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More about TRIS
Cosmetics,pharmaceuticalsand householdproducts-Fd Costnet.Toxicol.Vol. 18,no. 3 tration in the plasma was determined fluorometritally. Plasma testosterone concentrations were significantly lower in DEHP-treated rats than in the controls both before and after the administration of HCG, although HCG increased testosterone levels in both groups of rats. HCG stimulates androgen synthesis in the interstitial cells of the testes. It is suggested that the decrease in the secretion of testosterone produced by DEHP might lead to decreased testis weight and fertility.
PCB and reproduction
Orberg, J. (1978). Effects of pure chlorobiphenyls (2,4’,5-trichloiobiphenyl and 2,2’,4,4’,5,5’-hexachlorobiphenyl) on the post-natal growth in mice. Actu pharmac. tax. 42, 275.
Orberg J. (1979). Effects of pure chlorobiphenyls (2,4’,5trichlorobiphenyl and 2,2’,4,4’,5,5’-hexachlorobiphenyl) on the reproductive capacity in female mice. Acta pharmac. fox. 42, 323.
Polychlorinated biphenyls (PCBs) are persistent environmental contaminants which are likely to enter food chains. They have deleterious effects on reproduction in many animals (Barsotti et al. Fd Comet. Toxicol. 1976, 14, 99; Cired in F.C.T 1978 16, 289) and have been shown to be transferred from human mothers to foetuses and infants (Masuda et al. Fd Cosmet. Toxicol. 1978, 16, 543). Their effects upon reproductive capacity and post-natal growth and development are therefore of great interest. In the first experiment described, female mice were given 0.05 mg 2,4’,5-trichlorobiphenyl (TCB) or 0.05 mg 2,2’,4,4’,5,5’-hexachlorobiphenyl (HCB) from day 5 of gestation until day 22 after parturition and their offspring were studied. At birth, HCB-treated males were significantly heavier than either TCB-treated males or controls, and this difference was sustained
COSMETICS, PHARMACEUTICALS
325
until day 35 after birth. Females showed no weight difference until day 21, when HCB-treated females were heavier than controls and TCB-treated females. By day 35, both groups of treated females were significantly heavier than controls. The chlorobiphenyls affected the growth rates of the offspring. From day 21 to 35 the relative growth rates of both groups of treated males were significantly higher than those of control males. Fe author defined relative growth rate as the gain in body weight during the period, expressed as a percentage of the body. weight in the middle of the period, divided by the length of the period (O/dday).] During this period the absolute growth rate (bodyweight gain/day) of HCB-treated males was also significantly greater than that of control males. Both absolute and relative growth rates were greater in TCBtreated females than in HCB-treated or control females from day 21 to 35. From day 5 to 20 after birth in both males and females there were no significant differences in growth rates between the three groups. Further studies would be necessary to discover the physiological basis for the stimulation of growth rate by the two PCBs. The second experiment describes the effects on female mice of 0.05 or 0.5 mg HCB or TCB daily from day 1 to 6 of pregnancy. In both groups given the higher dose, frequencies of implanted ova were lower than in controls but at the lower dose no difference in implantation frequency appeared. The livers of mice given 0.5 mg HCB or 0.5 mg TCB daily contained higher concentrations of cytochrome P-450 on day 4 than those of animals taking the lower doses and of controls. There was no significant difference between animals given the same dose of HCB or TCB either in implantation frequency or in hepatic cytochrome P-450 levels.However, adipose tissue of HCB-treated mice contained a higher residual concentration than that of TCB-treated animals. No evidence emerged that biphenyls of high chlorine content have any more pronounced effect upon reproductive function than those of lower chlorine content.
AND HOUSEHOLD
PRODUCTS
absorption, has been demonstrated (ibid 1977, 15, 257; ibid 1980, 18, 207). In the study cited above Blum, A., Gold, M. D., Ames, B. N., Kenyon, C., the absorption by children of TRIS from treated Jones, F. R., Hett, E. A., Dougherty, R. C., Horning, E. C., Dzidic, I., Carroll, D. I., Stillwell, R. N. & The- sleepwearwas estimated by determining urinary levels not, J.-P. (1978). Children absorb tris-BP flame retar- of a TRIS metabolite, 2,3-dibromopropanol (DBP), dant from sleepwear: urine contains the mutagenic which is also mutagenic in the Ames test (Blum & Ames, Science, N.Y 1977, 195, 17). Urine from seven metabolite, 2,3-dibromopropanol. Science, N.Z 201, out of eight children wearing well-washed, TRIS1020. treated sleepwear contained about 0.5 ng DBP/ml, Tris-(2,3-dibromopropyl) phosphate (TRIS) has and that from an eighth child contained 5 ng DBP/ml. been shown to have genetic effects upon eukaryotic Traces of DBP were found in the urine of another cells as well as upon bacteria (Cited in F.C.T 1979, 17, child who was reported to have stopped wearing 98) and to produce skin tumours and stomach papil- TRIS-treated sleepwear 6 months earlier, but none of lomas after application to the skin of mice (ibid 1979, the TRIS metabolite was detected in the urine of a 17, 688). The migration of TRIS from fabrics during child and an adult who had never worn sleepwear’ laundering, and its variable degree of percutaneous treated with this flame retardant. More about TRIS
326
Test procedures, Experimental pathology--fd
A 7-year-old child, who had been wearing sleepwear that may have been treated with TRIS, wore new, TRIS-treated pyjamas *for 5 nights and then untreated sleepwear for the subsequent 5 nights. Morning urine samples were taken throughout the study. Before wearing the new, TRIS-treated pyjamas the child’s urine contained Q4ng DBP/ml. Samples taken after she had slept in the treated pyjamas contained up to 29 ng DBP/ml, and urine taken on the subsequent 5 days, when the child wore untreated
Cosmer. Toxicok Vol. 18, no. 3
sleepwear.contained DBP at levels of between 6 and 14 rig/ml. The amount of TRIS metabolite absorbed is likely to be substantially higher than is indicated by the level of DBP in the urine since such analysis does not account for the amounts of TRIS or its metabolites that are stored in body tissues or excreted in faeces. Such storage in the body may explain why DBP excretion in the urine continued even after exposure to treated garments had stopped.
TEST PROCEDURES Nitrosamiaes in test diets Walker, E. A., Castegnaro, M. & Griciute, L. (1979). N-Nitrosamines in the diet of experimental animals. Cancer Lett. 6, 175.
which was present in 91% of the samples at concentrations of up to 54ppb, although in the majority (75%) of the samples its concentration was only l-10 ppb. Other N-nitrosamines were also detected, generally at levels of less than 10ppb. N-NitrosoLast month we published an abstract of a report of diethylamine was present in 51% of samples,N-nitrothe presence of low levels of volatile N-nitrosamines sopiperidine in 19%, NPYR in 16%, N-nitrosodiproin laboratory-animal feeds (Cited in F.C.T. 1980, pylamine in 15% and N-nitrosodibutylamine in 9%. 18, 208. In an earlier study Katm et al. (Z. KrebsThe authors consider that the volatile N-nitrosforsch. 1977, 90, 321) found similar levels in 46 amines present in laboratory-animal feeds might consamples of such feeds: 37 of the samples contained tribute to the occurrence of spontaneous tumours in more than 1 ppb (b = 109) N-nitrosodimethylamine control animals. The incidence of these spontaneous (NDMA) and 27 contained more than 1 ppb N-nitro- tumours differs even among genetically pure strains of sopyrrolidine (NPYR). The authors of both these animals bred in different animal houses (Young & studies emphasized the need to minimize nitrosamine Hallowes in Pathology of Tumours in Laboratory Anilevels in laboratory-animal diets. Now a group of mals,p. 31, IARC, Lyon, 1973). It is suggested that an IARC workers report similar findings, but suggest international network of laboratories should be set up that these low levels of contamination of feeds with in which the levels of volatile N-nitrosamines in feeds compounds known to be animal carcinogens may be could be determined and compared with the incidence put to good experimental use. of tumours in control animals. Such collaboration Volatile N-nitrosamines were found to be common between laboratories would provide an economical contaminants in 87 samples of laboratory-animal method of acquiring data on the elfects of very low feeds. The most prevalent compound was NDMA, doses of N-nitrosamines in experimental animals.
EXPERIMENTAL
PATHOLOGY
Mapping organopbospbate-induced axonal degener- Tox. 1975, 34, 259). In the studies cited above, the ation spatial-temporal spread of axonal degeneration in organophosphorus neuropathy was investigated, and Bouldin, T. W. & Cavanagh, J. B. (1979). Organo- the authors have concluded that such neuropathy phosphorous neuropathy. I. A teased-fiber study of does not involve a dying-back pattern of degeneration the spatio-temporal spread of axonal degeneration. from the terminus of the axon, as was generally Am. J. Path. 94, 241. thought. Young adult cats were given a single ip injection of Bouldin, T. W. & Cavanagh, J. B. (1979). Organo- 40 mg di-isopropyl fluorophosphate/kg and were phosphorous neuropathy. II. A fine-structural study killed 14, 18, 20, 21 or 28 days later by intracardiac of the early stages of axonal degeneration. Am. J. infusion with aldehydes. Clinical signs of delayed Path; 94, 253. neurotoxicity appeared 16-18 days after dosing. A histological study of the central and peripheral nerSome organophosphorus compounds have delayed vous systemsrevealed the axonal degeneration at the neurotoxic effects in certain species,including man, distal ends of the long nerves that is typical of a causing irreparable ataxia and paralysis. About 8-14 dying-back neuropathy. However light-microscopic days after exposure the distal portions of the long examination of single nerve fibres teased from all axons of the central and peripheral nerves begin to levels of the left recurrent laryngeal nerve (LRLN) degenerate, and the first biochemical step in the pro- showed that although degeneration was limited to the duction~of the lesions is the inhibition of a nervous distal axons in the vast majority of fibres, it did not system enzyme, neurotoxic esterase (Johnson, Arch. begin at the axon terminus and progress back along
PCB and reproduction
Orberg, J. (1978). Effects of pure chlorobiphenyls (2,4’,5-trichloiobiphenyl and 2,2’,4,4’,5,5’-hexachlorobiphenyl) on the post-natal growth in mice. Actu pharmac. tax. 42, 275.
Orberg J. (1979). Effects of pure chlorobiphenyls (2,4’,5trichlorobiphenyl and 2,2’,4,4’,5,5’-hexachlorobiphenyl) on the reproductive capacity in female mice. Acta pharmac. fox. 42, 323.
Polychlorinated biphenyls (PCBs) are persistent environmental contaminants which are likely to enter food chains. They have deleterious effects on reproduction in many animals (Barsotti et al. Fd Comet. Toxicol. 1976, 14, 99; Cired in F.C.T 1978 16, 289) and have been shown to be transferred from human mothers to foetuses and infants (Masuda et al. Fd Cosmet. Toxicol. 1978, 16, 543). Their effects upon reproductive capacity and post-natal growth and development are therefore of great interest. In the first experiment described, female mice were given 0.05 mg 2,4’,5-trichlorobiphenyl (TCB) or 0.05 mg 2,2’,4,4’,5,5’-hexachlorobiphenyl (HCB) from day 5 of gestation until day 22 after parturition and their offspring were studied. At birth, HCB-treated males were significantly heavier than either TCB-treated males or controls, and this difference was sustained
COSMETICS, PHARMACEUTICALS
325
until day 35 after birth. Females showed no weight difference until day 21, when HCB-treated females were heavier than controls and TCB-treated females. By day 35, both groups of treated females were significantly heavier than controls. The chlorobiphenyls affected the growth rates of the offspring. From day 21 to 35 the relative growth rates of both groups of treated males were significantly higher than those of control males. Fe author defined relative growth rate as the gain in body weight during the period, expressed as a percentage of the body. weight in the middle of the period, divided by the length of the period (O/dday).] During this period the absolute growth rate (bodyweight gain/day) of HCB-treated males was also significantly greater than that of control males. Both absolute and relative growth rates were greater in TCBtreated females than in HCB-treated or control females from day 21 to 35. From day 5 to 20 after birth in both males and females there were no significant differences in growth rates between the three groups. Further studies would be necessary to discover the physiological basis for the stimulation of growth rate by the two PCBs. The second experiment describes the effects on female mice of 0.05 or 0.5 mg HCB or TCB daily from day 1 to 6 of pregnancy. In both groups given the higher dose, frequencies of implanted ova were lower than in controls but at the lower dose no difference in implantation frequency appeared. The livers of mice given 0.5 mg HCB or 0.5 mg TCB daily contained higher concentrations of cytochrome P-450 on day 4 than those of animals taking the lower doses and of controls. There was no significant difference between animals given the same dose of HCB or TCB either in implantation frequency or in hepatic cytochrome P-450 levels.However, adipose tissue of HCB-treated mice contained a higher residual concentration than that of TCB-treated animals. No evidence emerged that biphenyls of high chlorine content have any more pronounced effect upon reproductive function than those of lower chlorine content.
AND HOUSEHOLD
PRODUCTS
absorption, has been demonstrated (ibid 1977, 15, 257; ibid 1980, 18, 207). In the study cited above Blum, A., Gold, M. D., Ames, B. N., Kenyon, C., the absorption by children of TRIS from treated Jones, F. R., Hett, E. A., Dougherty, R. C., Horning, E. C., Dzidic, I., Carroll, D. I., Stillwell, R. N. & The- sleepwearwas estimated by determining urinary levels not, J.-P. (1978). Children absorb tris-BP flame retar- of a TRIS metabolite, 2,3-dibromopropanol (DBP), dant from sleepwear: urine contains the mutagenic which is also mutagenic in the Ames test (Blum & Ames, Science, N.Y 1977, 195, 17). Urine from seven metabolite, 2,3-dibromopropanol. Science, N.Z 201, out of eight children wearing well-washed, TRIS1020. treated sleepwear contained about 0.5 ng DBP/ml, Tris-(2,3-dibromopropyl) phosphate (TRIS) has and that from an eighth child contained 5 ng DBP/ml. been shown to have genetic effects upon eukaryotic Traces of DBP were found in the urine of another cells as well as upon bacteria (Cited in F.C.T 1979, 17, child who was reported to have stopped wearing 98) and to produce skin tumours and stomach papil- TRIS-treated sleepwear 6 months earlier, but none of lomas after application to the skin of mice (ibid 1979, the TRIS metabolite was detected in the urine of a 17, 688). The migration of TRIS from fabrics during child and an adult who had never worn sleepwear’ laundering, and its variable degree of percutaneous treated with this flame retardant. More about TRIS
326
Test procedures, Experimental pathology--fd
A 7-year-old child, who had been wearing sleepwear that may have been treated with TRIS, wore new, TRIS-treated pyjamas *for 5 nights and then untreated sleepwear for the subsequent 5 nights. Morning urine samples were taken throughout the study. Before wearing the new, TRIS-treated pyjamas the child’s urine contained Q4ng DBP/ml. Samples taken after she had slept in the treated pyjamas contained up to 29 ng DBP/ml, and urine taken on the subsequent 5 days, when the child wore untreated
Cosmer. Toxicok Vol. 18, no. 3
sleepwear.contained DBP at levels of between 6 and 14 rig/ml. The amount of TRIS metabolite absorbed is likely to be substantially higher than is indicated by the level of DBP in the urine since such analysis does not account for the amounts of TRIS or its metabolites that are stored in body tissues or excreted in faeces. Such storage in the body may explain why DBP excretion in the urine continued even after exposure to treated garments had stopped.
TEST PROCEDURES Nitrosamiaes in test diets Walker, E. A., Castegnaro, M. & Griciute, L. (1979). N-Nitrosamines in the diet of experimental animals. Cancer Lett. 6, 175.
which was present in 91% of the samples at concentrations of up to 54ppb, although in the majority (75%) of the samples its concentration was only l-10 ppb. Other N-nitrosamines were also detected, generally at levels of less than 10ppb. N-NitrosoLast month we published an abstract of a report of diethylamine was present in 51% of samples,N-nitrothe presence of low levels of volatile N-nitrosamines sopiperidine in 19%, NPYR in 16%, N-nitrosodiproin laboratory-animal feeds (Cited in F.C.T. 1980, pylamine in 15% and N-nitrosodibutylamine in 9%. 18, 208. In an earlier study Katm et al. (Z. KrebsThe authors consider that the volatile N-nitrosforsch. 1977, 90, 321) found similar levels in 46 amines present in laboratory-animal feeds might consamples of such feeds: 37 of the samples contained tribute to the occurrence of spontaneous tumours in more than 1 ppb (b = 109) N-nitrosodimethylamine control animals. The incidence of these spontaneous (NDMA) and 27 contained more than 1 ppb N-nitro- tumours differs even among genetically pure strains of sopyrrolidine (NPYR). The authors of both these animals bred in different animal houses (Young & studies emphasized the need to minimize nitrosamine Hallowes in Pathology of Tumours in Laboratory Anilevels in laboratory-animal diets. Now a group of mals,p. 31, IARC, Lyon, 1973). It is suggested that an IARC workers report similar findings, but suggest international network of laboratories should be set up that these low levels of contamination of feeds with in which the levels of volatile N-nitrosamines in feeds compounds known to be animal carcinogens may be could be determined and compared with the incidence put to good experimental use. of tumours in control animals. Such collaboration Volatile N-nitrosamines were found to be common between laboratories would provide an economical contaminants in 87 samples of laboratory-animal method of acquiring data on the elfects of very low feeds. The most prevalent compound was NDMA, doses of N-nitrosamines in experimental animals.
EXPERIMENTAL
PATHOLOGY
Mapping organopbospbate-induced axonal degener- Tox. 1975, 34, 259). In the studies cited above, the ation spatial-temporal spread of axonal degeneration in organophosphorus neuropathy was investigated, and Bouldin, T. W. & Cavanagh, J. B. (1979). Organo- the authors have concluded that such neuropathy phosphorous neuropathy. I. A teased-fiber study of does not involve a dying-back pattern of degeneration the spatio-temporal spread of axonal degeneration. from the terminus of the axon, as was generally Am. J. Path. 94, 241. thought. Young adult cats were given a single ip injection of Bouldin, T. W. & Cavanagh, J. B. (1979). Organo- 40 mg di-isopropyl fluorophosphate/kg and were phosphorous neuropathy. II. A fine-structural study killed 14, 18, 20, 21 or 28 days later by intracardiac of the early stages of axonal degeneration. Am. J. infusion with aldehydes. Clinical signs of delayed Path; 94, 253. neurotoxicity appeared 16-18 days after dosing. A histological study of the central and peripheral nerSome organophosphorus compounds have delayed vous systemsrevealed the axonal degeneration at the neurotoxic effects in certain species,including man, distal ends of the long nerves that is typical of a causing irreparable ataxia and paralysis. About 8-14 dying-back neuropathy. However light-microscopic days after exposure the distal portions of the long examination of single nerve fibres teased from all axons of the central and peripheral nerves begin to levels of the left recurrent laryngeal nerve (LRLN) degenerate, and the first biochemical step in the pro- showed that although degeneration was limited to the duction~of the lesions is the inhibition of a nervous distal axons in the vast majority of fibres, it did not system enzyme, neurotoxic esterase (Johnson, Arch. begin at the axon terminus and progress back along