Biomedical subjects

D C Dorman

Publications and source records attributed to D C Dorman.

At least 37 records · Page 2Linked to original sources

PubMed1995

Role of formate in methanol-induced exencephaly in CD-1 mice.

Mouse embryos develop exencephaly when dams are exposed by inhalation to high concentrations (> or = 10,000 ppm) of methanol on gestational day 8 (GD8; copulation plug = GD0). The present study examined the role of formate, an oxidative metabolite of methanol, in the development of methanol-induced exencephaly in CD-1 mice and cultured mouse embryos. The pharmacokinetics and developmental toxicity of sodium formate (750 mg/kg by gavage), a 6-hr methanol inhalation (10,000 or 15,000 ppm), or methanol gavage (1.5 g/kg) in pregnant CD-1 mice on GD8 were determined. Gross morphological evaluations for neural tube closure status in embryos or exencephaly in near-term fetuses were performed. Decidual swellings and maternal plasma were analyzed for methanol and formate. The mean (+/- S.E.M.) end-of-exposure plasma methanol concentration was 223 +/- 23 mM following the 6-hr, 15,000 ppm methanol inhalation. There were no changes in blood or decidual swelling formate concentrations under any of the methanol exposure conditions. Peak formate levels in plasma (1.05 +/- 0.2 mM; control 0.5 +/- 0.3 mM) and decidual swelling (2.0 +/- 0.2 mM; control 1.1 +/- 0.2 mM) from pregnant mice (GD8) given sodium formate (750 mg/kg, po) were similar to those observed following a 6-hr methanol inhalation of 15,000 ppm (plasma = 0.75 +/- 0.1 mM; decidual swelling = 2.2 +/- 0.3 mM) but did not result in exencephaly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Recent developments in methanol toxicity.

The disposition of methanol and its putative toxic metabolite formate has been studied in humans, non-human primates, and rodents after exposure to high, neurotoxic doses. The rate at which rodents detoxify formate is more rapid than that of primates. Formate, an endogenous biological substrate, is detoxified by metabolism to CO2 via a tetrahydrofolate-(THF) dependent pathway. Species with high hepatic THF levels, such as rodents, are less sensitive to the neurotoxic effects of large methanol doses compared with species with low THF levels, such as primates. Data on the capacity of primates to detoxify formate derived from inhalation of low levels of methanol are critical for assessing human risk from methanol fuels. Female cynomolgus monkeys exposed to low concentrations of [14C]methanol (10-200 ppm) for 2 h have blood levels of methanol-derived formate that are 100- to 1000-fold lower than endogenous levels of formate. Healthy human volunteers exposed at rest or during exercise to 200 ppm methanol for 6 h or exposed to 20 mg/kg orally have elevated blood levels of methanol, but blood formate concentrations are not significantly increased above endogenous concentrations. Deficiencies in THF may prolong blood levels of formate and increase the likelihood of toxic effects. Limited studies in non-human primates with low THF levels exposed to 900 ppm methanol for 2 h have shown that concentrations of methanol-derived formate in blood remain below endogenous levels. Thus human populations may not be at added risk of neurotoxic effects resulting from exposure to low levels of methanol.

Animals↗

PubMed1994

Pharmacokinetics of inhaled [14C]methanol and methanol-derived [14C]formate in normal and folate-deficient cynomolgus monkeys.

Large-scale use of methanol (MeOH) as an automotive fuel may increase exposure of the public to MeOH vapor, necessitating the need for additional data for an adequate human health risk assessment. Formate is accepted as the toxic metabolite of MeOH, its metabolism is folate-dependent, and potentially sensitive folate-deficient subpopulations (e.g., pregnant women) exist that may be at higher risk to low-level methanol exposure. This study determined the pharmacokinetics of [14C]MeOH and [14C]formate in normal and folate-deficient (FD) monkeys following inhalation of environmentally relevant concentrations of [14C]MeOH. Four normal adult female cynomolgus monkeys were anesthetized (isoflurane) and exposed by lung-only inhalation to 10, 45, 200, and 900 ppm [14C]MeOH for 2 hr. Monkeys were then placed on a FD diet until folate concentrations consistent with moderate deficiency (29-107 ng/ml) developed in red blood cells and then reexposed to 900 ppm (900-FD) for 2 hr. Average (+/- SD) end-of-exposure blood [14C]MeOH concentrations were 0.65 +/- 0.3, 3.0 +/- 0.8, 21 +/- 16, 106 +/- 84, and 211 +/- 71 microM, while average (+/- SD) peak blood [14C]formate concentrations were 0.07 +/- 0.02, 0.25 +/- 0.09, 2.3 +/- 2.9, 2.8 +/- 1.7, and 9.5 +/- 4.7 microM following MeOH inhalation at 10, 45, 200, 900, and 900-FD ppm, respectively. The blood concentration of [14C]MeOH-derived formate from all exposures was 10 to 1000 times lower than the endogenous blood formate concentration (0.1 to 0.2 mM) reported for monkeys. These results suggest that low-level exposure to MeOH would not result in elevated blood formate concentrations in humans under short-term exposure conditions.

Administration, Inhalation↗

PubMed1993

Acute methanol toxicity in minipigs.

The pig has been proposed as a potential animal model for methanol-induced neuro-ocular toxicosis in humans because of its low liver tetrahydrofolate levels and slower rate of formate metabolism compared to those of humans. To examine the validity of this animal model, 12 4-month-old female minipigs (minipig YU) were given a single oral dose of water or methanol at 1.0, 2.5, or 5.0 g/kg body wt by gavage (n = 3 pigs/dose). Dose-dependent signs of acute methanol intoxication, which included mild CNS depression, tremors, ataxia, and recumbency, developed within 0.5 to 2.0 hr, and resolved by 52 hr. Average maximum methanol concentrations in plasma, of 3100 +/- 700 (SD), 6200 +/- 2300, and 15,200 +/- 900 micrograms/ml were reached within 0.5 to 4 hr following methanol administration in animals given 1.0, 2.5, or 5.0 g methanol/kg, respectively. The mean initial elimination half-lives of methanol were 9.0 +/- 1.6, 22.4 +/- 6.1, and 18.9 +/- 4.3 hr, for 1, 2.5, and 5.0 g/kg doses, respectively. In 3 minipigs, a transient increase in plasma formate concentration (1.74-3.40 mEq/liter vs control = 0.5 +/- 0.3 mEq/liter) occurred 4 to 30 hr following methanol administration. Methanol- and formate-dosed pigs did not develop optic nerve lesions, toxicologically significant formate accumulation, or metabolic acidosis. Based on results following a single dose, female minipigs do not appear to be overtly sensitive to methanol and thus may not be a suitable animal model for acute methanol-induced neuro-ocular toxicosis.

Animals↗

PubMed1993

Phase-specific developmental toxicity in mice following maternal methanol inhalation.

Methanol is toxic to embryos of mice and rats when inhaled by dams at high concentrations. The present studies examined methanol-induced developmental toxicity following inhalation exposure (6 hr/day) of pregnant CD-1 mice to 5000, 10,000 or 15,000 ppm either throughout organogenesis (GD 6-15), during the period of neural tube development and closure (GD 7-9), or during a time of potential neural tube reopening (GD 9-11). Transient neurologic signs and reduced body weights were observed in up to 20% of dams exposed to 15,000 ppm. Examination of near-term fetuses revealed embryotoxicity (increased resorptions, reduced fetal weights, and/or fetal malformations) at 10,000 and 15,000 ppm, while 3-day exposures at 5000 ppm yielded no observable adverse effects. Terata included neural and ocular defects, cleft palate, hydronephrosis, deformed tails, and limb (paw and digit) anomalies. Neural tube defects and ocular lesions occurred after methanol inhalation between GD 7-9, while limb anomalies were induced only during GD 9-11; cleft palate and hydronephrosis were observed after exposure during either period. These findings were consistent with prior reports that maternal methanol inhalation at high levels induces developmental toxicity in a concentration-dependent manner. Furthermore, our data indicate that the spectrum of teratogenic effects depended upon both the timing (i.e., stage of embryonic development) and the number of methanol exposures.

Abnormalities, Drug-Induced↗

PubMed1993

The toxic effects of formate in dissociated primary mouse neural cell cultures.

Primary dissociated mouse cerebrocortical cell cultures containing both neurons and glial cells were used as an experimental model to study the neurotoxic effects of formate, the putative toxic metabolite of methanol. Neural cells were isolated and prepared from the cerebral cortex of fetal CD-1 mice on Gestational Day 15. Mature 7- to 15-day-old monolayer cultures were exposed to formate (0 to 240 mM) for 8 hr at 37 degrees C over a range of extracellular pH (6.0 to 7.6). Cytotoxicity was evaluated by histopathology, changes in membrane integrity (lactate dehydrogenase release, LDH; [14C]adenine nucleotide leakage), and mitochondrial metabolic activity [reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT]. Similar quantitative estimates of cell injury were obtained by LDH release or [14C]adenine nucleotide leakage from prelabeled cells. Exposure of neural cells produced time- and concentration-dependent toxic responses. The concentration of formate that resulted in 50% LDH leakage after an 8-hr incubation was estimated to be 45 mM. As determined by light microscopy, formate (20 to 60 mM) was specifically neuronotoxic, primarily affecting large polygonal neurons. Higher concentrations of formate (> or = 120 mM) induced nonspecific cytotoxicity. MTT reduction appeared to be a more sensitive endpoint by showing significant toxic effects at 20 mM (8-hr incubation), while significant leakage of LDH occurred only at formate concentrations > or = 60 mM. Total intracellular ATP concentration was significantly decreased following a 20 or 40 mM formate exposure for 8 hr. These results are consistent with the hypothesis that formate may inhibit mitochondrial function resulting in decreased intracellular ATP and formate-induced neurotoxicity.

Adenine Nucleotides↗

PubMed1992

Acute overdose of levothyroxine in a dog.

An overdose of up to 850 levothyroxine sodium tablets (0.2 mg) in a healthy 6-year-old 16.8-kg dog induced an episode of vomiting and hippus within 9 hours of ingestion. The dog was treated with activated charcoal and saline (magnesium sulfate) cathartic. Initially the serum concentration of thyroxine (T4) 4,900.9 nmol/L. On the second day, serum concentration of triiodothyronine (T3) was 5.3 nmol/L. Serum T4 concentration decreased slowly and was not determined to be normal until day 36. Serum T3 concentration was found to be normal on day 6. Serum alanine transaminase activity peaked on day 6 at 345 U/L. Significant abnormalities were not found during the following 36 days. Clinical signs of thyroid hormone toxicosis in dogs and cats include hyperactivity, lethargy, tachycardia, tachypnea, dyspnea, abnormal pupillary light reflexes, vomiting, and diarrhea. High overdoses of levothyroxine sodium in dogs should be managed by initial decontamination and administration of activated charcoal with a cathartic followed by supportive care.

Animals↗

PubMed1992

Neuropathologic findings of bromethalin toxicosis in the cat.

Ten random source male domestic shorthair cats, 2 to 6 years old and 3.0-4.4 kg body weight, were each given a single oral dose (1.5 mg/kg) of bromethalin (cat Nos. 1-5) or bait vehicle carrier (cat Nos. 6-10). Bromethalin-dosed cats developed a toxic syndrome characterized by ataxia, focal motor seizures, vocalization, decerebrate posture, decreased conscious proprioception, recumbency, depression, and semicoma. Bromethalin-dosed cats were euthanatized if seizure activity or hindlimb paralysis developed. Survival times were 48 hours (cat No. 1), 89 hours (cat No. 2), 90 hours (cat No. 3), and 97 hours (cat No. 4). Control cats (cat Nos. 6-10) and one bromethalin-dosed cat (cat No. 5) were euthanatized on day 20 after dosing. Spongy change (edema--characterized by the formation of vacuoles in extracellular spaces and myelin lamellae), hypertrophied fibrous astrocytes, and hypertrophied oligodendrocytes were observed in the white matter of the cerebrum, cerebellum, brain stem, spinal cord, and optic nerve of all bromethalin-dosed cats. Spongy change occasionally extended into contiguous cerebellar Purkinje cell layer and cerebral cortical gray matter. The severity of lesions varied among cats but was most pronounced in cat No. 5 (480 hours after dosing). A leukocytic inflammatory response, gitter cell (macrophage) response, or axonal degeneration was not observed in the vacuolated areas. Ultrastructural findings included separation of myelin lamellae at the interperiod lines with the formation of intramyelinic vacuoles (intramyelinic edema), rupture and coalescence of intramyelinic vacuoles into larger extracellular spaces (spongy change), and pronounced cytosolic edema of astrocytes and oligodendroglial cells.

Aniline Compounds↗

PubMed1992

Aldicarb toxicosis in a flock of sheep.

Aldicarb toxicosis was diagnosed in 200 sheep that died suddenly. Carbamate insecticide toxicosis was suspected based on observed clinical signs (hypersalivation, diarrhea, urination, paddling, seizures, miosis, and deaths occurring within 1 hour). Tissue samples were submitted from 4 Columbian ewes for pathologic and analytical evaluation. Severe diffuse pulmonary edema was observed on gross and histologic examination. Inhibition of cholinesterase activity in retina (21.2-68.1% of normal activity, n = 3), brain (40.6-45.6% of normal activity, n = 3), and whole blood (27% of normal activity, n = 1) supported a diagnosis of carbamate toxicosis. Reversal of brain and whole blood cholinesterase activities (reactivation factor greater than 1.4) following an in vitro 1 hour incubation at 37 C was also consistent with carbamate poisoning. Aldicarb toxicosis was confirmed following its detection in rumen contents at 1.5, 5.5, and 334 ppm using both high-pressure liquid chromatography with UV detection and gas chromatography with nitrogen/phosphorus detection.

Acetylcholinesterase↗

PubMed1992

Effects of an extract of Gingko biloba on bromethalin-induced cerebral lipid peroxidation and edema in rats.

The effects of administration of a commercially available extract of Gingko biloba (EGB) on bromethalin-induced brain lipid peroxidation and cerebral edema in adult male Sprague-Dawley rats was determined. Gingko biloba extract was given (100 mg/kg) by gavage immediately after bromethalin (1.0 mg/kg) administration. Rats were euthanatized at 24 hours after dosing. Brain lipid peroxidation was determined by measurement of brain malonaldehyde-thiobarbituric acid chromophore (MDA-TBA) concentration, brain sodium concentration, and brain water content. Treatment of bromethalin-dosed rats (10/group) with EGB was associated with a statistically significant (P less than 0.05) decrease in clinical sign severity, compared with bromethalin-dosed saline solution-treated rats. All rats given bromethalin and saline solution developed clinical signs of toxicosis including CNS depression, hind limb weakness, ataxia, paralysis, and coma. Some rats given bromethalin and EGB developed clinical signs, however, none developed hind limb paralysis. The brain MDA-TBA concentration (2.4 +/- 0.5 delta MDA-TBA concentration/mg of protein), percentage of water in brain tissue (80.3 +/- 0.30%), and brain sodium concentration (6.68 +/- 0.21 mg/g of dry weight) were significantly increased in rats given bromethalin and saline solution, compared with control rats given saline solution (1.0 +/- 0.1 delta MDA-TBA concentration/mg of protein; 78.1 +/- 0.33% water in brain tissue; 4.83 +/- 0.30 mg of brain Na+/g of dry weight) and rats given bromethalin and EGB (1.6 +/- 0.2 delta MDA-TBA concentration/mg of protein; 79.3 +/- 0.31% water in brain tissue; 5.37 +/- 0.34 mg of brain Na+/g of dry weight).(ABSTRACT TRUNCATED AT 250 WORDS)

Aniline Compounds↗

PubMed1991

Fatal propylene glycol toxicosis in a horse.

Toxicosis attributable to propylene glycol (1,2-propanediol) was suspected in an 8-year-old 450- to 500-kg male Quarter Horse. Clinical signs of toxicosis developed within 15 minutes of the accidental iatrogenic oral administration of 3.8 L of propylene glycol. Clinical signs of toxicosis included salivation, sweating, ataxia, and signs of pain. Additionally, at 24 hours after propylene glycol ingestion, the horse became increasingly atactic, had an abnormal breath odor, developed rapid shallow breathing, and was cyanotic. The horse died of apparent respiratory arrest 28 hours after the propylene glycol ingestion. Analysis of serum and combined urine and blood from the kidneys confirmed the presence of propylene glycol. Propylene glycol is used for the treatment and prevention of bovine ketosis, and is similar in appearance to mineral oil. The accidental administration of propylene glycol to horses may result in fatal poisoning.

Animals↗

PubMed1991

Neurotoxicology of pyrethrin and the pyrethroid insecticides.

Natural pyrethrin and synthetic pyrethroid insecticides have been considered among the safest classes of insecticides available. Pyrethrins and pyrethroids are classified on the basis of their chemical structures and their toxicologic, neurophysiologic and pharmacologic effects. Cellular effects of pyrethrin and pyrethroid insecticides have been postulated to involve interactions with sodium channels, receptor-ionophore complexes, neurotransmitters, and ATPases. Toxicity is a function of chemical structure, metabolism, route of exposure, and the presence or absence of synergists. Pyrethroid insecticides are neurotoxic, and the development and severity of clinical signs is proportional to the nervous tissue pyrethroid concentration. Type I pyrethroid poisoning in mice and rats produces a syndrome characterized by tremors, prostration and altered startle reflexes. Type II pyrethroid poisoning in mice and rats causes ataxia, convulsions, hyperactivity, choreoathetosis and profuse salivation. A presumptive diagnosis of pyrethrin/pyrethroid poisoning is based upon history of exposure, development of appropriate clinical signs, and chemical analysis for insecticide residues. Treatment of pyrethrin and pyrethroid toxicosis involves basic life support, seizure control when needed, and the prevention of further insecticide absorption.

Animals↗

PubMed1991

Electroencephalographic changes associated with bromethalin toxicosis in the dog.

Electroencephalogram (EEG) recordings were obtained before and during the clinical syndrome induced by a bromethalin rodenticide given to dogs. Nine dogs given 6.25 mg bromethalin/kg po developed clinical signs and EEG abnormalities 15 to 58 h postdosing. Predominant abnormal EEG changes included spike and spike-and-wave EEG patterns (66%), high voltage slow wave (HVSA, 50-150 microV, 1-6 Hz) activity (44%) photoconvulsive or photoparoxysmal irritative responses (44%), and marked voltage depression (dominant activity less than 10 microV) in all leads (33%).

Aniline Compounds↗

PubMed1990

Fenvalerate/N,N-diethyl-m-toluamide (Deet) toxicosis in two cats.

Toxicosis attributable to fenvalerate and N,N-diethyl-m-toluamide (Deet) exposure was suspected in 2 cats. Clinical signs of toxicosis developed within 4 to 6 hours of dermal application of the pesticide. Clinical signs of toxicosis seen in both cats included hypersalivation, ataxia, and depression. In addition, seizures were seen in 1 cat. Both cats died. Analysis of skin, kidney/urine, liver, and brain tissues confirmed the presence of fenvalerate and Deet. The pyrethroid fenvalerate and the insect repellent Deet are used for the control of fleas and ticks on cats. Suspected fenvalerate/Deet toxicosis in cats is associated with tremors, hypersalivation, ataxia, vomiting, depression, and seizures.

Animals↗

PubMed1990

Management of toxicoses.

This article provides information on the detoxification of and supportive care for poisoned animals. Involved are measures to control life-threatening manifestations of toxicoses, to remove agents from the digestive tract, skin, or eyes, and to promote removal of systemically absorbed toxicants. The use of these methods is often of paramount importance in an effort to limit organ damage and to enable a poisoned animal to survive.

Animals↗

PubMed1990

Toxicology of selected pesticides, drugs, and chemicals. Anticoagulant, cholecalciferol, and bromethalin-based rodenticides.

The control of rodent pests is a continuing goal of mankind. To this end, a multitude of rodenticides have been produced, each designed to kill rodents by exerting their toxic effects on various body systems. As examples, veterinarians have had to manage companion animal poisonings due to anticoagulant, sodium fluoroacetate (compound 1080), thallium, barium carbonate, and zinc phosphide-based rodenticides. Many of these rodenticides were introduced because of their anticipated safety in relation to nontarget species; unfortunately, this has not been the case. Veterinarians must attempt to identify the specific rodenticide involved in poisoning cases. Therapeutic success in these poisonings is often more dependent upon symptomatic and supportive care rather than the use of antidotal therapy.

Aniline Compounds↗

PubMed1990

Diethyltoluamide (DEET) insect repellent toxicosis.

Poisonings resulting from DEET are rarely encountered in companion animals. In human patients, DEET toxicosis has been associated with the development of a toxic encephalopathy characterized by tremors, seizures, behavioral changes, and abnormal movements. Generally, DEET toxicosis in companion animals is of short duration and is characterized by vomiting, tremors, ataxia, and excitation. Treatment for DEET toxicosis includes symptomatic therapy and decontamination.

Animals↗

PubMed1990

Toxicology of selected pesticides, drugs, and chemicals. Petroleum distillates and turpentine.

Companion animal exposures to volatile hydrocarbons and turpentine accounted for 2% of all calls received by the IAPIC in 1987. Volatile hydrocarbons are also used as vehicle solvents (e.g., pesticides), and both vehicle and active ingredients pose a significant hazard to companion animals. The most significant clinical effects of the hydrocarbons are related to aspiration pneumonia. The likelihood of aspiration is generally related to the compound's viscosity, with more volatile and most widely available compounds posing the greatest risk. Treatment generally is conservative. Gastrointestinal decontamination methods (e.g., emetics and activated charcoal administration) are used only in massive ingestions or when other toxicants are present in conjunction with the hydrocarbons. Oxygen therapy and cage rest are recommended for the dyspneic animal. Close monitoring of an exposed animal and symptomatic care as needed are also recommended for at least 12 hours after exposure.

Animals↗