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Acrylamide neurotoxicity under the microscope
Abstracts and comments--Fd Chem. Toxic. Vol. 20, No. 2 the exposure-response curve of Kuschner et al. (Ioc. cir.).
Acrylamide neurotoxicity under the microscope Burek, J. D., Albee, R. R., Beyer, J. E., Bell, T. J., Carreon, R. M, Morden, D. C., Wade, C. E., Hermann, E. A. & Gorzinski, S. J. (1980). Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recovery. J. envir. Path. Toxicol. 4 (5-6), 157. When we last discussed the neurotoxicity of acrylamide (Cited in F.C.T. 1981, 19, 395) we reported the results of a 13-wk study in Fischer rats. Although that study provided some useful information on the subchronic toxicity of the compound, it did not investigate fully the ultrastructural changes induced by acrylamide ingestion. Such changes have been examined in the present study in which groups of ten female and 23-29 male Fischer rats were given 0, 0'05, 0.2, 1, 5 or 20mg acrylamide/kg body weight/day in their drinkingwater for about 90 days. Ten males in each dose group were kept, untreated, for a further 144 days to observe recovery. The onset of neuropathy was evaluated by the landing foot-spread (hind-limb splaying) method following a drop from a height of 12 in. (ibid 1978, 16, t89). Autopsies were performed on 59 males and 60 females at the end of dosing and on four males from each dose group after the recovery period. Body weights were determined weekly, and blood and urine samples were taken during dosing and recovery. Nervous tissues were examined using light and electron microscopy. The effects observed at the end of the treatment period in the highest dose group---hind-limb neuropathy and decreased body-weight gain--were similar to those seen in the previous study (ibid 1981, 19, 395) but in addition atrophy of the skeletal muscle, testicular atrophy and distended urinary bladders were observed, possibly occurring as a result of nervous damage. After 144 days of recovery, the effects in the high-dose group were almost completely reversed. In the earlier study no adverse effects had been observed at the 5-mg/kg level but peripheral nerve degeneration was observed at this level in the present experiment. These effects were less marked than in the highdose group and appeared to have reversed completely after 111 days of recovery. In rats given 1 mg/kg/day, a minimal treatment-related effect was observed in males at the end of the treatment period, and this was limited to very slight nerve degeneration observed under the electron microscope (nervous tissue from females was not examined by electron microscopy). The degeneration appeared to have reversed after 25 days of recovery. No treatment-related effects were observed in any of the rats given 0"05 or 0"2 mg/kg/ day. The study demonstrates the apparent reversibility of acrylamide neurotoxicity in the rat, even following a large toxic insult. In addition, acrylamide-induced nervous tissue toxicity does not appear to be a 'dyingback' neuropathy; in this study the nervous lesions were observed to be multifocal and involved an
243
apparently random degeneration along individual axons. Some areas within a single axon were fragmented, some swollen, some had myelin loss and still others were normal. These changes were not found in a sequence, and apparently normal areas were often located between degenerative areas.
No teratogenicity from ethyl acrylate in rats Murray, J. S., Miller, R. R., Deacon, M. M., Hanley, T. R., Jr, Hayes, W. C., Rao, K. S. & John, J. A. (1981). Teratological evaluation of inhaled ethyl acrylate in rats. Toxic. appl. Pharmac. 60, 106. Ethyl acrylate is used extensively in the manufacture of a variety of plastics and resins. Its toxicity is low following inhalation exposure in a number of animal species. No significant adverse effects were observed in rats exposed to 70ppm ethyl acrylate for 7 hr/day liar 30 days (Pozzani et ai. j . imt. Hyg. Toxicol. 1949, 31, 311) and exposure of rabbits, guineapigs and rats to 75 ppm for 50 7-hr periods over 72 days caused no ill-effects (Treon et al. ibid 1949, 31, 317). However, the ACGIH has recently lowered its recommended TLV for ethyl acrylate for 25 to 5 ppm (TLVs: Threshold Limit Values for Chemical Substances and Physical Aoents in the Workroom Air with lntended Changes for 1981, p. 18. ACGIH, Cincinnati, OH, 1981). The authors cited above investigated the teratogenic potential of ethyl acrylate by exposing groups of 33 Sprague-Dawley rats, in inhalation chambers, to filtered room air, or to 50 or 150ppm ethyl acrylate for 6 hr/day on days 6--15 of gestation. The rats were killed on day 21 of gestation. Signs of maternal toxicity, including decreased weight gain and food consumption and increased water consumption, were observed at the 150-ppm exposure level. Exposure to ethyl acrylate had no effect on mean litter size, the incidence of resorptions or the foetal sex ratio. The mean body weight of foetuses of dams exposed to 150 ppm ethyl acrylate was significantly increased, but the authors concluded that this was not toxicologically significant. The incidence of major malformations was slightly but not significantly increased among foetuses in the 150-ppm exposure group. In this group three foetuses from three different litters had major malformations compared with none in either the lower dose group or the controls. A significant decrease in the incidence of delayed ossification of the cervical centra was observed in both of the groups exposed to ethyl acrylate compared with the controls, and there was a significantly lower number of foetuses with delayed ossification of the sternebrae in the group exposed at the higher level. However it was considered that these effects were not treatment related. The authors conclude on the basis of this study that inhalation of 50 or 150ppm ethyl acrylate during the stage of major organogenesis is not teratogenic in the rat.
Benzoyl peroxide is a promoter in mice Slaga, T. J., Klein-Szanto, A. J. P., Triplett, L. L., Yotti, L. P. & Trosko, J. E. (1981). Skin tumor-pro-
Acrylamide neurotoxicity under the microscope Burek, J. D., Albee, R. R., Beyer, J. E., Bell, T. J., Carreon, R. M, Morden, D. C., Wade, C. E., Hermann, E. A. & Gorzinski, S. J. (1980). Subchronic toxicity of acrylamide administered to rats in the drinking water followed by up to 144 days of recovery. J. envir. Path. Toxicol. 4 (5-6), 157. When we last discussed the neurotoxicity of acrylamide (Cited in F.C.T. 1981, 19, 395) we reported the results of a 13-wk study in Fischer rats. Although that study provided some useful information on the subchronic toxicity of the compound, it did not investigate fully the ultrastructural changes induced by acrylamide ingestion. Such changes have been examined in the present study in which groups of ten female and 23-29 male Fischer rats were given 0, 0'05, 0.2, 1, 5 or 20mg acrylamide/kg body weight/day in their drinkingwater for about 90 days. Ten males in each dose group were kept, untreated, for a further 144 days to observe recovery. The onset of neuropathy was evaluated by the landing foot-spread (hind-limb splaying) method following a drop from a height of 12 in. (ibid 1978, 16, t89). Autopsies were performed on 59 males and 60 females at the end of dosing and on four males from each dose group after the recovery period. Body weights were determined weekly, and blood and urine samples were taken during dosing and recovery. Nervous tissues were examined using light and electron microscopy. The effects observed at the end of the treatment period in the highest dose group---hind-limb neuropathy and decreased body-weight gain--were similar to those seen in the previous study (ibid 1981, 19, 395) but in addition atrophy of the skeletal muscle, testicular atrophy and distended urinary bladders were observed, possibly occurring as a result of nervous damage. After 144 days of recovery, the effects in the high-dose group were almost completely reversed. In the earlier study no adverse effects had been observed at the 5-mg/kg level but peripheral nerve degeneration was observed at this level in the present experiment. These effects were less marked than in the highdose group and appeared to have reversed completely after 111 days of recovery. In rats given 1 mg/kg/day, a minimal treatment-related effect was observed in males at the end of the treatment period, and this was limited to very slight nerve degeneration observed under the electron microscope (nervous tissue from females was not examined by electron microscopy). The degeneration appeared to have reversed after 25 days of recovery. No treatment-related effects were observed in any of the rats given 0"05 or 0"2 mg/kg/ day. The study demonstrates the apparent reversibility of acrylamide neurotoxicity in the rat, even following a large toxic insult. In addition, acrylamide-induced nervous tissue toxicity does not appear to be a 'dyingback' neuropathy; in this study the nervous lesions were observed to be multifocal and involved an
243
apparently random degeneration along individual axons. Some areas within a single axon were fragmented, some swollen, some had myelin loss and still others were normal. These changes were not found in a sequence, and apparently normal areas were often located between degenerative areas.
No teratogenicity from ethyl acrylate in rats Murray, J. S., Miller, R. R., Deacon, M. M., Hanley, T. R., Jr, Hayes, W. C., Rao, K. S. & John, J. A. (1981). Teratological evaluation of inhaled ethyl acrylate in rats. Toxic. appl. Pharmac. 60, 106. Ethyl acrylate is used extensively in the manufacture of a variety of plastics and resins. Its toxicity is low following inhalation exposure in a number of animal species. No significant adverse effects were observed in rats exposed to 70ppm ethyl acrylate for 7 hr/day liar 30 days (Pozzani et ai. j . imt. Hyg. Toxicol. 1949, 31, 311) and exposure of rabbits, guineapigs and rats to 75 ppm for 50 7-hr periods over 72 days caused no ill-effects (Treon et al. ibid 1949, 31, 317). However, the ACGIH has recently lowered its recommended TLV for ethyl acrylate for 25 to 5 ppm (TLVs: Threshold Limit Values for Chemical Substances and Physical Aoents in the Workroom Air with lntended Changes for 1981, p. 18. ACGIH, Cincinnati, OH, 1981). The authors cited above investigated the teratogenic potential of ethyl acrylate by exposing groups of 33 Sprague-Dawley rats, in inhalation chambers, to filtered room air, or to 50 or 150ppm ethyl acrylate for 6 hr/day on days 6--15 of gestation. The rats were killed on day 21 of gestation. Signs of maternal toxicity, including decreased weight gain and food consumption and increased water consumption, were observed at the 150-ppm exposure level. Exposure to ethyl acrylate had no effect on mean litter size, the incidence of resorptions or the foetal sex ratio. The mean body weight of foetuses of dams exposed to 150 ppm ethyl acrylate was significantly increased, but the authors concluded that this was not toxicologically significant. The incidence of major malformations was slightly but not significantly increased among foetuses in the 150-ppm exposure group. In this group three foetuses from three different litters had major malformations compared with none in either the lower dose group or the controls. A significant decrease in the incidence of delayed ossification of the cervical centra was observed in both of the groups exposed to ethyl acrylate compared with the controls, and there was a significantly lower number of foetuses with delayed ossification of the sternebrae in the group exposed at the higher level. However it was considered that these effects were not treatment related. The authors conclude on the basis of this study that inhalation of 50 or 150ppm ethyl acrylate during the stage of major organogenesis is not teratogenic in the rat.
Benzoyl peroxide is a promoter in mice Slaga, T. J., Klein-Szanto, A. J. P., Triplett, L. L., Yotti, L. P. & Trosko, J. E. (1981). Skin tumor-pro-