Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Walter J. Krasavage is active.

Publication


Featured researches published by Walter J. Krasavage.


Toxicology and Applied Pharmacology | 1980

The relative neurotoxicity of methyl-n-butyl ketone, n-hexane and their metabolites.

Walter J. Krasavage; John L. O'Donoghue; G.D. DiVincenzo; C.J. Terhaar

Methyl n-butyl ketone (MnBK) and n-hexane produce a polyneuropathy in experimental animals. Metabolic studies have revealed that both of these compounds are metabolized to similar metabolites; that is 2-hexanol, 5-hydroxy-2-hexanone, 2,5-hexanediol, and 2,5-hexanedione. The latter two metabolites have been shown to be neurotoxins and the former two may be neurotoxic by virtue of the fact that both are metabolized to 2,5-hexanedione. The relative neurotoxicity of MnBK, n-hexane, and their metabolites was compared by administering equimolar doses of each compound by gavage to groups of male rats, 5 days/week over a 90-day period. A control group was given distilled water. The endpoint used to determine relative neurotoxicity was the time (days) required to produce clinical evidence of severe hindlimb weakness or paralysis. All test compounds produced both clinical and histologic evidence of neuropathy. Morphologically, this nerve damage was identical to that previously described following MnBK, n-hexane, and 2,5-hexanedione administration. The relative neurotoxicity of the test compounds in decreasing order of potency was: 2,5-hexanedione, 5-hydroxy-2-hexanone, 2,5-hexanediol, methyl-n-butyl ketone, 2-hexanol, and n-hexane. The neurotoxic potency was directly related to the amount of 2,5-hexanedione produced by each compound as determined by measuring the area under the serum concentration-time curve of 2,5-hexanedione. Additionally, atrophy of testicular germinal epithelium similar to that previously reported for 2,5-hexanedione occurred in the animals receiving 2,5-hexanedione, 2,5-hexanediol, 5-hydroxy-2-hexanone, MnBK, and 2-hexanol. n-Hexane administration had a lesser effect on the germinal epithelium than did the other compounds. Effects on body weight response and feed consumption paralleled the neurotoxic potency of each compound.


Toxicology and Applied Pharmacology | 1978

Studies on the respiratory uptake and excretion and the skin absorption of methyl n-butyl ketone in humans and dogs

G.D. DiVincenzo; M.L. Hamilton; C.J. Kaplan; Walter J. Krasavage; John L. O'Donoghue

Abstract Methyl n-butyl ketone (MnBK) has produced peripheral neuropathy in experimental animals and is implicated in an occupationally produced neuropathy. Since occupational exposure to MnBK is by inhalation or skin contact, both the absorption and elimination of MnBK vapor and its absorption through skin were investigated. Studies were carried out first with male beagle dogs and subsequently with human volunteers. Humans exposed for 7.5 hours to 10 or 50 ppm or for 4 hr to 100 ppm of MnBK vapor absorbed between 75 and 92% of the inhaled vapor. Unchanged MnBK was not eliminated extensively in the postexposure breath or in urine. 2,5-Hexanedione, a metabolite of MnBK known to be neurotoxic in rats, was found in the serum of humans exposed to either 50 or 100 ppm of MnBK. The absorption and elimination of MnBK in dogs was similar to that observed in humans. The skin absorption of [1-14C]MnBK or a 9 1 ( v v ) mixture of methyl ethyl ketone (MEK) [1- 14 C]MnBK was determined by excretion analysis. Two volunteers exposed by skin contact to [1-14C]MnBK absorbed 4.8 μg min−1 cm−2 and 8.0 μg min−1 cm−2, respectively. Skin exposure to MEK [1- 14 C]MnBK resulted in the respective absorption of 4.2 and 5.6 μg min−1 cm−2 by two individuals. Two volunteers given an oral dose of [1-14C]MnBK (2 μCi; 0.1 mg/kg) excreted 49.9 and 29.0% of the dose, respectively, as respiratory 14CO2 within 3 to 5 days and 27.6 and 25.0% of the dose, respectively, in urine within 8 days. Both [1-14C]MnBK and MEK [1- 14 C]MnBK were absorbed through the skin of dogs. These findings show that MnBK is readily absorbed by the lungs, the gastrointestinal tract, and through the skin, is not eliminated extensively unchanged in breath or urine, and is metabolized to CO2 and 2,5-hexanedione. Radioactivity derived from [1-14C]MnBK was excreted slowly by man, suggesting that repeated daily exposure to high concentrations of MnBK may lead to a prolonged exposure to neurotoxic metabolites.


Toxicological Sciences | 1992

A study of developmental toxicity of hydroquinone in the rabbit

S. J. Murphy; R. E. Schroeder; Ann M. Blacker; Walter J. Krasavage; J.C. English

To obtain information on potential developmental toxicity, hydroquinone (HQ) was administered to pregnant New Zealand White rabbits (18 mated per dose group) in aqueous solution (0, 25, 75, or 150 mg HQ/kg/day) by gavage on Gestation Days (GD) 6 to 18. Caesarean sections were performed on GD 30. Doses of 75 and 150 mg/kg/day adversely affected feed consumption and/or body weights of dams during the treatment period. At these doses, however, treatment-related effects were not evident from physical observations, liver and kidney weights, premature delivery incidence, and caesarean sectioning data. The NOEL for maternal toxicity was 25 mg/kg/day. In the 150 mg/kg/day dose group, total incidences of external, visceral, and skeletal findings for fetuses did not differ statistically from controls. Slight, statistically insignificant, increases were found, however, in the incidences of ocular and minor skeletal malformations (micro-ophthalmia, vertebral/rib defects, angulated hyoid arch) on both a per fetus and a per litter basis. Under the conditions of this study, HQ at 150 mg/kg/day produced minimal developmental alterations in the presence of maternal toxicity. The NOEL for developmental toxicity was 75 mg/kg/day.


Toxicological Sciences | 1992

Hydroquinone: A developmental toxicity study in rats☆

Walter J. Krasavage; Ann M. Blacker; J. Caroline English; Susan J. Murphy

To determine the potential developmental toxicity of hydroquinone (HQ), pregnant rats (COBS-CD-BR) were given 0, 30, 100, or 300 mg/kg HQ by gavage on the 6th through the 15th days of gestation. Maternal effects included a slight, but significant (p less than or equal to 0.05), reduction in body weight gain and feed consumption for the 300 mg/kg HQ dams. Reproductive indices, i.e., pregnancy rate, numbers of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, fetal sex ratio, pre- and postimplantation losses, and gravid uterine weights, were not affected by treatment with HQ. A slightly reduced (p less than or equal to 0.05) mean fetal body weight seen at the 300 mg/kg dose level was associated with the slightly reduced body weight gain seen for the dams at this dose level. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed no HQ-related malformations. The incidences of gross external variations (small hematomas) and internal soft tissue variations (dilated renal pelvis, hydronephrosis, and hydroureter) in the HQ-treated litters were not statistically different from the control incidences. Skeletal variations (delayed ossification of membranous skull bones, hyoid bone, thoracic centra 1-3, sacral arches 3 and 4, and bilobed thoracic centra 9-13) were seen with similar frequency in the control and HQ-treated groups. A statistically significant increase in the incidence of total common vertebral variations seen at the 300 mg/kg HQ dose level was not considered toxicologically significant. The incidences of total skeletal variations were not statistically different between the control and the HQ-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Toxicological Sciences | 1993

A two-generation reproduction study with hydroquinone in rats

A. M. Blacker; R. E. Schroeder; J.C. English; S. J. Murphy; Walter J. Krasavage; Glenn S. Simon

The effects of hydroquinone (HQ) on reproductive performance and fertility were assessed in a two-generation study with CD Sprague-Dawley rats (one litter per generation). HQ was administered in an aqueous solution by gavage at doses of 0, 15, 50, and 150 mg/kg/day. F0 and F1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the F0 or F1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/day in several F0 and F1 parental animals and in a single F0 male at 50 mg/kg/day. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of HQ on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for F0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the F1 parental males in the 50 and 150 mg/kg/day dose groups at several intervals during the premating, mating, and postmating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon postmortem examination, no treatment-related gross lesions were observed in either the F0 or F1 parental animals or their weanlings. Histopathologic examination of reproductive tissues and pituitary glands from high-dose F0 and F1 parental animals did not reveal any changes related to treatment with HQ.(ABSTRACT TRUNCATED AT 250 WORDS)


Toxicology and Applied Pharmacology | 1972

The reversibility of increased rat liver weights and microsomal processing enzymes after feeding high levels of 2,2,4-trimethyl-1,3-pentanediol diisobutyrate☆

Walter J. Krasavage; K.S. Tischer; R.L. Roudabush

Abstract 2,2,4-Trimethyl-1,3-pentanediol diisobutyrate (TXIB) was fed to male and female albino rats at concentrations of 0.1 and 1.0% in the diet. In 3 experiments run concurrently, animals were fed the diets for (A) 52 days, (B) 99 days and (C) 52 days, then changed to a control diet for 47 days or fed a control diet for 52 days, then changed to the TXIB diet for 47 days. This design was adopted to determine whether increased liver weights previously seen with this compound were reproducible and reversible if the compound was with-drawn. Body weights, feed consumption, general appearance and behavior of all animals were recorded. Routine hematologic examinations, alkaline phosphatase and SGOT determinations were performed. Tissues were collected for histopathology, and selected organs were weighed for organ weight comparisons. Liver tissue was prepared for assay of the microsomal glucose-6-phosphatase, p-nitroanisole demethylase, UDP-p-aminophenol and UDP-bilirubin-β- d -glucuronyl transferase. The only consistent changes were an increasesin relative liver weights and increases in p-nitroanisole demethylase, UDP-p-aminophenol and bilirubin glucuronyl transferase. These changes occurred in both sexes, but only in the animals fed the high dose level and only when the animals were ingesting the compound at the time of sacrifice. These changes were not seen in animals fed the 1.0% diet for the first 52 days and the control diet the last 47 days. It appears, there-fore, that high doses of TXIB cause significant adaptive changes in the rat liver, and these changes are reversible if the animal is returned to a normal diet. Male rats given ip injections of 100 mg/kg TXIB or the parent glycol (TMPD®) for 7 days had elevated demethylase activity when compared to the controls. This change was not seen at 25 mg/kg, and neither dose level of either compound affected the bilirubin glucuronyl transferase activity.


Journal of the American College of Toxicology | 1993

Toxicology of Diethylene Glycol Butyl Ether 4. Dermal Subchronic/Reproduction Study in Rats:

Carol S. Auletta; Raymond E. Schroeder; Walter J. Krasavage; C. R. Stack

The subchronic and reproductive toxicity of diethylene glycol butyl ether (DGBE) by the dermal route was evaluated in Sprague-Dawley rats using a novel combined protocol. DGBE was administered dermally at 10 or 30% v/v in aqueous solutions or undiluted (100%) for 13 weeks under occlusion, 6 hr/day, 5 days/week at a maximum attainable volume of 2 mL/kg. Satellite groups of male and female rats were treated with the top dose of DGBE for 13 weeks, mated, and the females were treated through day 20 of gestation and allowed to deliver and nurse their offspring through day 21 of lactation (weaning). DGBE produced dermal irritation, which was dependent on concentration in incidence, severity, and time of onset and was more severe in females than in males. No corresponding histopathology was evident. The only suggestion of a systemic effect was a slightly increased incidence of urinary occult blood at study termination in the females receiving the 30% or 100% DGBE dose. There was no evidence of histopathologic changes in the testes, and vaginal cytology indicated no adverse effect on estrous cycling. There were no effects on reproductive performance of the DGBE-treated males and females. Litters delivered by treated females contained the same number of live pups as control litters and the growth and survival of pups within the treated litters was comparable to control. No reproductive or systemic toxicity was observed at the highest dose tested—2 g/kg/day.


Toxicology and Applied Pharmacology | 1982

Commercial-grade methyl heptyl ketone (5-methyl-2-octanone) neurotoxicity: Contribution of 5-nonanone

John L. O'Donoghue; Walter J. Krasavage; G.D. DiVincenzo; Donald A. Ziegler

Abstract Methyl heptyl ketone (MHK) was the only one of a series of commercial-grade, aliphatic solvents tested (i.e., diisoamyl ketone, diisobutyl ketone, methyl isoamyl ketone, di- n -propyl ketone, and n -heptane) that produced toxic neuropathy in laboratory rats. The neuropathy produced by MHK was clinically and morphologically identical to that previously reported for n -hexane, methyl n -butyl ketone (M n BK), and 2,5-hexanedione. GC-MS analyses of MHK revealed that it was a mixture of approximately 72% 5-methyl-2-octanone (5M2O), 12% 5-nonanone, 0.8% M n BK, and 15.2% C 7 –C 10 ketones and alkanes. Experimentation with purified samples of 5M2O and 5-nonanone resulted in clinical neurotoxicity with 5-nonanone at doses 4.3 times higher than in the commercial mixture. Neurotoxicity was not produced with 5M2O. By combining 5M2O and 5-nonanone in the same proportion as in MHK, the degree of neurotoxicity seen with MHK was reproduced, suggesting that 5M2O potentiates 5-nonanone approximately sixfold. When an equimolar dose of methyl ethyl ketone (MEK) was substituted for 5M2O, little or no potentiation was observed. These findings suggest that MEK, a potentiator of n -hexane and M n BK neurotoxicity, is not a universal potentiator for this type of toxic neuropathy. Serum analyses of rats given MHK showed concentrations of M n BK that could only be accounted for by the metabolic transformation of 5-nonanone to M n BK. Thus commercial-grade MHK neurotoxicity appears principally to be due to the neurotoxic properties of 5-nonanone potentiated by 5M2O. Metabolic studies confirmed the in vivo conversion of 5-nonanone to 2,5-nonanedione, M n BK, and 2,5-hexanedione, the latter of which is the most active neurotoxic metabolite of n -hexane and M n BK. The neurotoxicities of n -hexane, M n BK, and 5-nonanone are linked by virtue of their metabolism to a γ-diketone, 2,5-hexanedione.


Toxicological Sciences | 1990

ETHYLENE GLYCOL MONOPROPYL ETHER : A DEVELOPMENTAL TOXICITY STUDY IN RABBITS

Walter J. Krasavage; Ruth S. Hosenfeld; Gary V. Katz

To determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), groups of pregnant New Zealand white rabbits were exposed to target concentrations of 0, 125, 250, or 500 ppm EGPE vapors for 6 hr a day on Days 6-18 of gestation. Maternal effects included a slight reduction in feed consumption during the first week of treatment at the 250- and 500-ppm exposure levels and slightly reduced body weight gain at the 500-ppm level compared to those of the controls, but the differences were not statistically significant. One doe exposed to 500 ppm had red-colored urine during the 24-hr period following the second exposure. Hematologic determinations, absolute and relative organ weights, and observations at necropsy revealed no treatment-related maternal effects. Reproductive indices, i.e., pregnancy rate, number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal body weights, fetal sex ratio, and the gravid uterine and corrected body weights, were not affected by exposures to EGPE. The occurrences of external and internal soft tissue malformations and variations and the incidences of skeletal malformations in the EGPE-exposed groups were not significantly different from those in the control group. Common skeletal variations, in many instances, were seen less frequently in EGPE-exposed fetuses than in control fetuses. In those cases where the incidence of fetuses with a skeletal variation was greater for EGPE-exposed fetuses than that for control fetuses, the number of litters involved was not significantly different from that of the control group. Thus, EGPE vapor concentrations as high as 500 ppm did not produce teratogenicity or other developmental toxicity in the rabbit conceptus.


Drug and Chemical Toxicology | 1984

Lack of Lung Damage in Mice Following Administration of Tertiary Butylhydroquinone

Walter J. Krasavage; John L. O'Donoghue

Tertiary butylhydroquinone (TBHQ), a phenolic antioxidant used in foods, was tested for its potential to produce lung damage in mice similar to that seen following administration of butylated hydroxytoluene (BHT). Male mice (CRL:CD-1) were given single intraperitoneal injections of 62.5, 125, 250 or 500 mg/kg TBHQ or 300, 625 or 1230 mg/kg BHT in corn oil. Survivors were killed five days after treatment and the lungs were removed, weighed, and processed for histologic examination. Lung weights of the TBHQ treated animals were comparable to the controls, while BHT produced a statistically significant increase in lung weight. Histologically, BHT produced hyperplasia of pulmonary pneumocytes as previously reported. No treatment-related lung lesions were seen in the TBHQ mice. The results of this study indicate that TBHQ does not produce pulmonary lesions in mice.

Collaboration


Dive into the Walter J. Krasavage's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

S. J. Murphy

Goodyear Tire and Rubber Company

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge