J. R. P. Cabral

Investigation of the acute toxicity of some trimethyl and triethyl phosphorothioates with particular reference to those causing lung damage

The acute toxicity of trimethyl and triethylphosphorothioates present as impurities in technical organophosphorus insecticides has been examined in rats. Although the majority of these compounds caused cholinergic signs, in some a second phase of toxicity affecting the lung was also seen. Rats after recovering from the cholinergic phase of poisoning showed respiratory distress and died 3–6 days after dosing with a massive increase in lung weight, associated with progressive diffuse interstitial thickening maximal on day 4. For two compounds no cholinergic toxicity was observed and narcosis was the predominant sign of poisoning.Pretreatment with phenobarbitone, piperonyl butoxide or SKF525A protected rats against lung toxicity caused by trimethylphosphorothioate and dithioate but only phenobarbitone was effective against OOS-triethylphosphorothioate lung toxicity.Direct intrabronchial instillation of OSS-trimethylphosphorodithioate and OOS-triethylphosphorothioate, both of which had been shown to cause lung damage after other routes of dosing, did not greatly increase the toxicity of these two compounds, suggesting that they are not directly toxic to the lung and probably require metabolism.

Cellular responses to trialkylphosphorothioate-induced injury in rat lung

Various trialkylphosphorothioates occur as impurities in many organophosphorus pesticides. In addition to the immediate, cholinergic symptoms usually associated with the toxicity of organophosphorus compounds an oral LD50 dose of O,S,S-trimethyl phosphorodithioate or O,O,S-triethyl phosphorothioate to rats, resulted in the delayed development of lung lesions and often death within 4 days.This study attributes the late crisis to impaired lung function resulting from massive alveolar oedema and cellular responses to the selective destruction of type I pneumocytes. Proliferation of type II pneumocytes produced an epithelium of very large cells which resulted in a thick blood/alveolus barrier and also occluded much of the alveolar lumen. Debris from the type I pneumocytes was liberated into the alveolar lumen resulting in leukocytic infiltration of the interstitial tissue and an increase in the number of alveolar macrophages.The lung morphology of animals surviving the crisis period returned to normal within a further 4 days with the transformation of many hypertrophic type II pneumocytes into type I alveolar lining cells.

Goitre and wasting induced in hamsters by hexachlorobenzene

Male Syrian hamsters were treated with hexachlorobenzene (HCB) in their diet at levels of 100 ppm for 28 weeks, 200 ppm for 18 and 28 weeks, and 500 ppm for 6 weeks. All treatments caused at least a 2.5- to 3-fold increase in thyroid size, mainly by enlargement of some follicles. Serum thyroxine (T4) levels were unchanged, whereas levels of triiodothyronine (T3) eventually became depressed by >60%. Uptake of 131I into thyroids was induced approximately 3-fold when estimated after feeding HCB (500 ppm) for 3 or 6 weeks. Hamsters also lost weight by depletion of adipose tissue, leading to 50% mortality in longer experiments. Results were distinct from the effects of the known antithyroid agent 3-aminotriazole or amitrole (200 ppm for 28 weeks), which did not affect survival and although causing thyroid enlargement depressed serum T4 and significantly elevated T3. The effects of HCB in hamsters were also different from those in rats (500 ppm HCB for 6 weeks) in which there was only a small increase in thyroid size (1.3-fold), serum levels of T3 were only slightly depressed but T4 levels were reduced by 74%. These studies are discussed with reference to the effects of other polyhalogenated aromatic chemicals on the thyroid, serum thyroid hormone levels and lethality.

Carcinogenicity study of the pesticide maleic hydrazide in mice

The carcinogenicity of the pesticide maleic hydrazide (MH) was studied in C57BL/B6 mice. After subcutaneous (s.c.) administration no significant increase in the incidence of liver-cell tumours was seen over that in solvent-treated controls, and although a statistically significant difference in the incidence of liver-cell tumours was observed between treated and untreated males, this was considered biologically inadequate as evidence of carcinogenic effect. When MH was administered orally, no significant increase in the incidence of liver-cell tumours was seen. These results partially confirm the negative finding of a recent parallel study in rats [1].

Sex Difference in the Susceptibility of Rats to the Development of Porphyria and Hepatic Tumours caused by Hexachlorobenzene

The hypolipidaemic agent nafenopin (Su-13437) belongs to a class of structurally diverse compounds which induce a proliferation of the hepatic peroxisome compartment after short-term treatment. Life-long feeding of such compounds is associated with an increased incidence of liver tumours. However, the mechanism by which such compounds induce these tumours is not known, nor is it clear whether a causal relation exists between the peroxisome proliferation and the hepatocarcinogenicity. Nafenopin is not mutagenic in the standard Ames test or in several other tests for genotoxic activity. However, nafenopin is known to induce certain mono-oxygenase activities and to alter the pattern of cytochrome P-450 isoenzymes. Consequently, it may be more appropriate to assess the mutagenic activity of nafenopin by using an activating system isolated from animals pretreated with the compound. Nafenopin also induces several peroxisomal oxidase activities, particularly fatty acid ~-oxidation. Thus it is conceivable that excess hydrogen peroxide production associated with this enzyme induction may lead to oxidative DNA damage as suggested by Reddy et al. (1980). We have tested both these possibilities. Nafenopin was not mutagenic to Salmonella typhimurium TA 98, TA 100, TA 1535, TA 1537, TA 1538 or TA 102 either directly or after activation by S-9 fractions isolated from control, Aroclor 1254or nafenopin-treated rats, in the presence or absence of uridine diphosphate (UDP)-glucuronic acid. However, treatment of rats with nafenopin (200 mg/kg for 7 days) or the structurally related clofibrate (300 mg/kg for 7 days) was accompanied by slight increases in the amount of hepatic nuclear DNA eluted from polycarbonate filters (3 )JLm pore size) under alkaline conditions. In a 5 h elution period (6 ml/h) 6.7% of the DNA from control rats was eluted from the filters (n = 23). This value was increased about 3.5-fold by clofibrate treatment (n = 8) and 2-fold by nafenopin treatment (n = 11). Further studies suggested that hydrogen peroxide was not responsible for the observed effects. The significance of these findings is under investigation.