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Chlorinated hydrocarbons and the liver
588
The chemical environment
The paper cited above points to some more factors relevant to the question of Cr allergy. Aqueous solutions of various Cr vt and Cr'" compounds, in concentrations of 5~o with 2~o Triton X-100, were applied to the shaved skin of guinea-pigs on ten occasions at intervals of 24 hr. Tests for sensitization were made by applying 0'5~o solutions of the various compounds after an interval of 8 wk or more. The Cr w compounds (chromate and dichromate) elicited a high degree of sensitization. Tests with Cr rl~ compounds in the form of the hydrated chloride, a urea complex or the triethylenediamine chelate demonstrated a sensitizing capacity inversely proportional to the strength of Cr bonding in the complex, while waterinsoluble Cr nl compounds showed only weak sensitizing potential. 2917. More data on children exposed to lead Landrigan, P. J., Whitworth, R. H., Baloh, R. W., Staehling, N. W., Barthel, W. F. & Rosenblum, B. F. (1975). Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet I, 708. A major issue in connexion with the possible effects of environmental lead on children is the question of whether blood levels of 40-80#g/100ml have an adverse effect on the nervous system (Cited in F.C.T. 1975, 13, 280). Claims have been made in the past that blood-lead levels of this order might result in behavioural abnormalities, a slight impairment of voluntary muscle activity and weakness of peripheral nerves (ibid 1975, 13, 281). The findings were not consistent, however, and in an attempt at further clarification, the authors cited above examined a group of 46 children between the ages of 3 and 15 yr who were symptom-free but who had blood-lead concentrations of 40-68 #g/100 ml and a second group of 78 comparable children with individual blood-lead levels below 40/~g/100 ml and a group mean of 27 #g/100 ml. All the children lived near a large lead-emitting oresmelter in Texas. Special intelligence tests designed to evaluate performance IQ indicated that the children with the high blood-lead levels performed less well than the children with the lower levels, but ratings of full-scale IQ, general behaviour and hyperactivity did not differ between the two groups. Clinically, the children with a high blood-lead level showed some weakness of the muscles of the forearm compared with the control group, a finding which may have been an indication of low-grade motor neuropathy. 2918. Tellurium on the brain Agnew, W. F., Snyder, D. A. & Cheng, J. T. (1974) Metabolic inhibition of iodide transport in choroid plexus and ciliary body by tellurium and selenium. Microvasc. Res. 8, 156. It has been shown in rats that tellurium (Te) crosses the placental barrier and causes hydrocephalus in offspring, the phenomenon being associated with Te accumulation in the choroid plexus of the lateral and fourth ventricles of the brain (Cited in F.C.T. 1973, 11,922). In unpublished work mentioned in the paper cited above, prolonged feeding of Te to rats resulted in Te accumulation in the ciliary body of the eye.
The paper cited reports in vitro and in vivo experiments designed to show whether Te accumulation in these two areas is due to active transport and to compare the effects of Te and selenium (Se) on the active transport of iodide in the choroid plexus and ciliary body. When incubated for i hr with 127mTe (as tellurite), the isolated ciliary body (dissected out with the iris) or choroid plexus of the rabbit showed a roughly fivefold concentration of Te compared with the content of the surrounding medium. This accumulation of Te was not inhibited by digitoxin or by thiocyanate, but iodoacetate, which blocks anaerobic glycolysis, significantly decreased the Te uptake of the ciliary body although not of the choroid plexus, pChloromercuribenzoate, which has been shown to block the binding of Te to protein, decreased Te uptake by both types of tissue. Both tellurite and selenite reduced the iodine-131 (131I) uptake of these tissues significantly in vitro. The in vivo effect of intramuscular injections of finely powdered metallic Te or Se given in doses of 50 mg/kg twice weekly for 4 wk was also studied. Te injections inhibited ~3~I transport by the ciliary body and choroid plexus, while Se injections did not. These results indicate that Te accumulation depends mainly on protein-binding rather than on an active transport process. It appears that Te is enzymically active and is able to inhibit at least one energydependent transport system in the choroid plexus. This activity, combined with the ability of Te to cross the placental barrier and accumulate selectively in the foetal choroid plexus, provides some explanation for the hydrocephalus-inducing potential of Te. 2919. Chlorinated hydrocarbons and the liver Traiger, G. J. & Plaa, (1974). Chlorinated hydrocarbon toxicity. Potentiation by isopropyl alcohol and acetone. Archs envir. Hlth 28, 276. It has already been shown that pretreatment of dogs with ethanol potentiates the hepatotoxicity of chloroform and carbon tetrachloride, but not that of trichloroethylene or 1,1,1-trichloroethane (Cited in F.C.T. 1968, 6, 808). It appears, therefore, that ethanol potentiates the effects only of those chlorinated hydrocarbons that already possess marked hepatotoxicity. Now the picture has been extended to cover the possible influence of isopropanol and its metabolite, acetone, on the hepatotoxicity of chlorinated solvents. Mice were given acetone or isopropanol in an orally intubated dose of 2.5 ml/kg (as a 25~o, v/v, solution) 18 hr before receiving an ip injection of chloroform, trichloroethylene or 1,1,1- or 1,1,2-trichloroethane. The chlorinated hydrocarbons were given in corn oil in a range of doses around the threshold for induction of liver damage, as assessed by an increase in the activity of serum glutamic pyruvic transaminase (SGPT). The known hepatotoxicities of the chlorinated hydrocarbons tested decrease in the following order: chloroform > 1,1,2-trichloroethane > trichloroethylene> 1,1,1-trichloroethane. The augmentation of hepatotoxicity by prior treatment with acetone or isopropanol correlated with this ranking, potentiation being maximal with chloroform and negligible with
The chemical environment l,l,l-trichloroethane. Both acetone and isopropanol potentiated the hepatotoxicity of doses of 1,1,2-trichloroethane that, when administered alone, had no effect on SGPT activity. With trichloroethylene, a dose of 1-5 mg/kg was required to demonstrate any marked potentiation by isopropano'l. Preliminary studies indicate that similar effects are exerted by inhaled acetone or isopropanol, both of which are commonly encountered industrial solvents, but while further work on this aspect is clearly required, the current study suggests that the likelihood of hazardous interaction between these two types of solvent should be largely predictable on the basis of the hepatotoxic potential of the halogenated hydrocarbon.
2920. Hepatitis in workers exposed to diaminodiphenylmethane McGill, D. B. & Motto, J. D. (1974). An industrial outbreak of toxic hepatitis due to methylenedianiline. New Engl. J. Med. 291,278. The hepatotoxicity of 4,4'-diaminodiphenylmethane (DDM) has been demonstrated in a variety of animal species (Cited in F.C.T. 1967, 5, 115; ibid 1975, 13, 480) and, following the accidental contamination of a bag of flour, also in man (ibid 1967, 5, 120). However, the paper cited above apparently provides the first report of liver damage resulting from industrial handling. Between 1966 and 1972, 12 cases of hepatitis were identified among workers in a large manufacturing firm. All the cases involved men employed in folding and kneading with cloth-gloved hands a hot epoxyresin mixture containing 10% DDM. The mixture was subsequently cooled and pulverized into a fine powder which settled rapidly on workers and their surroundings, but the provision of masks and exhaust ventilation was thought to obviate any inhalation hazard. The atmospheric concentration of DDM in 1969, checked after the first three cases of hepatitis had been reported, was 0.1 ppm, and in 1971 (after diagnosis of a further five cases) this was lowered to 0"018ppm by the installation of more exhaust vents. However, this and other measures, including partial enclosure of the work area, daily clean overalls and showers, failed to prevent another two cases. The atmospheric concentration of DDM was subsequently lowered to 0-0064 ppm and the wearing of protective helmets with separate air supplies became mandatory, but in spite of this two further cases occurred. At this stage, oral and dermal treatment of rabbits with floor sweepings from the mill provided further evidence that DDM was the cause of the hepatitis. Sweepings collected after addition of DDM to the reaction mixture produced clear evidence of hepatotoxicity in the animals, while those collected earlier and shown to be free of DDM gave negative results. Orily by the introduction of complete air-supplied PVC suits with attached rubber gloves, and the subsequent development of a fully-enclosed automated blending system, were further cases finally prevented. Symptoms displayed by the victims included weakness, jaundice and dark urine, accompanied in the majority by abdominal pain, nausea and vomiting and sometimes also by headache, acholic stools, prur-
589
itus, rashes and pains in the muscles and joints. Biochemical evidence of liver damage was provided by greatly increased serum levels of bilirubin, glutamicoxalacetic transaminase and alkaline phosphatase. All those affected became ill within 1-18 days of working intensively with DDM and recovered within 7 wk. Similar symptoms were displayed by a worker in another company, temporarily contracted to pulverize DDM. Of 21 other similarly exposed workers who were interviewed, four recalled symptoms apparently consistent with hepatitis. The gloves of the men handling the resin mixture always became ragged, holey and saturated with the material, and it appeared likely that the chief route of entry for DDM was through the skin of the hands. When re-examined between 9 months and 5"5 yr later, none of these hepatitis patients showed any clinical or biochemical evidence of chronic liver disease.
2921. Carcinogenesis by 3,3'-diehlom-4,4'-diaminodiphenyl ether Herrmann, I. F., Schauer, A. u. Kamke, W. (1973). Morphologische und histochemische Untersuchungen w~hrend der Cancerogenese des ~iusseren Geh6rganges der Ratte, induziert durch 3.3'Dichlor-4,4'diaminodiphenyl~ther. Arch. Oto-Rhino-Lar. 206, 11. The possibility that administration of 3,Y-dichloro4,4'-diaminodiphenylether (DDDE) to rats might induce carcinoma of the auditory canal was first suggested by Steinhoff & Grundmann (Naturwissenschaften 1970, 57, 676). The present paper describes the appearance of multiple lesions of the epithelium of the auditory canal and/or deep ceruminal gland in rats after administration of 400 mg DDDE/kg/wk for a total period of 200-340 days by sc injection into the back. In all the animals undergoing this treatment, these tissues showed sharply defined areas of high alkalinephosphatase activity and reduced lactate-dehydrogenase and NADH-dehydrogenase activity, compared with the same regions in untreated animals or with the regenerating epithelium of rats in which the superficial tissue of the auditory canal and gland had been deliberately damaged. 5-Bromoindoxyl-acetate esterase activity, which is characteristically high in sebaceous-gland tissue, was lost in the same areas in the DDDE-treated animals. After 310 days, foci of epithelial hyperplasia and a high incidence of papillomas and adenomas were evident in the DDDE-affected areas and after 390 days four of the treated animals showed papillary carcinomas, squamous-cell carcinomas and carcinomas of the ceruminal gland. The enzyme changes detected in this study in the early stages of ear-duct and sebaceous-gland carcinogenesis are similar to those that have been shown to occur in the early stages of neoplasia of the nasal mucous membranes.
2922. Teratogenie approach to DES problem Staff, A. & Mattingly, R. F. (1974). Vaginal adenosis: A precancerous lesion? Am. J. Obstet. Gynec. 120, 666. An interesting view has recently been put forward in connexion with the occurrence of vaginal adenocarcinoma in young girls exposed prenatally to diethylstilboestrol (DES).
The chemical environment
The paper cited above points to some more factors relevant to the question of Cr allergy. Aqueous solutions of various Cr vt and Cr'" compounds, in concentrations of 5~o with 2~o Triton X-100, were applied to the shaved skin of guinea-pigs on ten occasions at intervals of 24 hr. Tests for sensitization were made by applying 0'5~o solutions of the various compounds after an interval of 8 wk or more. The Cr w compounds (chromate and dichromate) elicited a high degree of sensitization. Tests with Cr rl~ compounds in the form of the hydrated chloride, a urea complex or the triethylenediamine chelate demonstrated a sensitizing capacity inversely proportional to the strength of Cr bonding in the complex, while waterinsoluble Cr nl compounds showed only weak sensitizing potential. 2917. More data on children exposed to lead Landrigan, P. J., Whitworth, R. H., Baloh, R. W., Staehling, N. W., Barthel, W. F. & Rosenblum, B. F. (1975). Neuropsychological dysfunction in children with chronic low-level lead absorption. Lancet I, 708. A major issue in connexion with the possible effects of environmental lead on children is the question of whether blood levels of 40-80#g/100ml have an adverse effect on the nervous system (Cited in F.C.T. 1975, 13, 280). Claims have been made in the past that blood-lead levels of this order might result in behavioural abnormalities, a slight impairment of voluntary muscle activity and weakness of peripheral nerves (ibid 1975, 13, 281). The findings were not consistent, however, and in an attempt at further clarification, the authors cited above examined a group of 46 children between the ages of 3 and 15 yr who were symptom-free but who had blood-lead concentrations of 40-68 #g/100 ml and a second group of 78 comparable children with individual blood-lead levels below 40/~g/100 ml and a group mean of 27 #g/100 ml. All the children lived near a large lead-emitting oresmelter in Texas. Special intelligence tests designed to evaluate performance IQ indicated that the children with the high blood-lead levels performed less well than the children with the lower levels, but ratings of full-scale IQ, general behaviour and hyperactivity did not differ between the two groups. Clinically, the children with a high blood-lead level showed some weakness of the muscles of the forearm compared with the control group, a finding which may have been an indication of low-grade motor neuropathy. 2918. Tellurium on the brain Agnew, W. F., Snyder, D. A. & Cheng, J. T. (1974) Metabolic inhibition of iodide transport in choroid plexus and ciliary body by tellurium and selenium. Microvasc. Res. 8, 156. It has been shown in rats that tellurium (Te) crosses the placental barrier and causes hydrocephalus in offspring, the phenomenon being associated with Te accumulation in the choroid plexus of the lateral and fourth ventricles of the brain (Cited in F.C.T. 1973, 11,922). In unpublished work mentioned in the paper cited above, prolonged feeding of Te to rats resulted in Te accumulation in the ciliary body of the eye.
The paper cited reports in vitro and in vivo experiments designed to show whether Te accumulation in these two areas is due to active transport and to compare the effects of Te and selenium (Se) on the active transport of iodide in the choroid plexus and ciliary body. When incubated for i hr with 127mTe (as tellurite), the isolated ciliary body (dissected out with the iris) or choroid plexus of the rabbit showed a roughly fivefold concentration of Te compared with the content of the surrounding medium. This accumulation of Te was not inhibited by digitoxin or by thiocyanate, but iodoacetate, which blocks anaerobic glycolysis, significantly decreased the Te uptake of the ciliary body although not of the choroid plexus, pChloromercuribenzoate, which has been shown to block the binding of Te to protein, decreased Te uptake by both types of tissue. Both tellurite and selenite reduced the iodine-131 (131I) uptake of these tissues significantly in vitro. The in vivo effect of intramuscular injections of finely powdered metallic Te or Se given in doses of 50 mg/kg twice weekly for 4 wk was also studied. Te injections inhibited ~3~I transport by the ciliary body and choroid plexus, while Se injections did not. These results indicate that Te accumulation depends mainly on protein-binding rather than on an active transport process. It appears that Te is enzymically active and is able to inhibit at least one energydependent transport system in the choroid plexus. This activity, combined with the ability of Te to cross the placental barrier and accumulate selectively in the foetal choroid plexus, provides some explanation for the hydrocephalus-inducing potential of Te. 2919. Chlorinated hydrocarbons and the liver Traiger, G. J. & Plaa, (1974). Chlorinated hydrocarbon toxicity. Potentiation by isopropyl alcohol and acetone. Archs envir. Hlth 28, 276. It has already been shown that pretreatment of dogs with ethanol potentiates the hepatotoxicity of chloroform and carbon tetrachloride, but not that of trichloroethylene or 1,1,1-trichloroethane (Cited in F.C.T. 1968, 6, 808). It appears, therefore, that ethanol potentiates the effects only of those chlorinated hydrocarbons that already possess marked hepatotoxicity. Now the picture has been extended to cover the possible influence of isopropanol and its metabolite, acetone, on the hepatotoxicity of chlorinated solvents. Mice were given acetone or isopropanol in an orally intubated dose of 2.5 ml/kg (as a 25~o, v/v, solution) 18 hr before receiving an ip injection of chloroform, trichloroethylene or 1,1,1- or 1,1,2-trichloroethane. The chlorinated hydrocarbons were given in corn oil in a range of doses around the threshold for induction of liver damage, as assessed by an increase in the activity of serum glutamic pyruvic transaminase (SGPT). The known hepatotoxicities of the chlorinated hydrocarbons tested decrease in the following order: chloroform > 1,1,2-trichloroethane > trichloroethylene> 1,1,1-trichloroethane. The augmentation of hepatotoxicity by prior treatment with acetone or isopropanol correlated with this ranking, potentiation being maximal with chloroform and negligible with
The chemical environment l,l,l-trichloroethane. Both acetone and isopropanol potentiated the hepatotoxicity of doses of 1,1,2-trichloroethane that, when administered alone, had no effect on SGPT activity. With trichloroethylene, a dose of 1-5 mg/kg was required to demonstrate any marked potentiation by isopropano'l. Preliminary studies indicate that similar effects are exerted by inhaled acetone or isopropanol, both of which are commonly encountered industrial solvents, but while further work on this aspect is clearly required, the current study suggests that the likelihood of hazardous interaction between these two types of solvent should be largely predictable on the basis of the hepatotoxic potential of the halogenated hydrocarbon.
2920. Hepatitis in workers exposed to diaminodiphenylmethane McGill, D. B. & Motto, J. D. (1974). An industrial outbreak of toxic hepatitis due to methylenedianiline. New Engl. J. Med. 291,278. The hepatotoxicity of 4,4'-diaminodiphenylmethane (DDM) has been demonstrated in a variety of animal species (Cited in F.C.T. 1967, 5, 115; ibid 1975, 13, 480) and, following the accidental contamination of a bag of flour, also in man (ibid 1967, 5, 120). However, the paper cited above apparently provides the first report of liver damage resulting from industrial handling. Between 1966 and 1972, 12 cases of hepatitis were identified among workers in a large manufacturing firm. All the cases involved men employed in folding and kneading with cloth-gloved hands a hot epoxyresin mixture containing 10% DDM. The mixture was subsequently cooled and pulverized into a fine powder which settled rapidly on workers and their surroundings, but the provision of masks and exhaust ventilation was thought to obviate any inhalation hazard. The atmospheric concentration of DDM in 1969, checked after the first three cases of hepatitis had been reported, was 0.1 ppm, and in 1971 (after diagnosis of a further five cases) this was lowered to 0"018ppm by the installation of more exhaust vents. However, this and other measures, including partial enclosure of the work area, daily clean overalls and showers, failed to prevent another two cases. The atmospheric concentration of DDM was subsequently lowered to 0-0064 ppm and the wearing of protective helmets with separate air supplies became mandatory, but in spite of this two further cases occurred. At this stage, oral and dermal treatment of rabbits with floor sweepings from the mill provided further evidence that DDM was the cause of the hepatitis. Sweepings collected after addition of DDM to the reaction mixture produced clear evidence of hepatotoxicity in the animals, while those collected earlier and shown to be free of DDM gave negative results. Orily by the introduction of complete air-supplied PVC suits with attached rubber gloves, and the subsequent development of a fully-enclosed automated blending system, were further cases finally prevented. Symptoms displayed by the victims included weakness, jaundice and dark urine, accompanied in the majority by abdominal pain, nausea and vomiting and sometimes also by headache, acholic stools, prur-
589
itus, rashes and pains in the muscles and joints. Biochemical evidence of liver damage was provided by greatly increased serum levels of bilirubin, glutamicoxalacetic transaminase and alkaline phosphatase. All those affected became ill within 1-18 days of working intensively with DDM and recovered within 7 wk. Similar symptoms were displayed by a worker in another company, temporarily contracted to pulverize DDM. Of 21 other similarly exposed workers who were interviewed, four recalled symptoms apparently consistent with hepatitis. The gloves of the men handling the resin mixture always became ragged, holey and saturated with the material, and it appeared likely that the chief route of entry for DDM was through the skin of the hands. When re-examined between 9 months and 5"5 yr later, none of these hepatitis patients showed any clinical or biochemical evidence of chronic liver disease.
2921. Carcinogenesis by 3,3'-diehlom-4,4'-diaminodiphenyl ether Herrmann, I. F., Schauer, A. u. Kamke, W. (1973). Morphologische und histochemische Untersuchungen w~hrend der Cancerogenese des ~iusseren Geh6rganges der Ratte, induziert durch 3.3'Dichlor-4,4'diaminodiphenyl~ther. Arch. Oto-Rhino-Lar. 206, 11. The possibility that administration of 3,Y-dichloro4,4'-diaminodiphenylether (DDDE) to rats might induce carcinoma of the auditory canal was first suggested by Steinhoff & Grundmann (Naturwissenschaften 1970, 57, 676). The present paper describes the appearance of multiple lesions of the epithelium of the auditory canal and/or deep ceruminal gland in rats after administration of 400 mg DDDE/kg/wk for a total period of 200-340 days by sc injection into the back. In all the animals undergoing this treatment, these tissues showed sharply defined areas of high alkalinephosphatase activity and reduced lactate-dehydrogenase and NADH-dehydrogenase activity, compared with the same regions in untreated animals or with the regenerating epithelium of rats in which the superficial tissue of the auditory canal and gland had been deliberately damaged. 5-Bromoindoxyl-acetate esterase activity, which is characteristically high in sebaceous-gland tissue, was lost in the same areas in the DDDE-treated animals. After 310 days, foci of epithelial hyperplasia and a high incidence of papillomas and adenomas were evident in the DDDE-affected areas and after 390 days four of the treated animals showed papillary carcinomas, squamous-cell carcinomas and carcinomas of the ceruminal gland. The enzyme changes detected in this study in the early stages of ear-duct and sebaceous-gland carcinogenesis are similar to those that have been shown to occur in the early stages of neoplasia of the nasal mucous membranes.
2922. Teratogenie approach to DES problem Staff, A. & Mattingly, R. F. (1974). Vaginal adenosis: A precancerous lesion? Am. J. Obstet. Gynec. 120, 666. An interesting view has recently been put forward in connexion with the occurrence of vaginal adenocarcinoma in young girls exposed prenatally to diethylstilboestrol (DES).