Characterizing the noncancer toxicity of mixtures using concepts from the TTC and quantitative models of uncertainty in mixture toxicity.

This article explores the use of an approach for setting default values for the noncancer toxicity, developed as part of the Threshold of Toxicological Concern (TTC), for the evaluation of the chronic noncarcinogenic effects of certain chemical mixtures. Individuals are exposed to many mixtures where there are little or no toxicological data on some or all of the mixture components. The approach developed in the TTC can provide a basis for conservative estimates of the toxicity of the mixture components when compound-specific data are not available.

Terrestrial field dissipation of diclosulam at four sites in the United States.

The soil dissipation of diclosulam was studied using 14C-labeled and nonradiolabeled material in Mississippi, North Carolina, Georgia, and Illinois between 1994 and 1997. The test substance was preemergence broadcast applied at target rates of 35 and 37 g ai x ha(-1) for the 14C-labeled and the nonradiolabeled studies, respectively. The degradation of diclosulam was rapid with half-lives ranging from 13 to 43 days at the four sites.

Aerobic metabolism of diclosulam on U.S. and South American soils.

Degradation of the sulfonanilide herbicide diclosulam was studied on nine soils from three countries to determine the rates and products of aerobic metabolism. Diclosulam was applied to four agricultural soils from the United States, three from Argentina, and two from Brazil at a rate of 0.1 ppm, equivalent to approximately twice the maximum field application rate of 52 g of active ingredient/ha.

Central and peripheral components of the inhibitory actions of 5-HTP on ethanol consumption in the rat.

When administered under a backward conditioning paradigm, 5-HTP administration resulted in a decrease in ethanol intake followed by a persistently decreased ethanol consumption. A central component to this inhibitory effect was suggested by the inability of xylamidine to significantly reduce the initial inhibitory effect of 5-HTP. The persistent rejection was prevented by xylamidine.

Interactive dopaminergic and noradrenergic systems in the regulation of thirst in the rat.

Twenty-three hours of fluid deprivation led to elevated plasma levels of corticosterone and free fatty acids, as well as increased whole brain dopamine levels, in rats. Drinking could be initiated in water-replete rats by administration of single doses of the dopamine agonist, pergolide, the dopamine beta-hydroxylase inhibitor, diethyldithiocarbamate, the alpha-adrenergic antagonist, phenoxybenzamine, or the beta-adrenergic agonist, isoproterenol. In each case, the response to these agents was reduced or ameliorated by cotreatment with the dopamine antagonist, pimozide.

Use of serotonin-active drugs in alcohol preference studies.

Interest in finding a cure for alcoholism has sparked enthusiastic research into drugs that might accomplish this goal. Since decreases in brain serotonin had been shown to influence voluntary ethanol ingestion, numerous studies were conducted with the intent of establishing a basis on which a treatment for the alcoholic could be based. Along the path of discovery many inconsistencies have been encountered.

Tetrahydro-beta-carbolines in alcoholic beverages: quantitation, neurochemical and ethanol drinking effects.

Two THBC compounds, 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and 1-methyl-1,2,3,4-tetrahydro-beta-carboxylic acid, have been quantitated in beers and wines and their neurochemical and drinking effects studied.

Effects of benzodiazepines on taste aversions in a two-bottle choice paradigm.

Diazepam (DZ) and chlordiazepoxide (CDP) were tested for their ability to antagonize LiCl-established conditioned taste aversions (CTAs) to saccharin in a two-bottle free-choice paradigm. CTAs to saccharin were established in male Sprague-Dawley rats on a chronic fluid-deprivation schedule by the administration of LiCl (3 mEq/kg, IP) following a forced-choice exposure to a novel saccharin solution (0.1%, w/v).

Method for quantitative operant response measurement during inhalation exposure.

A method for pharmacologic and toxicologic investigation of operant responses during inhalation exposure has been developed. The method was tested with rats. Toluene was utilized as a reference chemical.

Effects of anorexigenic agents on deprivation-induced fluid consumption by rats.

The effects of single doses of anorexigenic agents were determined on deprivation-induced fluid consumption by rats. The most potent compound was D-amphetamine; the least potent was benzphetamine. The data suggest that these drugs are not capable of causing true physical dependence in man.

Unreliability of the rat stomach fundus as a predictor of hallucinogenic activity in substituted phenethylamines.

A series of three isomeric 2,4,5-substituted monoethoxy dimethoxy phenylisopropylamines were compared for their contractile effect in the rat fundus as potential antagonists to the effect of serotonin in the fundus. The three isomers were also evaluated for their discriminative stimulus properties in rats that had been trained to discriminate injections of saline from LSD tartrate (0.08 mg/kg).

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogues of hallucinogenic phenethylamines: lack of LSD-like biological activity.

cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine were synthesized as conformationally restricted analogues of hallucinogenic phenylisopropylamines. In rats trained to discriminate saline from LSD (0.08 mg/kg, ip) in a two-lever drug discrimination paradigm, no generalization of the LSD stimulus to the cis trimethoxy compound occurred at doses up to 20 mg/kg.

Substituent branching in phenethylamine-type hallucinogens: a comparison of 1-[2,5-dimethoxy-4-(2-butyl)phenyl]-2-aminopropane and 1-[2,5-dimethoxy-4-(2-methylpropyl)phenyl]-2-aminopropane.

Two novel hallucinogen analogues related to 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP) were synthesized and evaluated in the two-lever drug discrimination paradigm by using 0.08 mg/kg of LSD as the training drug stimulus. The two compounds differ from each other only with respect to the point of branching in the 4-alkyl group.

Effects of toluene inhalation on brain biogenic amines in the rat.

The effects of toluene exposure on the biogenic amine concentrations in the central nervous system were investigated in the rat. Toluene was administered via inhalation to groups of rats at concentrations of 0, l00, 300, or 1000 ppm. After an 8-h continuous exposure, animals were sacrificed and whole brain concentrations of dopamine (DA), norepinephrine (NE), and 5-hydroxytryptamine (5-HT) were determined.

Stress, endogenous opioids and salt intake.

The effect of stress on NaCl intake was examined in mice given a choice of water and 1.5% NaCl to drink. Immobilization of mice for 15-min and 24-h food deprivation resulted in a 2.

5-hydroxytryptophan-induced conditioned taste aversion to ethanol in the rat.

This experiment was conducted to determine the efficacy of 5-HTP in producing conditioned taste aversions (CTAs) to ethanol in rats restricted to a one-hour daily access to fluid. Administration of 100 mg/kg of DL-5-HTP immediately following novel exposure to ethanol resulted in an aversion of such magnitude that some rats refused to consume the ethanol solution. Since ethanol was the only fluid available to these rats, they eventually died, presumably of dehydration.

Differential activity of enantiomers of amphetamine in rats.

Administration of single doses of d-amphetamine (0.5-4.0 mg/kg i.

Effects of resination on actions of anorexigenic agents.

The salt and resinated forms of three anorexigenic agents, d-amphetamine, d,1-amphetamine, and phentermine were examined in rats using two test systems. Appetite depression was determined using a deprivation-induced food consumption test and central stimulatory activity was measured by a two-lever continuous avoidance responding task. Dose-response and time-response studies indicated that the resinated forms of all three compounds had a delayed onset of action as anorexigenic agents and a reduced degree of central stimulatory activity as compared to the salt forms.

A simple animal test system to predict the likelihood of a drug causing human physical dependence.

The test system utilizes adult, male, Sprague-Dawley rats to consume their entire daily water intake in a single 60 minute session. The results of administering various doses of more than 70 therapeutic agents 15 minutes prior to the test session permit the classification of drugs into two categories. Group I drugs cause only a dose-dependent reduction in water intake, beginning at a threshold value below which no effect is seen.

The effects of DL-5-hydroxytryptophan on ethanol consumption by rats.

Rats were offered access to either distilled water or a 12% v/v solution of ethanol as their only fluid during a one hour period daily. After daily fluid consumption has achieved a stable baseline, either distilled water or DL-5-hydroxytryptophan (5HTP) in doses of 50, 100 or 200 mg/kg was injected intraperitoneally one hour prior to the drinking session. While each of the three doses of 5HTP caused a significant reduction in ethanol intake, distilled water had no effect.

Drug interactions with brain biogenic amines and the effects of amphetamine isomers on locomotor activity.

Administration of single IP doses of 1.0 or 4.0 mg/kg of d-amphetamine evoked an increase in mouse spontaneous motor activity (SMA); in contrast, 1.