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8 Recommendations Review of the scientific literature by the Subcommittee on Arsenic identified several subjects on which additional information is needed. If the following recommendations for research are successfully carried out, the new knowledge thereby generated should allow a more accu- rate assessment of the environmental impact of arsenic compounds. 1. Further epidemiologic and laboratory experimental research should be conducted on the question of the possible carcinogenicity of arsenic compounds. The possible carcinogenicity of arsenic remains controversial, and it is urged that more studies be done to settle this issue. A group of experts should be convened to address this question specifically and to recommend and oversee studies in man and experi- mental animals designed to resolve the enigma. Experts in the follow- ing subjects should be on the working group: pathology of cancer; epidemiology; statistics; chemistry, biochemistry, and metabolism of arsenic; and experimental design (especially as the last relates to the many possible confounding factors that may modify carcinogenesis). Numerous opportunities exist for additional epidemiologic work, and follownp studies should be performed on populations that have been inadvertently exposed to arsenic. The problem of experimental arsenic cancer in laboratory animals also requires more effort, and a series of 227

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228 ARSENIC studies designed as rationally as possible should be carried out, to determine whether arsenic can be demonstrated to be a carcinogen under experimentally controlled conditions. In such studies, careful attention should be given to various experimental characteristics, such as the species of animal, the dosage of arsenical administered, the nature of arsenical tested, the duration of arsenical exposure, and the route of exposure to the arsenical. Possible cocarcinogenic effects of arsenic compounds with other chemicals should also be considered. 2. More research is required to clarify the effects of long-term low-dose exposures to arsenic on man, domestic animals, wildlife, and aquatic organisms. Recent studies using sensitive indicators of biochemical toxicity, such as alterations in enzyme activity, or physiologic criteria of poisoning, such as impaired reproductive per- formance, have suggested subtle changes in association with exposures of arsenic that were previously thought to be innocuous. How pertinent such results are to environmental problems is not certain, but at least the preliminary experiments should be confirmed or refuted and an attempt made to put such experiments into perspective. 3. Additional studies on the possible teratogenic and mutagenic effects of arsenicals need to be carried out. All experimental teratology studies that have been carried out with arsenic compounds have used doses far in excess of those likely ever to be encountered as a result of environmental contamination. Research with more realistic doses should be encouraged, to evaluate whether arsenic in the environment actually constitutes a teratogenic risk. Experiments carried out with humans previously treated medically with arsenicals revealed chromosomal abnormalities, which suggest a mutagenic potential for some arsenic compounds. Again, however, the doses of arsenic given to patients in the past were higher than any reasonable degree of environmental arsenic exposure that one would expect. Nevertheless, the positive results argue strongly for further work along these lines. 4. Much more effort is required regarding the inhalation toxicology of arsenic. The physiologic significance of some of the experiments in this field is open to debate, but the observation that biologic changes occur under some conditions apparently is not. Alterations in metabolic or biochemical characteristics are observed in association with exposures that seem very low. This work needs to be repeated, and any possible physiologic relevance of these data needs to be pointed out. 5. Possible metabolic interrelationships of arsenic with other pollu- tants should be explored. Metabolic antagonisms between arsenic and some minerals suggest that arsenic may have antagonistic or synergis

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Recommendations 229 tic effects with other pollutants. This illustrates the fact that environ- mental standards for pollutants cannot be set in isolation, but should take into account possible interactions among pollutants. 6. The use of the rat as an experimental animal in studies of arsenic metabolism should be strongly discouraged. The rat has a unique arsenic metabolism that is totally unlike that of man or other mammals. Therefore, research conducted with rats is difficult to apply to man; such research has led to many misinterpretations. One such miscon- ception is the idea that arsenic is retained in the body to the same extent as heavy metals, such as lead, mercury, and cadmium. 7. More information about the chemical nature of arsenic in soil, water, foodstuffs, and plant and animal tissues is desirable. The behavior of arsenic in the food chain cannot be fully understood without increased knowledge of the various chemical forms of arsenic. The data are very incomplete, although it is clear that the naturally occurring arsenic in foods is metabolized quite differently from inor- ganic arsenicals. The recent attempts to characterize the arsenolipids in marine oils show what can be accomplished in this direction, but more effort is warranted. The forms of arsenic in foods have unknown toxicity and environmental behavior. Further examination of their identity, toxicity, and fate in the environment is needed, so that their significance to both man and his environment can be assessed. 8. Better analytic techniques and sample-handling procedures for arsenic compounds need to be developed. Most current analytic tech- niques for arsenic give values only for the total amount of arsenic in the sample and do not characterize the various chemical forms of arsenic present. Because the toxicity and ecologic behavior of arsenic depend strictly on its chemical forms, means to identify these forms are needed. Recent evidence has also suggested that the equilibrium vapor pressure of some arsenic compounds (e.g., arsenic trioxides is great enough for appreciable losses to occur as a result of sublimation when dust particles are collected on high-volume air samplers. Sublimation losses may also occur during sample storage or drying. Surveillance personnel need to be alerted to these possible problems of analysis, and alternative procedures may have to be worked out. Once acceptable methods for the determination of arsenic compounds are established, routine monitoring of arsenic in environmental samples should be undertaken. 9. An economic assessment should be made of the possible effects that not using arsenical pesticides Would have on food and fiber production. The organic arsenical pesticides play an important role in protecting crops and livestock from damaging pests. Current use is

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230 ARSENIC estimated at 15,000-20,000 tons (13,500-18,000 tonnes) a year. Loss of these pesticides or major price adjustments due to low availability of starting materials (arsenic trioxides could have a major economic impact on American agriculture. It is urgent to assess the domestic and foreign consequences of the loss of these compounds. 1O. Guidelines on the disposal of arsenical wastes should be de- veloped. Arsenic is an unavoidable by-product of smelting operations. It must be used, stored, or disposed of safely. For pesticides, the safe disposal of containers is important. Slag from smelting operations, as well as the arsenic trioxide that is collected, must be used or disposed of in an acceptable manner. Perpetual storage should most likely be avoided. 11. Additional work is needed to elucidate the biochemical mecha- nisms responsible for arsenic poisoning. Although the toxic effects of trivalent arsenicals are accounted for reasonably well on the basis of their reactivity with sulfhydryl groups, the mechanism of action of pentavalent arsenicals, both organic and inorganic, is much less under- stood. Careful metabolic studies should be carried out to determine whether pentavalent arsenicals are reduced to trivalent arsenicals in vivo and, if so, to what extent. 12. Experiments should be carried out to establish whether animals can adapt to the toxic effects of arsenic. It seems to be well docu- mented that microbial systems can adapt to toxic concentrations of arsenic, although the precise molecular mechanism of this effect is unknown. Recent results that indicated that mammals also can adapt to arsenic to a limited extent should be followed up, and additional work along these lines should be encouraged. 13. The possible effect of arsenicals in decreasing the ability to resist infection needs to be investigatedfurther. The mechanism of this effect of arsenic, inhibition of interferon formation or action, is of both theoretical and practical interest. If this work can be verified, the implications for public health could be considerable. 14. Arsenic should be studied as a possible nutritionally essential trace element. The occasional favorable effects of arsenic in animal metabolism suggest that it may play a physiologic role at very low concentrations. Such a role has recently been shown in experiments using modern techniques in trace-element research, but these studies need to be verified and expanded. 15. The mechanism of action of arsenical "growth-promoting" agents should be studied. Although many theories have been advanced in an attempt to explain the growth-promoting effect of organic penta

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Recommendations 231 valent arsenicals, none of these hypotheses seems totally satisfactory. If these compounds are to be continued in use, a better understanding of their mode of action might allow the design of equally active yet less toxic compounds. 16. Studies on environmental characteristics that can affect the redistribution of arsenic within the ecosystem should be undertaken. Environmental conditions can seriously affect the toxicity of arsenical residues in soils. Dissipation of applied arsenicals is subject to changes in rate and is a function of the environment and the arsenical. Informa- tion is needed on how these dissipation rates can be changed to prevent the buildup of toxic residues. 17. An estimate of annual arsenic use in agriculture is needed. The exact annual production, distribution, imports, exports, and inven- tories of arsenical pesticides are unknown. Furthermore, it is impossi- ble with current estimates to predict market trends as influenced by shortages in petroleum-based feedstocks, development of new pes- ticides, or any other economic change. Consequently, the short- or long-term environmental impact of continued arsenic use on agricul- tural production cannot be determined.

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