Biomedical subjects
Publications and source records attributed to W E Braselton.
A dog was treated for fleas with the application of pennyroyal oil obtained by the owner at a health food store. Vomiting ensued within 2 hours, and despite emergency treatment, the dog died within 48 hours. At necropsy, pennyroyal oil was determined to be the cause of death.
Poisoning with tropine alkaloids from cultivated plants and pharmaceuticals is an uncommon cause of delirium and coma. We report a patient with a toxic delirium following ingestion of the tropine alkaloid-containing root of Datura innoxia. Thin-layer chromatography and gas chromatography/mass spectrometry confirmed the presence of atropine and scopolamine in samples of the ingested root. Routine clinical toxin screens may not include an assay for tropine alkaloids. A specific tropine alkaloid assay may provide supporting evidence. The clinical, electroencephalographic, and therapeutic aspects of anticholinergic poisoning are discussed.
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Mass spectrometry/mass spectrometry (MS/MS) with collision-activated dissociation (CAD) was utilized to unequivocally distinguish 1,3-indandione rodenticides in 2 cases of anticoagulant toxicosis. Anecdotal evidence provided by the veterinarian in a case involving feedlot cows and physical evidence at the site of occurrence in a similar case involving lambs strongly implicated diphenadione (diphacinone; DP) in both instances. However, high performance liquid chromatography indicated chlorophacinone (CP), not DP, was present in the blood samples obtained from both cows and lambs. Intact 1,3-indandiones exhibit poor gas chromatographic properties, so procedures were developed for analysis by MS/MS using a direct exposure probe for sample introduction. The EI mass spectra of DP and CP contained a base peak at m/z 173, with molecular ions (M+) at m/z 340 and m/z 374 (Cl isotope cluster), respectively. Corresponding MS/MS CAD parent ion spectra of m/z 173 showed an ion of m/z 340 for DP and 374 (Cl cluster) for CP. CAD analysis of the blood extracts showed a parent ion scan of m/z 173 identical to that of CP, with the m/z 374 (Cl cluster). (Additional evidence was obtained by MS/MS examination of the CAD daughter ion spectrum of m/z 374.) Blood extracts from the affected animals revealed CAD daughter ion spectra for m/z 374 identical to that of reference CP. Positive confirmation of CP in both cases led to identification of the source of the toxicant and prevention of further animal exposures.
Mink were fed diets that contained 0, 34, or 102 ppb (micrograms/kg) aflatoxins with or without 0.5% hydrated sodium calcium aluminosilicate (HSCAS) and/or 1.0% activated charcoal (AC) for 77 days. Consumption of the diet that contained 34 ppb aflatoxins was lethal to 20% of the mink, while 102 ppb dietary aflatoxins resulted in 100% mortality within 53 days. The addition of AC to the diet containing 102 ppb aflatoxins reduced mortality and increased survival time of the mink while the addition of HSCAS, alone or in combination with AC, prevented mortality. Histologic examination of livers and kidneys from the mink demonstrated liver lesions ranging from extremely severe in mink fed 102 ppb aflatoxin to mild to moderate in those that received 34 ppb aflatoxins. The addition of HSCAS and/or AC to the diets that contained 102 ppb aflatoxins reduced or essentially eliminated histopathologic lesions in the livers. No histopathologic alterations associated with the dietary treatments were observed in the kidneys.
The capacity of N-oxidized metabolites of 4,4'-methylenebis(2-chloroaniline) (MBOCA) to form hemoglobin (Hb) adducts was determined in vitro, and the formation of Hb adducts following in vivo administration of MBOCA was assessed with or without prior induction of cytochrome P-450 enzymes with phenobarbital or beta-naphthoflavone. Hb adduct formation was determined by electron-capture GLC of MBOCA as the heptafluorobutyryl derivative following mild acid hydrolysis of protein-bound MBOCA. The method was confirmed by gas chromatography-mass spectrometry with selected ion monitoring. N-hydroxy- and mononitroso-MBOCA, but not MBOCA itself, formed adducts to rat and human Hb in vitro in a dose-related manner. Binding was inhibited by cysteine and glutathione but not oxidized glutathione or methionine. Intravenous administration of as little as 0.04 mumol/kg N-hydroxy-MBOCA to rats resulted in measurable formation of MBOCA-Hb adducts (0.9 ng/50 mg Hb). Intraperitoneal administration of 0.5-50 mg/kg MBOCA to rats, and subcutaneous administration of 5-500 mg/kg MBOCA to rats and 4-100 mg/kg to guinea pigs resulted in dose-related formation of Hb adducts. MBOCA-Hb remained elevated in blood for greater than 10 weeks following a single subcutaneous dose in guinea pigs. Pretreatment of rats with phenobarbital induced microsomal benzphetamine N-demethylase (BND) activity and resulted in a small increase in in vitro N- and ortho-hydroxylation of MBOCA, but did not increase in vivo Hb adducts.(ABSTRACT TRUNCATED AT 250 WORDS)
Rats were fed polybrominated biphenyls (PBBs) at 0.1 to 100.0 ppm for 14 d and then treated to hasten the removal of PBBs with 0, 5, or 10% mineral oil (MO) and/or 0, 15, 30, or 45% feed restriction (FR) for 21 d. PBB body burdens were determined at d 14 and expressed on a log-log basis by Y = 0.91X + 2.179 (r2 = 0.974), where X = log of PBB concentration in diet (ppm) and Y = log of PBB body burden (micrograms). After 21 d withdrawal, body burdens were expressed by the equation Y = 0.787X + 2.218 (r2 = 0.95). The most effective withdrawal treatment was 10% MO + 45% FR producing a reduction of body burdens inversely related to prior body burdens (69% at 0.1 ppm to 23% at 100 ppm). Body weights and fat content were significantly (p less than or equal to .05) reduced by feed restriction, with fat content only 39% of controls at 21 d off. Mortality averaged 0, 13.6, and 35.8% for rats fed 0, 5, or 10% MO, and 25, 15, 8.6, and 3.7% for rats feed restricted at 0, 15, 30, and 45%, respectively. Histopathology of the dead and moribund rats indicated that the clinical signs were not characteristic of PBB toxicity. In a second experiment, safflower oil at 3.5% or excess vitamins prevented the mortality and clinical signs associated with MO during withdrawal from 100 ppm PBBs. Based on these data and those in the literature, PBBs interfere with vitamin utilization.
Oxidized metabolites of 4,4'-methylenebis(2-chloroaniline) (MBOCA) were tested for direct mutagenicity in a Salmonella typhimurium assay and for effects on gap-junctional communication of WB-F344 rat liver cells. The mutagenicities of the N-hydroxy, mononitroso and o-hydroxy (ring) metabolites of MBOCA were assayed without adding activating enzyme systems, using the frame-shift sensitive strain TA98 and the base pair substitution sensitive strain TA100. The mutagenicity of the hydroxylamine was demonstrated by a linear increase in the formation of mutant colonies in both strains, with a formation of two revertants/nmol by TA98 and 21 revertants/nmol by TA100. The mononitroso metabolite showed a slight positive effect on TA100, but effects were masked by its cytotoxicity towards this strain. This metabolite was neither mutagenic nor cytotoxic to TA98. The o-hydroxy and the dinitroso metabolites were negative for mutagenicity at concentrations up to 50 and 500 micrograms/plate, respectively. The effects of parent MBOCA and N-hydroxy, mononitroso and o-hydroxy metabolites on cell-cell communication were determined by a scrape loading/fluorescent dye transfer technique. Cytotoxicity was assessed by determination of colony-forming efficiency and lactate dehydrogenase release. MBOCA itself caused an inhibition of dye transfer at concentrations of 7.5, 11.3 and 15 nmol/ml, whereas measures of cytotoxicity were not seen until 15 and 30 nmol/ml for LDH release and plating efficiency, respectively. None of the oxidized metabolites were active in inhibiting dye transfer at non-cytotoxic concentrations.
To assess the potential for mycotoxin contamination of the human food supply following the 1988 U.S. drought, 92 grain food samples were purchased from retail outlets in the summer of 1989 and surveyed for aflatoxin B1, zearalenone, and deoxynivalenol (DON [vomitoxin]) by monoclonal antibody-based competitive enzyme-linked immunosorbent assay (ELISA). Only one sample (buckwheat flour) was found to contain aflatoxin B1 (12 ng/g), whereas zearalenone was found in 26% of the samples at a mean concentration of 19 ng/g. In contrast, the DON ELISA was positive in 50% of the samples at a detection level of 1.0 micrograms/g. Between 63 and 88% of corn cereals, wheat flour/muffin mixes, rice cereals, and corn meal/muffin mixes yielded positive results for DON, whereas 25 to 50% of oat cereals, wheat- and oat-based cookies/crackers, corn chips, popcorn, and mixed-grain cereals were positive for DON. The mean DON content of the positive samples was 4.0 micrograms/g, and the minimum and maximum levels were 1.2 and 19 micrograms/g, respectively. When positive ELISA samples were also analyzed by high-performance liquid chromatography, a strong correlation between the two methods was found. The presence of DON in the two highest samples, corn meal and mixed-grain cereal, which contained 19 and 16 micrograms/g, respectively, was quantitatively confirmed by gas chromatography-mass spectrometry. The results indicated that DON was present in 1989 retail food products at concentrations that exceeded those found in previous market surveys and that have been experimentally associated with impaired animal health.
Adult and kit male and female natural dark ranch mink (Mustela vison) were fed a conventional diet supplemented with 0, 500, 1,000, or 1,500 ppm zinc, as ZnSO4.7H2O, for 144 days. No marked adverse effects were observed in feed consumption, body weight gains, hematologic parameters, fur quality, or survival. Zinc concentrations in liver, kidney, and pancreas of the mink increased in direct proportion to the zinc content of the diet. Histopathologic examination of the livers, kidneys, and pancreata revealed no lesions indicative of zinc toxicosis. The results indicate that mink can tolerate at least 1,500 ppm dietary zinc, as ZnSO4.7H2O, for several months without apparent adverse effects.
The increasing sophistication of toxicologic analyses offered by veterinary diagnostic laboratories provides the practitioner with a valuable resource for the diagnosis of companion and exotic animal toxicoses. The availability of such testing is a valuable service that can be offered to veterinary clientele. Appropriate and timely toxicologic testing may permit more successful treatment of affected patients and protect animals and humans from hazardous exposure that might occur if a responsible toxicant goes unrecognized. Perhaps the most critical point to keep in mind, however, is that no matter how sophisticated the toxicologic laboratory is, a correct diagnosis is dependent upon the submission of appropriate biologic and environmental samples.
A litter of 5-week-old Doberman Pinschers with pustular dermatitis was treated dermally with a hexachlorophene-containing emulsion. Shortly after a second treatment, all of the puppies developed neurologic signs consisting of muscle tremors, ataxia, and apparent muscle weakness. The clinical history and signs, histologic lesions within the central nervous system, and measurement of hexachlorophene in liver and kidney tissue confirmed a diagnosis of hexachlorophene toxicosis.
Blood levels of free, sulfate, and glucuronide conjugates of norethindrone (NE) and its ring A reduced metabolites 17alpha-ethynyl-5beta-estrane-3alpha, 17beta-diol and 17alpha-ethynyl-5alpha-estrane-3alpha, 17beta-diol were measured in a female volunteer who received six consecutive daily doses of 2.5 mg. of NE and in four female volunteers undergoing chronic treatment with Orthonovum 2 mg. (2 mg. of NE and 0.1 mg. of mestranol [ME]). The blood levels were quantified by gas chromatograph-mass spectrometry. During treatment for 6 days with 2.5 mg. of NE daily, the 3 hour blood levels of NE and the ring A reduced metabolites increased in a stepwise fashion. During long-term treatment the concentrations of NE, NE sulfate, and the conjugates of the ring A reduced metabolites were seen to build up to a peak at approximately the midpoint of the treatment phase of each cycle, and drop to near baseline during the time when no drug was administered. Individuals varied as to their tendency to accumulate the drug and metabolites, and as to the relative proportion of metabolites formed.
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Since the original studies of Patak et al. in 1975 revealed that the antihypertensive and natriuretic effects of furosemide were markedly blunted or abrogated by indomethacin in both normotensive and hypertensive man, it has been postulated that the ameliorative effects of furosemide in human essential hypertension might be mediated by release of intrarenal prostaglandins. To study the direct effects of furosemide on prostaglandin biosynthesis and release, slices of rabbit renal medulla were incubated in Krebs-Ringer bicarbonate buffer, glucose 10 mM, 1-14C-arachidonic acid (AA) 10 microM, HSA /g/100 ml, 30 min 37 degrees C. Measurements were made of radioactive AA leads to PGE2, and total endogenous immunoreactive PGE2 production (iPGE2) with and without the addition of furosemide (10 microgram/ml) to the media. In the absence of furosemide AA leads to PGE2 was 73 +/- 22 nmol/30 min/g and in the presence of furosemide it fell to 30 +/- 4 nmol/30min/g. iPGE2 was 33 +/- / ng/30 min/mg and decreased to 25 +/- 3 mg with furosemide. These results indicate that the natriuresis and antihypertensive effect of furosemide in vivo, which is associated with a significant increase in urinary PGE2, is not the result of a direct stimulation of furosemide on prostaglandin synthesis but may result from a decrease in PGE metabolism, conversion to another biologically active prostaglandin or possibly be a reflection of events secondary to a direct effect of furosemide on renal hemodynamics and electrolyte excretion.
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A method is described for measurement of chlorpropamide, tolbutamide, and the tolbutamide metabolites hydroxymethyltolbutamide and carbotytolbutamide in blood. It consists of formation of the thermally stable methyl-trifluoroacetyl derivatives of chlorpropamide and tolbutamide, and the methyl-heptafluorobutyryl derivatives of hydroxymethyltolbutamide and carboxytolbutamide, which are then analyzed by electron-capture gas chromatography. Measurements of blood levels of the compounds with this method have been verified by quantitation of the same samples using gas chromatography-mass spectrometry in the mass fragmentography mode. Blood level values and beta-phase half-time disappearance rates of chlorpropamide, tolbutamide, hydroxymethyltolbutamide, and carboxytolbutamide were measured in normal volunteers following an oral dose of chlorpropamide or tolbutamide. Blood levels of the four compounds were also determined in a few diabetics receiving continuous daily treatment.