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2595. A puff of aldehyde
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THE CHEMICAL ENVIRONMENT
2594. Placental transport of tell~dm Agnew, W. F. (1972). Transplacental uptake of 127mtellurium studied by whole-body autoradiography. Teratology 6, 331. Tellurium (Te) given to rats at a dietary level of 500 ppm on days 10-15 of gestation has been shown to cross the placental barrier and cause hydrocephalus in the offspring (Cited in F.C.T. 1973, 11, 337). Direct tissue counts and whole-body autoradiography have now been used to determine the specific localization of radioactive Te in rat foetuses at various stages of gestation following ip injection of the dams with a single dose of ~27mTe (0"250"35 mg/kg; 600/zCi) on day 7, 8, 9, 10, 11, 14, 15, 17 or 20. Each rat was anaesthetized 24 hr after the injection, maternal blood was sampled by cardiac puncture and the uterus was removed for study of the uterine horns, foetuses and placentae. No grossly toxic effects were observed in the 24 hr following injection. The levels of radioactivity in all the tissues studied, including the maternal blood, were less than 1 of the injected dose, but Te was shown to have reached the foetuses by days 9 and l0 of gestation (the period of sensitivity for hydrocephalus induction). As foetal age increased, an increasing restriction on Te transport was exercised by the placenta, the mean offspring/ maternal blood ratio of radioactivity decreasing from 0.3 on days 8-11 to 0.16 on days 12-21. Autoradiographs of late foetuses showed a marked accumulation of Te in the choroid plexus of the lateral and fourth ventricles and the development of a blood-brain barrier to Te was apparent by day 18. Relatively high Te levels in liver were demonstrated from day 12. The fact that hydrocephalus is the only foetal abnormality so far associated with Te administration during pregnancy and the present demonstration of its presence in the early embryo in significant quantities suggests that Te may act directly on embryonic rather than on maternal processes. Moreover, the preferential uptake of Te by the developing choroid plexus, which plays a crucial role in the elaboration and reabsorption of cerebrospinal fluid, suggests the interesting possibility that Te may interfere directly with choroid-plexus function.
2595. A puff of aldehyde Egle, J. L., Jr. (1972). Retention of inhaled acetaldehyde in the dog. Archs envir. Hlth 24, 354. Egle, J. L., Jr. (1972). Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Archs Path. 94, 119. Egle, J. L., Jr. (1972). Effects of inhaled acetaldehyde and propionaldehyde on blood pressure and heart rate. To.xic. appl. Pharmac. 23, 131. Aldehydes are important constituents of tobacco smoke. We have seen in a previous paper by the author cited above that, in man, the retention of acetaldehyde is independent of the depth of inhalation but may vary from 45-70% with increasing duration of ventilation (Cited in F.C.T. 1971, 9, 596). Since the concentration of acetaldehyde in tobacco smoke may approach 81/~g/40-ml puff, acetaldehyde retention may have a bearing on the development of cardiovascular disease (as the compound is a sympathomimetic) and on alterations in brain metabolism in smokers. A need for further investigation was therefore indicated. In the first paper cited, the author reports that, in dogs exposed to 0-4-0-8 #g acetaldehyde/ ml, total respiratory-tract retention varied from 61% for respiratory rates of 7-9/rain to
THE CHEMICAL ENVIRONMENT
923
44 % for rates of 44--70/min. These figures are very close to those already reported for the comparable study in man (Cited in F.C.T. 1971, 9, 596). Uptake of acetaldehyde was greater in the upper than in the lower respiratory tract, and was unrelated to tidal volume (within limits of 100-240 ml) or to inhaled concentration (tested over a range of 0.1-3.00 ~g/ml). The second paper reports a parallel study showing that the total respiratory-tract uptake of formaldehyde inhaled by dogs in concentrations in the range of 0.15-0.35/~g/ml was nearly complete and was considerably higher than the uptake of propionaldehyde (tested in the 0.4--0.6 #g/ml range) or acrolein (also tested at 0.4-0.6 #g/ml). The uptake of formaldehyde was close to 100% regardless of concentration, respiratory rate or tidal volume. Retention of acrolein was around 80 % regardless of the ventilatory rate or concentration, but showed some decline (from 86 to 77%) as tidal volume increased from 100 to 160 ml. Total-tract retention of propionaldehyde was also in the 75-80 ~o range, but this varied inversely with the ventilatory rate. Propionaldehyde retention was greater than that of acrolein in the lower respiratory tract and lower in the upper tract. The third paper describes how inhalation of 0.5-30 #g acetaldehyde/ml or 3-200 #g propionaldehyde/ml for 1-min periods affected the blood pressure and heart rate of anaesthetized rats. With acetaldehyde in concentrations of 3/~g/ml or more and with slightly higher concentrations of propionaldehyde, blood pressure rose significantly, falling back again to normal levels some 5 sec after exposure ceased. With acetaldehyde in concentrations of 12-25/~g/ml, the heart rate was accelerated, and slightly higher levels of propionaldehyde again had a similar effect. These findings indicate that higher concentrations of acetaldehyde and propionaldehyde than occur in cigarette smoke would probably be required to affect blood pressure and heart rate in man.
2596. Toxicity profile of 2-chloroethyl isocyanate Hofmann, A. u. Neufelder, M. (1972). Tierexperimentelle Untersuchungen zur gewerbetoxikologischen Beurteilung yon 2-Chlor~ithylisocyanat. Arch. Tox. 29, 73. The oral LDso of 2-chloroethyl isocyanate was found to be 396 mg/kg in male rats and 630 mg/kg in female mice. Lethal doses caused death within I-3 hr, and this was preceded by abrupt liberation of much stomach gas. Survivors suffered hair loss over the next 5 days, and at the end ofthe 7-day observation period autopsy revealed marked irritation and ridging of the stomach wall. When dropped into the rabbit eye, 5 ~1 of this isocyanate caused severe conjunctival irritation and diffuse superficial keratitis. Corneal transparency was not restored for 14 clays or more. Application to the skin in rabbits induced redness and mild swelling, and histological examination showed marked inflammatory changes and oedema of the dermis. Inhalation provoked no systemic toxicity but caused irritation of the respiratory tract. In rats, the inhalation LCso of 2-chloroethyl isocyanate was 6.3 ppm with a 6-hr exposure period. Rats exposed to 3.1-3.8 ppm for 10 days survived, but on examination 14 days later showed tracheobronchitis and bronchopneumonia, although no lesions were found elsewhere in the body. In view of these effects, a threshold limit value of 0.02 ppm 2-chloroethyl isocyanate is suggested. 2597. A carcinogenicity test on formaldehyde Rosenkranz, H. S. (1972). Formaldehyde as a possible carcinogen. Bull. env. contam. & Toxicol. (U.S.) 8, 242.
THE CHEMICAL ENVIRONMENT
2594. Placental transport of tell~dm Agnew, W. F. (1972). Transplacental uptake of 127mtellurium studied by whole-body autoradiography. Teratology 6, 331. Tellurium (Te) given to rats at a dietary level of 500 ppm on days 10-15 of gestation has been shown to cross the placental barrier and cause hydrocephalus in the offspring (Cited in F.C.T. 1973, 11, 337). Direct tissue counts and whole-body autoradiography have now been used to determine the specific localization of radioactive Te in rat foetuses at various stages of gestation following ip injection of the dams with a single dose of ~27mTe (0"250"35 mg/kg; 600/zCi) on day 7, 8, 9, 10, 11, 14, 15, 17 or 20. Each rat was anaesthetized 24 hr after the injection, maternal blood was sampled by cardiac puncture and the uterus was removed for study of the uterine horns, foetuses and placentae. No grossly toxic effects were observed in the 24 hr following injection. The levels of radioactivity in all the tissues studied, including the maternal blood, were less than 1 of the injected dose, but Te was shown to have reached the foetuses by days 9 and l0 of gestation (the period of sensitivity for hydrocephalus induction). As foetal age increased, an increasing restriction on Te transport was exercised by the placenta, the mean offspring/ maternal blood ratio of radioactivity decreasing from 0.3 on days 8-11 to 0.16 on days 12-21. Autoradiographs of late foetuses showed a marked accumulation of Te in the choroid plexus of the lateral and fourth ventricles and the development of a blood-brain barrier to Te was apparent by day 18. Relatively high Te levels in liver were demonstrated from day 12. The fact that hydrocephalus is the only foetal abnormality so far associated with Te administration during pregnancy and the present demonstration of its presence in the early embryo in significant quantities suggests that Te may act directly on embryonic rather than on maternal processes. Moreover, the preferential uptake of Te by the developing choroid plexus, which plays a crucial role in the elaboration and reabsorption of cerebrospinal fluid, suggests the interesting possibility that Te may interfere directly with choroid-plexus function.
2595. A puff of aldehyde Egle, J. L., Jr. (1972). Retention of inhaled acetaldehyde in the dog. Archs envir. Hlth 24, 354. Egle, J. L., Jr. (1972). Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Archs Path. 94, 119. Egle, J. L., Jr. (1972). Effects of inhaled acetaldehyde and propionaldehyde on blood pressure and heart rate. To.xic. appl. Pharmac. 23, 131. Aldehydes are important constituents of tobacco smoke. We have seen in a previous paper by the author cited above that, in man, the retention of acetaldehyde is independent of the depth of inhalation but may vary from 45-70% with increasing duration of ventilation (Cited in F.C.T. 1971, 9, 596). Since the concentration of acetaldehyde in tobacco smoke may approach 81/~g/40-ml puff, acetaldehyde retention may have a bearing on the development of cardiovascular disease (as the compound is a sympathomimetic) and on alterations in brain metabolism in smokers. A need for further investigation was therefore indicated. In the first paper cited, the author reports that, in dogs exposed to 0-4-0-8 #g acetaldehyde/ ml, total respiratory-tract retention varied from 61% for respiratory rates of 7-9/rain to
THE CHEMICAL ENVIRONMENT
923
44 % for rates of 44--70/min. These figures are very close to those already reported for the comparable study in man (Cited in F.C.T. 1971, 9, 596). Uptake of acetaldehyde was greater in the upper than in the lower respiratory tract, and was unrelated to tidal volume (within limits of 100-240 ml) or to inhaled concentration (tested over a range of 0.1-3.00 ~g/ml). The second paper reports a parallel study showing that the total respiratory-tract uptake of formaldehyde inhaled by dogs in concentrations in the range of 0.15-0.35/~g/ml was nearly complete and was considerably higher than the uptake of propionaldehyde (tested in the 0.4--0.6 #g/ml range) or acrolein (also tested at 0.4-0.6 #g/ml). The uptake of formaldehyde was close to 100% regardless of concentration, respiratory rate or tidal volume. Retention of acrolein was around 80 % regardless of the ventilatory rate or concentration, but showed some decline (from 86 to 77%) as tidal volume increased from 100 to 160 ml. Total-tract retention of propionaldehyde was also in the 75-80 ~o range, but this varied inversely with the ventilatory rate. Propionaldehyde retention was greater than that of acrolein in the lower respiratory tract and lower in the upper tract. The third paper describes how inhalation of 0.5-30 #g acetaldehyde/ml or 3-200 #g propionaldehyde/ml for 1-min periods affected the blood pressure and heart rate of anaesthetized rats. With acetaldehyde in concentrations of 3/~g/ml or more and with slightly higher concentrations of propionaldehyde, blood pressure rose significantly, falling back again to normal levels some 5 sec after exposure ceased. With acetaldehyde in concentrations of 12-25/~g/ml, the heart rate was accelerated, and slightly higher levels of propionaldehyde again had a similar effect. These findings indicate that higher concentrations of acetaldehyde and propionaldehyde than occur in cigarette smoke would probably be required to affect blood pressure and heart rate in man.
2596. Toxicity profile of 2-chloroethyl isocyanate Hofmann, A. u. Neufelder, M. (1972). Tierexperimentelle Untersuchungen zur gewerbetoxikologischen Beurteilung yon 2-Chlor~ithylisocyanat. Arch. Tox. 29, 73. The oral LDso of 2-chloroethyl isocyanate was found to be 396 mg/kg in male rats and 630 mg/kg in female mice. Lethal doses caused death within I-3 hr, and this was preceded by abrupt liberation of much stomach gas. Survivors suffered hair loss over the next 5 days, and at the end ofthe 7-day observation period autopsy revealed marked irritation and ridging of the stomach wall. When dropped into the rabbit eye, 5 ~1 of this isocyanate caused severe conjunctival irritation and diffuse superficial keratitis. Corneal transparency was not restored for 14 clays or more. Application to the skin in rabbits induced redness and mild swelling, and histological examination showed marked inflammatory changes and oedema of the dermis. Inhalation provoked no systemic toxicity but caused irritation of the respiratory tract. In rats, the inhalation LCso of 2-chloroethyl isocyanate was 6.3 ppm with a 6-hr exposure period. Rats exposed to 3.1-3.8 ppm for 10 days survived, but on examination 14 days later showed tracheobronchitis and bronchopneumonia, although no lesions were found elsewhere in the body. In view of these effects, a threshold limit value of 0.02 ppm 2-chloroethyl isocyanate is suggested. 2597. A carcinogenicity test on formaldehyde Rosenkranz, H. S. (1972). Formaldehyde as a possible carcinogen. Bull. env. contam. & Toxicol. (U.S.) 8, 242.