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OCR for page 173
6
Biologic Effects of
Arsenic on Man
TOXICITY
The medicinal use of arsenic, although practiced for hundreds of years,
apparently reached a peak in the middle to late 1800's and was a major
mainstay in the limited medical armamentarium of the time. 8~5 Fowler's
solution, containing arsenic trioxide at 10 mg/ml (arsenic at about 7.6
mg/rnl), was prescribed for symptomatic relief of many conditions,
ranging from acute infections (although the germ theory of disease was
not widely accepted until the time of Pasteur, 1822-1895, and Koch,
1843-1910) to epilepsy, asthma, and chronic, recurring skin eruptions,
such as psoriasis and eczema. Thus, many patients received arsenic
for periods of months and years. It was in such patients that the conse-
quences of long-term administration of arsenic were first recognized to
be palmer and planter hyperkeratoses, characteristic pigmentary
changes on the trunk, and a variety of cancerous and precancerous
lesions on the hands, feet, and trunk. There was, in fact, some initial
confusion: psoriasis was, for a while, mistakenly thought to be a
precancerous condition.33~852 Neubauer has provided an extensive
review of these matters.585
The therapeutic usefulness of arsenic is apparently such that it has
not been easily abandoned by the medical profession. Some justifica
173
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174
ARSENIC
tions for its use were cited by Pillsbury et al. in 1956;645 and a 1972 English
text860 stated that a possible use of Fowler's solution is "in elderly
patients with bullous disease when steroids are contra-indicated."
Fierz cited patient satisfaction in a large number of patients inter-
viewed, including 55 of 64 with psoriasis.253
Although still used, especially in Europe,253 Fowler's solution has
not appeared in the U.S. Pharmacopoeia since 1950; arsenic trioxide is
listed as a reagent in the eighteenth revision, published in 1970.
However, both inorganic and organic arsenic preparations are still
manufactured for medical and veterinary use in this country; and there
is evidence that some goes to people who find it useful in ''tonics" and
for a wide variety of symptoms (more than 400 gal, or 1.5 m3 of
Fowler's solution were produced in 19741. In addition to the use of
medicinal arsenic, there was, during the nineteenth and early twentieth
centuries, widespread use of rat poisons and insecticides that con-
tained arsenic and that left residue on fruits and vegetables. The
combination of these two major ''reservoirs" appears to have resulted
in a relatively high frequency of both deliberate and accidental arsenic
poisonings, some of them grotesque, such as the mistaken use of
powdered arsenic trioxide for talcum powder, which resulted in the
deaths of 17 children.362 Thus, physicians of the day were simulta-
neously using arsenic therapeutically and treating the consequences of
excessive exposure from environmental sources. As DOT and organic
pesticides fall into disfavor, increasing use of arsenicals as pesticides
and herbicides may again increase the concentration of arsenic in the
general environment. This, in turn, would require a renewed ''index of
suspicion" by modern physicians for the possibility of arsenic toxicity.
Somewhat more recent, but overlapping with the earlier period, has
been the involvement of physicians in recognition of and treatment for
exposures to arsenic associated with the industrial revolution.
Reactions to Contact with Arsenic
Arsenic was at one time used in disreputable ''cancer pastes" for its
caustic properties. Causticity is a property of arsenic trioxide, and a
greater or lesser degree of skin irritation, particularly in creases and
where clothing binds, is the primary symptom in smelter workers or
their families exposed to dusts with a high arsenic content.79382 A
striking consequence of direct contact with the mucous membranes of
the nose is perforation of the nasal septum, sometimes occurring after
only a week or two of exposure.79222648 Better working conditions,
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Biologic Effects of Arsenic on Man
175
including improved opportunities for personal hygiene, have reduced
the incidence of this problem.382 842
That topical exposure to arsenic results in local inflammation and
vesiculation such as that seen with the war gas lewisite has been of
interest to investigators, including those who developed dimercaprol
(British antilewisite) at the time of World War II.333 It is thought that
the physical integrity of the epidermis depends on intact pyruvate
metabolism and that the sulibydryl-combining properties of arsenicals
inhibit the sulfhydryl-containing enzymes related to this pathway.334
This hypothesis has not been subjected to analysis by modern der-
matologic biochemical techniques.
Besides acting as primary irritants, many arsenicals function as
contact allergens, so that very low, noncaustic concentrations may
result in either vesiculation or folliculitis in previously sensitized
people. Holmqvist studied workers in a large copper-ore smelting
facility over a 2-year period and concluded that most of their skin
eruptions were based on this mechanism.365 He noted that, on patch
testing, to of arsenic workers reacted to concentrations of sodium
arsenite, sodium arsenate, and arsenic pentoxide that caused reactions
in only 35% of "other" and 30~o of new employees. Holmqvist
suggested that selection of nonsensitized workers or "hardening" of
the skin of those who were allergic functioned to control the incidence
of hypersensitivity reactions.365 His extensive literature review and
study of 71 patients did not suggest that any of the late cutaneous
sequelae of arsenic ingestion are seen after chronic contact with the
material, but no evidence (such as urinary arsenic content) was pre-
sented to indicate the extent to which these workers were absorbing
arsenic through the skin and mucous membranes into the systemic
circulation.
Evidence of systemic absorption of arsenic secondary to ex-
ternal exposure has been repeatedly recorded, usually in the form
of increased urinary arsenic content correlated with the work
week.543 633 648 842 Little or no information is available to apply to
questions of the quantity of arsenic, its physical and chemical form,
and the duration of cutaneous or inhalation exposure required to result
in significant systemic effects. It should be noted, however, that
evidence of significant systemic concentrations of arsenic has been
found in several studies of the incidence of lung cancer in populations
exposed to arsenic dusts. The possibility that the effect, if any, of
arsenic in this condition operates through a general body mechanism,
rather than directly on lung tissue, should not be ignored.
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176
Acute Arsenic Poisoning
ARSENIC
Exposure to arsenic sufficient to cause severe acute systemic symp-
toms requiring prompt medical attention usually occurs through
ingestion of contaminated food or drink. The signs and symptoms are
somewhat variable in degree and timing and depend on the form and
amount of arsenic, the age of the patient, and other unknown factors. 862
The major characteristics of acute arsenic poisoning are profound
gastrointestinal damage and cardiac abnormalities.
According to Holland,362 tP 408) symptoms may appear within 8 min if
the poison is in solution, but may be delayed up to 10 h if it is solid and
taken with a meal. The signs, which are variable, range from excruciat-
ing abdominal pain and forceful vomiting to cramps in the legs,
restlessness, and spasms. "A feeble, frequent, and irregular pulse
ushers in the other symptoms of collapse, the livid and anxious face,
sunken eyes Edehydration?], cold and clammy skin Eshock?~.... A
small proportion of the cases are classed as 'nervous' or 'cerebral'
because . . . the . . . conspicuous . . . phenomena are . . . prostra-
tion, stupor, convulsions, paralysis, collapse, and death in coma."
Only a small fraction of patients will develop any kind of skin reaction
secondary to acute arsenic poisoning. Presumably, the arsenic must be
absorbed from the damaged gut and find its way to the skin. The usual
reaction in these circumstances is an acute exfoliative erythroderma,
probably reflecting the fact that arsenic is a capillary and epidermal
poison 333,362
Subacute Arsenic Poisoning
Systemic exposure to amounts of arsenic sufficient to cause symptoms
but inadequate to produce systemic collapse is of particular interest.
The patient may go for weeks with gradually increasing or variable
signs and symptoms related to several organ systems and giving the
appearance of a progressive chronic disease state. If death occurs, it
may appear to have been the consequence of the inexorable course of
an obscure "natural" disease. This appearance has contributed to the
popularity of arsenic as an agent of homicide. Skin manifestations of
such victims are particularly important, in that they may offer critical
clues in the unraveling of a mystery.
The method of arriving at a therapeutic dose of Fowler's solution
was based on finding the patient's tolerance to increasing but nontoxic
doses. As described by Holland,362 the patient was given 5 drops (about
9 mg of arsenic trioxide, or 6.8 mg of arsenic) "well diluted, after meals
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Biologic Effects of Arsenic on Man
177
fi.e., three times a day], increasing the dose one drop daily until the
disease is under control or until the eyelids puff and the bowels move
too freely.... The dose is then reduced to a safer quantity, and
persisted in until the warning returns, when it is again reduced....
Occasionally persons are encountered fin whom] even the minimum
dose will produce unpleasant effects," such as one case of eryth-
roderma after 10 mg of arsenic trioxide (7.6 mg of arsenic) taken over
a 2-day period.
Holland's descriptions of arsenic poisoning were based on personal
observation and reports of suicides and criminal cases in which rat or
fly poison, as well as Fowler's solution, had been used.362 Occasion-
ally, enthusiastic patients would overdo their use of medicinal arsenic,
but this was uncommon, because of the associated discomfort. Holland
described subacute poisoning as producing loss of appetite, fainting,
nausea and some vomiting, dry throat, shooting pains, diarrhea, ner-
vous weakness, tingling of the hands and feet, jaundice, and erythema.
Longer exposure resulted in dry, falling hair; brittle, loose nails;
eczema; darker skin; exfoliation; and a horny condition of the palms
and soles.
In 1901, Reynolds reported on the clinical findings in over 500
patients that he had personally followed.235 These patients had been
drinking for many months 2-16 pints a day of beer contaminated with
arsenic. The measured amount of arsenic in the beer was such that "a
moderate drinker would only take a tithe of the quantity of arsenic
which Ewould be prescribed for] an epileptic." Therefore, the possible
additive role of alcohol to the observed symptoms merited considera-
tion. Reynolds felt that the clinical manifestations were of four distinct
"types" based on whether cardiac, skin, or necrologic symptoms
predominated or were equally mixed, and he noted that these features
and the sequence of their appearance were in accordance with several
previously reported episodes of arsenic poisoning.665
First to appear were digestive symptoms, especially vomiting and
diarrhea, to the extent that some patients gave up drinking beer,
because it did not ''agree with" them. Most, obviously, did not have so
definitive a reason to stop their intake of the poison, and a few were
said to have had a stimulation of the appetite.
Catarrhal symptons conjunctivitis, rhinitis, laryngitis, and bron-
chitis appeared in a few weeks, with various skin eruptions. The
generalized mucous-membrane symptoms suggested a selective sen-
sitivity of these organs. Hoarseness due to thickening of the vocal
cords and hemoptysis were mentioned.
Insidious development of necrologic signs and symptoms began
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178
ARSENIC
before the appearance of the classical skin lesions, but could be so
vague as to go undiagnosed for many weeks. Involvement of the
nervous system began with sensory changes, including paresthesias,
hyperesthesias, and neuralgias. Marked muscle tenderness was found
to be of major diagnostic value. Motor weakness of all degrees,
including paralysis with muscle atrophy progressing from distal to
proximal groups, was a frequent observation. Mental confusion, espe-
cially memory for time and place, was observed; but Reynolds felt that
it was less frequent than in straightforward chronic alcoholism and so
discounted any effect of arsenic on the cerebral cortex.
Left-side heart failure with severe peripheral edema was observed in
one-fourth of the patients, and the 13 deaths in this series were all due
to congestive heart failure. It is not clear whether this feature and the
muscle tenderness described above were direct effects of arsenic on
muscle fibers or secondary to its action on blood capillaries and nerve
tissue supplying the affected tissue. Skin changes were present to some
extent in all the patients, and a facial edema with an associated dusky
red color was so typical that it provided a major clue to the diagnosis on
first sight of the patient. The most outstanding problem was eryth-
romelalgia: the patients complained of pain (possibly related to
neuritis) combined with redness and swelling of the extremities, par-
ticularly the palms and soles. Excessive perspiration was regularly a
feature of the painful, hot, red, swollen feet, and patients would not
tolerate bedclothes or walking. Various short-lived generalized ery-
thematous eruptions ranging from urticarial to measles-like were fol-
lowed by slight thickening and darkening of the skin, especially in the
folds.
Pigmentation was ''generally not present in light-complexioned pa-
tients, or merely amounts to a darkening of pre-existing freckles. In
darker people it is practically always present in greater or less degree
fend] follows . . . the erythematous blush."665 The distribution of the
early stages of the pigmentation was noted to be around scars, the
neck, the armpits, the nipples, and, generally more markedly, the
trunk; and in some patients, it showed '~well-marked lighter spots like
'rain-drops,'" leading to a punctiform or patchy appearance with the
patches tending to run together to form a more or less continuous
discoloration. A desquamation similar to that seen in scarlet fever
might occur, with some lightening of the dark skin.
The familiar arsenical keratoses of the palms and soles were a late
manifestation and took several forms: ''it may be in a few isolated scaly
masses, either thin or very heaped up in marked prominences, fort the
whole palm or sole is thickly covered with large white or dirty grey
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Biologic Effects of Arsenic on Man
179
scales." Reynolds, who watched these processes evolve in his pa-
tients, noted that "in cases where there is no pigmentation keratosis
may be present and forms a most valuable aid in the diagnosis of a case
which might otherwise appear to be merely one of alcoholic paralysis.
The process is very slow (many weeks) in its development."665
Reynolds also described the nail changes of subacute arsenic poison-
ing, observable some weeks after the intake of the poison was stopped,
permitting normal nail to grow out and thus revealing the "transverse
white ridge across the nail; proximal to this the nail is normal, but distal
to it the nail is whiter, cracked, thin, and towards the tip almost papery
and much flattened. In some cases there have been a series of parallel
transverse ridges on the nails almost suggesting a series of week-end
'drinking bouts,' ~ ~ 665 This feature of arsenic exposure, commonly given
the appellation "Mees lines" on the basis of a 1919 description,537 was
also reported by Aldrich, 9 before Mees's report.
Viruses were not known in Reynolds's day, and his observation that
21 of his patients had herpes zoster led him to speculate that arsenic
might play a role in the etiology of this condition. Modern recognition
that herpes zoster is frequently seen in patients with depressed immu-
nity suggests that the patients in Reynolds's series had had a suppres-
si'on of their immune capacity. It is interesting to note that arsenic was
used therapeutically for asthma, psoriasis, and eczema-conditions
that also respond to therapy with a modern immunosuppressant,
prednisone (see Harter and Novitch335.
Since Reynolds's time, reports of subacute arsenic intoxication have
tended to confirm his observations, although none has provided such
carefully detailed material on so large a group of affected people. Even
acknowledging Reynolds's own misgivings about the contribution of
alcohol to the necrologic manifestations and allegations that selenium,
not arsenic, could have been at fault,268 this article still stands as the
definitive medical description of subacute poisoning with ingested
arsenic.
The likelihood that selenium was also present in variable amounts in
the contaminated beer deserves special attention, in view of the many
interesting and unresolved questions about relationships between this
element and arsenic. Tunnicliffe and Rosenheim8°° made the analyses
on which they based their conclusion "that selenium compounds have
played a definite role in the recent beer-poisoning epidemic." These
authors went on to state, however, that this role was "subsidiary to
that of arsenic." Willcox863 evaluated the available tests for arsenic and
concluded that "the poisoning could not have been due to selenium
primarily and arsenic secondarily." Tunnicliffe's testimony before the
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180
ARSENIC
Royal Commission on Arsenical Poisoning684 reaffirmed the secondary
role of selenium in the epidemic, suggesting that cases of atypical
wasting and unusually severe necrologic disease may have resulted
from excessive selenium. Certainly, repeated testimony before the
Commission by various chemists demonstrated repeatedly the pres-
ence of toxic amounts of arsenic in beer from several parts of the
country 319609428,477,631,683,685,686
Mizuta et al. reported on 220 patients of all ages who had been
poisoned by contaminated soy sauce, with an average estimated inges-
tion of roughly 3 mg of arsenic (probably as calcium arsenate) daily for
2-3 weeks. In this group, 85% had facial edema and anorexia; fewer
than logo were said to have exanthemata, desquamation, and pigmen-
tation; and about 20% had peripheral neuropathy.550 Except for
headaches and fevers, the findings in these patients appear to be very
similar to those reported by Reynolds, allowing for the more acute
nature of the episode and the natural differences in emphasis between
physicians separated by two generations and half the world.
The Japanese report offered additional information based on the
availability of modern diagnostic techniques. Thus, although most
patients' livers were enlarged, relatively few abnormalities were found
in liver function tests; and the description of five liver biopsies was not
particularly impressive. (Zachariae et al. found no differences between
liver biopsies of 44 psoriatic patients with a history of arsenic therapy
and 37 similar patients without such history.888) Conversely, there were
no findings on clinical evaluation of the heart and no evidence of the
congestive failure seen in Reynolds's somewhat more chronic patients;
but electrocardiograms were abnormal in 16 of 20 patients, confirming
the reports of Josephson et al.403 and Nagai et al.574
It is of interest that the Japanese patients' symptoms tended to
diminish after 5 or 6 days, despite continued intake of arsenic, and that
necrologic symptoms became prominent as much as 2 weeks after
arsenic ingestion was discontinued, at which time urinary arsenic
content remained high. Hair was found to contain arsenic at 3.8-13.0
,ug/g (ppm) near the root, compared with 0-1.5 ,uglg near the end and
0.4-2.8 ,uglg in control hair samples.
In the early 1960's, physicians in Antofagasta, Chile, noted der-
matologic manifestations and some deaths, particularly among chil-
dren, that were traced to a water supply containing arsenic at 0.8 ppm.
This water supply had been in operation only since 1958. In 1971,
Borgono and Greiber reported on a series of studies of the inhabitants
of this city.86 Of 21 children referred to Santiago for evaluation and
treatment after 1962, 16 had recurrent bronchopneumonia during the
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Biologic Effects of Arsenic on Man
181
first years of life, and all had bronchiectasis. All 21 had been referred
because of abnormal skin color and hyperkeratosis. Peripheral vascu-
lar manifestations in these children included Raynaud's syndrome,
ischemia of the tongue, hemiplegia with partial occlusion of the carotid
artery, mesenteric arterial thrombosis, and myocardial ischemia. One
autopsy showed hyperplasia of the arterial media.
In a survey of 27,088 schoolchildren, 12~o were found to have the
cutaneous changes of arsenism; one-fourth to one-third of these had
suggestive systemic symptoms. Eleven percent had acrocyanosis. One
hundred eighty inhabitants of Antofagasta were compared with 98
people who resided in a city (Iquique) having a normal water supply.
Most of the people studied were less than 20 years old. Of the
Antofagasta residents, 144 had abnormal skin pigmentation, compared
with none in the 98 control subjects. In the 18O, 30~o and 22% had
Raynaud's syndrome and acrocyanosis, respectively. Other findings
are shown in Tables 6-1 and 6-2.
The vascular diseases and the repeated episodes of pneumonia with
bronchiectasis observed in the children of this population are dramatic
and deserve special attention. Clearly, exposure to significant amounts
of arsenic from an earlier age may result in a clinical picture in growing
children different from that seen in adults.
TABLE 6-1 Clinical Manifestations among 180
Antofagasta and 98 Iquique Inhabitants a
Manifestation
Incidence in
Antofagasta,
Incidence
in Iquique,
Bronchopulmonary disease history 14.9 5.3
Abnormal skin pigmentation 80.0 0.0
Hyperkeratosis 36.1 0.0
Chronic coryza 59.7 1.0
Lip herpes 12.7 0.0
Chronic cough 28.3 4.0
Cardiovascular manifestations:
Raynaud~s syndrome 30.0 0.0
Acrocyanosis 22.0 0.0
Angina pectoris 0.0 0.0
Hypertension 5.0 10.0
Chronic diarrhea 7.2 0.0
Abdominal pain 39.1 2.0
aDerived from Borgono and Greiber.86
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182
ARSENIC
TABLE 6-2 Clinical Manifestations among 180
Antofagasta Inhabitants according to Skin
Pigmentation, 1969a
Manifestation
Incidence in
Persons with Incidence in
Abnormal Skin Persons with
Pigmentation Normal Skin
(N = 144), 56 (N = 36), pro
Bronchopulmonary disease history
Hyperkeratosis
Chronic cough
Lip herpes
Cardiovascular manifestations:
Raynaud's syndrome
Acrocyanosis
Angina pectorals
Hypertension
Chronic diarrhea
Abdominal pain
38.8
24.3
4.1
6.2
40.9
39.1
15.9 6.2
43.7
38.8
14.5
3.1
3.1
3.1
9.3
12.5
0.0
0.0
0.0
28.1
Derived from Borgono and Greiber.86
The Raynaud's phenomenon and acrocyanosis in this population are
reminiscent of the report from Taiwan by Tseng et al. and suggest that
chronic arsenism has effects on the vasculature (possibly the neural
control of arteries) that are correlated with the more acute phe-
nomena described by Reynolds and others as erythromelalgia and
acrocyanosis. 798
Tseng et al. surveyed a group of 40,421 (from a population ''at risk"
of 103,154) and found hyperpigmentation in 18.4%, keratotic lesions in
7.1%, and blackfoot disease apparently secondary to arterial spasm
in the legs in 0.9%.798 They also found an apparent tenfold increase in
the incidence of skin cancer in patients over 59 years old. The latter
figure is difficult to evaluate, because the usual incidence of these
cancers in Taiwan was not given. All these phenomena were shown to
increase with increasing arsenic concentration in the well water of the
37 villages studied. They also increased with age, but the earliest ages
noted for specific findings were 3 years for the characteristic hyper-
pigmentation, 4 years for keratoses, and 24 years for skin cancer. The
concentration of arsenic in the wells ranged from 0.017 to 1.097 ppm.
No cases of melanosis, keratosis, or skin cancer were found in a group
of 2,552 people living in an area where the wells contained almost no
arsenic.
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Biologic Effects of Arsenic on Man
183
Feinglass reported on 13 persons exposed for 2.5 months to well
water contaminated with buried insecticide.244 Most patients were seen
only once, and the most prominent feature was intermittent gastroin-
testinal symptoms related to water ingestion. Two of the 13 had nail
changes, and five (of eight in whom it was measured) had increased
arsenic content of the scalp hair. The author did not mention edema,
exanthema, hyperpigmentation, or hyperkeratosis.
Heyman et al. studied 41 patients retrospectively in an effort to
evaluate the response of arsenical neuropathy to sA~.35i In the 21
patients for whom a history of skin lesions was mentioned, there was a
prominence of branny desquamation 1-3 weeks after the exposure and
a notable incidence of ''herpetic lesions of the mouth."
There are many scattered case reports of subacute to chronic arsenic
poisoning. Silver and Wainman provided a meticulous description of a
patient who ingested approximately 8.8 mg of arsenic trioxide as
Fowler's solution daily for a total period of 28 months, as a remedy for
asthma.733 Signs of arsenic poisoning, manifest as increased freckling
and as darkening of the nipples, first appeared in association with
gastrointestinal symptoms after 13 months; redness and puffiness
about the eyes and hyperkeratoses developed at approximately 1.5
years. Neurologic symptoms in the form of paresthesias and weakness
were the last to be noted, occurring after 2 years. When the arsenic
intake was stopped, the pigmentation lightened, the hyperkeratoses
remained, and the asthma became more difficult to control. This report
is instructive, because the nature of episodes of accidental arsenic
poisoning does not usually permit definitive analysis of the amount or
duration of exposure necessary to produce reactions. However, many
authors have suggested that there is substantial variation in individual
susceptibility to any given symptom or sign. The increased likelihood
that hyperpigmentation will occur in people whose skin is naturally
darker supports this concept, as does the fact that relatively small
fractions of the exposed population have any given feature.
Perry et al.633 noted, however, that all of a group of chemical
workers handling inorganic arsenic compounds had pigmentary changes
and that one-third of them had ''warts," although these were not
well described. They reported that the cutaneous ''changes were so
evident that Ethe examiner] could readily tell whether the man . . . was
a chemical worker."633 All these handlers had increased urinary arse-
nic compatible in degree with the extent of exposure; this indicates
systemic absorption of the arsenic from dust, probably through the
lungs and skin.
Pinto and McGill studied urinary arsenic content in workers exposed
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Biologic Effects of Arsenic on Man
205
skin carcinogenesis in these experiments. Many tumors developed in
the positive control mice, beginning as early as 6 weeks after treatment
began.
Baroni, van Esch, and Saffiotti52 carried out a similar study with
male and female Swiss mice, testing the oral effects of potassium
arsenite (100 ppm in drinking water) as an initiator with croton oil
promotion and as a promoter with DMBA and urethane initiation. Local
skin applications of sodium arsenate were tested as a promoter after
initiation with DMBA or urethane. The arsenicals had no effect on
tumorigenesis; and only a very slight degree of keratosis was observed.
Milner546 used three strains of mice that differed in susceptibility to
the induction of skin tumors by the application to the skin of
methylcholanthrene-impregnated paraffin disks for 2-3 weeks. The
treated site was transplanted syngeneically and observed for 8 weeks
for tumor formation. Arsenic trioxide (100 ppm in drinking water) was
administered either during methylcholanthrene exposure, to animals
with transplanted skin, or both. Arsenic exposure produced a small
increase in the yield of papillomas in the low-susceptibility strain, a
small decrease in the high-susceptibility strain, and no effect in the
intermediate-susceptibility strain.
Byron et al.~23 fed either sodium arsenite or sodium arsenate to
Osborne-Mendel rats in a 2-year study at dietary concentrations of
15-250 ppm for arsenite and 30~00 ppm for arsenate. No carcinogenic
activity of either material was found. These investigators also did a
2-year arsenic feeding experiment on dogs, with negative results;
however, this was an inadequate observation period for studying
carcinogenic responses in dogs.
Hueper and Payne373 incorporated arsenic trioxide in the drinking
water (either plain or with 12~o ethanol) of groups of rats and mice. The
initial concentration of 4 mg/liter was increased by 2 mg/liter each
month to a maximum of 34 mg/liter at 15 months. Thus, the daily intake
of arsenic trioxide ranged from 0.1 to 0.8 mg/rat. The administration of
arsenic trioxide was continued until 24 months. Neither the rats nor the
mice developed any cancers in suspected target organs skin, lung,
and liver.
Kanisawa and Schroeder406 and Schroeder et al.7~i found no car-
cinogenic effects on mice exposed from weaning to senescence to
potassium arsenite at 5 ppm in drinking water406 or on rats on the same
regimen.7~i
Kroes et al.440 studied the carcinogenicity of lead arsenate and
sodium arsenate with sPF-Wistar-derived male and female rats. In
addition, some groups were intubated with a subcarcinogenic dose of
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206
ARSENIC
diethylnitrosamine to investigate a possible synergistic action leading
to lung tumors. Food intake and body weights were recorded, and
complete gross and microscopic examinations were made on all ani-
mals. Lead arsenate that was incorporated in the diet at 1,850 ppm was
toxic and caused increased mortality; an adenoma of the renal cortex
and a bile duct carcinoma were found in this group, but no significance
can be attached to one or two tumors in any group. No cancer was
associated with the feeding of lead arsenate at 463 ppm or sodium
Arsenate at 416 ppm. No synergism with the nitrosamines was ob-
served. There was a high spontaneous-tumor incidence in this experi-
ment. The test diets were fed to female rats from the time of parturition
until the young were weaned, and these young were the test animals.
Surviving rats were killed after 29 months of feeding.
As Fraumeni has pointed out, it is largely because laboratory studies
have not succeeded in producing tumors in animals that arsenic has not
been accepted universally as a carcinogen.267
Evaluation
Skin Cancer
There is evidence from clinical observations and occupational and
population studies that inorganic arsenic is a skin carcinogen in man.
There is a characteristic sequence of skin effects of chronic exposure to
arsenic that involves hyperpigmentation initially, then hyperkeratosis
(keratosis), and finally skin cancer.~87 This sequence has been ob-
served under a variety of circumstances involving chronic exposure:
potassium arsenite (Fowler~s solution) was used medicinally,585 vine-
yard workers used sprays and/or dusting powders containing arsenic
compounds and drank arsenic-contaminated wine,~0i 679 chemical
workers manufactured sodium arsenite for use as a sheep dip, 633 and
residents of a southwest area of Taiwan had as their only source of
drinking water for over 45 years artesian wells contaminated by arsenic
from geologic deposits.798 The similarity of responses under these
diverse circumstances is important, because studies in human popula-
tions always involve variables that cannot be controlled as in labora-
tory experiments; hence, the credibility of information derived from
human studies depends on the demonstration of comparable effects
under different conditions. This requirement has been amply met with
arsenic as a cause of skin cancer.
The earliest skin effect of chronic arsenic exposure, hyperpigmenta-
tion (melanosis), occurs in a dappled pattern predominantly in unex
OCR for page 207
Biologic Effects of Arsenic on Man
207
posed areas. After the onset of melanosis, the skin begins to atrophy in
a patchy way in hyperpigmented areas, with the formation of keratoses
that are the pathognomonic lesions of chronic arsenic exposure.~87
Only a small proportion of the keratoses evolve into skin cancer, and
this takes place only after very many years. The sequence is illustrated
by the Taiwan data the prevalence of melanosis, keratosis, and skin
cancer reached logo in the male population roughly at ages of 18, 30,
and 60 years, respectively.798 Chronic exposure to inorganic arsenic
thus causes a slowly progressive form of patchy skin damage involving
the epidermis and adnexal structures, as well as the underlying dermis,
with the precancerous keratoses and cancers forming in the areas of
chronic atrophy. The chronic damage and tumorigenesis resulting from
arsenic are similar to the effects of ionizing and ultraviolet radiation on
the skin.
Arsenical skin cancer is readily distinguished from skin cancer
induced by sunlight, in that it occurs predominantly on surfaces that
are shielded from sunlight and multiple lesions are much more com-
mon; for example, in 428 of the 429 cases of skin cancer studied in
Taiwan, there was more than one cancer.~87
Substantial doses of inorganic arsenic are required to produce an
appreciable incidence of skin cancer. The average intake of persons
treated with Fowler's solution who developed skin cancer was around
20-30 g. The prevalence of skin cancer in Taiwanese men exposed to
drinking water containing arsenic at 0.3-0.6 ppm was about 15% at age
60 and over. The normal incidence is 2-3%. On the basis of a 2-liter/day
water intake for the period over which the artesian wells were used (45
years), the total arsenic intake must have been about 15 g, which is
roughly in the same domain as that in clinical cases of the use of
Fowler's solution. Thus, the Taiwanese data that demonstrated the
requirement for large doses of arsenic to obtain even a modest yield of
skin cancer are consistent with the relatively low frequency of skin
cancer in patients treated with Fowler's solution. The low potency of
inorganic arsenic may explain why no skin effects have been reported
in people treated for syphilis with organic arsenicals, inasmuch as the
total doses amounted to only a few grams. However, it is also possible
that the metabolism of the organic arsenicals is sufficiently different to
preclude the occurrence of skin cancer and other forms of arsenical
damage even at higher doses.
The relative frequency of melanosis, keratosis, and skin cancer was
roughly similar in the Taiwanese population and the chemical workers
who manufactured sheep dip. On direct examination, the latter showed
a 90%0 prevalence of melanosis and a 30~o prevalence of keratosis, for a
OCR for page 208
208
ARSENIC
ratio of melanosis to keratosis of 3: 1. At comparable ages, the
Taiwanese showed a ratio of about 4: 1. Two of the nine keratosis
patients in the sheep-dip factory had already been treated for skin
cancer, and the proportionality between keratosis and skin cancer was
about the same in Taiwan. As in the Taiwan experience, the sheep-dip
chemical workers had been exposed to large doses of inorganic arsenic
(up to I g/year), but much of this was by inhalation.
It is possible that the trivalent and pentavalent forms of inorganic
arsenic produce the same effects on skin. This is of interest, particu-
larly in view of the different metabolic patterns of trivalent and penta-
valent inorganic arsenic the former by interaction with sulfhydryl
groups and the latter by substituting for phosphate. The clinical use
of Fowler's solution and the manufacture of sodium arsenite as a sheep
dip both involved exposure to trivalent inorganic arsenic. The two
categories of people developed similar skin responses. The Rhodesian
gold miners, in whom the incidence of typical arsenical keratoses was
very high, were exposed to arsenopyrite, in which the arsenic becomes
trivalent on weathering; the reactions of arsenopyrite in the body are
unknown (K. J. Irgolic, personal communication). The chemical form
of arsenic in the Taiwanese artesian-well water is also unknown;
however, the reported occurrence of methane gas in the water could
preclude the existence of arsenic in the pentavalent form (K. J. Irgolic,
personal communication).
Lung Cancer
Of the published reports on mortality from respiratory cancer in copper
smelters, the most impressive is that of Lee and Fraumeni.4~2 The
study involved a population of 8,047 white male smelter workers who
were followed for 26 years; for each employee, information was
available on time, place, and duration of employment, maximal arsenic
and sulfur dioxide exposures (descriptive, rather than numerical), and
cause of death. The life-table method was used to evaluate age-specif~c
mortality rates for the various causes of death, and the rates were
compared with those of the states in which the smelters were. The
number of deaths available for analysis was very substantial 1,877.
The study demonstrated a systematic gradient for respiratory cancer
according to the magnitude and duration of exposure to both arsenic
and sulfur dioxide. These agents, however, were inseparably linked,
because of the nature of the smelter operations. The amount of excess
cancer was impressive, with an eightfold increase in the workers who
had the heaviest arsenic exposure for the longest duration, i.e., more
OCR for page 209
Biologic Effects of Arsenic on Man
209
than 15 years. The latent period the interval between first employ-
ment and death from respiratory cancer was extraordinarily long and
was inversely related to the magnitude of exposure: 34, 39, and 41
years for the categories of heavy, medium, and light arsenic exposure.
There were deficiencies in the study, some of which were unavoidable.
For example, no indication was given of whether the study population
was representative of the total worker population; the exposure rank-
ings were based on the maximal arsenic concentrations, rather than
weighted averages derived from work histories. No quantitative data
were available on exposure. No attempt was made to validate the
stated causes of death. No smoking histories were obtained. However,
none of these deficiencies could be seriously regarded as invalidating
the conclusions of the study.
The Kuratsune report dealt with a smaller study that compared
lung-cancer mortality rates calculated from the 22 deaths that occurred
in a 30-year period in a smelter town with the lung-cancer experience in
the same period in a neighboring city and in Japan as a whole.443 The
standardized mortality rate for males in the smelter towns was 4 times
higher than that for the rest of the country, but equal to that for women.
This fourfold excess is comparable with the 3.3-fold excess observed in
the Lee-Fraumeni study. Although many of the men in the town
worked in the refinery, a much higher proportion of the lung-cancer
cases, compared with controls, occurred in men who were heavily
exposed to arsenic as smelter operators. As in the case of the Lee-
Fraumeni study, the latent period from first exposure to the diagnosis
of lung cancer was very long, ranging from 26 to 48 years. The duration
of employment was also very long, with a median of about 30 years,
although two cases occurred in people who worked for only 2-3 years.
Two lung-cancer studies of the American Smelting and Refining
Company smelter have produced conflicting results. The 1963 Pinto
and Bennett report examined the proportional mortality from lung
cancer in a total of 229 deaths in the period 1946-1960.647 This study
dealt only with pensioners and workers who died during their employ-
ment and did not include people who had left the plant. The reported
data showed that the 18 lung-cancer deaths in the plant population as a
whole indicated a rate that was higher than the rate in the state of
Washington. However, the excess lung cancer for the plant as a whole
was due to the high occurrence in controls, i.e., in workers who were
considered not to have arsenic exposure. Milham and Strong, by
contrast, found, in the years 1950-1971, that there were records of 39
deaths due to respiratory cancer in Pierce County (the smelter locale)
in people who were stated to have worked at the smelter.543 Applica
OCR for page 210
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OCR for page 211
Biologic Effects of Arsenic on Man
211
tion of U.S. mortality rates to the published figures for the smelter
population at risk yielded an expected number of 18 respiratory-cancer
deaths, compared with the 39 deaths observed.
Pinto et al. (S. S. Pinto, V. Henderson, and P. Enterline, "Mortality
experience of arsenic exposed workers," unpublished data) recently
resolved the discrepancy between the Pinto and Bennett647 and Milham
and Strong543 papers in a study of the same smelter that reevaluated the
exposure categories used in the Pinto and Bennett paper647 (which were
apparently in error) and also included a longer observation period and
therefore more deaths. The data, in Table 6-5, include a total of 32
respiratory-cancer cases and show a progressive increase in stan-
dardized mortality ratio with increasing arsenic exposure. The
arsenic-exposure index was calculated as a weighted average based on
urinary arsenic concentration and duration of employment. It is of
interest that the eightfold excess in respiratory cancer for workers with
the highest exposures and the threefold excess for all the smelter
workers reported by Pinto et al. (see Table 6-5) were very close to the
figures reported by Lee and Fraumeni460 and Kuratsune.443
The studies described here indicated that excess respiratory cancer
occurs in copper-smelter workers as a function of the magnitude and
duration of exposure to arsenic, with latent periods of three to four
decades from the time of initial exposure. However, the studies do not
permit a resolution of the issue of whether concomitant exposure to
sulfur dioxide and other smelter dusts is necessary for the carcinogenic
response. Evidence from studies involving entirely different circum-
stances of exposure including workers in three pesticide manufactur-
ing plants,352 609* vintners who applied pesticides,~0~ 679 and Rhodesian
gold miners606-suggests that sulfur dioxide and other unspecified
smelter dusts are not essential cofactors for the respiratory car-
cinogenicity of arsenic. All the nonsmelter studies had obvious limita-
tions, but the lung-cancer excess in each study was relatively large and,
taken as a group, they provide significant evidence that arsenic is a
lung carcinogen.
The Hill-Faning study of 75 deaths in a sheep-dip factory used the
indirect method of proportional mortality to evaluate the small group of
22 deaths from cancer; seven of them were cancers of the respiratory
tract, compared with an expected 2.4 deaths.352 The Dow arsenic
workers609 were evaluated in two ways: by an analysis of death records
of those who died from lung cancer (28, or 16.2%, of 173 chemical
*Also, A. Baetjer, M. Levin, and A. Lilienfeld, "Analysis of mortality experience of
Allied Chemical plant," unpublished data.
OCR for page 212
212
ARSENIC
worker deaths, compared with 104, or 5.7%, of 1,809 control-case
deaths), and then, as a retrospective cohort study, a comparison of the
mortality from respiratory cancer (obtained from the records used in
the first approach) among 603 persons identified as having worked in
the arsenic plant from 1940 to 1973 with the mortality among the
corresponding U.S. white male population. The two approaches gave
essentially the same results a threefold to fourfold excess. However,
the puzzling aspect of the data is that almost 60~o of the respiratory-
cancer deaths were in people who had worked with arsenic for less
than a year, three decades earlier. Most of the arsenic workers were
unskilled short-term employees, of whom a large proportion left the
company after a brief period of employment. The followup study,
however, dealt only with the people who remained in the company. A
confirmation of the excess lung cancer in a followup of short-term
arsenic workers who left the company would be very useful. Neverthe-
less, there were about a dozen cases in people who worked longer than
a year and who were in the highest dose categories, where the excess
risk was maximal- fourfold to sixfold. It is possible that the apparent
twofold excess in lung cancer in the lower exposure categories, includ-
ing those who worked with arsenic for less than a year, would not be
ascribable to arsenic, because there was no change in cancer risk over
a very wide range of total doses (0.04-1.56 g). Furthermore, these low
dose categories consisted predominantly of short-term unskilled work-
ers who as a group might have had higher exposures to other hazardous
chemicals than the controls.
The Allied Chemical Company pesticide manufacturing operations
produced a range of products, including some arsenical compounds. A
preliminary study of the proportional mortality among retired em-
ployees showed a sevenfold excess of lung cancer that accounted for
about 40~o of all deaths (A. M. Baetjer, personal communication). Both
the Dow and Allied studies also showed a few excess deaths from
lymphoma and Hodgkin's disease. The results of a more detailed study
of the Allied Chemical Company that is now in progress will be very
useful.
Arsenic sprays and dusts were widely used in Germany between
1925 and 1942, at which time they were banned. ]0~9679 Vineyard workers
also drank wine containing arsenic. Hundreds of workers developed
acute and chronic arsenic poisoning. In the 1950's, vineyard workers
with lung cancer began to appear in hospitals serving the vineyard
regions. An association between arsenic and lung cancer is further
suggested by the high proportion of vineyard workers with lung cancer
OCR for page 213
Biologic Effects of Arsenic on Man
213
who had the characteristic hyperpigmentation and keratoses associated
with chronic arsenic exposure.
The same high degree of association of skin arsenism and lung cancer
occurred in Rhodesian gold miners who were heavily exposed to
arsenopyr~te dust.606 In the period 1957-1963, the occurrence of 37
cases of lung cancer in gold miners represented an incidence of
206/100,000, compared with 34/100,000 for adult males in the Gwanda
region of Rhodesia. This represents a sixfold difference in lung cancer
. .
In miners.
The probability of death from lung cancer in persons with keratosis
shown in Table 6-6 ranges from 32 to 56%, which is roughly 5-10 times
higher than might be expected.
The data suggest that there is a very high risk of lung cancer when
the exposure to inorganic arsenic dust is high enough to cause
keratoses.
Liver Cancer
The only evidence that arsenic is a liver carcinogen comes from
German vintners. Thirteen of the 27 persons whose autopsies were
reported by Roth679 had cirrhosis, and three had angiosarcoma, a rare
form of liver cancer associated with exposure to a vinyl chemical and
Thorotrast. Only two cases of angiosarcoma have been reported in
people treated with Fowler's solution.663 There is no evidence of either
cirrhosis or liver damage in any of the other studies on arsenic. It is
possible that the combined effect of a high alcohol intake and arsenic is
TABLE 6-6 Frequency of Lung Cancer in Persons with Keratoses
Who Had Heavy Exposure to Arsenical Dusts
(a) (b)
No. Cases of No. Cases of b/a,
Subjects Keratosis Lung Cancer ~Reference
Rhodesian gold miners 40 13 32 606
Vintners (Braun) 16 9 56 101
Vintners (Roth) 30 10 33 679
Sheep-dip workersa 12 5 42 633
Total 98 37 38
aAssumes that 41 chemical workers who died in 1910-1943 had the same skin changes as chemical
workers examined in 1946.
OCR for page 214
214
ARSENIC
responsible for the unusual forms of cirrhosis and liver cancer ob-
served in vintners. It should also be pointed out that the chemical form
. . · · .
Of arsenic In wine Is unknown.
Experimentally Induc ed Cant er
The fact that there is no established method for producing cancer by
treatment with any form of arsenic in an animal model system is an
enigma. One must conclude either that arsenic is not a carcinogen or
that particular circumstances not yet achieved are essential to demon-
strate a role for arsenic in experimental carcinogenesis. A conclusion
that carcinogenesis by arsenic is restricted to humans (or cows, horses,
and deer425 is highly suspect. Therefore, much effort should be spent in
attempting to find conditions in which the presence or absence of
arsenic determines the appearance or nonappearance of cancer in an
animal model. Some questions need to be explored (their answers may
account for the variable incidence of human cancer associated with
arsenic exposure):
· Potassium arsenite, arsenic trioxide, and possibly other com-
pounds of arsenic appear to have an unusual propensity to alter
epithelial morphology (at least in humans), often acting as irritants and
causing hyperplasia, as well as hyperkeratosis. Thus, appropriate
forms of arsenic should be tested with known lung carcinogens for
synergistic action. Possibilities include the ferric oxide-benzopyrene
model in the hamster developed by Saffiotti et al.699 and the sulfur
dioxide-benzopyrene inhalation model of Kuschner and Laskin.444
Controls designed to test exposure to arsenicals alone should be
included; properly controlled long-term inhalation studies have not
been done.
Although both Barone et al.52 and Boutwell9~ based their tests in
mouse skin on a possible cocarcinogenic role for arsenic and found
none, additional experiments of this nature are reasonable.
Moreover, because morphologic changes in epithelial tissue are
ascribed to arsenic, and because vitamin A and some retinoids control
normal epithelial morphology,754 it is appropriate to design experiments
in which vitamin A deficiency is induced in animals as a test system for
arsenical carcinogenicity (and cocarcinogenicity). In experimental
animals, vitamin A deficiency increases susceptibility to chemical
carcinogenesis, and high dietary concentrations of retinoids have re-
markable ability to prevent chemical carcinogenesis in epithelial tis-
sues,754 including skin, breast, and lung.
OCR for page 215
Biologic Effects of Arsenic on Man
215
Again, because arsenicals alter epithelial morphology, the possibility
that the function of mucus-secreting cells or of the ciliated cells of the
lung is interfered with by respirable particles bearing arsenic580 should
be investigated. Interference with mucus secretion or ciliary action
would facilitate the action of a carcinogen, such as tobacco smoke,
entering the lungs.
· Because compounds of arsenic and the heavy metals that may be
associated with them are enzyme poisons, it is possible that chronic
exposure to abnormal amounts of these substances partially poisons
enzymes that inactivate carcinogens. Model systems might be devised
to test this possibility.
· The interaction of arsenic with some essential nutrients, such as
sodium selenite and potassium iodide, is known. This should be
considered in designing animal models.
Peoples626 has shown that potassium arsenite and sodium arsenate
are detoxified via methylation pathways. Biologic changes attributable
to arsenic might be accentuated in animals fed diets that are low in
labile methyl groups.
· The administration of some carcinogens to pregnant females may
result in an unusually high incidence or early development of cancer in
the offspring. Because one such test, by Osswald and Goerttler,607
resulted in an unusual incidence of leukemia in mice, it is especially
urgent to design appropriate transplacental tests. Repetition of such a
test is essential. The credibility of the Osswald and Goerttler study is
limited by their failure to give the vehicle solution to the controls.
· Because of the failure of repeated tests in lower animals to show
carcinogenicity due to arsenicals, consideration should be given to the
use of nonhuman primates as test animals.
These are only a few examples of approaches to the problem of
ascertaining whether an animal model may be devised to account for
the association of human cancer with exposure to arsenic.
Representative terms from entire chapter:
lung cancer
