Kaj Roholm's 1937 Classic Summary of: Fluorine Intoxication
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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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