Enhanced neurotoxicity of 3,3'-iminodipropionitrile following carbon tetrachloride pretreatment in the rat.

The consequences of 3,3'-iminodipropionitrile (IDPN) exposure in animals merits attention both because of its unique neurotoxic effects and as a potential model compound of human dyskinetic disorders. An important question that remains to be determined is whether IDPN itself or a putative active metabolite is responsible for the neurotoxic actions of the chemical in vivo. The present work tested the hypothesis that IDPN must be metabolized by the liver to an active metabolite to become neurotoxic. Thus a reduction in IDPN neurotoxicity would be expected when liver function is compromised. Male Long-Evans rats were given ip injections of saline, 100 (IDPN1) or 200 (IDPN2) mg/kg of IDPN for three days. Half of the animals in each IDPN dose group received corn oil po and the other half 1 g/kg of the hepatotoxicant carbon tetrachloride (CCl4) for three days, starting one day before IDPN administration. Body weights were obtained regularly after exposure. Horizontal and vertical motor activity, and acoustic startle response were monitored prior to, and 1,3,9 and 16 weeks after IDPN exposure. An observational rating score was obtained at 1, 3 and 9 weeks. Auditory thresholds for 5- and 40-kHz tones were estimated by reflex modification procedures at 10 weeks. Animals receiving IDPN2 alone displayed the overt behavioral signs characteristic of IDPN intoxication (postural disturbances, head dyskinesias, backward walking, circling, increased motor activity, and decreased startle response). They also showed weight loss, hyperactivity, a transient rearing deficit, decreased startle amplitudes and elevated auditory thresholds for low- and high-frequency tones. None of these symptoms were observed in the animals treated with CCl4 alone, and only a mild transient effect on the observational rating score was shown by the IDPN1 alone animals. In contrast, IDPN1/CCl4 resulted in the same or higher toxicity than the IDPN2 treatment. IDPN2/CCl4 resulted in severe toxicity (38% mortality over a two-week period) and enhanced body weight and behavioral effects compared to IDPN2 alone group. Impairment of xenobiotic biotransformation was confirmed by elevated pentobarbital sleeping time in animals under the same CCl4 dosing regimen. In conclusion, pretreatment with hepatotoxic dosages of CCl4 leads to increased toxicity of IDPN. This suggests that hepatic transformation of the chemical is not required for the manifestation of IDPN-induced neurotoxicity, but instead may be involved in the detoxification of this compound.     

Smoking habits and attitudes of medical students towards smoking and antismoking campaigns in nine Asian countries. The Tobacco and Health Committee of the International Union Against Tuberculosis and Lung Diseases.

As part of a world survey of the habits, knowledge and attitudes of medical students regarding tobacco we report a study in 15 medical schools from nine Asian countries. Some 1646 first year and 1587 final year students were included, of whom 59% were male. The prevalence of daily smoking in males was 4% in first year and 11% in final year; of occasional smoking 18% and 24% respectively, both with considerable variations between countries. The rates were very low in women. Male exsmokers varied from 3% to 24% in different centres. Overall, 33% of smokers had made a serious attempt to quit; 44% expected to have succeeded within 5 years. Over 80% of non- or exsmokers, but only 60% of smokers, thought smoking was harmful to health. There was gross underestimation of tobacco's causal role in a number of important diseases, e.g. coronary artery disease, peripheral vascular disease, emphysema, bladder cancer and neonatal mortality. There were notable defects both in training and in motivation to counsel smoking patients. There was only partial knowledge of legislative and other measures to discourage smoking, e.g. only 44% of final year students (26% of smokers) thought increased taxation an important measure. In knowledge and attitudes there was little difference between the sexes, but in most aspects smokers had notably lower scores.     

Learning and memory deficits in rats following exposure to 3,3'-iminodipropionitrile

Rats were examined using a learning and memory test battery 4 weeks following exposure to 3,3'-iminodipropionitrile (IDPN). Initial testing revealed deficits in olfactory discrimination and passive avoidance (PA) conditioning. In order to dissociate learning and performance effects, additional tests were conducted. First, to rule out the possibility that IDPN reduced the aversiveness of foot shock, rats were tested in a simple shock sensitivity paradigm. The results indicated no change in shock sensitivity produced by IDPN. Second, to determine if the hyperactivity produced by IDPN was responsible for deficits in conditioning, several additional tests were conducted including (a) repeated-trials active avoidance (AA) and PA conditioning, (b) a PA study which included both a 1- and 24-hr training-testing interval, and (c) long-delay flavor-aversion conditioning. Rats treated with IDPN required more conditioning trials to reach criterion on both AA and PA procedures suggesting that they were capable of performing the required response but acquired those responses at a much slower rate. The deficits in PA conditioning were similar at both the 1- and 24-hr training-testing interval. Finally, the effects of IDPN on flavor-aversion conditioning depended on the delay separating flavor intake and lithium administration during conditioning. Rats treated with IDPN demonstrated robust flavor aversions when trained with a 30-min but not with a 6-hr delay. In summary, the neurotoxic profile of effects produced by IDPN must be expanded to include a prominent cognitive component characterized by protracted deficits in learning and memory capacity. The present experiment illustrates how chemically induced disruption of learning and memory produced by IDPN can be experimentally dissociated from associate neurological symptoms using a simple, routine battery of neurobehavioral tests.     

Pyrethroids and enhanced inhibition in the hippocampus of the rat

The pyrethroid insecticides have been divided into two classes on the basis of their biochemical actions and behavioral indices of toxicity. Both types of pyrethroids have effects on sodium conductance, and Type II pyrethroids have been reported to antagonize gamma-aminobutyric acid (GABA) by interacting with the t-butyl-bicyclophosphorothionate (TBPS)/picrotoxinin binding site. The dentate gyrus of the hippocampus is equipped with GABAergic recurrent inhibitory circuits. The present experiment was designed to demonstrate dissociation in the biochemistry of pyrethroids by activating the perforant path with pairs of stimulus pulses and monitoring the recurrent inhibition in this circuit. Antagonism of GABA leads to a reduction in inhibition, measured as an increase in the size of the population spike in response to the second pulse of the pair. The GABAergic properties of the pyrethroids were assessed by examining paired pulse inhibition before and after oral treatment with 20 mg/kg of cismethrin (Type I), 20 mg/kg of fenvalerate, or 10 mg/kg of deltamethrin (Type IIs). Input/output (I/O) functions revealed a reduction in excitatory postsynaptic potential (EPSP) following cismethrin and deltamethrin. Population spike height was unaffected. Fenvalerate had no effect on I/O functions. In contrast to the prediction of reduced inhibition following treatment with Type II pyrethroids, deltamethrin and fenvalerate increased inhibition up to 500 and 150 ms interpulse intervals, respectively. Cismethrin was without effect on paired pulse inhibition. These findings fail to provide evidence of GABA antagonistic properties of Type II pyrethroids and may be best explained by a differential effect of these three pyrethroids on sodium channel kinetics.