a wide range of toxic effects in laboratory animals including reproductive and developmental toxicity, as well as hematotoxicity. Alkoxyacetic acids are the major metabolites of ethylene glycol ethers and are considered to be the proximate toxic metabolites. The structure-toxicity relationships of these acids are well documented in the reproductive and developmental systems. Therefore, current studies were conducted to investigate the structure-activity relationships of these acids for hematotoxicity in rat blood in vitro. Results presented here indicate that the effects of various alkoxyacetic acids on rat erythrocytes are qualitatively similar and comprise early swelling followed by hemolysis. The ranking of the activity of these acids was as follows: butoxyacetic acid (BAA) greater than propoxyacetic acid approximately equal to pentoxyacetic acid greater than ethoxyacetic acid greater than methoxyacetic acid. Furthermore, this effect of alkoxyacetic acids was associated with a parallel decrease in blood ATP levels. It is currently unknown if swelling or ATP depletion is the primary effect of these acids. In addition, at equimolar concentrations neither heptanoic, butoxypropionic, nor propoxypropionic acids caused any significant effect on rat erythrocytes in vitro. This suggests that the presence and position of the ether linkage, as it is in BAA, are critical for the development of hematotoxicity. Studies of the relationship between the toxic effect of BAA and its partitioning between erythrocytes and plasma showed that the concentration of [14C]BAA in plasma remained relatively constant while that in the erythrocytes increased as a function of time. This pattern of BAA distribution between plasma and erythrocytes was parallel to erythrocyte swelling. Incubation of BAA with rat blood for 30 min followed by removal of BAA by washing the erythrocytes twice and then continuing the incubation revealed that erythrocyte swelling was not reversible, however, the rate of swelling declined significantly.

Acetates↗
PubMed1987

Calcium channel blockers protect against ethanol- and indomethacin-induced gastric lesions in rats.

The current studies were designed to investigate the effect of calcium channel blockers on chemically induced gastric lesions in rats. Results of this study indicate that pretreatment of male F344 rats with the calcium channel blockers verapamil, diltiazem, or Mg2+ significantly protected against ethanol- and indomethacin-induced gastric lesions as demonstrated by gross and histopathologic evaluation. Treatment of rats with calcium channel blockers before ethanol or indomethacin administration resulted in a significant decline in the mean number of lesions per glandular stomach, the damaged area of the glandular stomach, and the severity of lesions. Calcium channel blockers also caused a significant decline in the incidence of indomethacin-induced gastric lesions, but had no effect on the incidence of ethanol-induced gastric lesions. These results offer the first evidence that calcium channel blockers may play an important role in the protection against chemically induced gastric lesions and thereby offer insight into the mechanism of gastric ulcer formation. It is speculated that this knowledge may prove important in the development of new and improved therapies for the treatment and prevention of gastric ulcers in humans.

Animals↗
PubMed1987

Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats.

Heavy production as well as the diversity of 2-butoxyethanol (BE) uses, which include preparation of products intended for household uses, pose a high risk of human exposure to BE. The current studies were designed to investigate the acute toxicity of BE and to evaluate the effect of age on BE-induced toxicity in F344 male rats. Data presented in this report show that BE causes severe acute hemolytic anemia resulting in significant increases in the concentration of free plasma hemoglobin. Secondary to the hemolytic effects, BE also caused hemoglobinuria as well as histopathologic changes in the liver and kidney. These effects of BE were dose- and time-dependent. Further, both the hemolytic effects and the secondary effects of BE were age dependent with older rats being more sensitive than younger rats. The metabolic basis of the greater susceptibility of older rats to BE-induced toxicity was investigated by comparing BE metabolism in adult (9- to 13-week-old) and young (4- to 5-week-old) rats. These studies revealed that there was a significantly higher portion of the administered dose eliminated by young rats as CO2 as compared to that eliminated by older rats. Similarly, a significantly higher portion of the administered dose was excreted in the urine of young rats. HPLC analysis of the urinary metabolites of BE in adult and young rats showed that the ratio of butoxyacetic acid (BAA)/BE-glucuronide + BE - sulfate (previously thought to reflect an activation/detoxification index of BE; see text) was significantly higher in older rats. We currently believe that the increase in the activation/detoxification index in older rats is caused by decreased degradation of BAA to CO2 (as evident by the lower percentage of the dose excreted as CO2 by older rats) and by depressed urinary excretion of BAA (as evident from the lower percentage of the dose excreted in the urine of older rats.

Administration, Oral↗
PubMed1987

Ethyl acrylate distribution, macromolecular binding, excretion, and metabolism in male Fisher 344 rats.

We have demonstrated previously that ethyl acrylate causes severe acute forestomach (nonglandular portion of the stomach) toxicity in rats. Ethyl acrylate was also shown to cause forestomach tumors when administered to rats chronically by gavage. The current studies were designed to investigate ethyl acrylate distribution, excretion, and metabolism, as well as the macromolecular interactions of ethyl acrylate (EtAc) in the forestomach (target organ) and liver (nontarget organ). 2,3-[14C]Ethyl acrylate was administered in corn oil at 100, 200, or 400 mg/kg by gavage. Data presented here show that the radioactivity derived from EtAc is rapidly absorbed after gavage administration and distributed into all major tissues of male F344 rats. The highest concentration of EtAc-derived radioactivity was detected in the forestomach, glandular stomach, intestine, liver, and kidney at 4 and 24 hr after dosing. The highest percentage of EtAc-derived radioactivity was found in the lipid fraction of the liver. In the forestomach, the highest percentage of EtAc-derived radioactivity was found in the protein fraction. The major route of EtAc excretion was CO2 exhalation (approximately 70% of the administered dose in 24 hr) followed by the urinary excretion. Two metabolites were identified in the urine, namely, N-acetyl-s-(2-carboxyethyl)cysteine and N-acetyl-s-(2-carboxyethyl) cysteine ethyl ester. This suggests that Michael-like addition of sulfhydryls to acrylate is a pathway of EtAc metabolism. Hydrolysis of the ethyl ester may occur before or after conjugation. Further degradation of the GSH conjugates resulted in the formation of the mercapturic acids detected in the urine of EtAc-treated rats.

Acrylates↗