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96. Toxic effects in pigs of hexachloronaphthalene
126
GENERAL RESIDUES
ate]0) and malathion [O,O-dimethyl-S-(1,2-dicarbethoxyethyl) phosphorodithioate](II), has been reported to be more toxic than a simple addition of the toxic effects of each agent would have indicated CKarczmar et al., Fed. Prec. 1959, 18, 409). Potentiation of toxicity may be due to I protecting II from metabolic breakdown (Murphy & Dubois, Prec. Soc. exp. Biol., N . Y . 1957, 96, 813). Giving 1 before II should, if this is so, prove more toxic than giving either I and II simultaneously or II before I. Potentiation of inhibition of central nervous system cholinesterases has been described following combined I and H administration (Awad & Karczmar, Fed. Prec. 1960, 19, 276) but the relation of the degree of inhibition to toxicity is not known. The present paper reports a study carried out in dogs designed to show whether addition or potentiation of toxicity occurs, to investigate the relation of the degree of inhibition of central nervous system cholinesterases produced by I and II to toxic effects, and to determine the influence of giving various dosage sequences. In all the experiments in this study, dogs were given intravenous doses of technical grade I and II (97.8-98.0~o purity). It was found that at certain dose levels, regardless of the dosage sequence employed, combined administration of I and II produced deaths, in spite of the fact that the individual dose levels used were not lethal given singly and would not have been so on combined administration if simple addition of the toxic effects had occurred. At lower doses, potentiation was much influenced by the sequence of dosage. Five-fold potentiation resulted if l was given 30 min before II, a lesser effect followed simultaneous dosage of I and II and the least effect resulted when II preceded I. The time at which toxic effects appeared tended to be related to the period at which I reached its peak of effect i.e. 30 rain after administration. Potentiation of cortical and medullary acetylcholinesterase inhibition was observed when 2 mg I/kg was given before 10 mg II/kg but not by the other 2 dosage sequences; 3 mg I/kg and 60 mg ll/kg hob ever produced potentiation regardless of the dosage sequence. It was found that death due to I could be correlated with the degree of inhibition of central anticholinesterases, particularly the vital medullary enzyme. This is probably not so for II which inhibits the peripheral acetylcholinesterases to a greater extent than the central enzymes of which the medullary enzyme was less inhibited than the cortical acetylcholinesterase. II may well be toxic due to an effect unrelated to anticholinesterase inhibition. The ineffectiveness of oxime treatment in II poisoning supports this view. Karczmar, A. C., Awad, O. & Blachut, K. (1962). Toxicity arising from joint intravenous administration of EPN and malathion to dogs. Toxicol. appl. Pharmacol. 4, 133. 95. DIETARY HEXACHLOROBENZENE INDUCES CUTANEOUS PORPHYRIA Several thousand people in Turkey suffered from
cutaneous porphyria following the ingestion of flour containing 1-2 parts per thousand of hexachlorobenzene (I) (Trop. Dis. Bull. 1961, 58, 951). The effects on white rats of 1 month's ingestion of a diet containing 2 parts per thousand of I were studied. After 12-14 days obvious pathological changes were seen. The animals became thin and the fur became scanty, rough and brown. Haemorrhagic crusts formed on the brows, snouts and paws. In addition, there developed an abnormal stance, difficulty in standing and a deflection of the head to the right. After 12 days massive excretion of porphyrins in urine and faeces occurred. The animals died in an emaciated state in 3-6 weeks, when intense fatty degeneration of the liver with centrilobular necrosis was observed. After 14 days, half of the animals received in addition, subcutaneous injections of adenosine-5monophosphate (II) as a possible antidote. In these animals the liver changes were less severe and urinary porphyrin excretion was much lower or zero. After 14 days treatment with II, the skin lesions disappeared, and the fur improved; neurological signs were either arrested or did not appear, though emaciation was still present. Gajdos, A. & Gajdos-T6r6k, M. (1961). Porphyrie exp6rimentale du Rat blanc provoqu6e par l'hexachlorobenz6ne. Action th6rapeutique de l'acide ad6nosine-5-monophosphorique. C.R. Soc. Biol., Paris 155, 446.
96. TOXIC EFFECTS IN PIGS OF HEXACHLORONAPHTHALENE Hexachloronaphthalene (I) has many uses on farms as an insecticide. Accidental ingestion by cows, causes a condition characterized principally by the appearance of abnormally high amounts of keratin in the skin, extreme depression of plasma vitamin A levels and retarded growth or emaciation. Microscopic examination shows degeneration of the liver and kidney and abnormalities of the reproductive apparatus (Hansel et al. Cornell Vet. 1953, 43, 311 ; Bell, Vet. Med. 1953, 48, 135). I is known to be less toxic to sheep (Brock et al. Amer. J. Vet. Res. 1957, 18, 625), but the effects of I on pigs, the subject o f the present paper, have not so far been reported. Six pigs (8-weeks-old) were given 10 mg/kg body weight for 8 or 9 consecutive days. After 14 days the average plasma vitamin A level fell from 27-6.6 lag/100 ml in pigs receiving I and the animals showed reduced weight gains, depression and loss o f appetite. Some loss of control of the limbs was evidenced by the appearance of an abnormal gait. Histological examination showed the following lesions: degenerative changes of liver and kidneys, subacute interstitial duodenitis and keratinization o f the vaginal mucosa. Huber, W. G. & Link, R. P. (1962). Toxic effects o f bexachloronaphthalene on swine. Toxicol. appL Pharmacol. 4, 257.
GENERAL RESIDUES
ate]0) and malathion [O,O-dimethyl-S-(1,2-dicarbethoxyethyl) phosphorodithioate](II), has been reported to be more toxic than a simple addition of the toxic effects of each agent would have indicated CKarczmar et al., Fed. Prec. 1959, 18, 409). Potentiation of toxicity may be due to I protecting II from metabolic breakdown (Murphy & Dubois, Prec. Soc. exp. Biol., N . Y . 1957, 96, 813). Giving 1 before II should, if this is so, prove more toxic than giving either I and II simultaneously or II before I. Potentiation of inhibition of central nervous system cholinesterases has been described following combined I and H administration (Awad & Karczmar, Fed. Prec. 1960, 19, 276) but the relation of the degree of inhibition to toxicity is not known. The present paper reports a study carried out in dogs designed to show whether addition or potentiation of toxicity occurs, to investigate the relation of the degree of inhibition of central nervous system cholinesterases produced by I and II to toxic effects, and to determine the influence of giving various dosage sequences. In all the experiments in this study, dogs were given intravenous doses of technical grade I and II (97.8-98.0~o purity). It was found that at certain dose levels, regardless of the dosage sequence employed, combined administration of I and II produced deaths, in spite of the fact that the individual dose levels used were not lethal given singly and would not have been so on combined administration if simple addition of the toxic effects had occurred. At lower doses, potentiation was much influenced by the sequence of dosage. Five-fold potentiation resulted if l was given 30 min before II, a lesser effect followed simultaneous dosage of I and II and the least effect resulted when II preceded I. The time at which toxic effects appeared tended to be related to the period at which I reached its peak of effect i.e. 30 rain after administration. Potentiation of cortical and medullary acetylcholinesterase inhibition was observed when 2 mg I/kg was given before 10 mg II/kg but not by the other 2 dosage sequences; 3 mg I/kg and 60 mg ll/kg hob ever produced potentiation regardless of the dosage sequence. It was found that death due to I could be correlated with the degree of inhibition of central anticholinesterases, particularly the vital medullary enzyme. This is probably not so for II which inhibits the peripheral acetylcholinesterases to a greater extent than the central enzymes of which the medullary enzyme was less inhibited than the cortical acetylcholinesterase. II may well be toxic due to an effect unrelated to anticholinesterase inhibition. The ineffectiveness of oxime treatment in II poisoning supports this view. Karczmar, A. C., Awad, O. & Blachut, K. (1962). Toxicity arising from joint intravenous administration of EPN and malathion to dogs. Toxicol. appl. Pharmacol. 4, 133. 95. DIETARY HEXACHLOROBENZENE INDUCES CUTANEOUS PORPHYRIA Several thousand people in Turkey suffered from
cutaneous porphyria following the ingestion of flour containing 1-2 parts per thousand of hexachlorobenzene (I) (Trop. Dis. Bull. 1961, 58, 951). The effects on white rats of 1 month's ingestion of a diet containing 2 parts per thousand of I were studied. After 12-14 days obvious pathological changes were seen. The animals became thin and the fur became scanty, rough and brown. Haemorrhagic crusts formed on the brows, snouts and paws. In addition, there developed an abnormal stance, difficulty in standing and a deflection of the head to the right. After 12 days massive excretion of porphyrins in urine and faeces occurred. The animals died in an emaciated state in 3-6 weeks, when intense fatty degeneration of the liver with centrilobular necrosis was observed. After 14 days, half of the animals received in addition, subcutaneous injections of adenosine-5monophosphate (II) as a possible antidote. In these animals the liver changes were less severe and urinary porphyrin excretion was much lower or zero. After 14 days treatment with II, the skin lesions disappeared, and the fur improved; neurological signs were either arrested or did not appear, though emaciation was still present. Gajdos, A. & Gajdos-T6r6k, M. (1961). Porphyrie exp6rimentale du Rat blanc provoqu6e par l'hexachlorobenz6ne. Action th6rapeutique de l'acide ad6nosine-5-monophosphorique. C.R. Soc. Biol., Paris 155, 446.
96. TOXIC EFFECTS IN PIGS OF HEXACHLORONAPHTHALENE Hexachloronaphthalene (I) has many uses on farms as an insecticide. Accidental ingestion by cows, causes a condition characterized principally by the appearance of abnormally high amounts of keratin in the skin, extreme depression of plasma vitamin A levels and retarded growth or emaciation. Microscopic examination shows degeneration of the liver and kidney and abnormalities of the reproductive apparatus (Hansel et al. Cornell Vet. 1953, 43, 311 ; Bell, Vet. Med. 1953, 48, 135). I is known to be less toxic to sheep (Brock et al. Amer. J. Vet. Res. 1957, 18, 625), but the effects of I on pigs, the subject o f the present paper, have not so far been reported. Six pigs (8-weeks-old) were given 10 mg/kg body weight for 8 or 9 consecutive days. After 14 days the average plasma vitamin A level fell from 27-6.6 lag/100 ml in pigs receiving I and the animals showed reduced weight gains, depression and loss o f appetite. Some loss of control of the limbs was evidenced by the appearance of an abnormal gait. Histological examination showed the following lesions: degenerative changes of liver and kidneys, subacute interstitial duodenitis and keratinization o f the vaginal mucosa. Huber, W. G. & Link, R. P. (1962). Toxic effects o f bexachloronaphthalene on swine. Toxicol. appL Pharmacol. 4, 257.