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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
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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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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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Representative terms from entire chapter:
chemical forms
