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Methyl bromide in the stomach
FdChem To~lc Vol 23. No 1. pp 121-127,1985 Printed m Great Britain
0278-6915/85 $300 + 000 PergamonPress Ltd
Information Section METHYL BROMIDE IN THE STOMACH Methyl bromide (MB) is widely used as a soil fumigant and for the prevention of infestation m crops during storage There have been a large number of recorded incidents of poisoning of humans by MB, but relatively few animal studtes have been carried out In a comprehensive revtew of the toxicology of MB, Alexeeff & Kilgore (in Residue Reviews, Vol 88, ed. F A. Gunther, p. 101. SpringerVerlag, 1983) reported that no studies had yet been carried out on the carclnogenlclty of MB in laboratory animals. They commented that such studies were needed in view of the known (albeit generally fatrly low) mutagenic potenttal of MB (e.g. Djalah-Behzad et al. Mutation Res. 1981, 84, l; Slmmon et al. Devs Toxicol. envir. Sci 1977, 2, 249; Voogd et al. Mutation Res. 1982, 97, 233). Danse et al. (Toxtc. appl. Pharmac. 1984, 72, 262) have now pubhshed the results of a subchronlc oral toxtcity study of MB in rats. The oral route was chosen since MB residues have been found In drinking-water (Simmon et al loc. clt) and may also occur in food tf fumigation ts not properly carried out. Danse et al. (loc clt.) report that a preliminary study showed that rats given 50 mg MB (in groundnut otl)/kg body weight by gavage for 4 wk developed eptthehal hyperplasla, hyperkeratosis and ulceration of the forestomach. They have subsequently carried out a 90-day study, focusing their attention on effects in the forestomach Groups of ten male and ten female Wistar rats were given 0, 0 4, 2, 10 or 50 mg MB (In groundnut oil)/kg body wetght by gavage five times per wk for 13 wk. At the end of the study diffuse hyperplasia of the forestomach was observed in all of the rats in the 50-mg/kg group, and seven of the males and six of the females had developed well-differentiated squamous-cell carcinomas of the forestomach Two males
in this group also had forestomach papillomas. In nine of the affected rats the carcinoma showed minimal invasion, but m the other four there was clear invasion through the muscularls mucosae In some rats the tumour was associated with ulceration and a proliferative inflammatory reaction in the underlying layers of the stomach wall No lung or liver metastases of the squamous-cell carcinomas were detected. No tumours were observed in the forestomachs of any of the rats in the other dose groups Slight diffuse hyperplasla occurred in the forestomachs of 15 of the rats given 10 mg MB/kg body weight and in three of those given 2 mg/kg. In the highest dose group there were several other effects that were considered to be secondary to the lesions in the forestomach. These included decreased food consumption m both sexes and, in males, decreased body-weight gain, slight anaemia, increased neutrophihc granulocyte counts and, in the spleen, decreased haemoslderosls and increased haematopoiests. Danse et al. (loc. cit) suggest that the diffuse hyperplasla observed occurs as a reaction to the direct cytotoxic effects of MB. Therefore, they regard MB as a potent stimulator of cell growth which will promote a carcinogenic process. They speculate that, even if MB does have tumour-mlttatlng activity, the risk of a carcmogenlc response at low exposure levels that do not induce hyperplasia may be very small. Although humans may ingest MB in produce contaminated by fumigation during storage or in drinking-water contaminated by residues from soil fumigation, the levels of such exposure are likely to be very low Greater human exposure ts likely to occur through inhalation but results of long-term inhalation studies are not yet available.
HAEMATOLOGICAL EFFECTS OF CHLORINE IN DRINKING-WATER The chlorination of drinking-water has been under question because it leads to the formation of chlormated organic compounds, some of which are suspected carcinogens. However, relatively little attention has been paid to the safety of inorganic chlorine in the water This may be partly because an early rat study revealed an absence of haematological, pathological or other effects from drinkingwater containing free chlorine at 100 ppm and administered over seven generations (Druckrey, Fd Cosmet Toxicol. 1968, 6, 147) It was later 121
reported that mice given drinking-water containing 25-30 ppm total chlorine for 1 month showed decreases m macrophage levels in peritoneal exudate and in the tumorlcidal function of the macrophages in vitro when compared with controls given normal tap-water containing 0.5-1 ppm chlorine (Fldler, Nature, Lond. 1977, 270, 735). On the other hand, no definite effects on the immune response could be detected in a subsequent 120-day mouse study, in which the water contained 15 or 30 ppm residual chlorine (Hermann et al. Lab Anita. Sci 1982, 32,
0278-6915/85 $300 + 000 PergamonPress Ltd
Information Section METHYL BROMIDE IN THE STOMACH Methyl bromide (MB) is widely used as a soil fumigant and for the prevention of infestation m crops during storage There have been a large number of recorded incidents of poisoning of humans by MB, but relatively few animal studtes have been carried out In a comprehensive revtew of the toxicology of MB, Alexeeff & Kilgore (in Residue Reviews, Vol 88, ed. F A. Gunther, p. 101. SpringerVerlag, 1983) reported that no studies had yet been carried out on the carclnogenlclty of MB in laboratory animals. They commented that such studies were needed in view of the known (albeit generally fatrly low) mutagenic potenttal of MB (e.g. Djalah-Behzad et al. Mutation Res. 1981, 84, l; Slmmon et al. Devs Toxicol. envir. Sci 1977, 2, 249; Voogd et al. Mutation Res. 1982, 97, 233). Danse et al. (Toxtc. appl. Pharmac. 1984, 72, 262) have now pubhshed the results of a subchronlc oral toxtcity study of MB in rats. The oral route was chosen since MB residues have been found In drinking-water (Simmon et al loc. clt) and may also occur in food tf fumigation ts not properly carried out. Danse et al. (loc clt.) report that a preliminary study showed that rats given 50 mg MB (in groundnut otl)/kg body weight by gavage for 4 wk developed eptthehal hyperplasla, hyperkeratosis and ulceration of the forestomach. They have subsequently carried out a 90-day study, focusing their attention on effects in the forestomach Groups of ten male and ten female Wistar rats were given 0, 0 4, 2, 10 or 50 mg MB (In groundnut oil)/kg body wetght by gavage five times per wk for 13 wk. At the end of the study diffuse hyperplasia of the forestomach was observed in all of the rats in the 50-mg/kg group, and seven of the males and six of the females had developed well-differentiated squamous-cell carcinomas of the forestomach Two males
in this group also had forestomach papillomas. In nine of the affected rats the carcinoma showed minimal invasion, but m the other four there was clear invasion through the muscularls mucosae In some rats the tumour was associated with ulceration and a proliferative inflammatory reaction in the underlying layers of the stomach wall No lung or liver metastases of the squamous-cell carcinomas were detected. No tumours were observed in the forestomachs of any of the rats in the other dose groups Slight diffuse hyperplasla occurred in the forestomachs of 15 of the rats given 10 mg MB/kg body weight and in three of those given 2 mg/kg. In the highest dose group there were several other effects that were considered to be secondary to the lesions in the forestomach. These included decreased food consumption m both sexes and, in males, decreased body-weight gain, slight anaemia, increased neutrophihc granulocyte counts and, in the spleen, decreased haemoslderosls and increased haematopoiests. Danse et al. (loc. cit) suggest that the diffuse hyperplasla observed occurs as a reaction to the direct cytotoxic effects of MB. Therefore, they regard MB as a potent stimulator of cell growth which will promote a carcinogenic process. They speculate that, even if MB does have tumour-mlttatlng activity, the risk of a carcmogenlc response at low exposure levels that do not induce hyperplasia may be very small. Although humans may ingest MB in produce contaminated by fumigation during storage or in drinking-water contaminated by residues from soil fumigation, the levels of such exposure are likely to be very low Greater human exposure ts likely to occur through inhalation but results of long-term inhalation studies are not yet available.
HAEMATOLOGICAL EFFECTS OF CHLORINE IN DRINKING-WATER The chlorination of drinking-water has been under question because it leads to the formation of chlormated organic compounds, some of which are suspected carcinogens. However, relatively little attention has been paid to the safety of inorganic chlorine in the water This may be partly because an early rat study revealed an absence of haematological, pathological or other effects from drinkingwater containing free chlorine at 100 ppm and administered over seven generations (Druckrey, Fd Cosmet Toxicol. 1968, 6, 147) It was later 121
reported that mice given drinking-water containing 25-30 ppm total chlorine for 1 month showed decreases m macrophage levels in peritoneal exudate and in the tumorlcidal function of the macrophages in vitro when compared with controls given normal tap-water containing 0.5-1 ppm chlorine (Fldler, Nature, Lond. 1977, 270, 735). On the other hand, no definite effects on the immune response could be detected in a subsequent 120-day mouse study, in which the water contained 15 or 30 ppm residual chlorine (Hermann et al. Lab Anita. Sci 1982, 32,