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695. More kidney stones from ethylene glycol
620
PROCESSING AND PACKAGING CONTAMINANTS
tensive literature review, the authors have compared the fate and toxicity of these 3 types of organomercurials with those of inorganic mercuric compounds. The mercurials are all absorbed readily through the lungs and gastro-intestinal tract, but poorly through the skin. In practice, inhalation is the main route of absorption, although severe cases of poisoning have occurred, for example, following consumption of bread made from grain treated with a mercurial fungicide. During transport in the blood stream, the organic compounds are bound mainly to the erythrocytes, while the major part of the inorganic mercury is carried on the plasma proteins. The aryl, alkoxyalkyl and inorganic compounds disappear rapidly from the blood and accumulate in the kidneys, prior to excretion, but the fall in blood concentration is slower in the case of the alkyl mercurials and kidney levels are much lower. Levels of mercury in the brain are higher when an alkyl compound has been absorbed than after absorption of compound in the other groups, but this may reflect a higher level in the blood supply, rather than in the actual brain tissue. The higher blood level and lower kidney content following absorption of an alkyl mercuri~ll is reflected in a slower rate of excretion during a period of repeated administration, compared with that occurring during administration of the other types. These are excreted fairly rapidly, so long as the dose given is not large enough to injure the excretory organs. Only very small amounts of the alkyl compounds appear in the urine, the greater part being excreted in the faeces. The excretion rate of all groups increases with the amount given, and this rate increase probably continues until equilibrium is reached between the amounts administered and excreted. This point is reached later in the case of the alkyl compounds, i.e. when the concentration in the body is higher, and there is, therefore, a greater tendency for accumulation of compounds of this type than of the others. This difference offers an explanation for the fact' that cases of poisoning in man occur more frequently with alkyl than with other mercurials. Another factor which may make the alkyl compounds a more potent hazard is their volatility, which is generally higher than that of the aryls or alkoxyalkyls. The volatility of the alkyls can, however, be reduced by a careful choice of anion. [Readers will find a report of Berlin & Ullberg's autoradiographic studies on the behaviour of mercury in the mouse in these pages (Cited in F.C.T. 1964, 2, 73).]
PROCESSING AND PACKAGING CONTAMINANTS 695. More kidney stones from ethylene glycol Vaille, C., Debray, C., Martin, E., Souchard, M. & Roz6, C. (1964). Nature des concrrtions rrnales dans la lithiase exprrimentale h l'rthylrne-glycol chez le rat. Ann. pharm, franc. 22, 59. David, H. & Uerlings, Ingrid. (1964). Die Wirkung der Athylenglykolvergiftung auf das submikroskopische Bild der Rattenniere. Acta biol. reed. germ. 12, 203. Earlier papers by Vaille et al. (Cited in F.C.T. 1964, 2, 73) have discussed the deposition of calcium oxalate in the kidneys of rats given ethylene glycol (I) at 1 ~o in drinking water. A far higher incidence of kidney stones was found in male rats than in females and an attempt was made to explain this difference on the grounds of the different influence on metabolism exerted by the male and female hormones. The most recent paper in this series describes more precisely the nature of the crystals found in the kidneys of rats in which lithiasis has been induced by administration of I. On the basis of microscopic studies and infrared spectroscopy, it is concluded that the crystals consist almost exclusively of calcium oxalate monohydrate although in some cases of extreme lithiasis, there is some evidence for the presence of crystals of the trihydrate. The authors pose the question as to why the monohydrate is formed in preference to the trihydrate, but do not attempt an explanation. In some female rats, histological appearance
PROCESSING AND PACKAGING CONTAMINANTS
621
of the kidney suggested the presence of small deposits of calcium phosphate, but this could not be confirmed with the extraction methods used. David & Uerlings (cited above) make no distinction between the findings in male and female rats, but describe in some detail kidney changes detected with the electron microscope following daily administration of approximately 3 ml I/kg over a period of 1-6 days. There was no change in the submicroscopic structure of the glomerulus and effects in the distal region of the convoluted tubule were limited to a rise in liquid content, leading to increased vacuolation in the cells. In the proximal region, however, there were marked changes, including an increase in the cytosomes, which coalesced to form crystals. Lightmicroscope studies showed these to be calcium oxalate crystals, which were subsequently detached into the lumen where they formed larger accretions. The metabolic disruption caused by I also increased the production of the substances forming the tubular basal membrane, which consequently became thickened. In addition, necrotic and regenerative changes were seen in the epithelial cells. The necrotic cells were similar in appearance to those seen in cases of mercuric chloride or lead poisoning. It is suggested that I is eliminated via the glomerulus and then reabsorbed by the cells of the proximal tubules, where the metabolic disturbances result from changes in the ionic balance, due to accumulation of I and its degradation products, glycollic, oxalic and glyoxylic acids and glyoxal.
696. Toxicology of a PVC stabilizer Nothdurft, H. & Mohr, H.-J. (1964). Zur Vertrhglichkeit von 2-Phenylindol aufgrund langfristiger Fiitterungsversuche an Ratten. Arch. Toxikol. 20, 220. From time to time doubts have been cast about the suitability of 2-phenylindole (I) as a heat stabilizer for polyvinyl chloride which is to be used for food packaging. It is however recommended for this purpose, in concentrations up to 1 ~o, by the German Federal Office of Health and a number of studies of its toxicity have been carried out in W. Germany. Klimmer & Nebel (Arzneimittel-Forsch. 1960, 10, 44), for example, found the acute oral LD50 of I in rats to be above 6000 mg/kg and administered 100 mg I/day/rat by stomach tube for 2 months without causing any detectable damage. The present feeding trials were conducted in two parts. One test was continued for I yr and was designed particularly to demonstrate any histological damage, while the other was a 2-yr carcinogenicity test. Each test was carried out on a group receiving a diet containing 1000 ppm I, and a matched control group. This dietary level is equivalent to the ingestion of 50-100 mg/kg body weight/day or at least 3-7 g I/rat/yr. Rats were weighed at fortnightly intervals throughout the l-yr test and no difference in growth rate or terminal weight was detected between the test and control groups. It was concluded from this that the food consumption, which was not recorded, could not have been adversely affected by the presence of I in the diet. No deaths occurred during the year, but on completion of the test 15 control and 13 test animals were killed off for histological studies of the pancreas, stomach, small and large intestines, kidneys, adrenals, spleen, liver, sternum, thoracic wall, bladder, all sex organs, thymus, lungs, heart, skeletal muscle, lymph nodes from several sites, salivary glands, thyroid, parathyroid, hypophysis and brain. No significant differences between the test and control groups were found in any organs. No evidence of carcinogenic action was detected in the 2-yr test. Only 15 out of 152 test animals and 20 out of 200 controls survived to the end of the second yr, but the incidence of benign and malignant tumours was comparable in both groups. A similar pattern was also found in a third group of animals, in which the incidence of spontaneous tumours had been recorded for another investigation. Moreover, there was no increase in the frequency of occurrence of any particular type of tumour in the test group.
PROCESSING AND PACKAGING CONTAMINANTS
tensive literature review, the authors have compared the fate and toxicity of these 3 types of organomercurials with those of inorganic mercuric compounds. The mercurials are all absorbed readily through the lungs and gastro-intestinal tract, but poorly through the skin. In practice, inhalation is the main route of absorption, although severe cases of poisoning have occurred, for example, following consumption of bread made from grain treated with a mercurial fungicide. During transport in the blood stream, the organic compounds are bound mainly to the erythrocytes, while the major part of the inorganic mercury is carried on the plasma proteins. The aryl, alkoxyalkyl and inorganic compounds disappear rapidly from the blood and accumulate in the kidneys, prior to excretion, but the fall in blood concentration is slower in the case of the alkyl mercurials and kidney levels are much lower. Levels of mercury in the brain are higher when an alkyl compound has been absorbed than after absorption of compound in the other groups, but this may reflect a higher level in the blood supply, rather than in the actual brain tissue. The higher blood level and lower kidney content following absorption of an alkyl mercuri~ll is reflected in a slower rate of excretion during a period of repeated administration, compared with that occurring during administration of the other types. These are excreted fairly rapidly, so long as the dose given is not large enough to injure the excretory organs. Only very small amounts of the alkyl compounds appear in the urine, the greater part being excreted in the faeces. The excretion rate of all groups increases with the amount given, and this rate increase probably continues until equilibrium is reached between the amounts administered and excreted. This point is reached later in the case of the alkyl compounds, i.e. when the concentration in the body is higher, and there is, therefore, a greater tendency for accumulation of compounds of this type than of the others. This difference offers an explanation for the fact' that cases of poisoning in man occur more frequently with alkyl than with other mercurials. Another factor which may make the alkyl compounds a more potent hazard is their volatility, which is generally higher than that of the aryls or alkoxyalkyls. The volatility of the alkyls can, however, be reduced by a careful choice of anion. [Readers will find a report of Berlin & Ullberg's autoradiographic studies on the behaviour of mercury in the mouse in these pages (Cited in F.C.T. 1964, 2, 73).]
PROCESSING AND PACKAGING CONTAMINANTS 695. More kidney stones from ethylene glycol Vaille, C., Debray, C., Martin, E., Souchard, M. & Roz6, C. (1964). Nature des concrrtions rrnales dans la lithiase exprrimentale h l'rthylrne-glycol chez le rat. Ann. pharm, franc. 22, 59. David, H. & Uerlings, Ingrid. (1964). Die Wirkung der Athylenglykolvergiftung auf das submikroskopische Bild der Rattenniere. Acta biol. reed. germ. 12, 203. Earlier papers by Vaille et al. (Cited in F.C.T. 1964, 2, 73) have discussed the deposition of calcium oxalate in the kidneys of rats given ethylene glycol (I) at 1 ~o in drinking water. A far higher incidence of kidney stones was found in male rats than in females and an attempt was made to explain this difference on the grounds of the different influence on metabolism exerted by the male and female hormones. The most recent paper in this series describes more precisely the nature of the crystals found in the kidneys of rats in which lithiasis has been induced by administration of I. On the basis of microscopic studies and infrared spectroscopy, it is concluded that the crystals consist almost exclusively of calcium oxalate monohydrate although in some cases of extreme lithiasis, there is some evidence for the presence of crystals of the trihydrate. The authors pose the question as to why the monohydrate is formed in preference to the trihydrate, but do not attempt an explanation. In some female rats, histological appearance
PROCESSING AND PACKAGING CONTAMINANTS
621
of the kidney suggested the presence of small deposits of calcium phosphate, but this could not be confirmed with the extraction methods used. David & Uerlings (cited above) make no distinction between the findings in male and female rats, but describe in some detail kidney changes detected with the electron microscope following daily administration of approximately 3 ml I/kg over a period of 1-6 days. There was no change in the submicroscopic structure of the glomerulus and effects in the distal region of the convoluted tubule were limited to a rise in liquid content, leading to increased vacuolation in the cells. In the proximal region, however, there were marked changes, including an increase in the cytosomes, which coalesced to form crystals. Lightmicroscope studies showed these to be calcium oxalate crystals, which were subsequently detached into the lumen where they formed larger accretions. The metabolic disruption caused by I also increased the production of the substances forming the tubular basal membrane, which consequently became thickened. In addition, necrotic and regenerative changes were seen in the epithelial cells. The necrotic cells were similar in appearance to those seen in cases of mercuric chloride or lead poisoning. It is suggested that I is eliminated via the glomerulus and then reabsorbed by the cells of the proximal tubules, where the metabolic disturbances result from changes in the ionic balance, due to accumulation of I and its degradation products, glycollic, oxalic and glyoxylic acids and glyoxal.
696. Toxicology of a PVC stabilizer Nothdurft, H. & Mohr, H.-J. (1964). Zur Vertrhglichkeit von 2-Phenylindol aufgrund langfristiger Fiitterungsversuche an Ratten. Arch. Toxikol. 20, 220. From time to time doubts have been cast about the suitability of 2-phenylindole (I) as a heat stabilizer for polyvinyl chloride which is to be used for food packaging. It is however recommended for this purpose, in concentrations up to 1 ~o, by the German Federal Office of Health and a number of studies of its toxicity have been carried out in W. Germany. Klimmer & Nebel (Arzneimittel-Forsch. 1960, 10, 44), for example, found the acute oral LD50 of I in rats to be above 6000 mg/kg and administered 100 mg I/day/rat by stomach tube for 2 months without causing any detectable damage. The present feeding trials were conducted in two parts. One test was continued for I yr and was designed particularly to demonstrate any histological damage, while the other was a 2-yr carcinogenicity test. Each test was carried out on a group receiving a diet containing 1000 ppm I, and a matched control group. This dietary level is equivalent to the ingestion of 50-100 mg/kg body weight/day or at least 3-7 g I/rat/yr. Rats were weighed at fortnightly intervals throughout the l-yr test and no difference in growth rate or terminal weight was detected between the test and control groups. It was concluded from this that the food consumption, which was not recorded, could not have been adversely affected by the presence of I in the diet. No deaths occurred during the year, but on completion of the test 15 control and 13 test animals were killed off for histological studies of the pancreas, stomach, small and large intestines, kidneys, adrenals, spleen, liver, sternum, thoracic wall, bladder, all sex organs, thymus, lungs, heart, skeletal muscle, lymph nodes from several sites, salivary glands, thyroid, parathyroid, hypophysis and brain. No significant differences between the test and control groups were found in any organs. No evidence of carcinogenic action was detected in the 2-yr test. Only 15 out of 152 test animals and 20 out of 200 controls survived to the end of the second yr, but the incidence of benign and malignant tumours was comparable in both groups. A similar pattern was also found in a third group of animals, in which the incidence of spontaneous tumours had been recorded for another investigation. Moreover, there was no increase in the frequency of occurrence of any particular type of tumour in the test group.