Julius M. Coon

Effects of organochlorine insecticides on the toxicity and in vitro plasma detoxication of paraoxon

Abstract Experiments are described which show that normal mouse plasma may inactivate low concentrations of paraoxon (1.2 × 10−6 m ) in vitro by a nonenzymatic binding process. Binding of paraoxon in plasma appeared to proceed rapidly since there was no difference in the anticholinesterase activity of the reaction mixture after 5, 15, 30, and 60 min of incubation time. Pretreatment of mice with a single dose of aldrin reduced both their mortality from a toxic dose of paraoxon and the “free paraoxon” levels in their plasma when it was incubated in vitro with paraoxon. There was a significant correlation between percent mortality and “free paraoxon” levels when aldrin was administered in doses ranging from 1 to 12 mg/kg or at intervals of 1–24 days before the toxicity or plasma test. A similar relationship between gross toxicity and “free paraoxon” was observed after pretreatment with the insecticides dieldrin, DDT, or chlordane. These results suggest that an increased plasma binding after treatment with organochlorine insecticides may be an important mechanism of the protection against paraoxon toxicity.

Effect of DDT on the toxicity and metabolism of parathion in mice

Abstract Pretreatment with DDT or DDE protected mice against the toxicity of the organophosphate parathion, but not against the toxicity of its active metabolite, paraoxon. In accord with these results, DDT pretreatment protected against the inhibition of plasma, whole blood and brain cholinesterase by parathion, but did not protect against the inhibition of whole blood or brain cholinesterase following paraoxon. In contrast to what might be expected from the toxicity studies, liver microsomes and 900 g supernatant fractions of the liver from mice treated with DDT or DDE converted more parathion to the active metabolite paraoxon than did controls. The rate of detoxication of paraoxon by these liver fractions was not affected by DDT or DDE treatment. DDT pretreatment prolonged hexobarbital sleeping time in the mouse. This response is in opposition to the usual decrease in sleeping time seen with DDT and other microsomal enzyme stimulants in the rat. An increased rate of conversion of parathion to the inactive product, diethyl phosphorothionic acid, has been suggested as a possible mechanism by which DDT pretreatment protects against the toxcity of parathion.

Nicotine inhibition of the metabolism of 3,4-benzopyrene, a carcinogen in tobacco smoke.

A decreased rate of biliary excretion of radioactive metabolites of 3,4-benzopyrene was observed in rats given a single dose of nicotine. Prior treatment of rats with nicotine decreased benzopyrene hydroxylase activity in homogenates of liver, lung, and small intestine. The addition of nicotine to incubated tissues also decreased benzopyrene hydroxylase activity. These findings show that nicotine inhibits the metabolism of 3,4-benzopyrene in vivo and in vitro.

Effect of the insecticides toxaphene and carbaryl on induction of lung tumors by benzo[a]pyrene in the mouse.

The insecticides toxaphene and carbaryl, when fed in the diet alone for 20 wk, were not tumorigenic to female A/J mice. Dietary levels of these insecticides were investigated for their effects on the incidence of lung tumors induced by oral administration of benzo[a]pyrene (BP). A significant reduction in BP-induced lung tumors was found after feeding 100 ppm toxaphene for 12 wk or 200 ppm for 20 wk. In contrast, 1000 ppm carbaryl fed for 20 wk caused a significant enhancement of BP-induced lung tumors. Mice that received toxaphene in the diet alone, or toxaphene and BP, showed an increase in BP hydroxylase activity in the liver and a decrease in enzyme activity in the lung. Carbaryl and BP increased BP hydroxylase activity in the lung without altering enzyme activity in the liver. Inhibition of lung BP hydroxylase activity was paralleled by a reduction in BP-induced lung tumors in mice fed toxaphene. Conversely, increased lung BP hydroxylase activity was associated with an enhancement of BP-induced lung tumors in animals fed carbaryl. The metabolism of BP by organs susceptible to BP-induced tumors and possible mechanisms for interactions with the insecticides are discussed.

Effect of acute ethanol intoxication on the distribution of dieldrin in mice.

Abstract Ethanol (6.3 g/kg) or a calorically equivalent quantity of glucose was administered po to groups of adult male Swiss-Webster mice previously given a single po dose of dieldrin (16 mg/kg). Dieldrin levels were significantly elevated in plasma and liver 16 hr after ethanol administration. There was also an increase in total liver lipids 8 and 16 hr after ethanol. Although ethanol decreased the urine volume, there was no significant reduction in the total dieldrin excreted in the urine during the first 16 hr after ethanol. There was no difference between ethanol and glucose treated animals in respect to dieldrin levels in epididymal fat at 8, 16 and 24 hr after ethanol or glucose. Since ethanol did not decrease the concentration of dieldrin in epididymal fat, it appears that mobilization of dieldrin from storage sites in adipose tissue may not be primarily responsible for the observed increase in dieldrin levels in plasma and liver after ethanol. It is suggested that a decrease in urinary excretion of dieldrin following ethanol accounts for the increase in dieldrin levels in the tissues.

Effect of paraoxon on the hypnotic action of chloral hydrate

Abstract Paraoxon decreased induction time (IT) and increased the duration of the loss-of-righting-reflex time (LORRT) of chloral hydrate (CH) and trichloroethanol (TCE) in mice. Atropine sulfate, but not the peripherally acting agents atropine methylnitrate and pralidoxime, prevented these effects of paraoxon on the activity of CH, suggesting that such effects may be mediated through a central cholinergic mechanism. Mice treated with paraoxon showed higher concentrations of CH and lower concentrations of TCE in brain and plasma 15 min after CH. However, paraoxon treatment of animals did not affect the rate of metabolism of CH by homogenates of their livers. Paraoxon treatment increased the permeability of the blood brain barrier to TCE at 5 min, but not at 30 min, after the administration of CH. The increased brain permeability to TCE may partially explain the shortened IT of CH in animals. Decreased brain concentrations of CH and TCE at both the loss and return of the righting reflex indicated that paraoxon increased the sensitivity of the brain to the depressant action of these hypnotics. Paraoxon, known to cause hypoxia, also caused hypothermia. The paraoxon-induced hypothermia, but not the effects on IT and LORRT, was prevented at 36°C ambient temperature. A single dose of sodium nitrite produced effects similar to those of paraoxon on the hypnotic activity of CH and TCE. It is suggested that a decreased rate of metabolism and an increased sensitivity of the central nervous system due to hypoxia is the primary mechanism by which paraoxon shortens the IT and prolongs the LORRT of CH and TCE.

EVALUATION OF CYCLAMATE AND SACCHARIN

Publisher Summary After about 20 years of the widespread use of the cyclamates, and more than 80 years of the extensive worldwide use of saccharin, during which millions of people have consumed these agents for long periods of time, no evidence of adverse effects on human health has come to light. This fact does not prove that one or the other of these substances has not produced some subtle, insidious, harmful effect. The specific causes of long-delayed effects are often very difficult to identify. In the investigations of the toxicity and assessment of safety of the cyclamates and saccharin, the greatest attention has been directed toward the question of their possible carcinogenicity, especially for the urinary bladder. In the case of the cyclamates, the problems of possible cardiovascular damage and testicular atrophy have yet to be settled, though these issues do not appear to be critical. In the case of saccharin, the only remaining uncertainty seems to be the question whether it can produce malignant tumors in the urinary bladder. Numerous studies of the possible teratogenic, mutagenic, or other reproductive effects of these agents have not shown cause for undue concern in these respects.