Biomethylation of inorganic arsenic

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Natural products, Occupational

health-Fd

NATURAL

Comet. Toxicol. Vol. 19, no. 3

PRODUCTS

Carcinogenicity of betel quid ingredients Bhide, S. V., Shivapurkar, N. M., Gothoskar, S. V. & Radadive, K. J. (1979). Carcinogenicity of betel quid ingredients: feeding mice with aqueous extract and the polyphenol fraction of betel nut. Br. J. Cancer 40, 922.

aqueous extracts of betel nuts or leaves, or a polyphenol fraction of the nuts extracted in ethyl acetate. Controls were treated with distilled water. No tumours were observed in the controls (20 Swissmice and 20 Cl7 mice). Tumours were not apparent in the 15 Swiss mice treated with the aqueous leaf extract; indeed previous unpublished studies were said to have The chewing of betel quid, (a mixture of betel nut suggested that the leaf might have a protective effect fragments and lime with or without added tobacco against simultaneous administration of nut extract. Of the 21 Swissmice dosed with the aqueous nut and spices,wrapped in a betel vine leaf) is a popular and long-established custom in India and the Far extract, seven developed liver tumours (five hepatocelEast. However, the practice has been implicated as an lular carcinomas and two haemangiomas). Two lung aetiological factor in the development of cancer of the adenocarcinomas, one squamous-cell carcinoma, one upper alimentary tract and results of experiments in adenocarcinoma of the stomach, and one caseof leukwhich betel extracts have been applied to the buccal aemia also occurred in this group. In the Cl7 mice epithelia of hamsters and baboons tend to support (30) treated similarly, three squamous-cell carcinomas this (Cited in F.C.T. 1971, 9, 919; ibid 1973, 11, 926). of the forestomach, two adenocarcinomas of the glanIn vitro, betel leaf extracts have been shown to indular stomach, one lung adenocarcinoma and two crease the frequency of chromatid aberrations in cul- cases of leukaemia were observed. The authors tured human lymphocytes (Sadasivan et al. Mutation explain that these species differences may reflect a Res. 1978, 57, 183). Although the causative element higher liver-tissue susceptibility to the effects of a has yet to be identified, arecoline, the main alkaloid weak carcinogen in the Swissmice or reflect a lack of present, and its metabolite arecaidine, have both been the enzymesrequired for carcinogen activation or forshown to be alkylating agents (Cited in F.C.T 1970, 8, mation in the Cl7 mice. The 18 Swiss mice treated 114). with the polyphenol fraction did not develop tumours Groups of approximately lO-wk-old male mice of the gastro-intestinal tract. However, two tumours were dosed with 0.1 ml of various betel fractions once of the salivary gland and one haemangioma of the daily, Sdays/wk, throughout life. The fractions were liver were observed.

OCCUPATIONAL Biomethylatioo of inorganic arsenic

HEALTH

monomethylated arsenic (MMAs), were found in the urine and faecesof all three species.After oral dosing Odanaka, Y., Matano, 0. & Goto, S. (1980). Biomethylation of inorganic arsenic by the rat and some the urine of all three contained 14.1-17.7% inorganic arsenic and 09+6% MMAs, but the rat excreted laboratory animals. Bull. enuir. Contum. Toxicol. 24, only 2.2% of the dose as DMAs in the urine whereas 452. the equivalent values for the mouse and hamster were Rodent experiments have often failed to reproduce 30 and 21.5% respectively. The faecesof all three speeffects such as the increased incidence of lung, lym- cies contained 24.2-28.8x inorganic arsenic and phatic and skin cancer (Federal Register 1975, 40, 7.7-13.9x MMAs, but here again the DMAs values 3392; Cited in F.C.T 1981, 19, 132) or angiosarcoma differed widely, being 1.1% for the rat, 144% for the of the liver (ibid 1976, 14, 507) observed in arsenic- mouse and 1.4’/, for the hamster. exposed humans. Methylation has been suggestedas a After iv dosing, 42447.6% of the dose was present mechanism of detoxification of inorganic arsenic in in the urine of all three species as inorganic arsenic mammals (ibid 1976, 14, 507; ibid 1980, 18, 102) and and 07-2.1% as MMAs. The urinary values for the present authors have investigated interspecies dif- DMAs were 2.7% for the rat, 37.4% for the mouse and .---. ferencesin the excretion of methylated and non-meth- 39.7% for the hamster. Total metabolites found in the ylated arsenic metabolites. faecesafter iv dosing amounted to lessthan 4% of the Within 48 hr of the oral administration, in water, of dose for all three species.Similar iv studies in rabbits a single dose of 5 mg arsenic acid/kg, urinary excre- and cats showed that the chief urinary metabolites tion accounted for 17.2, 48.5 and 43.8% and faecal were DMAs and inorganic arsenic, as in the mice and excretion for 33.0, 48.8 and 44.1% of the original dose hamsters. Two days after oral or iv treatment the tissue distriin rats, mice and hamsters, respectively. In these animals, and others treated with a single intravenous (iv) bution of arsenic metabolites in the rats, mice and injection of 1 mg arsenic acid/kg in saline solution, hamsters was examined. The total amount of arsenic totals of 88 and 97% of the dose were found within in rat blood (c. 40”/, of the dose) greatly exceeded that 48 hr in the urine and faecesof the mice and hamsters in the other species and was virtually all present as but only 50% was recovered from the rat in the same DMAs. About 2% of the dose was found in the liver time, most of the remainder being found in the blood. and 06+7% in the kidneys; here again DMAs was Three metabolites, containing respectively in- the major metabolite. The residual arsenic levels in organic ar%&~dimethylatedthylated arsenic (DMAs) and the tissues of the mice and hamsters were too low to

Occupationalhealth--Fd Cosmet.Toxic& Vol. 19,no. 3 be identified. The biliary excretion of arsenic in rats following oral dosing was found to represent 45% of the original dose in 24 hr and occurred mainly as MMAs. Thus the rat is distinguished from the mouse and the hamster in that a large amount of DMAs is bound in the blood and consequently far less is excreted in the urine.

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setting of the 2O-yrminimum for follow-up may have underestimated the extent of respiratory tumours in this population, since some deaths occurring 18 and 19 yr after initial exposure were due to this cause.The results followed a similar pattern , when different approaches to the analysis of the data were used. However, the study showed that it was not just total dust exposure that was important. The group was divided into three according to duration of exposure and subdivided according to average concenCancer and asbestosworkers tration of exposure to give nine groups. There was a Weill, H., Hughes, J. & Waggenspack, C. (1979). general indication of increasing risk with duration Influence of dose and fiber type on respiratory malig- that was concentration-dependent and of increasing nancy risk in asbestos cement manufacturing. Am. risk with concentration that was duration-dependent. Rev. resp. Dis. 120, 345. The results showed the importance of both factors in Becauseof the extremely serious health hazard that estimating risk. asbestos presents, it is particularly important to To determine the possible influence of fibre type on ensure that current exposure standards have the best respiratory malignancy, workers with exposure to possible scientific foundations. The study described chrysotile only were compared with two groups of here attempts to relate the risk both to levels and to workers who were also exposed to crocidolite, the types of fibre exposure. The authors investigated the first during steady employment in the pipe plant and effects of asbestoson mortality in 5645 men who had the second during occasional maintenance work worked for at least 1 month in one of two plants there. Workers exposed to amosite were excluded manufacturing asbestos-cement building materials in from this study. It was found that crocidolite New Orleans. The cohort study was limited to men enhanced the risk of respiratory malignancy particuwith a follow-up of at least 20 yr. An attempt to trace larly for workers intermittently exposed, generally to identified personnel via the Social Security Adminis- high concentrations of dust for short periods of time. tration identified 11% as having died by the end of This confirmed results previously reported in rats 1974 and death certificates were traced for 91% of (ibid 1974, 12, 592). these. It was assumed that all other members of the study were alive at that time although they were not Acrylamide neurotoxicity in rats all positively traced. Estimates of dust exposure were based on total airborne particulate measurements Tilson, H. A., Cabe, P. A. & Spencer, P. S. (1979). using the midget impinger at various locations Acrylamide neurotoxicity in rats: a correlated neurothroughout the two plants. It was assumed that behavioral and pathological study. Neurotoxicology 1, pre-1950 levels did not differ from those recorded 89. when sampling was initiated in the early 1950s. The neurotoxicity of acrylamide in laboratory aniThe sampling data resulted in a table of dust con- mals, and as a result of industrial exposure, in man is centrations and estimated fibre content for each job well documented (Cited in F.C.T. 1978, 16, 188). In by month and year. These were combined with work chronic poisoning the effects appear to be cumulative, histories to give an exposure profile for each subject. but often reversible, producing a distal to .proximal In addition, a worker’s total dust exposure was ‘dying-back’ peripheral neuropathy. Most previous recorded in millions of particles per cubic foot-year investigations of acrylamide neurotoxicity have (mppcf-yr) for ihe first 20yr of his employment. Sub- involved either pathological bioassay or behavioural jects were classified into five total-dust categories, studies.The study cited above compares simultaneous 110, 11-50, 51-100, 101-200 and >2OO mppcf-yr. morphological and behavioural effects at different Mean length of follow-up and mean age at initial ex- stagesof intoxication of acrylamide-treated _ -...-. .__rats. posure were comparable in these groups. No data on Groups of ten male I%&% gbino rats were303 smoking habits were available. The data from the with 0, 5, 10 or 20mg acrylamide/kg by gavage in death certificates were compared with standard race- distilled water three times a week for 13 wk, whilst age-cause-specificrates for US and Louisiana male rats in another control group were handled but were populations for 195O-1970. otherwise untreated. Body weights were monitored Standard mortality ratios (SMRs) (100x observed and behavioural tests were carried out during the number of deaths/no. expected) were obtained for week prior to dosing and after 1,4,7, 10 and-13 wk of various causesfor each of the five exposure categories. dosing, the latter to assessany weaknessin hindlimbs, Deaths for which certificates were not located were forelimbs or overall motor activity. At the end of the allocated among causes in the same proportions as dosing periodall ten rats in the lO-mg/kg group and those with certificates. No excessmortality occurred half of the rats in the 2O-mg/kg and in the distilledin any exposure group for any cause other than res- water groups were killed and examined for histopathpiratory neoplasms. There was no excessrisk of gas- ological evidence of damage in the medulla oblonno-intestinal neoplasms, as had been found in some gata, mid-thigh sections of the sciatic nerve and indiprevious studies (Cited in F.C.?: 1972, 10, 575). In the vidual ti ial nerve branch fibres. The remaining rats two highest exposure groups (total dust exposures of from the high-dose group and the water-treated con101-200 and > 200 mppcf-yr) the SMRs for malignant trols w e given further behavioural tests 1 and 5 wk YJ end of dosing and were then killXZid neoplasms of the respiratory system were significantly after the increased to values of 29 and 226. The arbitrary morphologically examined. No effects were observed