Harold H. Borgstedt

Reduction of Dimethylsulfoxide to Dimethylsulfide in the Cat

A peculiar sweetish odor was noted in the exhaled breath of cats treated with dimethylsulfoxide. By means of gas chromatographic and mass spectrographic techniques, the responsible compound was identified as dimethylsilfid.

A structure-activity prediction model of carcinogenicity based on NCI/NTP assays and food additives.

Structure-activity relationships (SARs) in chemistry represent a set of techniques by which biological effects and physical-chemical properties can be modelled for a set of chemicals. These methods have been applied to the design of pharmaceuticals, pesticides, and herbicides, among other desired endpoints. SAR applications for such endpoints have been mostly popularized by Hansch et al. (Hansch, 1979) in the US. It was not until recently that SAR methods have been applied to toxicity endpoints. As far as carcinogenicity endpoints are concerned, the efforts have involved but a few investigators, notably Wishnok (Wishnok, 1976; Wishnok, 1978), Jurs and his associates (Jurs, 1979; Chou, 1979; Yuan, 1980; Yuta, 1981 ), and the present author and his collaborators (Enslein, 1982; Enslein, 1983; Enslein, 1984a). In the following sections, we will describe the most recent models of carcinogenicity that we have developed. Estimates from these models can be used for decision-making for carcinogenic risk assessment, setting testing priorities, and aiding in the development of new chemical entities. These estimates should not be used in a vacuum, but in the context of other information available on the specific chemicals.

Salmonella mutagenicity and rodent carcinogenicity: quantitative structure-activity relationships.

Based on a compilation of 222 reports of rodent nominal lifetime carcinogenicity bioassays by the NCI/NTP on the one hand, and corresponding Salmonella mutagenicity bioassays (Ames tests) on the other, Ashby and Tennant (1988) have divided the carcinogens and non-carcinogens into genotoxic (Ames test positive) and non-genotoxic (Ames test negative) groups and discussed structural characteristics common to each of these groups. The Ames test alone was deemed to be adequate for the identification of genotoxicity because other short-term bioassays, and even combinations, or batteries, appeared to offer no significant advantages. From the results of this study it is possible to achieve (1) a division of the carcinogens into the same genotoxic and non-genotoxic groups, and (2) a division of the non-genotoxic compounds into the same carcinogenic and non-carcinogenic groups, solely on the basis of structure-activity relationships, with a classification accuracy of approx. 95%. (1) An equation comprising 8 sigma molecular charge descriptors, 2 molecular connectivity indices (MCIs), 2 kappa molecular shape descriptors and one MOLSTAC substructure descriptor achieved discrimination between genotoxic and non-genotoxic carcinogens with an accuracy of 94.5%. (2) Another equation comprising 8 sigma molecular charge descriptors, 3 MCIs, one kappa shape descriptor and 12 substructural descriptors achieved discrimination between non-genotoxic carcinogens and non-genotoxic non-carcinogens with an accuracy of 95.2%. These SAR models are suitable for the distinction between (1) genotoxic and non-genotoxic carcinogens and (2) carcinogenic and non-carcinogenic non-genotoxins, both in the absence of animal bioassay data.

A QSAR model for the estimation of carcinogenicity: example application to an azo-dye

Since carcinogenicity bioassays are time-consuming, costly, and use animal resources, structure-activity relationship equations which model toxicological end-points have been developed to make available alternative methods which approximate the results that could be obtained from bioassays but which are less expensive and time-consuming and use fewer, if any, animals. These equations are based on sets of bioassay results and explain the end-point under consideration in terms of substructural and other parameters which describe the chemical entities. The resulting equations--or models--can then be used to estimate--or predict--the end-point for new structures. The estimation is followed by validation procedures.

The Uptake and Distribution of Four Inhalation Anesthetics in Dogs

In a series of 21 experiments, 13 large mongrel dogs anesthetized with sodium pentobarbital were ventilated with constant concentrations of ethylene (1.4 per cent), cyclopropane (0.9 per cent), halothane (0.6 per cent) and diethyl ether (0.7 per cent). More than 15,000 measurements of alveolar gas, arterial blood, brain, muscle, and central venous blood concentrations of the anesthetics were made by gas chromatography and compared with concentrations predicted by a relatively simple mathematical model. The model was found to be capable of predicting actual anesthetic concentrations with an average error of ±11.4 per cent. The error did not vary significantly under conditions of increased alveolar ventilation or decreased cardiac output. The average prediction was 5.9 per cent higher than the average actual concentration, suggesting a loss of anesthetic by diffusion or metabolism, or both, which is not accounted for by the model. The demonstrated ability of the model to predict anesthetic uptake and distribution suggests that such a model may eventually be used for predicting and controlling anesthetic uptake during surgery.

Uptake and distribution of inhalation anesthetics agents in clinical practice.

N THE administration of inhalation anesI thetic agents, uptake and distribution are of major importance because the rate at which the anesthetic accumulates in such organs as the brain and the heart determines whether and when there will be analgesia, excitement, surgical anesthesia, or even respiratory or cardiac arrest. If all inhalation anesthetics reached equilibrium in the brain and heart with the inspired gas within a few seconds or minutes, their level in these organs would always approximate that in the inspired mixture, and studies of the uptake and distribution of such anesthetics would be unnecessary. Actually, the time required for the brain to reach 50 per cent equilibration with a constant inhaled concentration varies from approximately 2.6 minutes for ethylene to 345 minutes for methoxyflurane.

Prediction of Rat Oral LD50 From Daphnia Magna LC50 and Chemical Structure

A structure-activity model (QSAR) of rat oral LD50 toxicity based on Daphnia magna LC50 values and structural parameters has been developed. Even though the two species represent widely different animals, it is possible to achieve reasonably good predictions of the mammalian endpoint. A regression equation based on 147 diverse chemicals for which both endpoints were available has a correlation coefficient square of 0.75. The independent parameters consisted of molecular connectivity indexes, both simple and valence adjusted, and substructural keys acting as covariates for the different series of compounds in the data base. 50% of the compounds can be predicted within a factor of 1.7 and 95% within a factor of 6 of the actual values. These results demonstrate that it is possible to develop i nterspecies QSAR equations for toxicological and, possibly, efficacy endpoints. The same principles can be used to model different routes of administration.

A simplified digital method for predicting anesthetic uptake and distribution

Abstract A simple, yet flexible and accurate method of calculating anesthetic uptake and distribution is presented. The basic program is described with modifications which allow calculations of anesthetic uptake and distribution under a wide variety of biological conditions. Data are included for making predictions of anesthetic uptake and distribution in man and also examples to illustrate some predictions which may be made.

Rate of pulmonary excretion of paraldehyde in man

Abstract Subjects given oral doses of paraldehyde exhale about 7% of the administered dose within 4 hours. Paraldehyde itself is the only detectable exhaled excretion product. The excreted percentages do not depend on dose. The concentrations of paraldehyde in the exhaled air are unaffected by changes in ventilatory minute volume; the amounts excreted per time unit, however, are proportional to the volume of respiration. Dead space analyses showed that paraldehyde is excreted across alveolar membranes in a fashion similar to CO 2 . These findings lend an experimental basis to the clinical practice of hyperventilation in patients who have ingested toxic amounts of paraldehyde.

Rate of respiratory excretion of dimethylsulfide in cats given dimethylsulfoxide.

Abstract Cats given dimethylsulfoxide intravenously exhale 3% of the administered dose as the volatile metabolite dimethylsulfide within 5 hours. The rate of respiratory excretion of dimethylsulfide appears to be limited by the rate of its metabolic production, rather than by respiratory factors. The liver does not appear to be a major site of the reduction of dimethylsulfoxide to dimethylsulfide because hepatectomy does not significantly affect the rate of dimethylsulfide excretion. Dimethylsulfoxide is reduced in vitro to dimethylsulfide by cysteine and glutathione, suggesting a nonenzymatic conversion.