W. N. Aldridge

Further observations on the neurotoxicity of organophosphorus compounds

Abstract Twenty-two organophosphorus compounds have been given to adult hens to test their ability to produce a delayed neurotoxic effect like that produced by triorthocresyl phosphate. Fourteen compounds falling in several structurally homologous groups were active. All of them inhibited in vitro esterases of chicken CNS. No biochemical mechanism for this toxic effect can be put forward.

Trialkylleads and oxidative phosphorylation: A study of the action of trialkylleads upon Rat liver mitochondria and Rat brain cortex slices

Abstract A study has been made of the actions of trialkylleads upon processes associated with oxidative phosphorylation in rat liver mitochondria and rat brain slices. Trialkyltins and trialkylleads have similar actions upon these processes. This similar biochemical behaviour is consistent with similar chemical properties. However, their toxic effects in animals differ and these cannot be explained.

Action on mitochondria and toxicity of metabolites of tri-n-butyltin derivatives

Abstract Tri- n -butyltin derivatives are metabolized by a cytochrome P450-dependent rat liver microsomal monooxygenase system and by mice to yield carbon-hydroxylated metabolites, i.e. the α-, β-, γ- and δ-hydroxybutyl-dibutyltin derivatives, as well as the corresponding γ-ketone. The latter three metabolites are sufficiently stable at physiological pH for comparisons with tributyltin chloride with regard to their action on mitochondrial functions and intraperitoneal toxicity to mice. The δ-hydroxy compound differs most greatly from the other metabolites in potency for altering mitochondrial functions possibly because of its greater polarity or its lower propensity for intramolecular coordination of the introduced oxygen with the tin atom. The γ-hydroxy, δ-hydroxy and γ-keto compounds are less toxic to mice than tributyltin derivatives and do not increase the water content of the brain under conditions where triethyltin bromide does.

Esterases and neurotoxicity of some organophosphorus compounds.

Abstract The inhibition by organophosphorus compounds in vivo of two esterases present in chicken brain and spinal cord (phenyl phenyl-acetate and phenyl 3-phenylpropionate as substrates) has been studied. Although both esterases are inhibited by compounds which cause ataxia in chickens, they are also inhibited by those which do not. Therefore, inhibition of these esterases is unlikely to be involved in the production of the lesion in the chicken central nervous system.

Biochemical changes in rat liver after acute beryllium poisoning

Rats were injected intravenously with 0.75 mg Be/kg and the effects upon liver metabolism were investigated within the first 24 hr. Poisoned animals showed an impaired loss of liver glycogen during fasting. Studies upon the incorporation of labelled glucose into liver glycogen, the ability of poisoned livers to resynthesize glycogen and determination of the concentration of glucose-6-phosphate failed, however, to establish a relationship between changes in glycogen metabolism in vivo and the highly specific inhibition of phosphoglucomutase by beryllium in vitro. Microsomal, lysosomal and mitochondrial enzyme systems were little affected. Therefore, no specific action of beryllium was found and though a very powerful necrogenic agent, beryllium differs markedly from other hepatotoxins.

Increase in cerebral fluid in rats after treatment with triethyltin

Abstract After intravenous injection of triethyltinsulphate into rats the increase in cerebral water is influenced by the environmental temperature. If at 5° or 19° there is a delay of 12 hr before the brain water rises but if at 34° it rises from the time of injection. The sensitivity to triethyltin of the adenosine triphosphatase stimulated by Na + and K + has been reexamined. From both in vitro and in vivo experiments it is concluded that this enzyme is not directly involved in the increase in cerebral fluid.

TOXICOLOGICAL AND BIOCHEMICAL STUDIES ON SOME TRIALKYLGERMANIUM COMPOUNDS.

The toxicity of triethyl-and tri-n-butyl-germanium acetates has been studied after their administration to rats. Both compounds had a low toxicity. Triethylgermanium had less than one-tenth of the toxicity of triethyltin or triethyl-lead and, unlike them, it did not appear to have a predominant action on the central nervous system. In biochemical studies in vitro, tri-n-butylgermanium was found to be more active than trimethyl-, triethyl- or tri-n-propyl-germanium in inhibiting both glucose oxidation by slices of rat brain cortex and processes involved in oxidative phosphorylation by rat liver mitochondria. All the germanium compounds tested had less than one-hundredth the activity of the corresponding trialkyltin and trialkyl-lead compounds.

Studies on the metabolism of the pneumotoxin O,S,S-trimethyl phosphorodithioate. I. Lung and liver microsomes

The metabolism of O,S,S-trimethyl phosphorodithioate (OSSMe), a pneumotoxic impurity in some organophosphorus insecticides, was investigated in rat lung and liver microsomal preparations, using OSSMe labelled with 3H or 14C on one of its thiolo-methyl (CH3S-) groups. Production of O,S-dimethyl phosphorothioate (OSMeO-) and binding of radioactivity to protein were NADPH-dependent and were shown to be, at least partly, cytochrome P-450-dependent processes in both lung and liver microsomes. Incubation with reduced glutathione prevented the binding of radioactivity without affecting OSMeO- production. The Km for the conversion of OSSMe to OSMeO- was 15-fold lower in lung (0.30 +/- 0.07 mM) than in liver (4.63 +/- 2.42 mM) microsomes. These results show that cytochrome P-450-dependent mixed-function oxidase is implicated in at least part of the metabolic activation of OSSMe, and suggest that the pulmonary isozyme(s) are more active at metabolizing OSSMe than hepatic isozymes. It is speculated, on the basis of literature data on other sulphur-containing chemicals, that the metabolic activation of OSSMe involves oxidation of a thiolo-sulphur, with subsequent formation of CH3-S-S-protein disulphides.

Toxicology of Impurities in Malathion: Potentiation of Malathion Toxicity and Lung Toxicity Caused by Trialkyl Phosphorothioates

Organophosphorus compounds were first synthesised in the 1930s and because of their high toxicity were initially considered for use as chemical warfare agents. Since that time they have been developed for peaceful purposes and their effects on biological systems have been intensively studied. They are well known for their inhibition of acetylcholinesterase and there is considerable knowledge on their structure-activity relationships. The variety of directly toxic compounds is very large. Many compounds, although inactive in vitro, are metabolised in vivo to active inhibitors of esterases; this has greatly extended the range of toxic organophosphorus structures. It is not surprising therefore that amongst these structures, compounds are found with biological activities other than, and in addition to, those depending on inactivation of acetylcholinesterase. The range of structures and biological reactions are illustrated in figures 11.1 and 11.2.