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Hepatitis and toxic substances

Hepatitis and toxic substances

Hepatitis and employment: Liver and toxic substances in the workplace

By Dr. Christine COLLAT

Internist in Industrial Medicine
Strasbourg
This paper appears on the site of l'AIMT 67
If you have comments or suggestions in order to improve this informative document, please contact the authort Dr Christine COLLAT
 
 
 
 

 

INTRODUCTION
The most important ways to eliminate toxic substances are the hepatobiliary and the renal channels. The liver converts the toxic substances in metabolites often very aggressive against the organism themselves.

The industrial substances, which are responsible for toxic actions on the liver can exert direct effect on the hepatic cells and thus bring about lesions in the periportal regions of the hepatic lobules or mostly they will be toxic after oxidation by the microsomal system and then the lesions will develop in the centrolobular zones. These two forms of direct hepatic toxicity depend on the dose. There is an other type of toxic action due to the immune allergic mechanism, which causes an indirect hepatic toxicity e.g. halothane; in this case the symptomatology does not depend on the dose but is very much linked to the repetition of the exposure.

1. ACUTE CYTOLYTIC TOXIC HEPATIC DISEASES

The oxidation of certain xenobiotics by the various isoenzymes, constituting the system of the mono-oxygenases in cytochrome P 450, produces instable metabolites, aggressive substances of various chemical nature (e.g. free radicals for tetrachloromethane) which will attack the cellular constituents.

The lesions initiated in this way will predominate in the centrolobular zone. Protection systems exist in the middle of the cell itself so as to limit the action of the reactive metabolites: self-restraint of the formation of metabolites by destruction of the cytochrome P 450, inactivation by conjugation with the glutathione. Only if the capacity of inactivation by glutathione is exceeded the reactive metabolite will put its toxicity into effect. The knowledge of these mechanisms is on the basis of the therapeutic proposals: administration of N-acetyl cysteine, precursor of glutathione.

CARBON TETRACHLORIDE

Carbon tetrachloride or tetrachloromethane (CCl4) is a halogen aliphatic hydrocarbon derived from methane. This chlorine-containing solvent is a colourless and volatile liquid. The respiratory routes are the most important entrances, but percutaneous absorption can contribute to the hepatotoxicity.

Sources of exposure

Its use is very much restricted on account of the fact that its toxicity can manifest itself after simple inhaling. Carbon tetrachloride was formerly used as a dry-cleaning solvent (it has been almost entirely displaced from this application by tetrachloroethylene, which is much more stable and less toxic) and in fire-extinguishers because it is a nonflammable liquid. Its use in fire-extinguishers has been forbidden because of its danger of intoxication, particularly at elevated temperature (circular of 30.06.61 concerning the ban on fire-extinguishers filled with tetrachloromethane). Nowadays it is used:

  • As intermediate in the chemical industry: starting material for manufacturing (di)chlorofluoromethane (a refrigerant and propellant), compound of chlorine, extraction agent.
  • in research as a laboratory reagent.

Manufacturing is forbidden since 10 January 1995 on account of the strong toxicity and the depletion of the ozone layer in the stratosphere (Council regulation CE nr. 3093/94 of 15th December 1994, concerning substances depleting the ozone layer).

Pathogenesis

Carbon tetrachloride is not directly active on the hepatic cellules. There is a splitting of the carbon tetrachloride, which leads to the generation of free radicals, alone responsible for the poisoning symptoms. The hepatotoxicity depends on the dose. The lesions will predominate in the centrolobular region.

Clinical symptoms

Acute exposure manifests itself by a disorder of the central nervous system (excitement and after that somnolence, headache, visual disturbances, dizziness, coma) then due to gastro-intestinal troubles (nausea, vomiting, abdominal pains, diarrhoea) which induce pseudo-chirurgical digestive forms often together with the beginnings of a fever, followed by a hepatic disorder (hepatic cytolysis on account of necrosis) 12 to 24 hours later.

The patient usually shows a sensible hepatomegaly, sometimes icterus or subicterus and dark brown urine. In the field of biology the transaminases may reach a very high level (above 100 N) and the PT as well as factor V reduced in a variable way, evidence of hepatocellular insufficiency.

On the 2nd or 3rd day the liver disease is complicated with acute oligo-anuric tubulopathy (on account of necrosis of the tubules) accompanied by peripheral oedemata and hypertension. The pulmonary oedema, an often occurring complication of the intoxication, is due to renal insufficiency and to direct lesions of the alveolar wall.
Chronic alcoholism, cause of an induction of the microsomal hepatic enzymes, is an aggravating factor as demonstrated at collective intoxications with identical exposure. The acute toxicity is also enhanced by trichloroethylene, ketones and phenobarbital.

The proposed treatment is the administration of N-acetyl cysteine (Mucomyst°), precursor of glutathione, which restores stock of the cellular glutathione and the free radicals neutralizes. The prognosis for this intoxication is good thanks to the haemodialysis. Recovery usually occurs without sequel.

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CHLOROFORM

Chloroform or trichloromethane (CHCl3) has been abandoned as an anaesthetic on account of its toxicity to liver and heart (ventricular hyperexcitability). At present chloroform is still used a chemical intermediate.

1,2 DICHLOROPROPANE (CHC 13-CHCl-CH3)

Mainly used as a solvent and a stripper for paint and varnish, as a degreaser for metals and textiles and also used for the extraction of oil , fat and wax, for organic compounds and the treatment of soils. It entrains a hepatocytar necrosis initially accompanied with a depression of the central nervous system and sometimes with a haemolysis and a CIVD.
 

1,3 DICHLOROPROPENE or DPC

It is used for the fumigation of soils before planting to destroy the nematodes, which sponge on potatoes, vegetables, tobacco and in the culture of greenhouse plants. It is absorbed easily by either inhalation or percutaneous.. Mucocutaneous projection provokes chemical burns. The inhalation of vapours causes otorhinolaryngological and respiratory irritation accompanied with conjunctivitis and symptoms of inebriety and narcotics.

The hepatotoxicity is not documented: not one hepatorenal disease has been described after an occupational intoxication.

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1,2 DIBROMOETHANE ET 1,2 DICHLOROETHANE OR ETHYLENE CHLORIDE
 

Ethylene chloride is mainly used in the synthesis of monomer vinyl chloride. They rarely are the cause of an accident involving humans. Six cases are reported with 1,2 dibromoethane, one of which deadly. This solvent entrains a double disease, a hepatic and renal one.

BROMOBENZENE AND CHLOROBENZENE

Bromobenzene is mainly used in organic synthesis.

Chlorobenzene is used:

  • as a thinner in the paint and varnish industry;
  • as a degreaser in the textile and metal industry;
  • as an extraction agent;
  • in the manufacturing of colouring agents and certain inks;
  • in the manufacturing of fungicides and certain insecticides;
  • in organic syntheses.

They are exceptionally responsible for liver diseases in humans.

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1,1,2,2 TETRACHLOROETHANE

Tetrachloroethane is a chlorine-containing aliphatic hydrochloric acid. Very hepatotoxic, responsible for hepatitis mixed with icterus, can evolve to cirrhosis. It is used as a chlorine-containing solvent of cellulose acetate and has entrained mixed hepatic diseases in aviation during the two world wars. At present tetrachloroethane has been abandoned as a solvent and is used exclusively as a basic product in chemical synthesis in research laboratories.

 

2. OTHER CHLORINE-CONTAINING SOLVENTS

Trichlororethylene and tetrachloroethylene (perchloroethylene) are not hepatotoxics. The only observations of toxic hepatites, reported by sniffers of these substances, were due to trichloroethylene containing nephro- and hepatotoxic substances (carbon tetrachloride and 1,2-dichloropropane).

2 NITROPROPANE

Used as a solvent for epoxy resins, inks and adhesives, it has induced fulminant hepatites due to inhalation in closed space after an initial noisy symptomatology associated with an inebriety-narcotic syndrome, digestive troubles, headache, ataxia, dyspnoea and thoracic pains. The hepatitis is in general very grave, manifestation retarded for 2 or 3 days with major cytolysis (transaminases above 100 N). Methemoglobinemy (hemiglobinemy) is possible. The greater part of the published cases experiences a fulminant evolution, which results in death on account of terminal hepatocellular insufficiency.
The diagnosis can be confirmed by blood titration of 2-nitropropane..

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DIMETHYLFORMAMIDE (DMF)

It is a solvent responsible for a very bad odour (poison), absorption by transcutaneous (transdermal) routes is as important as absorption by inhalation. As DMF is little volatile, the majority of the occupational intoxications is due to prolonged or repeated contamination of the skin. Latex- and neoprene gloves are DMF permeable

Sources of exposure

DMF is very often used as a solvent in the industries of synthetic materials (acrylic fibres) and synthetic leathers. It also is a solvent for pesticides, glues, paints, varnish or inks (wiping off graffiti) and some medicaments used in veterinary medicine

Clinical symptoms

DMF can provoke a mostly benign hepatic cytolysis after single contact or a contact repeated on various days. The observed effects are sometimes grave dermatitis, keratoconjunctivitis, and a painful abdominal syndrome, a depression of the central nervous system, a cytolytic hepatitis and an Antabuse effect.

  • The hepatitis usually turns up 24 hours to 3 days after contamination by DMF. The transaminases have only been augmented moderately in most cases. Histologically, the hepatic disease is a fatty liver at first, then a centrolobular necrosis. The gravity of the lesion depends on the dose. The disease may be severe if the taking of DMF is considerable (a deathly case has been published), however, in most of the cases there is an evolution towards recovery without sequel. The more severe the contamination has been, the more the disease is retarded (the inhibition of its own metabolism by DMF probably explains this particularity).
  • The painful abdominal syndrome manifests itself by general epigastric cramps, as well as by nausea and vomiting.
  • The Antabuse syndrome appears after alcohol consumption, because DMF is a powerful inhibitor of aldehydic dehydrogenases. The syndrome manifests itself by a peripheral vasodilatation predominantly in the face and the upper part of the trunk, a nodal tachycardia, hypotension, headache, dizziness, perspiration, vomiting.
  • The depressant effect of the central nervous system brings on asthenia, headache, dizziness, somnolence

    Occupational intoxications by DMF are not rare. They are made possible by an inconstant signalisation of DMF in labelling commercial preparations as well as wearing improper skin protective clothing

Treatment in use is the administration of N-acetylcysteine

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PYRIDINE

It’s a heterocyclic sulphurous solvent used in laboratories as reagent, as intermediate for insecticides and medicaments and also as solvent in the rubber industry. Pyridine has brought on cytolytic hepatitis after oral administration. The odour is very nauseating at work, perceptible from 1 ppm (part per million), inhalation is limited.

PHOSPHORUS

At present hepatitis due to phosphor is exceptional on account of the suppression of phosphorous raticides and phosphorous matches. The inflammation is due to the ingestion of white phosphor or zinc phosphide. Necrosis comes on at doses of less than 100 mg and predominates in the periportal zone.

ARSENIC

Sources of exposure

Arsenic is present as impurity in a number of ores. The most important circumstances of occupational exposure are:
the action of a gas on arsenic-containing ores at elevated temperatures (esp. at brass-foundries, but also at gold-, lead- and zincfoundries); the manufacture of organoarsenicals; the treatment of wood with the ACC fungicides; the glass and the crystal works (refining glass); the tannery; the manufacture of pesticides and the treatment of the vine.

Clinical symptoms

The acute toxicity manifests itself in a multivisceral disease due to the direct cytotoxicity to the endothelial cellules of the digestive tissue (intense gastro-enteritis with profuse diarrhoea, vomiting), on the nervous tissue (cerebral oedema, convulsions), the hepatic tissue (cytolysis), the renal tissue (renal insufficiency due to tubular necrosis), the medullar (hypoplasia) and the myocardial tissue (conduction and excitability troubles, cardiogenic shock). The always very slow recovery is characterized by a skin and hair-nail-tooth disease, and most of all by sensomotor polyneuropathy.

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ARSENIC TRIHYDRIDE

Arsenic with hydrogen of arsine is a colourless poisonous gas heavier than air. Penetration into the organism occurs exclusively by the respiratory routes. Arsenic trihydride is the most poisonous of all arsenic derivative.

Sources of exposure

Apart from some applications in the electronics industry as a dopant to manufacture semiconductors and in organic synthesis, the formation of arsine is mostly accidental.

The main circumstances of accidental release of arsine occur in the metallurgy: treatment of ore containing arsenic as a impurity (zinc, copper, tin, lead and cobalt); removal of boiler-scale by means of chemical acid; bronzing of art objects; the restoration of paintings containing arsenic derivatives. This risk exists whenever arsenic comes in contact with beginning hydrogen or acid solutions.

Clinical symptoms

Arsenic hydrogen provokes a massive intravascular haemolysis with anaemia and haemoglobinuria. Peracute intoxication can induce death due to cardiovascular collapse immediately after the exposure.
According to the intensity of the exposure the symptomatology of severe accidents is initiated by a general malaise and headache, paresthesia of the limbs, trembling, perspiration, nausea, vomiting and abdominal lumbar pains, next come progressively a state of shock with paleness and cyanosis and an acute oligoanuric renal insufficiency, linked to the intratubular precipitation of free haemoglobin and to a direct toxicity of the renal parenchyma with red urine. There often exists a moderate hepatic cytolysis, emerged after the 24th hour with an elevation of transaminases of 1,5 to 2 N. The hepatitis may be retarded. The picture can then be complicated by a moderate hyperthermia, an intense mucocutaneous icterus with tender hepatomegaly, a CIVD and rhabdomyolysis.

Decease occurs in about 10 to 25 % of the cases in accordance with the series, the evolution may be characterized by the installation of arsenical complications: alopecia, peripheral neuropathy, megaloblastic anaemia. Sequels e.g. chronic renal insufficiency with HTA also are possible.

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LEAD

Some rare observations report hepatic cytolysis due to massive intoxication

CADMIUM

Sources of exposure

It is used in the composition of alloys with steel, zinc and copper. It permits the fabrication of batteries and rechargeable accumulators and anti-corrosive electroplating or immersion.

The mineral cadmium compounds are stabilizers for plastic substances and yellow or orange pigments for paints, inks and enamel. They are also used for the manufacture of fuses, photo-electric cells, semiconductors and luminescent substances

Clinical symptoms

Concentrated oxide vapours and fumes are caustic for the respiratory routes in acute accidents and can bring on chemic pneumonia, ‘cadmic pneumonia’ and even organic OAP.

The inhalation of moderately concentrated vapours and fumes may be the source of an episode of ‘metalworkers’ fever’. Exceptionally the respiration disease can be complicated by a hepatic (cytolysis) and renal disease (proximal tubulopathy with phospho-gluco-amino diabetes).

Biological diagnosis

Is made by blood titration of cadmium. The normal percentage is less than 5 microgram/1..

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Dinitrophenol (intermediate for the synthesis of colorants, explosives, developers for photos and pesticides) and dinitro-orthocresol are substances decoupling oxidative mitochondrial phosphorylation and being able to cause an accidental hepatic necrosis by acute and massive intoxication.

Sources of exposure

Organochlorine is used as an insecticide to treat soils and seeds. The organochlorine compounds, such as DDT, are being progressively phased out of use. As they are fat-soluble and very stable, they accumulate and remain in the fatty tissues of the body for prolonged periods.

Clinical symptoms

In grave forms of acute intoxication symptoms include digestive troubles (vomiting, diarrhoea, abdominal pains) then mental confusion, muscle tremors and ataxia and further general convulsions and coma.
The picture is accompanied with a metabolic acidosis and can be complicated with either rhabdomyolysis, or sometimes with hepatic cytolysis (lindane) or renal tubulopathy linked to myoglobinuria. Myocardial hyperexcitability and a pulmonary oedema are possible esp. when lindane is involved. There is no specific antidote.

Biological diagnosis

Blood titration of organochlorine.

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They can be found in some commercial preparations e.g. Phénochlor, Pyralène mixed with trichlorobenzene. The fact that PCB’s are almost non-biodegradable is a major problem of ecotoxicity (bioaccumulation along the food chain). Their pyrolysis at temperatures between 450 and 700° C releases hydrochloric acid, carbon monoxide, polychlorodibenzofurans (PCDF) as well as traces of polychlorodibenzodioxins (PCDD)..

Sources of exposure

Till the mid-1970s PCB’s were used as hydraulic fluid, lubricants, additives for plastic or as energy and on account of their incombustibility as insulating fluids in powerful transformers and electrical condensers.

In France the decree of 8th July 1975 has limited their application to closed electrical circuits, in principle little vulnerable to fire. Since 1st July 86 it has been forbidden to throw them on the market in new systems throughout the entire EEC.
Nowadays the interventions in the numerous electrical installations still containing PCB’s represent the most important form of occupational exposure.

In 1976 the breakdown of a reactor for the synthesis of 2,4,5-trichlorophenol induced an environmental exposure to lethal polychlorodibenzodioxins (PCDD) in Seveso, near Milan.

Clinical symptoms

Acute exposure due to fire of a transformer containing PCB means exposure to the products of pyrolysis: hydrochloric acid, PCDF and PCDD. PCDD is considered responsible for most of the observed symptoms:

  • General malaise with nausea, headache, irritation of the eye, otorhinolaryngological and respiratory troubles due to hydrochloric acid.
  • chloracne can develop several months after the exposure, the intensity in proportion to the contamination and persistent for several years..
  • biological hepatic anomalies (moderate elevation of triglycerides, of the ?GT, transaminases, of the APs) often with hepatomegaly.
  • Asthenia, cognitive perturbations (memory defects, prolongation of reaction time), moodiness.

Biological diagnosis

The plasma titration of the PCBs is an indirect means to evaluate the exposure to furans and dioxins, products of pyrolysis. However, such titration is always delicate, long and expensive.

Hydrazine (N2 H4) is one of a series of compounds called hydronitrogens and a powerful reducing agent. It is used in the synthesis of various pesticides, as a base for blowing agents that make the holes in foam rubber, in the manufacture of colorants and a corrosion inhibitor in boilers. It is a colourless, poisonous fluid with an ammonialike odour.

Hydrazine reacts with acids and some metallic salts, and the products are used in the manufacture of certain explosives and agricultural fungicides.

Hydrazine reacts with organic compounds to form alkyl hydrazines, used as fuel in rocket and jet propulsion. Other reactions with organic compounds yield hydrazones and hydrazides, which are used in such pharmaceuticals as isoniazid (in the treatment of tuberculosis) and dihydrazalin and as chemical intermediates in the production of polymers and photographic chemicals.

The mucocutaneous projection provokes chemical burns, differing in intensity according to concentration and duration of the contact. The vapours cause very much irritation of the respiratory routes and can be the source of an organic OAP.

Hydrazine brings on a lowering of the epileptogenic threshold.

Hydrazine also is responsible for haemolysis and hepatorenal diseases.

NITROSAMINES

The paramount source of exogenous human exposure to nitrosamines is tobacco. Certain occupational activities can be the source of exposure: the leather and rubber industry and the metallurgy.

Nitrosamines, esp. dimethylnitrosamine, are hepatotoxic. Reports of occupational human intoxications are rare.

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DIAMINODIPHENYLMETHANE (DDM) of 4,4-methylene dianiline (MDA)

Sources of exposure

It is an aromatic amine, widely used as a hardener in epoxy resins, in polyurethanes and as an antioxidant in rubber.
In France the decree of 28th August 1989 allows the use of concentrations above 0,1 % exclusively for research or analysis.

Clinical symptoms

  • In acute accidents DDM brings on a mixed hepatitis associated with a hepatocytic necrosis and cholestasis. The acute symptomatology consists of pains in the right hypochondria, followed by fever, myalgia, headache, cutaneous rash, afterwards frank icterus with pruritus. The elevation of the conjugated bilirubin associates biologically the alkaline phosphatases and the transaminases in a moderate way, less than 10N. According to all published cases recovery has worked out spontaneously and without consequences.
  • By chronic exposure DDM can be responsible for an isolated asymptomatic elevation of the transaminases and/or the bilirubin and/or the alkaline phosphatases at concentrations, much lower than the VME, considering the predominant percutaneous penetration.

Surveillance of exposed people

The transcutaneous penetration by this very fat-soluble amine justifies the follow-up after the occupational exposure by measuring the DDM in the urine and biological surveillance of the hepatic function.

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HALOTHANE

Halothane or fluothane is a halogen ethane derivate (2-bromo, 2-chloro, 1,1,1-trifluorethane). During of after the induction of the anesthesia the intermediary metabolism, cytochrome P 450, brings on the formation of several electrophilic derivates responsible for lipidic peroxidation.

At present it is accepted that these cellular alterations engender secondarily a sensibility to halothane in certain individuals, thus explaining the aggravation of lesions at iterative administration and the sporadic appearance of toxic hepatitides.

Clinical symptoms

Hepatitides due to halothane are observed essentially in patients anaesthetized by halothane and they are exceptional. Even more rare are occupational intoxications in anaesthetists and personnel at the operating theatre or the delivery room.

Hepatitis develops when halothane is administered successively at short intervals and manifests itself on the 5th day after the anaesthesia by cytolytic icterus accompanied with general manifestations of hypersensitivity (rash, fever, hypereosinophilia).
The prognosis of these hepatitides is bad (50% deceases) and developing into hepatocellular insufficiency.
Diagnosis is based on giving evidence of specific auto-antibodies directed at the hepatocytic membrane.
Prevention is assured by the realization of an antipollution system and occupation in closed circuit. Enflurane also used is exceptionally hepatotoxic but isoflurane is not regarded as hepatotoxic.
At present the standard circumstances of exposure to various industrial hepatotoxic substances as mentioned before have become exceptional thanks to measures in order to replace the most toxic substances and to a normative policy defining the limiting values of the concentrations at the above-mentioned workrooms.
Since the early eighties new studies have been published about hepatic hazards by exposure to slightly hepatotoxic mixtures (common industrial situation, e.g. solvents in paint shops and factories) knowing that certain substances (e.g. ketones) exert a potentiating effect e.g. the simultaneous ingestion of alcohol or certain medicaments.

The effect of alcohol consumption is obvious and justifies a purposive, clinical and biological surveillance of employees exposed to solvents and showing personal risk factors (alcohol, medicaments).

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We are talking about either (usually) portal fibrosis, or cirrhosis complicated or otherwise, or portal hypertension (PHT), or splenomegaly with leukopenia and thrombocytopenia, or oesophageal varices with digestive haemorrhages, or primitive cancer of the liver.

ARSENIC

Arsenic in the form of trioxide has been used in medical therapy as Fowler’s liqueur in the treatment of certain dermatoses, notably psoriasis. This metalloid is found in numerous metalliferous ores and is used in certain pesticides to treat vines.

  • Chronic intoxication due to ingestion or inhalation of arsenic brings on portal fibrosis. Portal hypertension of the presinusoidal type is important and may cause digestive haemorrhages due to oesophageal varices. The responsibility of arsenic for the development of cirrhosis has been mentioned in certain occupational groups, notably the wine-growers.
  • The chronic ingestion of arsenic may be on the basis of angiosarcomata and haemangio-endotheliomata. The delay of appearance is 40 years.

VINYL CHLORIDE or CHLOROETHYLENE

Monomer vinyl chloride (MVC) is an inflammable gas, which easily polymerizes under influence of oxygen, of heath and of certain catalysers. In industrial environment MVC is stored, transported and used principally in at high pressure liquefied condition.

Sources of exposure

Since the thirties MVC is used for the production of polyvinyl chloride (PVC), which is the basis of a great many plastic products (bottles, floor coverings, frameworks for windows, etc.). The most serious exposures are observed at workshops for polymerization during the cleaning and the descaling of autoclaves. The occupational exposure to MVC is officially limited (decree of 12.03.80: the average concentrations to be respected are 1 ppm for existing installations and 0,5 ppm for new ones).

The present constraints, which put pressure on the monomeric percentage of PVC, make the environmental risks negligible: less than 1 ppm for the foods sector and less than 10 ppm elsewhere.

Pathogenesis

The toxicity of MVC results from its transformation into reactive electrophilec metabolites: chloroethylene oxide and chloroacetaldehyde.

Clinical symptoms

Chronic exposure to MVC may provoke hepatic fibrosis, which may be associated with PHT, oesophageal varices, splenomegaly and trombocytopenia.

Prolonged exposure (more than 10 years) brings on a hepatic angiosarcoma, a tumour with a very serious prognosis (average chance of survival less than 1 year), which is very rare in the general population and develops from the cellules around the sinusoids.
The angiosarcoma appears with an average latency of 22 to 25 years associated or otherwise with a fibrosis. The clinical picture shows a painful hepatomegaly with icterus, ascites, haemoperitoneum, PHT.
The diagnosis is based on the imagery and the histology. Moreover MVC is responsible for the ‘disease of people descaling autoclaves’, which manifests itself by angioneurotonic troubles of the fingers, phenomena of acro-osteolysis sometimes accompanied with scleroderma.

Surveillance of exposed individuals

Polymerization of vinyl chloride belong to the jobs requiring special medical surveillance. Urine titration of thiodiglycolic acid is not important for exposures lower than 5 ppm. It may represent an indicator in case of accidental exposure to a high dose. The normal percentage is lower than or equal to 2 mg/1.

A post-occupational surveillance every 2 year has been proposed to the employees. The ultra-sound scan and the biological-hepatic balance remain the most important methods of investigation of this follow-up.

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CARBON TETRACHLORIDE

Chronic exposure brings on a fatty hepatic degeneration (steatosis), developing to cirrhosis (potentiated by administering acetone or ethanol) and a glomerular and tubulo-interstitial renal disease, which develops normally towards recovery (after renal purification).

Some cases of hepatocellular carcinomata are published.
A disease of the adrenal glands due to exposure to tetrachloromethane is also supposed.

POLYCHLORINATED BIPHENYL (PCB)

A steatosis hepatis (fatty liver), accompanied or otherwise with biological anomalies (elevation of transaminases, of triglycerides and/or of cholesterol) as well as a mild hepatomegaly are observed in labourers working in the industry for transformers and electrical condensers.

Epidemiological studies carried out in employees exposed to PCBs have not showed a higher mortality due to cancer of the liver.

The detection of a tumour on the liver e.g. an angiosarcoma should cause a systematic investigation into exposure to arsenic or vinyl chloride, taking into account its low prevalence (1 to 3 %) in the general population.

BERYLLIUM

The most important circumstances of occupational exposure are the beryllium metallurgy, the ceramic industry, the industry for electronic components, the glass industry and soldering with beryllium-containing electrodes. Berylliosis is a systemic industrial disease caused by poisoning with beryllium, usually involving the lungs but occasionally affecting only the skin. There are two forms: an acute illness occurring most frequently in workers extracting beryllium metal from ore or, manufacturing beryllium alloys, and a slow-developing chronic disease occurring in scientific and industrial workers who are exposed to beryllium-containing fumes and dust.

Chronic berylliosis is a multivisceral granulomatosis, predominating on the level of the lungs and there developing a disease near to sarcoidosis. Other visceral locations, notably on the level of liver, spleen and kidneys are only occasional.
The acute disease involves both skin and lungs, causing a burning rash, eye irritation, nasal discharge, a cough , and chest tightness. The skin disease is caused by direct contact with beryllium salts and the lung disease by inhalation of metal dust or beryllium compounds. Most of those affected by acute berylliosis recover within a few months, but a small number of patients develop a highly fatal inflammation of the lung within 72 hours after a brief, massive exposure to beryllium. The chronic disease may occur more than 15 years after exposure, although the later it develops, the milder it is likely to be. It generally causes shortness of breath, especially after exercise, exhaustion, and a dry cough and can produce a permanent, though moderate, disability.

The detection of a tumour on the liver e.g. an angiosarcoma should cause a systematic investigation into exposure to arsenic or vinyl chloride, taking into account its low prevalence (1 to 3 %) in the general population.

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