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2,3-Dibromo-1-propanol is a metabolite of the flame retardant tris(2,3-dibromopropyl) phosphate, previously shown to be a mutagen and carcinogen in experimental animals. Toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol were conducted by applying the chemical in 95% ethanol to the interscapular skin of male and female F344/N rats and B6C3F1 mice 5 days a week for 13 weeks in the prechronic study and 48-55 weeks (rats) or 36-42 weeks (mice) in the carcinogenicity study. In the 13-week study, 10 rats and 10 mice of each sex received doses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associated with chemical application occurred only in the high-dose (750 mg/kg) male mice. Chemical-related lesions were seen in the kidney of male rats, liver of female rats, and liver and lung of both sexes of mice. Based on the toxicity observed in the 13-week study, 50 rats of each sex received doses of 0, 188, or 375 mg/kg and 50 mice of each sex received 0, 88, or 177 mg/kg in the carcinogenicity study. The planned 2-year study was terminated early because of reduced survival of rats related to chemical-induced neoplasia and because of the appearance of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Nearly all dosed rats had malignant neoplasms at one or more sites, while only one control male and one control female had malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanol occurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa, esophagus, forestomach, intestines, liver, kidney, mammary gland (females), clitoral gland (females), spleen (males), and mesothelium (males). In mice, chemical-induced neoplasms occurred in the skin, forestomach, liver (males), and lung (males).

A survey was conducted of the community adjustment of 108 developmentally disabled (mentally retarded) persons who had spent at least three years in an institution in southeastern Ontario. On average, they had resided 3.5 years in the community, were 40 years of age, with a mental age of five years and a median IQ of 41, and most had one or more moderate to severe physical disabilities. During their most recent year living in the community it was found that their daily living skills remained unchanged compared with their skill level in the year prior to community placement. As well, the community staff rated them as average in level of performance and amount of supervision required compared with others of similar ability. About one third were found to have a moderate to severe behavioural/psychiatric problem with aggressive disruptive behaviour being most frequent. Of the two-thirds capable of being interviewed, over three-quarters expressed satisfaction with their present living, work, education and recreation environment and had no desire to return to the institution. Most had few if any meaningful relationships with non developmentally disabled persons other than caregivers. Support agency staff and psychiatric consultants identified additional service needs for those with behavioural/psychiatric problems who may be placed in the community.

Groups of 20 rats and 20 mice of each sex were administered monochloroacetic acid (MCAA) once daily, 5 days per week, in water by gavage for up to 13 weeks. Doses used were 0, 30, 60, 90, 120, or 150 mg/kg for rats and 0, 25, 50, 100, 150, or 200 mg/kg for mice. Compound-related deaths occurred at the four highest dose levels in rats and at the highest dose level in mice. Mean body weights of treated groups of rats and mice surviving until the end of the study were similar to those of the controls. A dose-related increase in blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, as well as a dose-related increase in the relative liver and kidney weights was observed in rats but not in mice. A dose-related increase in the incidence and severity of cardiomyopathy occurred in rats. This lesion may be related to the inhibition of heart mitochondrial aconitase activity. No compound-related lesions were observed in mice. The results of this study indicate that F344 rats are more sensitive than B6C3F1 mice; sexes within the species were equally sensitive. The no-observable-effect level was estimated as 30 mg MCAA/kg body weight for rats and 100 mg MCAA/kg body weight for mice.

2-Mercaptobenzimidazole (2-MBI), used in rubber processing, is a suspect carcinogen structurally related to ethylene thiourea. The inhalation toxicity of 2-MBI was evaluated in male and female F344/N rats exposed 6 hr/day, 5 days/week to respirable aerosols generated by spray atomization of aqueous suspensions of the 2-MBI powder and subsequent drying of the resulting aerosols. Twelve exposures at target concentrations of 0, 6.3, 12.5, 25.0, 50.0, or 100 mg/m3 of 2-MBI produced a dose-related reduction in body weight gains, thyroid follicular cell hyperplasia, adrenal cortex fatty change, and pituitary atrophy. Sub-chronic exposures were conducted at target concentrations of 0, 3.1, 6.2, 12.5, 25.0, and 50.0 mg/m3 of 2-MBI. Rats at greater than or equal to 25 mg/m3 displayed hunched posture, hypoactivity, and reduced body weight gain, with compound related mortality at the highest exposure level. Anemia; increased SGPT, SGOT, alkaline phosphatase, sorbitol dehydrogenase, BUN, and cholesterol; and reduced free fatty acid were seen in rats at greater than or equal to 25 mg/m3. Increased thyroid weight and thyroid follicular cell hyperplasia were noted in both sexes at greater than or equal to 6.2 mg/m3, with reduced triiodothyronine and thyroxine levels in both sexes at greater than or equal to 12.5 mg/m3. Thyroid follicular cell hyperplasia was also seen in rats at 3.1 mg/m3. Thymus weights were significantly reduced in both sexes at all exposure levels with liver weight increases at greater than or equal to 6.2 mg/m3. Exposure-related histopathologic changes included pituitary cytoplasmic vacuolization, adrenal cortex necrosis, lymphoid depletion, thymic atrophy, liver cell hypertrophy, renal mineralization and tubular atrophy, and hypocellularity of the bone marrow.

This study was designed to investigate the toxicity of intravenously administered alpha-tocopherol, alpha-tocopheryl acetate, and a polysorbate vehicle similar to that used in a commercial preparation of alpha-tocopheryl acetate intended for intravenous administration. Cesarean-delivered newborn rabbits fed intravenously were administered 100 mg of either alpha-tocopherol or alpha-tocopheryl acetate in a polysorbate vehicle, or the vehicle only, or no treatment for 6 or 7 days. Two intravenous diets were employed which differed in nutritional content and were termed low energy (LE) and high energy (HE). High concentrations of alpha-tocopherol were present in the tissues of all pups that received either treatment with alpha-tocopherol or alpha-tocopheryl acetate in the polysorbate vehicle, irrespective of the nutritional regimen. Pups in all treatment and control groups which received the LE diet had hepatic centrilobular degeneration, necrosis and pigment accumulation, which was attributed to malnutrition. No additional toxicities could be attributed to the vitamin E or polysorbate treatments. Administration of the HE diet eliminated the nutrition-related centrilobular degeneration, and revealed treatment-related liver changes. HE pups treated with alpha-tocopheryl acetate in the polysorbate vehicle had microscopic evidence of mild bile stasis and had elevated serum bilirubin. Minimal lipidosis or fatty change in the liver was observed only in alpha-tocopherol and alpha-tocopheryl acetate-treated pups. Lipidosis in the spleen was moderate in the alpha-tocopherol group and minimal in the alpha-tocopheryl acetate group. Lipidosis also occurred in the adrenal gland primarily in the alpha-tocopheryl acetate group.(ABSTRACT TRUNCATED AT 250 WORDS)

The subchronic toxicity of N,N-dimethylaniline (DMA) was studied by administration in corn oil by gavage at doses of 31.25, 62.5, 125, 250, 20, or 500 mg/kg body weight to groups of 10 male and 10 female F344 rats and B6C3F1 mice 5 d per week for 13 wk. No compound-related mortality was noted in either rats or mice. Significant decrease in body weight gain was observed in male rats at 250 and 500 mg/kg. The body weight gain of female rats and female mice was not adversely affected by the treatment. Clinical signs of toxicity (cyanosis and decrease in motor activity) occurred in both species and sexes in a dose-dependent fashion. Splenomegaly was observed in all treated groups of rats and mice, with the severity being dose-related. Microscopic examination revealed the presence of hemosiderin in the spleen, liver, testes, and kidney of treated rats and mice. Bone marrow hyperplasia and increased hematopoiesis in the spleen occurred in treated rats, and hematopoiesis was increased in the spleen and liver of treated mice. The severity of these lesions was dose-related. A no-observable-effect for mice was estimated at 31.25 mg/kg; however, a no-effect level was not reached in rats in this study. This suggests that rats are more sensitive than mice to the toxic effect of DMA.

Chronic renal failure is a serious health problem in the United States and other developed countries, and large amounts of public funds are being expended for what is essentially palliative treatment of this disease. Historical data also indicate increasing trends for urinary tract cancers of both sexes in the United States. Although the data on humans are not definitive, causal associations appear to exist between occupational exposures to some hydrocarbon solvents and chronic kidney disease, and there is preliminary evidence that suggests an association between organic chemical exposures and cancers of the urinary tract in humans. A review of more than 230 chemicals tested in two-year chronic toxicity studies by the National Toxicology Program (NTP)/National Cancer Institute (NCI) has identified two chemical classes that commonly produced nonneoplastic chronic renal disease in rodents: aromatic amines and organohalides. Tumors of the kidney were most frequently produced by alkyl or alkenyl halide compounds, while tumors of the bladder were caused by aromatic amines. Consistent with many literature reports, short-chain halogenated hydrocarbons appeared to have a propensity for causing a low incidence of renal tubular carcinoma in exposed rodents. Comparative analyses of the NTP/NCI studies did not indicate consistent sex or species differences in the nonneoplastic chronic toxic response, but chemically induced urinary tract cancers occurred more commonly in rats than in mice, and chemically induced cancers of the kidney occurred more commonly in males than in females. Viewed collectively, these data indicate a potential for organic chemicals, especially halogenated hydrocarbons and aromatic amines, to produce chronic kidney injury in humans and other mammalian species.(ABSTRACT TRUNCATED AT 250 WORDS)

Daily dermal administration for 90 days of 0.01 to 10 mg/kg of O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) technical grade (85%) in acetone (0.1 ml) on the unprotected back of the neck produced delayed neurotoxicity. Hens given 2.5 to 10 mg/kg daily doses also received daily doses of atropine sulfate for 5 or 6 days to protect against cholinergic acute toxicity. Severity of the clinical condition depended on the concentration of the daily dermal dose of EPN; i.e., while hens given small doses showed only ataxia, those treated with large doses progressed to paralysis and died. The most consistent histopathologic alteration was the degeneration of axons and myelin in the spinal cord which was identical to that found in positive control hens that received daily dermal doses of 5 or 10 mg/kg tri-o-cresyl phosphate (TOCP). Some of the hens treated daily with the smallest tested dose of EPN (0.001 mg/kg) which did not show clinical signs of delayed neurotoxicity showed equivocal histological changes in the spinal cord. EPN and TOCP treatments had a more profound effect on the activity of plasma butyrylcholinesterase than that of brain acetylcholinesterase (AchE). by contrast O,O,-diethyl O-4-nitrophenyl phosphorothioate (parathion) was more inhibitory to brain AChE. Negative control hens that were treated with 90 daily dermal doses of 1 mg/kg of parathion initially showed leg weakness followed by recovery. A group of hens that received the same volume of acetone (0.1 ml) daily remained normal.

Subchdronic administration of S,S,S-tributyl phosphorotrithioate (DEF) caused 3 toxicologic effects in hens, depending upon route of administration. Small delay oral doses (0.5--20 mg/kg) of DEF produced ataxia, which progressed to paralysis and death in some birds. Large daily oral doses (40 and 80 mg/kg) caused a 'late acute' effect 4 days after administration. The clinical signs of the late acute effect were identical to those produced by n-butyl mercaptan (nBM), a hydrolytic product of DEF, and were not relieved by atropine sulfate. The late acute effect of DEF overlapped with the clinical signs of delayed neurotoxicity. These hens died early, and while one hen showed histopathological lesions in peripheral nerves, another showed unequivocal lesions in the central nervous system. Topical application of daily doses of DEF consistently produced delayed neurotoxicity in the absence of late acute poisonining and was characterized by degeneration of the central and peripheral nerve tissues. Orally administered DEF was rapidly metabolized in the gastrointestinal tract to nBM, which apparently caused the late acute toxic effect. Topically administered DEF, which was not subjected to gastrointestinal tract hydrolysis, caused delayed neurotoxicity but did not produce a late acute effect.

Neurotoxicity was produced in 1-yr-old hens (five hens per treatment) by continual 90-d exposure in inhalation chambers to atmospheres containing 50, 100, 200, or 400 ppm technical grade methyl butyl ketone (MBK) containing 70% methyl n-butyl ketone (MnBK) and 30% methyl isobutyl ketone (MiBK). A 30-d observation period followed. Severity of clinical condition and progression or improvement of neurological deficit signs were dependent on the concentration of MBK and duration of exposure. Hens exposed to the two highest levels developed ataxia and paralysis; they died or were sacrificed before the designated exposure period ended. The intermediate level of MBK (100 ppm) caused severe ataxia; most treated hens showed no change in clinical condition during the observation period. Hens exposed to 50 ppm exhibited gross ataxia, with most demonstrating partial regression of neurological deficit after the exposure ceased. Hens exposed to the lowest tested level (10 ppm) remained normal. Only hens exposed to 400 or 200 ppm showed significant weight loss. Some hens from the 50-400 ppm treatment groups showed unequivocal histopathologic changes in the spinal cord and peripheral nerves. Severity of histopathologic changes depended on the level and duration of MBK exposure. These changes were characterized by excessive swelling, phagocytosis, degeneration, and demyelination of the axons.

The pharmacokinetics and metabolism of a single dermal 20.0 mg/kg of uniformly phenyl-labeled [14C]EPN (O-ethyl O-4-nitrophenyl [14C]phenylphosphonothioate) were investigated in adult male cats. Three treated cats were killed at each time interval: 0.5, 2, 4, 8, and 12. Radioactivity disappeared exponentially from administration site at a rate constant of 0.46 day-1, corresponding to a half-life of 1.5 days. Most of the absorbed radioactivity was excreted in the urine (29.9%). Only 3.2% of the 14C was recovered in the feces. No radioactivity was detected in expired CO2. Only traces of EPN were detected in the urine and feces. Most of the excreted 14C materials were identified as O-ethyl phenylphosphonothioic acid (EPPTA), O-ethyl phenylphosphonic acid (EPPA), and phenylphosphonic acid (PPA). The disposition studies showed that EPN was the major compound identified 0.5 day after administration in the brain, spinal cord, sciatic nerve, adipose tissue, plasma, muscle, liver, and kidney. Most of the radioactivity in the liver and kidney was identified after 4 days as EPPTA, EPPA, and PPA. Kinetic and distribution studies showed that EPN was eliminated from the tissues and plasma according to exponential kinetics. The half-life of the elimination of EPN from plasma was 9.1 days corresponding to a constant rate value of 0.076 day-1. Relative residence (RR) of EPN relative to plasma was longest in the sciatic nerve and shortest in the kidney.

Diets containing 2.5 or 5% D-mannitol were fed to groups of 50 F344 rats and 50 B6C3F1 mice of each sex for 103 wk. Similar groups served as controls. There were no significant differences in survival between treated and control rats or between treated and control mice. Mean body weights were similar in treated and control male rats and in treated and control female mice. Throughout the study, the mean body weights of female rats on the 5% diet were slightly (less than 10%) lower than those of the controls, and by the end of the study the mean body weights of treated male mice were slightly (c. 10%) higher than those of the controls. Feed consumption by treated and control animals was approximately the same in rats and mice of either sex. The incidence of dilation of the gastric fundal gland was higher (46%) in treated female rats than in the controls (12%). A mild nephrosis, characterized by focal vacuolization of the renal tubular epithelium, showed an increased incidence in treated mice of both sexes and was considered to be related to the administration of D-mannitol. There were no statistically significant increases in tumour incidence in any of the treated groups when compared with the corresponding controls. Under the conditions of this bioassay, D-mannitol was not shown to be carcinogenic for F344 rats or B6C3F1 mice of either sex.

Thirteen-week toxicity studies were conducted in groups of 10 F344 rats and B6C3F1 mice of each sex fed roxarsone at 0, 50, 100, 200, 400, or 800 ppm in the diet. Arsenic levels in blood, urine, kidneys, and liver of rats were measured in additional animals of each sex dosed with 100 or 400 ppm roxarsone. Compound-related mortality occurred in both sexes of rats at 800 ppm and mice at 800 and 400 ppm. Significant body weight gain depression occurred in both sexes of rats at 200, 400, and 800 ppm and mice at 800 ppm. Clinical signs of toxicity (trembling, ataxia, and pale skin) were seen primarily in rats and mice at 800 ppm. Lesions associated with roxarsone administration were noted only in the kidney of rats and were characterized by tubular necrosis and mineralization at the corticomedullary junction. Arsenic levels in urine, blood, liver, and kidneys increased over time and were directly proportional to the level of roxarsone in feed. These levels were greater than 6 times higher in rats than in mice and were about 2 time higher in males than in females. The no-observable-effect level for roxarsone toxicity was estimated at 100 ppm for rats and 200 ppm for mice. No hematology or clinical chemistry effects were found in rats or mice of either sex.

The changes in brain acetylcholinesterase (AChE), acid phosphatase (APase), and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNP), and plasma butyrylcholinesterase (BuChE) activities were investigated in hens treated with a single, dermal dose (100-1000 mg/kg) of S,S,S-tri-n-butyl phosphorotrithioate (DEF). Three control groups consisted of hens left untreated, given a single, dermal dose of 500 mg/kg tri-o-cresyl phosphate (TOCP, positive control for organophophorous compound-induced delayed neurotoxicity), or 10 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion, negative control). Brain AChE activity, determined 28 days after application, was significantly inhibited in hens given 500-1,000 mg/kg DEF and in TOCP- and parathion-treated hens. In contrast, brain APase and CNP activities were significantly higher in all treatments as compared with those of the untreated hens. Parathion, however, caused the least increase in these enzymatic activities as compared to DEF or TOCP. A single, dermal dose of DEF or TOCP also caused an initial decrease in plasma BuChE activity with maximum depression of enzymatic activity observed 1 to 7 days after administration. This decrease was dose dependent and the enzymatic activity showed partial recovery with time. Hens treated with single, dermal doses of DEF, ranging from 250 to 1000 mg/kg, developed ataxia which progressed to paralysis in some hens. Histopathologic examination revealed axon and myelin degeneration of the spinal cord and peripheral nerves of some hens. The severity and frequency of the neuropathologic lesions were dose dependent. Neurologic dysfunctions and neuropathologic lesions seen in DEF-treated hens were similar to those exhibited in TOCP-treated hens. While parathion produced acute cholinergic effects, it did not cause delayed neurotoxicity. The changes in brain and plasma enzymes are discussed in relation to their role in the pathogenesis of DEF-induced delayed neurotoxicity.

Chronic toxicity and carcinogenicity studies were conducted on D-mannitol and propyl gallate in F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were maintained on diets containing either 0, 2.5 or 5.0% D-mannitol or 0, 0.6 or 1.2% propyl gallate for 103 wk. D-Mannitol had no effect on survival or mean body weight of rats and mice, and feed consumption was approximately the same in control and treated groups in each species. Gastric fundal gland dilation occurred at a higher incidence in treated female rats than in controls. A mild nephrosis characterized by focal vacuolization of the renal tubular epithelium was observed in an increased incidence in treated mice. No significant increase in tumour incidence was observed in any of the treated groups in comparison with the corresponding controls. Survival of rats and mice given propyl gallate was similar to that of the controls. Mean body weights were lower in chemically exposed animals, and more so for females. Male rats exposed to propyl gallate showed an increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland. Tumours of the preputial gland, islet-cell tumours of the pancreas, and phaeochromocytoma of the adrenal gland occurred at a significantly (P less than 0.05) higher incidence in the low-dose male rats. Malignant lymphoma occurred with a positive trend in male mice (control 1/50, low dose 3/49 and high dose 8/50), and the incidence in the high-dose group was significantly (P less than 0.05) higher than in the control group. However, since the incidence in the control group was much less than the historical control rate (36/398 or 9%) in this laboratory, this apparent increase was not considered to be related to propyl gallate administration. Under the conditions of these studies, neither D-mannitol nor propyl gallate was considered to be carcinogenic to F344 rats or B6C3F1 mice of either sex.

Two-week repeated-dose and 13-week subchronic studies of HCBD were conducted in B6C3F1 mice. Groups of five mice/sex received 0, 30, 100, 300, 1,000, or 3,000 ppm HCBD in feed for 15 days. Toxic responses, primarily in the higher dose groups, included abnormal clinical signs (lethargy, hunched posture, rough coat, sensitivity to light, and/or incoordination), mortality (all mice in the top two dose groups died by day 7), body and organ weight depression, and gross and histopathological changes. The most prevalent microscopic lesion, seen in all HCBD-treated mice of both sexes, was renal tubular cell necrosis and/or regeneration. Regeneration was seen only in the lower dose groups. Thirteen-week studies were conducted in which groups of 10 mice/sex received 0, 1, 3, 10, 30, or 100 ppm HCBD in feed. No treatment-related clinical signs or mortality were observed. Body weight gain was reduced in the 30- and 100-ppm males (-49 and -56, respectively), and the 100-ppm females (-47). Significant reduction in kidney weights was seen in the 30- and 100-ppm males and 100-ppm females. A treatment-related increase in tubular cell regeneration in the renal cortex occurred in both male and female mice. This lesion was characterized by an increase both in number and basophilic staining intensity of the tubular epithelial cells. Regeneration was seen in the outer stripe of the outer medulla and extended into the medullary rays (pars recta); severity increased with dose. Female mice were more susceptible to the toxicity of HCBD than male mice. Although no adverse effects were observed at the 10-ppm level for male mice in the subchronic study, the regenerative lesion was present in female mice at 1 ppm, the lowest dose administered.

Carcinogenesis studies of benzyl acetate (a fragrance and flavoring agent) were conducted in F344 rats and B6C3F1 mice. The chemical was given in corn oil by gavage once daily, 5 days/week for 103 weeks, to groups of 50 animals of each sex and species. For rats the doses were 0, 250, and 500 mg/kg body weight and for mice the doses were 0, 500, and 1000 mg/kg. Mean body weights of control and dosed rats and mice were not affected adversely by benzyl acetate. The survival of control and low dose female mice was lower than that of the high dose group. A genital tract infection may have contributed to the reduced survival. No other significant difference in survival was observed for dosed rats or mice. Benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90% of the administered dose recovered as various metabolites in the urine within 24 h. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Under the conditions of these studies, benzyl acetate administration was associated with an increased incidence of acinar cell adenoma of the exocrine pancreas in male F344/N rats. No evidence of carcinogenicity was found for female F344/N rats. For male and female B6C3F1 mice there was evidence of carcinogenicity, in that benzyl acetate caused an increased incidence of hepatocellular neoplasms (particularly adenomas) and squamous cell neoplasms of the forestomach.

The neurotoxic action of inhaled technical grade methyl butyl ketone and dermally applied (O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN) was studied. Three groups of five hens each were treated 5 days/week for 90 days with a dermal dose of 1.0 mg/kg of EPN (85%) on the unprotected back of the neck. These groups were exposed simultaneously to 10, 50, or 100 ppm of technical methyl butyl ketone (MBK; methyl n-butyl ketone:methyl isobutyl ketone, 7:3) in inhalation chambers. A fourth group was treated only with the dose of EPN and a fifth group with only 100 ppm MBK. The control consisted of a group of five hens treated with a dose of 0.1 ml acetone. Treatment was followed by a 30-day observation period. Simultaneous exposure to EPN and MBK greatly enhanced the neurotoxicity produced when compared to the neurotoxicity produced by either chemical when applied alone. Continued exposure to EPN and MBK resulted in earlier onset and more severe signs of neurotoxicity than exposure to either individual compound. The severity and characteristics of histopathologic lesions in hens given the same daily dermal dose of EPN in combination with inhaled MBK depended on the MBK concentration. Histopathologic changes were more severe and prevalent in the 100 ppm MBK:1 mg/kg EPN group than in the others. In this group, Wallerian-type degeneration was seen along with paranodal axonal swellings. The morphology and distribution of these lesions were characteristic of those induced by MBK. In the 50 ppm MBK:1 mg/kg EPN group axonal swelling was evident but not clearly identifiable as paranodal. Hens treated with 10 ppm MBK:1 mg/kg EPN had minimal lesions with low incidence of axonal swellings. These were not as large as those seen in MBK neurotoxicity, but instead resembled the histopathologic lesions caused by EPN. The results indicate that the combined treatment gave a value for neurotoxicity coefficient which was two times the additive neurotoxic effect of each treatment alone. Pretreatment with three daily ip doses of 5 mmol/kg technical grade MBK or methyl n-butyl ketone (MnBK), equally increased chicken hepatic microsomal cytochrome P-450 content. Also, hepatic microsomes from MBK-treated hens metabolized [14C]EPN in vitro to [14C]EPN oxon to a much greater extent than those from control hens. These results suggest that MBK potentiates the neurotoxic effect of EPN, at least in part, by increasing the metabolic activation of EPN to the more neurotoxic metabolite EPN oxon.(ABSTRACT TRUNCATED AT 400 WORDS)

A 13-wk study was conducted by administering d-alpha-tocopheryl acetate (vitamin E) in corn oil by gavage to groups of ten male and ten female Fischer 344 rats at doses of 0, 125, 500 or 2000 mg/kg body weight daily for 13 wk. The dose of corn oil given was 3.5 ml/kg. Additional groups of ten males and ten females were included and served as untreated controls. Deaths occurred only in males at 2000 mg/kg. Vitamin E dosing had no effect on body weight or food consumption. The liver-to-body weight ratio of females at 2000 mg/kg was significantly increased. In males, high levels of vitamin E (2000 mg/kg) caused prolongation of both prothrombin and activated partial thromboplastin (APTT) times, reticulocytosis and a decrease in haematocrit values and haemoglobin concentrations. APTT was also lengthened in females at this dose level. High levels (2000 mg/kg) caused haemorrhagic diathesis in both males and females and increased medullary erythropoiesis in the spleen of one male. Vitamin E at all doses tested caused interstitial inflammation and adenomatous hyperplasia of the lung. The above findings indicate that vitamin E administration in excessive amounts is potentially toxic.