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Fluorine Intoxication Summary by Kaj Roholm
The starting point of the author’s investigations lies in Flemming
Moller and Gudjonsson’s description of the previously unknown fluorine
intoxication among workers at a Copenhagen factory, where cryolite is purified
and ground, giving off quantities of dust. As fluorine intoxication has not hitherto been thoroughly
enquired into, a systematic, critical-synthetic examination is made in Part I of
the numerous and little known works concerning the role played by fluorine in
biology. Most importance is
attached to the genesis of the various forms of intoxication, as well as to
their clinical and patho-anatomical picture. The occurrence of fluorine in inanimate and animate nature
is discussed in detail. After
Explaining the technique employed in the author’s investigation (Part II), a
full account is given in Part III of the result of the author’s studies on
human cryolite intoxication from the point of view of the clinical picture,
morbid anatomy and industrial hygiene.
A synoptic digest concludes this part. Part IV contains a description of the author’s intoxication
experiments on rats, pigs, calves and dogs, with a concluding summary of the
results obtained for each species of animal. In Part V, Discussion and Conclusions, the results of the
literature studies and the author’s investigations are summarized by means of a
brief, systematic examination of acute and chronic fluorine intoxication, the
possibilities of intoxication, and the prophylactic problems. A final chapter discusses the
physiological role possibly played by fluorine. The principal conclusions of the work are outlined below.
Occurrence of Fluoride in Nature
As a constant ingredient of eruptive rocks, fluorine is a widely
diffused element in inanimate nature.
Fluorine in soil, fresh water and seawater comes from that source. Volcanic products may contain
fluorine. Deposits of fluorine
minerals and rocks occur in the form of fluorspar, cryolite, apatite,
phosphorite. Normally, plants and
animals absorb small quantities of fluorine according to local factors. It is probable that there are traces of
fluorine in all organic tissue. As
there is an affinity between fluorine and calcium phosphate, fluorine
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is stored in bones and teeth. As a rule bone ash of terrestrial mammals contains 0.1-1%,
tooth ash 0.1-0.4% fluorine. Bones
and teeth of animals living in the sea contain about ten times as much
fluorine. In the teeth fluorine is
principally deposited in the dentine, to a lower degree in the enamel.
Effect on Enzymatic Processes and Protoplasm
Fluorine compounds affect a large number of enzymatic processes (e.g.
tissue respiration, blood coagulation, lactic acid formation in muscle, the
splitting of starch by yeast).
Generally the effect is inhibitory, but often a weak concentration of
fluorine is stimulating, a stronger one inhibitory. Active fluorine compounds destroy protoplasm and arrest
bacterial growth. Yeast cells can
become habituated to fluorine compounds.
It is doubtful whether the quantity of fluorine absorbed under normal
conditions is of any physiological significance. Experimentally, fluorine in quantities below the toxic limit
has a stimulating effect on growth processes. It has never been demonstrated nor is it probable, that
fluorine in physiological doses is necessary to or has a beneficial effect on
the development of the teeth.
Fluorine Compounds
From a toxicological point of view the fluorine compounds may be divided
into four groups: (1) Gaseous,
hydrogen fluoride (HF), silicon tetrafluoride (SiF4) and certain organic
compounds; (2) solutions of hydrofluoric acid (HF) and hydrofluosilicic acid (H2SiF6);
(3) relatively easily soluble fluorides and silicofluorides; (4) slowly soluble
compounds, especially cryolite (Na3AlF6) and calcium fluoride (CaF2), The first three groups play a part in
acute intoxications, all of them in chronic intoxications.
Acute Intoxication
Acute intoxication manifests itself by a mixture of local
irritation or corroding phenomena and symptoms due to absorption. Ingested perorally, fluorine compounds
in man produce vomiting, often haemrrhagic, diffuse abdominal pains, diarrhoea,
alternation between painful spasms and pareses, both localized and universal,
weakness, thirst, salivation, perspiration, dyspnoea, weak pulse, possibly
death. One or more of the symptoms
may be absent. Mammals present a
similar picture, also under parenteral administration of fluorine. The calcium content of the blood is
lowered. On respiration of gaseous
fluorine compounds there are irritation symptoms from the mucous membranes of
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the eye and air-passage, and more or less pronounced
symptoms due to absorption.
In acute intoxication the post-mortem findings are haemorrhagic
gastroenteritis with a tendency to necrosis, acute toxic nephritis, and varying
inflammatory changes in the lungs.
Dosis minima letalis depends upon the rate of absorption. For the mammals generally used in the
laboratory, d.m.l. is 23-90 mg. fluorine per Kg. body weight with peroral
administration. Man is much more
sensitive, 6-9 mg. fluorine per kg. having caused death. As a rule the lethal dose is much
higher, about 5-15 g. sodium fluoride.
The lethal intoxication mostly have a course of hours only.
Chronic Intoxication
The symptoms depend upon the dose, the time factor, the animal species,
the age of the individual, the composition of the diet, and other factors, some
of them unknown. The injurious
effect of fluorine is especially localized to bones and teeth. The intoxication has three different
forms which are capable of various combinations: (1) Degenerative tooth
changes; (2) diffuse osteosclerosis; (3) a generalized bone disease accompanied
by general symptoms and resembling the classical osteomalacia. The smallest dose that can produce the
various forms is uncertain as yet, but seems to rise from (1) to (3).
Dental changes have been observed in man and in many animals. Teeth already calcified are not
affected, or only slightly so, by fluorine ingestion. Teeth of parts of teeth calcifying during the period of ingestion
display degenerative changes which seem to be pathognomonic. In the lightest degrees the enamel is
dull, chalky-white, with yellow, brown or black pigmentation of the areas of
the teeth that are exposed to the light.
The more severe degrees are characterized by a hypoplastic,
low-resistant enamel and dentine.
The abnormally heavy wear may cause considerable functional
disturbances. The teeth may
present abnormities as to size, shape and position. Histologically degenerative changes are observed of the
enamel epithelium and formation of a hypoplastic, defectively calcified enamel
and dentine. The smallest dose
capable of producing just recognizable changes in the rat (under the hand
glass) is about 1 mg. fluorine per Kg. body weight per day. Man is much more sensitive, as about
0.07 mg. fluorine per kg. daily will cause macroscopic changes. These doses are not accompanied by
other known injurious effects on the organism.
Osteosclerosis in man is known as a systemic disease attacking all bones
and
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especially the cancellous bones. The X-ray examination reveals increased bone formation from
both periosteum and endosteum (narrowed medullary cavity, periosteal deposits). Cancellous bones densify and may give a
diffuse, structureless shadow. The
osseous ligaments calcify,
especially those of the vertebral column. Clinical observations include irregular thickenings of the
subcutaneous bone surfaces and reduction of motility in the vertebral column
and the thorax. Post-mortem
examination shows the bones to be massive, up to three times as heavy as normal
bone, and relatively brittle. The
surface is uneven, ligaments and joints capsules calcified, but not the
cartilage. Microscopical
examination reveals abnormally structured osseous tissue and excessive calcium
deposition; the calcium salts are partly precipitated in the form of irregular
granules. The general condition is
not affected, and no definite changes in other organs are observed; the teeth,
however, show signs of increased formation of cement and dentine. In man the disease is probably caused
by 0.20-0.35mg. fluorine daily per kg. body weight. The changes appear, however, only after several years of
regular fluorine ingestion. In the
rat a similar, if not identical, condition can be produced experimentally by
administration of fluorine over a period of months.
The osteomalacic condition is known to occur in a number of mammals, but
not in man. It is a link in a more
or less pronounced cachexia, manifested in the form of anorexia, emaciation,
anaemia, coarse and untidy coat, and sundry eye changes. Simultaneously there usually are signs
of manifest or latent tetany, especially a stiff and laborious gait, a tendency
to a reduction of blood calcium and tremor. The osseous system displays varying formation of exostoses,
especially on mandible and extremity bones. On necropsy the bones are found to light and soft, spongiosa
and compacta atrophic, but their thickness owing to periosteal deposits is
sometimes surprising. Microscopically
the disease is characterized by the formation of an abnormally structured
osseous tissue and a reduced and irregular calcification of the osteoid tissue,
with tendency toward a granular precipitation of the calcium salts. The pathoanatomical changes are similar
to rickets and classical osteomalacia, but cannot be identified with them. The parenchymatous organs, including
the bone marrow, display varying degrees of degeneration phenomena, and the
kidney also a mostly interstitial, contracting nephritis. The renal effect is not equally great
in the various animals. The dose
varies, but most frequently is about 15-20mg. fluorine daily per kg. body weight
(growing rats, pigs,dogs).
Herbivora seem to be more sensitive. The condition develops and death may occur in the course of weeks or months. An increased calcium requirement
(growth, pregnancy, lactation) expedites the development of the intoxication.
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Mode of Action of Fluorine
Fluorine is absorbed from the gastro-intestinal tract; gaseous fluorine
compounds may be absorbed through the lung. In what form fluorine is absorbed, circulated, stored or
excreted is not known. The
heaviest storage takes place in the bones and teeth, probably as a mixture of
hydroxyl- and fluorapatite. There is no deposition as crystalline calcium
fluoride. Fluorine is deposited
diffusely in the osseous system, but especially in the cancellous bones. Most probably fluorine can be deposited
in preformed enamel. All forms of
chronic intoxication have an increased fluorine content in bone and tooth ash
(from about 2 to 30%). As a rule,
fluorine in small quantities does not permeate placenta; yet the various
species react differently. In
woman and the rat fluorine is excreted in the milk.
In relatively large doses fluorine causes a negative calcium balance,
presumably by monopolizing the calcium of the organism; calcium fluoride is
very slowly soluble. The
calcioprive effect of fluorine cannot explain all the symptoms of the
intoxication. The osteosclerosis
is accompanied by increased mineral deposition, the tooth changes occur at such
small doses that direct calcium deficiency is out of the question. Fluorine must be assumed to have a
special effect on tissue. The
effect on osseous and dental tissue appears universally by (1) the formation of
an abnormally structured organic matrix, and (2) a calcification anomaly,
whereby the mineral salts of the bone are precipitated irregularly and in
discrete granules. Comparatively
small doses seem to produce increased growth and increased calcification,
comparatively large doses produce mostly atrophic processes and reduced
calcification. The osseous effect
of fluorine probably is the result of an influence on enzymatic processes
connected with the precipitation of the mineral salts, stimulative or
inhibitive according to circumstances.
It is possible, but not probable, that the effect on the calcium
metabolism is exerted via the parathyroid glands. Fluorine affects several metabolic processes, and presumably
the symptoms of intoxication have a complicated pathogenesis. There is a special relation between
vitamin C and fluorine.
Possibilities of Intoxication
Local corrosion phenomena are common in industry. Acute intoxication is
particularly often the result of an accident (mistaken identity); suicide and
murder are not unknown. In the
period from 1873-1935 a total of 112 cases of human poisoning were published,
60 of them fatal. Many cases of
animal poisoning have been described.
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The cases of spontaneous, chronic intoxication all arise from the
ingestion of fluorine through the gastro-intestinal tract. Gaseous fluorine
compounds may bring about chronic intoxication by absorption through the
lung. The known chronic
intoxications comprise (1) mottled teeth, a dental disease that is endemic in
man in certain parts of Europe, America, Africa and Asia; (2) osteosclerosis*
an occupation disease among cryolite workers in Copenhagen; (3) osteomalacia,
endemic among herbivora in the vicinity of certain manufacturing plants in
Europe; (4) darmous, a dental and mandible disease in herbivora in certain
parts of North Africa; (5)gaddur, a dental and osseous disease among herbivora
in Iceland after volcanic eruption.
Greater or smaller possibilities of intoxication are offered by:
Drinking water containing more than 1 mg. fluorine per liter; plants cultivated
in regions where the soil is especially rich in fluorine; extraction and use of
fluoric products. A number of the
uses of fluorine compounds are of interest, though they have not caused
intoxication so far as is known, i.e. spraying of edible plants with fluorine
compounds as insecticides, manuring with fluoric superphosphate, the addition
of fluorine compounds to food for preserving purposes, and the therapeutic
employment of fluorine compounds.
Prophylaxis
Restriction of the trade in fluorine compounds with the highest acute
toxicity. Prohibition against the
addition of fluorine compounds to food as preservatives. Maximum limits for the fluorine content
in edible plants sprayed with insecticides containing fluorine. Prohibition against the employment of
females and young people on work with fluorine compounds developing dust or
vapour. Protection and control of
workers exposed to the effects of fluorine. Recognition of chronic fluorine intoxication as an
occupation disease rating for compensation. Demand that industrial establishments should neutralize waste
products containing fluorine.
Cessation of the therapeutic use of fluorine compounds for children. Test for fluorine in the routine
analysis of drinking water, food, and cases of poisoning with vague
aetiology.
*) Recently, the osteosclerosis has been observed in persons
attacked by darmous and a man employed in a fertilizer factory, where he had
handled rock phosphate containing fluorine
The End
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