Clinical Aspects of Liver Diseases 30 Liver damage due to toxic substances

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30 Liver damage due to toxic substances

Page:

1 Historical review 564

2 Detoxification of toxic substances 565

3 Pathophysiology 565

4 Morphology 566

5 Toxic substances 566

5.1 Regulations governing occupational diseases 566

5.2 Industrial toxins 567

5.2.1 Halogenated hydrocarbons 567

5.2.2 Hydrocarbon derivatives 568

5.2.3 Aromatic amines 569

5.2.4 Inorganic substances 569

5.2.5 Thorotrast 569

5.3 Mycotoxins 570

5.4 Phytotoxins 570

5.4.1 3,4-benzpyrene 570

5.4.2 Pyrrolizidine alkaloids 570

5.4.3 Amanita phalloides 571

5.4.4 Helvella esculenta 571

5.5 Endotoxins 571

5.6 Drugs 571

6 Diagnosis 571

6.1 Chronic intoxication 571

6.2 Acute poisoning 572

7 Therapeutic aspects 572

8 Industrial hepatotoxic agents 573

앫 References (1⫺77) 574

(Figures 30.1 ⫺30.3; tables 30.1⫺30.3)

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䉴 The “chemicalization” of the environment in the course of the last 100 years has proceeded virtually without restraint, partly as a result of ever-advancing technologies and partly because of the continuously rising demands of society and increased industrial productivity. • The liver, however, which is at the centre of the detoxification mechanisms (s. pp 52 ⫺56), is not able to adapt to new demands on the detoxifica- tion process within three to four generations. Adapta- tions of this kind by an organ or an organism to harmful or life-threatening influences can only take place over a much longer period of time, if at all (as has been shown in the animal and plant kingdoms).

䉴 The “Chemicalization” of the workplace can be kept almost completely under control by compliance with industrial hygiene regulations. In this way, it is gen- erally possible to avoid toxic liver damage. Specific exposure can, however, be expected in occupational medicine in the following situations: (1.) inadequate protective measures at work, (2.) the appearance of new, hitherto unforeseen or (as yet) unknown toxic compounds following a particular incident or due to a change in working techniques, and (3.) the combined impact of various toxic substances, especially in con- junction with alcohol and/or drugs. • In agriculture, the increasing use of fertilizers, animal feed additives, preservatives and pesticides has become a considerable problem. The occurrence of disulfiram-like effects has also been observed. • Far too little attention is gen- erally paid to the risks of toxic liver damage encoun- tered in hobbies or do-it-yourself activities. Handling chemical substances ⫺ often in small, poorly venti- lated rooms over lengthy periods of time ⫺ can quite easily increase the danger of liver damage, although under normal circumstances there is nothing to fear if the manufacturer’s instructions are strictly adhered to. The risk of damaging one’s health is ⫺ often unconsciously ⫺ suppressed or indeed goes unnoticed.

For every liver disease that cannot be clarified with certainty, each differential diagnosis should always include toxic substances in food, at work, in the house or garden and in those places where people pursue leisure activities. It is extremely difficult to identify the causal noxa. In the individual case, however, identification can be of considerable importance for general assessment purposes and possibly when an expertise is required.

1 Historical review

In the 19

^th

century, cases were observed of workers in the match industry who suffered liver damage due to phosphorus contamination leading to acute hepatic dystrophy. • Since then, the relationship between exog- enous noxae and liver disease has been considered unequivocal.

䉴 Arsenic: Liver damage due to arsenic was first described in 1774 by

F. L. B ang

. In 1888

E. Z iegler et al.

reported on damage caused by arsenic to the hepatocytes and sinusoids with subsequent scarring. The occurrence of melanosis, hyperkeratosis and liver fibrosis or cirrhosis was described as “Reichenstein’s disease”

(L. G eyer, 1898)

. It was observed in Reichenstein (Silesia) and Freiberg (Sax- ony) and traced back to chronic arsenic poisoning caused by contaminated drinking water (containing up to 25 mg arsenic per litre). Toxic liver damage, even culminating in cirrhosis, due to the presence of arsenic in beer was observed in 1900. Over the following years, there were further reports of arsenic poisoning from drinking water, e. g. in Argentina

(A. A yerza, 1918)

, Mexico and Taiwan. In 1974 a comprehensive study was published on chronic arsenic poisoning caused by contamination of the river Tononce in Antofagasta (Chile): several hundred people became ill between 1955 and 1972; arsenic was even found in fruit juice, beer and cola as well as in milk and food. (76)

•

Arsenic was officially introduced as a pesticide in viniculture in 1925 (after it had already been used for this purpose for some time). Since 1942 its use as a pesticide has been banned. Consumption of the so- called wine-grower’s house drink led to severe liver damage, liver fibrosis with portal hypertension and even oesophageal varix bleeding, carcinoma and haemangioendothelioma of the liver. This homemade wine, which was produced by watering down the wine obtained from a second pressing of the grape skins and which had a low alcohol (3⫺5 vol. %) but high arsenic content, was consumed in large quantities (3⫺5 litres per day).

•

The severe arsenic poisoning of an aircraft pilot who had been spraying arsenic calcium carbonate dust as a pesticide was reported in 1930.

•

Extensive liver damage was also observed during the long-term treatment of psoriasis with Fowler’s solution.

•

Occurrences of well-water poisoning due to arsenic pesticides were registered as late as 1984 in the USA (2) (s. p. 569) and again in 1998 to an incredible extent in Bangladesh.

䉴 Thorotrast: Thorotrast was introduced into radiology by

^{K. F} rik et al.

in 1928 on the grounds of its excellent opaque properties and good tolerance. As early as 1933, the carcinogenic effect of ThO2

was pointed out by

C. O berling et al.

The occurrence of an angiosarcoma 12 years after the administration of thorotrast was reported by

H. E. M cMahon et al.

in 1947. Production was stopped in 1950, but thorotrast was still occasionally used up to 1958. All in all, about 1 million patients using thorotrast between 1928 and 1958 were examined.²³²ThO₂is a 90%α-emitter with a half-life of approximately 400 years. It is never excreted from the body.

Most of it (70⫺75 %) is stored in the liver, although the highest relative concentration per gram tissue is found in the spleen. In total, more than 125 thorotrast-induced cases of malignancy have been reported in the literature⫺ even 36, 39 and 44 years after administration. (23, 71) (s. figs. 30.2, 30.3) (s. p. 569)

䉴 Thioacetamide: In 1942 thioacetamide was introduced in the USA as a citrus fruit preservative. Shortly after ingestion of this fruit, liver damage (cell necrosis, steatosis) and cirrhosis occurred.

There were even reports of fatalities.

•

Animal experiments showed

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that the liver damage was caused with such rapidity and reliability by thioacetamide that this substance came to be used as the most potent poison (apart from CCl₄) for producing liver damage in animal experiments.

䉴 Vinyl chloride: Hepatolienal diseases caused by vinyl chloride were first reported in Russia in 1949

(S. L. T ribukh et al.)

. Severe changes to the liver were observed by

J. M. C ordier et al.

in France in 1960 and by

J. S uciu et al.

in Romania in 1963. The carcinogenic effect of vinyl chloride (VC) was demonstrated by

P. L. V iola

in animal experiments in 1970. Vinyl chloride can induce two dif- ferent types of liver tumour: haemangiosarcoma and hepatocellular carcinoma

(C. M altoni et al., 1974)

.

J. B. B lock

reported on haemangiosarcoma in more detail in 1974, and in 1976

J. M. G okel et al.

described hepatocellular carcinoma in persons exposed to VC.

The two forms of carcinoma may also occur simultaneously. (s.

p. 568)

䉴 Hexachlorobenzene: Between 1955 and 1959, more than 3,000 people in Turkey contracted porphyria cutanea tarda after hexachlorobenzene had been used as a preservative for cereals. (52) 䉴 Aflatoxin: Fatal liver necrosis was reported in about 100,000 turkeys and ducks in England by

A. J. S tevens et al.

in 1960. The causative agent was found to be aflatoxin from mouldy peanut meal in animal feed. (s. p. 571)

䉴 Methylene dianiline: In 1965 at least 84 people in the English town of Epping contracted toxic hepatitis with jaundice and cholestasis (⫽ Epping disease) after eating bread which contained flour that had been contaminated by a hardening agent for synthetic resin: methylene dianiline (4.4⬘-diaminodiphenyl methane). Histo- logically, portal infiltrations, manifestations of cholangitis and centrilobular cholestasis were found. Pronounced hepatomegaly was also reported. (33, 34, 48) (s. p. 569)

䉴 Polybrominated diphenylene: In 1973 in the USA, about 30,000 cattle and some 1.6 million chickens died or had to be slaughtered (so-called “Michigan catastrophe”) after being given feed to which a flame retardant containing polybrominated diphenylene had been mistakenly added in place of a fattening additive. However, none of the exposed persons showed any signs of poisoning. (1) 䉴 Dioxin: The first (8-fold chlorinated) dioxin was prepared as early as 1872 by the German chemists

M erz

and

W eith

. Tetrachlor- odiphenyl-p-dioxin (“dioxin”) was synthesized in 1957

(W. S ander- mann et al.)

. The first large-scale case of intoxication was reported in Virginia/USA in 1949. Following the accident at the BASF chemical plant in Germany in 1953, 6 of the affected 53 persons developed liver damage. In the period leading up to the chemical disaster in Seveso/Italy on 10^thJuly in 1976, there had been 21(!) such incidents reported in various countries, 6 of them in Germany

(B. H olmstedt, 1980)

. Following Seveso, some 27 years after the first chemical accident with dioxin in 1949, the irresponsible underesti- mation and ignorance of “chloracne” poisoning ⫺ known for nearly 3 decades⫺ finally became public knowledge. (s. p. 568) Only then was it evident that dioxin was “the most toxic carcino-

genic and teratogenic chemical substance ever made by man”.

䉴 Salad-oil: Since 1981 more than 24,000 persons have become ill (with 357 fatalities up to 1985) in Spain due to the consumption of salad-oil. The suspected cause was poisoning by oil which had been adulterated by being mixed with cheap industrial oil containing, among other things, aniline, acetanilide and quinoline. The patients showed generalized damage to the capillaries, including those of the liver. (64, 72)

2 Detoxification of toxic substances

Like medicaments, toxic substances can also enter the body by the oral, percutaneous, parenteral and respiratory routes. The

detoxification and elimination of toxic substances essentially takes place via the same

biotransformation mechanisms that are respon-

sible for the metabolism of drugs. (s. p. 544) Overall, the capacity of the liver to eliminate foreign substances is dependent both on microsomal enzyme activity (which is affected by a number of factors) and on the blood flow through the liver. (s. tab. 3.18) Biotransformation can, however, lead to the production of

biotoxo- metabolites (or biotoxometabonates), which are sometimes con-

siderably more toxic than the original substance taken up by the body or which (by reacting with cellular proteins) can lead to the development of new hazardous substances such as mutagens, carcinogens or antigens. (s. pp 52⫺56) (s. fig. 3.11) For the elimination of various toxic substances including cadmium, manganese, lead, etc., the

functions of the RES are also utilized. (s. p. 65) In addition,

the

antioxidant systems may be necessary for the elimination of

other toxic substances. (s. p. 67)

3 Pathophysiology

While medicaments (with few exceptions) can be regarded as facultative (indirect) hepatotoxins, almost all toxic chemicals act as obligate (direct) hepatotoxins.

(s. tab. 29.1; s. fig. 29.1) • The extent and type of hepatic damage caused by toxic substances is determined by a number of influencing factors. (s. tab. 30.1)

1. Amount of noxious substance 2. Concentration

3. Duration of action 4. Method of uptake 5. Extent of protein binding

6. Degree of distribution or accumulation of the noxa within the liver or other organs

7. Radioactivity of the substance 8. Excretability of the noxa

9. Previous liver damage or coexisting liver disease 10. Coexistent strain caused by alcohol and drugs 11. Age, gender

12. Nutritional status

Tab. 30.1: Factors influencing the extent and type of liver damage

caused by toxic substances

A variety of cellular sites of attack, sometimes very diffi- cult to differentiate and often in combination with one another, have to be considered with regard to the patho- mechanisms of liver damage. (s. tab. 30.2)

1. Direct toxic damage to membranes and organelles 2. Occurrence of biotoxometabolites

3. Formation of free radicals 4. Interactions with DNA

5. Interference with bilirubin metabolism 6. Interference with bile acid metabolism 7. Inhibition of protein synthesis

8. Inhibition of lipoprotein synthesis

Tab. 30.2: Pathogenic and pathophysiological mechanisms of liver

damage caused by toxic substances

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Liver damage caused by toxic substances sometimes only appears and is hence first recognizable after a la- tent period of several years. This applies particularly to radioactive substances (e. g. thorotrast, which has a latent period of up to 40 years). Exogenous factors (alcohol, medicaments and chemicals) can substantially impair the course and prognosis of intoxication. This may be due to (1.) acute multiple intoxication by simultaneous exposure to various toxic substances or (2.) the fact that the noxa is administered during the

“deficiency period” of a biotransformative induction, since toxic substances cause greater hepatic lesions in this phase.

In the individual case, the personal reaction to exposure to toxic substances can vary greatly. Long-term expos- ure to toxins, even in low concentrations, often leads to liver damage.

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4 Morphology

Upon the intake of direct toxic noxae, the detoxification systems of the liver are only able to react with adaptive processes in isolated cases. The “force of the respective toxicity” leads to cell damage so rapidly that there is generally no chance for time-consuming adaptation to take place.

Morphological changes due to toxic substances are characterized by four parenchymal alterations, which also occur in alcohol-mediated or drug-induced liver damage: (1.) enlargement of cells, (2.) steatosis, (3.) cholestasis, and (4.) necrosis. These changes are not spe- cific to particular noxae, even though a certain pattern of damage may predominate. There are frequent reports concerning fulminant liver failure. • In addition to these parenchymal changes, there may also be mesenchymal reactions with stellate cell activation, portal infiltration, reticular fibre sclerosis, fibrosis and vascular changes.

Parenchymal and mesenchymal alterations of varying degrees often occur in combination with each other. • After long-term exposure, the occurrence of liver fibro- sis, cirrhosis or even malignant tumours can be ex- pected. (s. pp 361, 495)

5 Toxic substances

Toxically relevant substances have been recognized as such either as a result of animal experiments or casuistic observations. Here, too, it has been seen that findings from animal experiments can only be applied to humans to a certain extent. The dosage and duration of expo- sure are extremely relevant: the lesion pattern after acute, high exposure (e. g. in an accident or attempted suicide) can differ considerably from that after chronic exposure (to both high and low quantities). • A clear

differentiation must be made from naturally occurring liver noxae and carcinogens. These can be present in plants, particularly in fungi (e. g. 3.4 ⬘-benzpyrene) and in bacteria (e. g. ethionine, endotoxins, 3.4 ⬘-benzpyrene).

As a result, beverages and foodstuffs sometimes contain toxic substances, which were present naturally in the original raw material, derive from intentionally added pesticides, preservatives and animal feed, or have been inadvertently introduced into the final product in some way. (s. tab. 30.3)

䉴 In 1988 we carried out a survey in 2,008 doctor’s prac- tices

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: liver damage was ascertained in 7,095 patients and confirmed morphologically in one third of cases.

Long-term exposure to commercially available chemi- cals was found in 9.3% of those questioned, whereby the liver damage was ascribed to such chemical noxae in 7.4% of cases. Regular simultaneous alcohol consump- tion was confirmed by 34.1% of these patients. The following (in order of frequency) were found to be long- term contact noxae probably responsible for liver dam- age: hydrocarbons, carbon tetrachloride, lead, phenols, trichloroethylene, methyl alcohol, aniline, vinyl chloride, chloroform, heavy metals, pesticides and herbicides, lyes, carbides, glue, nitrosamines, inorganic acids and dioxins. (s. tab. 30.3)

䉴 In a further survey in 2,650 doctor’s practices in Ger- many (G) and 340 in Austria (A) carried out by us in 1989, the following statistics were obtained

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: existing acute liver disease was ascribed to household chemicals in 11.2% (G) and 9.3% (A) of patients. The most common cause of existing chronic liver disease was thought to be job-related noxae in 23.4% (G) and 21.8%

(A) of cases; household chemicals were held to be responsible in 8.3% (G) and 7.2% (A) of patients. Sec- tors associated with the development of job-related toxic liver damage were found to be as follows: painting and varnishing trades in 46% (G) and 41.8% (A), min- eral oil processing industries (including the production of solvents, dyes and adhesives) in 35% (G) and 30.8%

(A), dry cleaning in 28.4% (G) and 38.8% (A), pesticide

production in 27.6% (G) and 24.8% (A), and food pres-

ervation in 2.5% (G) and 3.3% (A) of cases. • Genuine

proof that the respective noxa is the real and sole cause

of the disease can naturally only be provided in a small

number of cases. However, the high patient figures in

Austria and former West Germany considerably

increase the validity of these findings. (s. tab. 30.3)

5.1 Regulations governing occupational diseases

In the current German regulations on occupational dis-

eases due to industrial toxins, the respective substances

are divided into six classes and assigned specific num-

bers. Occupational disease is a legal term defined under

German accident insurance law; occupation-related dis-

ease is a medical diagnosis. In individual cases, diseases

can be recognized as occupation-related and appropri-

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ate compensation awarded, provided that they meet the pertinent legal requirements based on the most recent level of medical knowledge (so-called opening clause).

The following are of importance in hepatology:

Arsenic and its compounds Benzene and its homologues Dimethylformamide

Halogenated alkyl, aryl or alkylaryl oxides Halogenated hydrocarbons

Methyl alcohol (methanol)

Nitrobenzene or amino-benzene compounds (with their homologues or derivatives)

Phosphorus and its inorganic compounds

䉴 When there are good reasons for suspecting the exist- ence of an occupation-related disease, this must be reported immediately to the regional medical officer responsible for workplace health and safety, the respec- tive governmental department for industrial medicine or directly to the appropriate industrial accident insurance provider. • Notification is mandatory for every regis- tered doctor and dentist. No declaration of consent by the insured person is necessary, nor is there any right of objection. Notification does not constitute a breach of doctor-patient confidentiality. Insured persons or the employer can also report a suspected occupation-related disease themselves. In 1995 a total of 86,705 suspected cases were reported in Germany, of which about one fifth were accepted as occupational diseases.

䉴 The doctor’s obligation to report cases or suspected cases of poisoning is laid down in the German regula- tions on notification concerning toxic substances. This notification must be made in accordance with the Ger- man chemicals law using an appropriate form.

䉴 Food poisoning does not have to be reported to the authorities unless it involves a disease covered by the German Epidemic Control Act. It is, however, strongly advisable to inform the appropriate authorities when food poisoning occurs or is suspected (see, for example, regulations relating to aflatoxin).

As regards clarification by a medical expert, four points are of great importance: (1.) gathering information for compiling a comprehensive job-history (specific job characteristics, exposure pattern, materials used, pres- ence of additional chemical substances at the work- place), (2.) objectifying and quantifying the suspected liver noxa in the air (i. e. maximum allowable concentra- tion) and in the biological material used for the job, (3.) assessment of the hepatotoxic potency of the working materials on humans, and (4.) exclusion of other pos- sible causal factors (previous or present liver disease, alcohol, metabolic diseases, medicaments). In individual cases, discussion will focus on the extent or deterior- ation of already existing damage. Possible interference from potentially injurious factors must be taken into account. • Assessment of a reduction in earning capacity is made in accordance with the usual criteria for evalu-

ating liver diseases: (1.) fatty liver (20 ⫺40%), (2.) toxic hepatitis (20 ⫺40%), (3.) chronic hepatitis (40⫺60%), (4.) liver cirrhosis (40 ⫺100%), (5.) acute intoxication (100%), and (6.) malignant tumours (100%). The meas- ures for combating such occupation-related diseases are based on the principles of the respective employers’

liability insurance association:

1.

Prophylactic medical measures

⫺ recruitment criteria

⫺ monitoring criteria 2.

Technical measures

⫺ informing staff members

⫺ ventilation, monitoring the air in rooms (industrial threshold limit values), protective clothing, masks

⫺ technical modifications 3.

Medical and social measures

⫺ acceptance as an occupational disease

etc.

5.2 Industrial toxins

A tabular compilation of all important known toxins can be useful for recording suspected cases of liver dam- age by toxic agents. (s. tab. 30.3) • Some substances are described separately below.

(3, 7, 13, 14, 22, 24, 28, 39, 40, 47, 55⫺58, 62, 63, 65⫺67, 70)

• The following substances may cause cirrhosis or liver fibrosis:

Arsenic Iron

Cadmium Phosphorus

Carbon tetrachloride Tetrachloroethane Chloronaphthalene Tetranitromethylaniline

Copper Thioacetamide

Dichlorobenzene Trinitrotoluene Dimethylnitrosamine Vinyl chloride Dinitrotoluene

Some toxic substances can induce the formation of malignant tumours. This has been demonstrated in humans for some substances, whereas for others it has so far only been confirmed in animal experiments. Pro- tein deficiency appears to increase the frequency of car- cinoma considerably. Such substances include:

Acrylonitrile Tetrachlorodiphenyl-p-dioxin

Arsenic Thioacetamide

Butter yellow Thorium dioxide

Carbon tetrachloride Vinyl chloride Dimethylnitrosamine

5.2.1 Halogenated hydrocarbons

Aliphatic and aromatic halogenated hydrocarbons are

widely used as industrial reagents, cleaning agents and

solvents. The toxicity of the individual substances is

very varied, e. g. relative to trichloroethane (nominal

toxicity ⫽ 1), trichloroethylene, chloroform and carbon

tetrachloride have a toxicity of 8, 60 and 190, respect-

ively. (s. tab. 30.3)

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Chlorinated halogenated hydrocarbons can be taken up via the respiratory tract and via the skin (even perorally in suicide attempts). In addition, they are also dangerous in their solid form.

The so-called

perna disease is named after an insulating material

mainly consisting of “

perchloronaphthalene”. This substance,

which is commonly used in the electrical industry, produces toxic vapour during soldering; that may cause severe liver cell necrosis and acute liver dystrophy.

Acute and high-dosage intoxication by trichloroethylene leads to

severe symptoms associated with the central nervous system, but

not to (noteworthy) liver damage.

䉴 We were able to confirm this condition in a 29-year- old female patient with severe acute trichloroethylene poi- soning after taking 80 ⫺90 ml trichloroethylene perorally with suicidal intent. Despite a 6-day comatose state, intensive care produced a complete recovery. Throughout the 3-week period of treatment, all of the liver enzymes remained normal, and percutaneous liver biopsy yielded normal histology.

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In contrast, chronic exposure to trichloroethylene may lead to severe liver damage or even cirrhosis.

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Dichlorodiphenyl trichloroethane (DDT) was introduced as an

insecticide in 1941. Its use in Germany has been prohibited since 1971. Toxic liver damage (steatosis, necrosis) and fatalities following liver dystrophy have been described. The strongly lipophilic properties of DDT, its accumulation in fatty tissue over many years and its resistance to all forms of inactivation or de- gradation are indicative of its long-term toxic potential. It can also be detected in high concentrations in breast milk. DDT considerably increased induction of the cytochrome P-450 system: Japanese workers in the plastics industry were found to have reduced bilirubin values as a result of continuous and strong enzyme induction with subsequent accelerated coupling of glucuronic acid and increased excretion of bilirubin. Peroral intake of 3⫺6 g DDT (e.g.

with suicidal intent) causes fatal poisoning.

Carbon tetrachloride: Chronic intoxication due to year-long inhala-

tion of even small quantities of hydrocarbons, including carbon tetrachloride, can lead to the development of cirrhosis. An already existing fatty liver promotes the toxicity of CCl4through the elevated affinity of the adipose tissue. The presence of trichloroethylene, vitamin A and alcohol likewise increases the hepatotoxicity of even small quantities of CCl4. When there is a decrease in the activity of CCl₄-metabolizing enzymes (e. g. in cases of protein deficiency), a decrease in the toxicity of CCl₄can also be expected.

CCl4itself is atoxic; the high toxicity is produced by hepatic formation of the toxic radicals CCl₃, Cl and CHCl₃due to CYP 2E1, CYP 2B1 and CYP 2B2. (s. p. 400) Severe impairment of the membranes of the liver cells and their organelles produces massive and diffuse liver damage with steatosis and necrosis, which finally results in the collapse of liver functions, particularly haemostasis.

The degree of damage to the liver and kidneys by CCl₄can appa- rently be reduced by high intravenous doses of acetylcysteine. (4, 27, 59, 61, 75)

Vinyl chloride: The gaseous, pleasantly sweet smelling vinyl chlor-

ide (VC), which also has a slight anaesthetic effect, was formerly used in the production of polyvinyl chloride (PVC). Hepatolienal damage by VC was recognized in 1949 and 1960. (s. p. 565) As far as such cases could be recorded, a total of 109 fatalities occurred worldwide up to 1985. Symptoms included elevations of GPT, GOT, GDH, γ-GT and AP together with a decrease in ChE (60⫺70%), splenomegaly (40⫺50%), portal hypertension with oesophageal varices sometimes with bleeding (10⫺15%), as well as liver fibrosis and malignant tumours (haemangiosarcoma and/or hepatocellular carcinoma). (s. fig. 30.1) Laparoscopy shows strik-

ing Glisson’s capsule fibrosis (initially linear like a “star-filled

sky”). Histology reveals severe pre-/intrasinusoidal fibrosis, often

with cavernoma-like enlarged sinusoids. It was found that it is not the inhaled VC that is toxic, but rather the highly reactive epoxide chloroethylene oxide produced by biotransformation. Consider- ably improved regulations for protection have in the meantime pre- vented any new cases of the disease occurring, as far as we know.

However, in view of the long latency period of about 20 years, further manifestations of the disease must be expected. (10⫺12, 43⫺45, 69)

Fig. 30.1: Haemangiosarcoma in a case of disease induced by vinyl

chloride. Tumorous endothelial proliferation with blood cavities and vascular fissures containing erythrocytes (HE)

Dioxin: Of the approximately 200 isomers of dioxin, tetrachlorodi-

phenyl-p-dioxin (TCDD) is regarded as the most toxic: its half-life in the soil is about 10 years, whereas in humans and animals, the half-life is up to 1 year (as a result of its lipophilic properties). In the region of the liver, dioxin causes steatosis, cell necrosis, haemo- fuscin deposits and fibrosis with portal hypertension and oesophageal varices. In Missouri/USA in 1971, for instance, marked fibrosis was observed in poisoned animals following contact with contaminated oil. (s. p. 565) The long-term damage caused by this highly carcinogenic substance is particularly serious; this effect may be exacerbated by the simultaneous action of other chlorinated hydrocarbons, dibenzofurans or hexachlorocyclohexane.

Following the use of dioxin as a defoliant in the Vietnam war (“agent orange”), a four-fold increase in the frequency of liver cancer was recorded. The number of malformations as a result of VC-induced foetotoxicity was described as enormous.

5.2.2 Hydrocarbon derivatives

Pentachlorophenol: Because of its good fungicidal, pesticidal and

preservative properties, pentachlorophenol (PCP) is frequently used for industrial and domestic purposes. Numerous cases of intoxication, even via bath water, with considerable liver damage are known. Infant fatalities have been reported after nappies were washed with PCP. (77)

Polychlorinated biphenyls are still used in large quantities in elec-

trical and condenser technology. One of the main members of this group of substances is perchlorobiphenyl (PCB). In fires involving polychlorinated biphenyls, toxic dioxins can be released. Biphenyls lead to powerful induction of the cytochrome P-450 system.

Following exposure, biphenyls can be detected in adipose tissue and breast milk. Severe cases of liver damage, including fatalities, have been reported.

Hexachlorocyclohexane: During the production of this substance

from chlorine and benzene under the influence of light, various isomers are also formed, particularly the toxic substance lindane.

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Isomers of hexachlorocyclohexane (HCH) are found in air, soil, water, food and even breast milk. Lindane is used in large quantities in agriculture and forestry as a wood preservative as well as in veterinary medicine. Provided that the required safety measures are adhered to, no liver damage occurs during the production of lindane. On the other hand, liver cell necrosis was observed in animal experiments after HCH isomers were added to the feed; a carcinogenic effect was seen after long-term administration. An increased toxic potential is to be expected when there is simultaneous exposure to DDT, PCB, contraceptives, etc.

Paints and varnishes: On the basis of our experience (37, 38) and

data in the literature (13, 41), working as a painter, spray-varnisher or floor layer must be regarded as more hazardous in comparison to non-exposed groups with respect to toxic liver damage. Even though dispersion pigments are mainly (i. e. not exclusively) used, paints and sprays nevertheless contain a broad range of organic solvents and substances, including fungicides and pesticides.

Despite observance of the specified industrial threshold limit values, so-called combination effects can never be totally ruled out.

The risk of illness is hence elevated in single cases, and it may be further aggravated by additional individual factors. Elevated transaminases are found, while steatosis and focal necrosis have been demonstrated histologically.

䉴 It is always open to question as to what extent the risk threshold for chemical noxae may be exceeded due to altered technical working procedures and indi- vidual conditions despite compliance with the legal regulations. The recruitment and monitoring criteria prescribed by the employers’ liability insurance associa- tion are of great importance in this respect.

5.2.3 Aromatic amines

Methylene dianiline (4,4-diaminodiphenylmethane) is used as a

liquid hardening agent for epoxy resins. Its high hepatotoxicity was clearly seen in

Epping disease in 1965. (s. p. 565) In the following

decades (1974, 1985), severe toxic liver damage with liver cell necrosis, cholestasis and hepatomegaly was also found in workers who had been poisoned by percutaneous uptake of this substance (through carelessness). (33, 34, 48)

•

Other aromatic amines or nitrocompounds (e. g. dinitrobenzene: dye and paint industry; dinitrotoluene: explosives; dimethyl nitrosamine: anticorrosive agents) can likewise lead to steatosis and cell necrosis after sufficient exposure. (s. tab. 30.3)

5.2.4 Inorganic substances

Phosphorus: Poisoning by phosphorus and its inorganic compounds

is rare. While insoluble red phosphorus is only slightly toxic, yellow and (above all) white forms of phosphorus show considerable hepatotoxicity. Occasional instances of toxicosis occur through rat poison containing phosphorus. Phosphorus poisoning causes a loss of glycogen in the liver cells, subsequently leading to marked steatosis and cell necrosis with portal infiltration. Jaundice appears at an early stage. Transaminases are greatly elevated, whereas ChE and Quick’s value fall. Signs of increasing liver insufficiency and azotaemia are prognostically unfavourable symptoms. Postnecrotic cirrhosis (or scarred liver) can develop in survivors. (18)

Arsenic: Arsenic poisoning is of great medicohistorical interest. (s.

p. 564) Chronic arsenic intoxication can be caused by inhalation or, more often, by oral uptake. Steatosis and cell necrosis occur in the liver; fibrosis or cirrhosis with portal hypertension and oesophageal varices develop. The presence of liver adenoma and VOD as well as liver carcinoma or haemangioendothelioma has been described. (16, 42, 50, 53, 60, 76)

Lead: Lead poisoning (⫽ saturnism) results in mild, rapidly regres-

sive toxic hepatitis in about 30% of cases. Occasionally, eosino- philic, acid-resistant inclusions are found in the nuclei of the liver cells (so-called lead protein complexes). Steatosis and liver-cell necrosis have also been witnessed. Although there is a correlation between exposure to lead and severity of damage, individual sensi- tivity to lead can nevertheless vary. In addition, lead intoxication causes an inhibition of erythrocyteδ-aminolaevulinic acid dehy- dratase and an induction ofδ-aminolaevulinic acid synthase. This brings about the manifestation of acute intermittent porphyria. (8)

5.2.5 Thorotrast

䉴 The introduction of thorotrast into radiological diagnostics (1928) despite foreseeable radiation damage is not exactly a glori- ous chapter in the annals of 20^th century medicine. Thirty years passed before the administration of thorotrast was stopped (after numerous reports of severe organ damage and the development of malignancies). (s. p. 564)

•

The term

thorotrastosis subsumed (1.)

aplastic anaemia, leukaemia and osteomyelofibrosis, (2.) atrophy of lymphatic organs with scarring obliteration, (3.) fibrosis of the liver and spleen with the occurrence of scarred areas (⫽ dystrophia

lenta, H. F. B runner, 1955)

, (4.) development of scarred areas in the form of granulomas around thorotrast extravasations

(H. F. B run- ner, 1960)

, and (5.) occurrence of malignancies. (30, 32, 49)

Fig. 30.2: Thorotrast liver: dark brown colouring of the liver sur-

face with reticular bright white fibrosis

Fig. 30.3: Thorotrast liver: deposits of thorotrast in portal and

perisinusoidal macrophages; periportal fibrosis and inflammation

(8)

The development of FNH due to thoratrast was reported for the first time in 1998. (6) In the liver, thorotrast is initially stored in the Kupffer cells; after their destruction, it is deposited in the periportal areas. From here, periportal and periacinar fibrosis as well as Glisson’s capsule fibrosis develop. (s. figs. 30.2, 30.3)

5.3 Mycotoxins

䉴 The following hepatotoxic mycotoxins are worthy of note: aflatoxin (Aspergillus flavus), griseofulvin (Peni- cillium griseofulvum), ochratoxin A (Aspergillus ochra- ceus), maltrozyne (from the fermentation of rice wine) and luteoskyrin (Penicillium islandicum). Their toxicity is increased by protein deficiency in the organism.

A disease of epidemic proportions affected more than 1,000 persons in India in 1974. The patients suffered from jaundice and ascites. Histological examination revealed centroacinar necrosis, inflammatory mesenchy- mal reactions and bile-duct proliferation; fibrosis and septal formation, sometimes ultimately cirrhosis, were determined. Mortality was 10%. The cause was thought to be the additive effect of several unidentified mycotox- ins

(B. N. Tandon et al., 1977)

.

Aflatoxins: So far, 13 types of aflatoxin (B, G, M) have been identified in various Aspergillus fungi. Their great toxicity is due to their alkylating effect with blocking of the DNA-dependent RNA polymerase. The highest toxicity to date has been ascribed to aflatoxin B

₁

. Under warm and humid conditions, certain agricultural prod- ucts (rice, soybeans, peanuts, almonds, pistachios, hazel- nuts, cereals, etc.) are attacked by Aspergillus fungi. (s.

p. 565) Aflatoxins may be present in peanuts in vending machines. Some types (B, M) have also been detected in dairy products. Aflatoxins can be neither seen, smelt nor tasted. • Acute poisoning leads to jaundice, steatosis and liver cell necrosis; ascites and fulminant liver failure have likewise been observed. In cases of chronic intoxi- cation, it is possible that cholestasis, bile-duct prolifera- tion, fibrosis and the clinical picture of biliary cirrhosis will occur. Since 1968, aflatoxin has been regarded as the most potent hepatocarcinogenic substance; it can act alone as a carcinogen or, in the case of HBV infec- tion, as a co-carcinogen.

(15, 35, 46, 51)

(s. p. 507)

5.4 Phytotoxins

The plant kingdom contains numerous phytotoxins.

Their number is, however, far greater than has been real- ized so far. They are also of great significance as direct hepatotoxins. • The most important phytotoxins are considered to be the fungal poisons (e. g. amanitin, phal- loidin, gyromitrin), pyrrolizidine alkaloids, cycasin from the sago palm, safrol from the gassafras tree, tannins and 3.4 ⬘-benzpyrene.

Carcinogenic phytotoxins

Cycasin Pyrrolizidine alkaloids

Luteoskyrin Safrol

Maltrozyn Tannins

Ochratoxin A

There have been repeated reports of intoxication by still largely unknown phytotoxins: liver cell necrosis and cholestasis following the consumption of herbal medi- cine made from mulberry tree bark

(S. Tozuka et al., 1983)

, liver cell necrosis (even fatal) following the intake of a root extract from the distaff thistle

(G. Lemaigre et al., 1975)

, poisoning by a decoction from Callilepsis laureola

(J. Wainwright et al., 1977)

and due to mint oil

(J. B. Sulli- van et al., 1979)

.

5.4.1 3.4⬘-benzpyrene

This polycyclic, aromatic hydrocarbon is produced con- tinuously by almost all plants, irrespective of their habi- tat, and remains qualitatively and quantitatively con- stant. The normal content of the carcinogenic 3.4 ⬘- benzpyrene equals 1 µg/100 g dried plant material. (The assumed quantity of carcinogenic polycyclic hydrocar- bons ingested daily with food and drinking water is cal- culated at 10 µg/day.) Food of animal origin, even in roasted, smoked or grilled form, contains substantially less benzpyrene than plants do.

5.4.2 Pyrrolizidine alkaloids

Pyrrolizidine alkaloids are found in > 200 crotalaria, senecio and heliotrope plants, but only about 100 types are toxic. Even honey may contain such pyrrolizidine alkaloids collected in pollen by bees from these plants.

These alkaloids were held responsible for veno-occlusive disease simultaneously in South Africa

^{(K. B. M}okhobo)

and Jamaica

(K. R. Hill)

in 1951. As early as 1920, how- ever,

F. C. Willmot et al.

had reported on the development of cirrhosis due to senecio poisoning. Generally, intake was in the form of “bush tea”, such as an Indian herbal tea for psoriasis

(P. S. Gupta et al., 1963)

, a dubious form of mate´ tea

(J. D. McGee et al., 1976)

, an antirheumatic tea

(C. L. Lyford et al., 1976)

and a Mexican antitussive tea

(A. E. Stillman et al., 1977)

. Likewise in Europe, various types of herbal tea may contain senecio alkaloids. • Liver damage manifests as hepatomegaly, epigastric pain, a rise in liver enzymes and an occasional ascites.

Hepatomegaly is due to the 10 ⫺20 fold enlargement of

hepatocytes, which is a result of the anti-mitotic effect

of pyrrolizidine alkaloids. Centrolobular necrosis,

steatosis and obliterative hepatic endophlebitis as well

as an acute or chronic Budd-Chiari syndrome may

appear. Diagnosis is established with the aid of imaging

techniques. In cases of acute poisoning, death often

occurs within a few days. About half the affected per-

sons survive. Chronic intoxications sometimes lead to

the development of cirrhosis and possibly malignant

liver tumours. (s. p. 830)

(9)

5.4.3 Amanita phalloides

The highly poisonous Amanita phalloides is easily con- fused with the field mushroom and yellow knight fun- gus. About 15 ⫺25% of all fungal poisonings and 50 ⫺60% of all fatalities are due to the ingestion of Amanita phalloides. Four Amanita species can be distin- guished: (1.) Amanita phalloides (green type), (2.) Ama- nita virosa (white type), (3.) Amanita citrina mappa (yel- lowish type), and (4.) Amanita verna (spring amanita mushroom). The fungal toxins 움-amanitin and phalloi- din are not destroyed by drying or heating. Some 25 g of fungus contain about 4.0 ⫺4.5 mg α-amanitin, i.e.

one mushroom (approx. 50 g) is sufficient for the fatal poisoning of 1 ⫺2 persons. • The maximum serum value is reached within 3 hours of ingesting the fungal poison.

As a result of the enterohepatic circulation, the serum concentration remains virtually constant for about 18 hours before beginning to fall steadily. The latency period (5 ⫺24 h) is asymptomatic. In the gastrointestinal phase (24 ⫺48 h), vomiting, gastric spasms, diarrhoea and dehydration occur, with loss of electrolytes and zinc. Metabolic alkalosis can abruptly change into metabolic acidosis. This phase is caused by the rapid onset of phallotoxic action. The hepatorenal phase sets in from about the third day onwards, with hepatic ence- phalopathy, cerebral oedema, a rise in transaminases, jaundice, a drop in the clotting factors, and hypoglyc- aemia. Death due to haemorrhagic diathesis in coma and/or uraemia occurs within 5 days; later deaths are unknown (or very rare).

䉴 Wieland test: The section plane of the fungus, which is cut open, is rubbed on a newspaper. One drop of 6 NHCl is then added to the dried sap, which takes on a blue colouring in the presence of amanitin.

Therapy consists of gastric lavage, nasogastral intesti- nal lavage, for example with 100 g lactulose ⫹ active charcoal ⫹ Ringer’s solution and a high cleansing enema; haemoperfusion or forced diuresis can be car- ried out if necessary. • Silibinin (30 mg/kg BW in 500 ml glucose solution, four times daily) as well as peni- cillin G (1 mega/kg BW, i.v.) have proved their thera- peutic value. N-acetylcysteine, fresh plasma, glucose, AT III and vitamins can be administered as support- ive measures. The therapeutic success achieved with silibinin is good; it should be administered as soon as there is suspicion of amanita poisoning without waiting for the mushroom to be identified in the urine (RIA, HPCL). It is important to keep samples of the fungi, stomach contents, blood, urine, etc.

(5, 9, 17, 19, 20, 31, 54)

(s. pp 378, 383)

䉴 Our own experience with the immediate use of silibinin in three validated cases of poisoning showed almost reac- tion-free survival.

5.4.4 Helvella esculenta

The toxins in Helvella esculenta (Gyromitra esculenta) can be completely removed by boiling, but this boiled water must not be re-used as it contains the fungal poi- son. The toxin was found to be gyromitrin, a hydrazine derivative. Liver damage manifests as extensive cell necrosis. With a rapid rise in the transaminases and serum bilirubin, the illness progresses to liver insuffi- ciency followed by hepatic coma and death. • No anti- dote is known. • Therapy hence consists of thorough gastrointestinal lavage with the addition of active char- coal and, where applicable, haemoperfusion. It is also advisable to use supportive measures (see above), as well as ⫺ where appropriate ⫺ thioctic acid (5 ⫻ 200 mg i.v.), zinc and selenium.

5.5 Endotoxins

Endotoxins are fragments of long-chain lipopolysac- charides. They pass from the cell membrane ⫺ mainly from gram-negative bacteria in the intestine ⫺ into the circulation and, as potential hepatotoxins, subsequently lead to liver damage. In the liver cells, they bring about a decrease in the activity of tryptophan pyrrolase as well as an increase in the activity of tyrosine- α-ketoglutarate transaminase. It is therefore understandable that a con- tinuous flow of intestinal endotoxins via the portal vein may well exacerbate an existing liver disease, in particu- lar liver cirrhosis. At the same time, these endotoxins cause fever, leucopenia, blood clotting disorders and kinin activation. The burden on the RES leads to a rise in γ-globulins with a simultaneous depressor effect on albumin synthesis.

5.6 Drugs

Elevated transaminases are found in more than 60% of anicteric drug addicts. It is, however, difficult to relate the respective liver damage to a particular drug as there is usually abuse of several addictive substances, includ- ing alcohol ( ⫽ polytoxicomania). It is likewise ex- tremely difficult to obtain an accurate medical history from drug addicts. Examinations by liver biopsy have presented a picture of chronic non-specific, chronic per- sistent or active chronic hepatitis. • Recently, there have been increasing reports of Ecstasy intoxications (and even acute liver failure requiring liver transplantation) as well as the development of liver fibrosis following Ecstasy abuse.

(21, 25, 26, 29, 74)

6 Diagnosis

6.1 Chronic intoxication

The diagnosis of liver damage due to toxic substances

is based on a detailed medical history. In addition to

(10)

general anamnesis, precise information on alcohol intake and medication is of primary importance. Alco- hol and medication are regarded as substantial uncer- tainty factors in the differential diagnosis and assess- ment of liver damage due to chemical toxins. Knowledge of existing metabolic diseases and special aspects in the person’s lifestyle is also important. Even though sub- jective symptoms are generally uncharacteristic, obser- vations concerning the commencement of the illness, its intensity and, of course, any striking factors can never- theless simplify diagnostic clarification. The attempt to compile a comprehensive occupational history can then begin. A certain flair for detective work may sometimes be necessary in this connection. • It is important to obtain documentation of certain workplace-related chem- icals and working materials!

Objective clinical findings are obtained by physical examination, determination of laboratory parameters ( γ- GT, GPT, GOT, GDH, AP, ChE) and sonography. Clari- fication of hepatitis serology is necessary. Additional laboratory parameters for differential diagnosis or long- term monitoring (e. g. immunoglobulins, P-III-P, elec- trophoresis) may be recommended in individual cases.

Although these findings mainly serve to determine the hepatological status, the possibility or even probability of toxically induced liver damage can generally be assessed as well. In the individual case, the constellation of histological changes also facilitates an aetiological assessment. • Definitive elucidation can only be achieved once the respective occupational physician and industrial toxicologist have clarified the relevant condi- tions at the workplace. When there is any suspicion that the working environment has caused liver damage, it is necessary to notify the authorities, who will then insti- gate all requisite diagnostic measures and draw up expertises.

䉴 Objectification and quantification of the suspected liver noxa(e) at the workplace and in the respective industrial materials are carried out in accordance with the current state of knowledge concerning toxicology in occupational medicine. Even when the chemically induced liver damage is not obviously related to the patient’s place of work, it is nevertheless recommended to seek advice and help from institutions for occupational medicine and toxicology.

6.2 Acute poisoning

In cases of acute poisoning (e. g. after suicide attempts or industrial accidents), it is generally straightforward to connect the poisoning to a particular chemical noxa. Numerous poison information centres are acces- sible ⫺ round the clock (!) ⫺ for rapid toxicological and therapeutic consultation. The prognosis for poi- soning depends decisively on the early commencement of therapeutic measures. • For the initial care of cases of acute poisoning, the five-finger rule should be

observed: (1.) removal of the toxin, (2.) antidote ther- apy (if possible), (3.) elementary assistance (respir- ation, circulation), (4.) transport to the hospital, and (5.) collecting evidence of the intoxication (toxic sub- stances, etc.). • Medical confidentiality also applies in cases of acute intoxication.

7 Therapeutic aspects

䉴 Acute poisoning is the result of three parameters: toxin

⫹ toxin uptake ⫹ toxin action. Three corresponding therapeutic equivalents should be applied: antidote ther- apy ⫹ detoxification ⫹ first-aid treatment. Detoxifica- tion and first-aid treatment are generally at the fore until an antidote (provided one exists) can be used (informa- tion obtainable from special emergency centres for poi- sons or from an antidote list). Depending upon the type of toxin involved, detoxification can be effected by gastrointestinal lavage, diuretic therapy, blood exchange, peritoneal dialysis, haemodialysis, ultrafiltration or haemoperfusion. • In cases of severe intoxication with acute liver failure, liver transplantation is indicated.

(20, 25, 66)

In this context, a report has recently been pub- lished about the successful treatment of acute potassium dichromate poisoning by means of liver transplanta- tion.

(66)

䉴 In chronic intoxication, the therapeutic objective is removal of the patient from the site of exposure and elimination of the noxa from the body (e. g. detoxifica- tion measures, infusions of calcium-disodium EDTA in cases of lead poisoning, etc.). There is no justification whatsoever for therapeutic nihilism. With the aid of dietetic measures (if necessary) and adjuvant therapy (N-acetylcysteine, antioxidants, ursodeoxycholic acid, S-adenosyl-methionine, etc.), the clinical course and hence the prognosis can be favourably influenced. • Insufficient regression or inadequate normalization of laboratory parameters and histological changes despite removal of the patient from the area of exposure must arouse suspicion of a further, still existing noxa (alcohol, medicaments, other chemicals).

Despite the presence of numerous potential hepato-

toxic substances at the workplace, the frequency of

industrial toxic liver damage is nevertheless low. This

is no doubt due to the success of screening pro-

grammes in occupational medicine, tolerance limits

for toxic substances at the workplace as laid down by

law and careful compliance with all preventive meas-

ures. • However, experience has shown that one must

always reckon with new, potentially hepatotoxic sub-

stances. In fact, far more attention must be paid to

those chemicals belonging to the category of “recre-

ational and hobby noxae”, which are often handled

with an irresponsible disregard of all risks.

(11)

8 Industrial hepatotoxic agents

1.

Aliphatic halogenated hydrocarbons

⫹Chloroform (⫽ trichloromethane) Chloroprene (⫽ 2-chloro-1,3-butadiene)

⫹1,1-dichloroethane, 1,2-dichloroethane 1,1-dichloroethene, 1,2-dichloroethene Dichloromethane

Fluorchloromethane

Methyl bromide (⫽ monobromomethane) Methyl chloride (⫽ monochloromethane) Methylene chloride (⫽ dichloromethane) Methyliodide (⫽ monoiodomethane)

⫹Pentachloroethane

Propylene dichloride (⫽ dichloropropane)

⫹Tetrachloroethane Tetrachloroethene (PER)

⫹Tetrachloromethane (⫽ carbon tetrachloride) 1,1,1-trichloroethane, 1,1,2-trichloroethane

⫹Trichloroethen (TRI) Vinyl chloride

2.

Aromatic halogenated hydrocarbons

Benzyl chloride (⫽ monochlorobenzene) Chlorinated benzene derivatives Chlorinated naphthalenes

⫹Chlorobiphenyl

Dichlorodiphenyltrichloro-ethane (DDT)

⫹Perchlorobiphenyl (PCB)

3.

Aliphatic hydrocarbons and cycloalcans

Cyclohexane

Cyclopropane N-heptane N-hexane

4.

Aromatic hydrocarbons

Benzene

Diphenyl

⫹Naphthalene

Styrene (⫽ ethyl benzene) Toluene (⫽ methyl benzene) Xylene (⫽ dimethyl benzene) 5.

Aliphatic amines

2-acetylaminofluorene

Ethanolamine (⫽ aminoethanole) Ethylenediamine (⫽ 1,2-diaminoethane) 6.

Aromatic amines

4,4-diaminodiphenyl methane 3,3-dichlorobenzidine and its salts

4-dimethylamino-azobenzene (⫽ “butter yellow”) 4,4-methylene-bis(2-chloroaniline)

7._⫹

Nitro compounds

Dinitrobenzene

4,6-dinitro-o-cresol (DNOC)

⫹Dinitrophenole 2,4-dinitrotoluene Nitrobenzenel

Nitroparaffins (nitroalkanes) Nitrophenol

Nitropropane

N,N-dimethylnitrosamine

⫹Picric acid (⫽ 2,4,6-trinitrophenol) Tetryl (⫽ nitramine)

⫹Toluene diamine (⫽ neutral red)

⫹2,4,6-trinitrotoluene (TNT) 8.

Nitriles

Acetonitrile Acrylonitrile 9.

Acetates and silicates

Amyl, N-butyl, ethyl, isopropyl, methyl and N-propyl acetates Ethyl silicate

10.

Halogens and halogenides

Bromine

Bromide

Hydrobromic acid 11.

Ethers and epoxides

Diethyl ether

⫹Dioxane (⫽ 1,4-dioxane) Epichlorohydrin Ethylene oxide

Ethylglycol ether and derivatives 12.

Alcohols and derivatives

Allyl alcohol

Dichloropropanol (⫽ 1,3-dichloro-2-propanol) Ethanol (⫽ ethyl alcohol)

Ethylene chlorhydrin (⫽ 2-chloroethanol) Methanol (⫽ methyl alcohol)

13.

Carboxylic acids and anhydrides

Phthalic acid anhydride 14.

Phenols and derivatives

Cresol (⫽ methyl phenol) Pentachlorophenol (PCP) Phenol

15.

Cyanides and Cyanates

Cyanhydric acid (⫽ prussic acid)

⫹Isocyanate 16.

Pesticides

Dipyridyl (⫽ 2,2-bipyridine)

⫹Paraquat (⫽ paraquat dichloride)

⫹Thallium sulphate 17.

Other organic compounds

Aldehydes Betapropiolactone Carbon disulfide Dimethyl sulphate

⫹Hydrazine and derivatives Mercaptans

N,N-dimethylacetamide

⫹N,N-dimethylformamide N-nitrosodimethylamine Pyridine

Tetrachlorodiphenyl-p-dioxin (TCDD) Tetramethylthiuram disulphide (⫽ thiram) Turpentine

18.

Metal and inorganic compounds

⫹Arsenic

⫹Arsines Beryllium

Bismuth and bismuth compounds Boron and boron compounds Cadmium and cadmium compounds Carbonyle

Chromium and chromium compounds Germanium

Iron Copper Lead Manganese

Mercury and mercury compounds Nickel and nickel compounds Phosphine (⫽ hydrogen phosphide)

⫹Phosphorus and phosphorus compounds Selenium and selenium compounds Stibium (⫽ antimony hydrogen)

⫹Thallium and thallium compounds Thorium dioxide

Tin and tin compounds

Uranium and uranium compounds

Tab. 30.3: Table of important, mainly industrially used, toxic substances (selection). (

^⫹⫽ causes very severe liver damage, severe toxic hepatitis and acute liver failure) • We would appreciate any corrections, supplements or additions.

(12)

References:

1. Anderson, H.A., Wolff, M.S., Lilis, R., Holstein, E.C., Valciukas, J.A., Anderson, K.E., Petrocci, M., Sarkozzi, L., Selikoff, I.J.: Symptoms and clinical abnormalities following ingestion of polybrominated-biphenyl- contaminated food products. Ann. N. Y. Acad. Sci. 1979; 320: 684 ⫺702 2. Armstrong, C.W., Stroube, R.B., Rubio, T., Siudyla, E.A., Miller, G.B.:

Outbreak of fatal arsenic poisoning caused by contaminated drinking water. Arch. Environ. Hlth. 1984; 39: 276 ⫺279

3. Babany, G., Bernuau, J., Cailleux, A., Cadranel, J.-F., Degott, C., Erlinger, S., Benhamou, J.-P.: Severe monochlorobenzene-induced liver cell necrosis. Gastroenterology 1991; 101: 1734 ⫺1736

4. Bagnell, P.C., Ellenberger, H.A.: Obstructive jaundice due to a chlori- nated hydrocarbon in breast milk. Canad. Med. Ass. J. 1977; 117:

1047 ⫺1048

5. Bartoloni, S., Omer, F., Giannini, A., Botti, P., Caramelli, L., Ledda, F., Peruzzi, S., Zorn, M.: Amanita poisoning: a clinical-histopathological study of 64 cases of intoxication. Hepato-Gastroenterol. 1985; 32:

229 ⫺231

6. Beer, T.W., Carr, N.J., Buxton, P.J.: Thorotrast-associated nodular regenerative hyperplasia of the liver. J. Clin. Pathol. 1998; 51: 941 ⫺942 7. Boewer, C., Enderlein, G., Wollgast, U., Nawka, S., Palowski, H., Bleiber, R.: Epidemiological study on the hepatotoxicity of occupational toluene exposure. Int. Arch. Occup. Environ. Health 1988; 60: 181 ⫺186 8. Carton, J.A., Diaz, J., Vallina, E., Arribas, J.M.: Hepatitis bei Saturni-

mus. Dtsch. Med. Wschr. 1984; 109: 195 ⫺196

9. Covic, A., Goldsmith, D.J.A., Gusbeth-Tatomir, P., Volovat, C., Dimitriu, A.G., Cristogel, F., Bizo, A.: Successful use of molecular adsorbent regenerating system (MARS) dialysis for the treatment of fulminant hepatic failure in children accidentally poisoned by toxic mushroom ingestion. Liver Internat. 2003; 23 (Suppl. 3): 21 ⫺27

10. Creech, J.L., Johnson, M.N.: Angiosarcoma of liver in the manifacture of polyvinylchloride. J. Occup. Med. 1974; 16: 150 ⫺151

11. Dietz, A., Langbein, G., Permanetter, W.: Das Vinylchloridinduzierte hepatozelluläre Karzinom. Klin. Wschr. 1985; 63: 325 ⫺331

12. Doss, M., Lange, C.E., Vellman, G.: Vinylchloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria. Klin.

Wschr. 1984; 62: 175 ⫺178

13. Dossing, M., Arlien-Soborg, P., Petersen, L.M., Ranek, L.: Liver dam- age associated with occupational exposure to organic solvents in house painters. Eur. J. Clin. Invest. 1983; 13: 151 ⫺157

14. Dossing, M.: Occupational toxic liver damage. J. Hepatol. 1986; 3:

131 ⫺135

15. Enwonwu, C.O.: The role of dietary aflatoxin in the genesis of hepato- cellular cancer in developing countries. Lancet 1984/II; 956 ⫺958 16. Falk, H., Caldwell, G.G., Ishak, K.G., Thomas, L.B., Popper, H.: Arse-

nic-related hepatic angiosarcoma. Amer. J. Indust. Med. 1981; 2: 43 ⫺50 17. Faybik, P., Hetz, H., Baker, A., Bittermann, C., Berlakovich, G., Werba, A., Krenn, C.G., Steltzer, H.: Extracorporeal albumin dialysis in patients with Amanita phalloides poisoning. Liver Internat. 2003; 23 (Suppl.

3): 28 ⫺33

18. Fernandez, O.U.B., Canizares, L.L.: Acute hepatotoxicity from ingestion of yellow phosphorus-containing fireworks. J. Clin. Gastroenterol. 1995;

21: 139 ⫺142

19. Floersheim, G.L.: Treatment of human amatoxin mushroom poisoning:

myths and advances in therapy. Med. Toxicol. Adv. Drug Exp. 1987;

2: 1 ⫺9

20. Galler, G.W., Weisenberg, E., Brasitus, T.A.: Mushroom poisoning: the role of orthotopic liver transplantation. J. Clin. Gastroenterol. 1992;

15: 229 ⫺232

21. Gilbert, H.S., Stimmel, B.: Abnormal liver function and elevated hemo- globins in heroin addicts. Amer. J. Gastroenterol. 1975; 64: 49 ⫺54 22. Haratake, J., Furuta, A., Icasa, T., Wakasugi, C., Imazu, K.: Submassive

hepatic necrosis induced by dichloropropanol. Liver 1993; 13: 123 ⫺129 23. Hardt, M., Geisthövel, W.: Malignes Hämangioendotheliom der Leber 39 Jahre nach einmaliger Thorotrast-Applikation. Med. Klin. 1988;

83: 151 ⫺153

24. Harrison, R., Letz, G., Pasternak, G., Blanc, P.: Fulminant hepatic fail- ure after occupational exposure to 2-nitropropane. Ann. Intern. Med.

1987; 107: 466 ⫺468

25. Hellinger, A., Rauen, U., De Groot, H., Erhard, J.: Auxiliäre Lebertrans- plantation bei akutem Leberversagen nach Einnahme von 3,4-Methy- lendioxymetamphetamin (“Ecstasy”). Dtsch. Med. Wschr. 1997; 122:

716 ⫺720

26. Henry, J.A., Jeffreys, K.J., Dawling, S.: Toxicity and death from 3,4- methylenedioxymetamphetamine (“ecstasy”). Lancet 1992; 340:

384 ⫺387

27. Hoshino, T., Komatsu, M., Ono, T., Funaoka, M., Kato, J., Ishii, T., Kuramitsu, T., Miura, K., Masamune, O., Hojo, H.: A case of acute carbon tetrachloride poisoning. Acta Hepatol. Japon. 1994; 35:

882 ⫺886

28. Kaufmann, L., Höpker, W.W., Deutsch-Diescher, O.G., Seitz, H.K., Götz, R., Kommerell, B.: Leberschädigung durch chronische Cadmium- intoxikation. Leber Magen Darm 1984; 14: 103 ⫺106

29. Khakoo, S.I., Coles, C.J., Armstrong, J.S., Barry, R.E.: Hepatotoxicity and accelerated fibrosis following 3,4-methylenedioxymetamphetamine (“Ecstasy”) usage. J. Clin. Gastroenterol. 1995; 20: 244 ⫺247

30. Khan, A.A.: Thorotrast-associated liver cancer. Amer. J. Gastroenterol.

1985; 80: 699 ⫺703

31. Kleist-Retzow, von, J.-C., Vierzig, A., Fuchshuber, A., Roth, B., Michalk, D.V.: Klinik und Therapie der Knollenblätterpilzvergiftung im Kindes- alter. Mschr. Kinderheilk. 1995; 143: 1118 ⫺1127

32. Kojiro, M., Kawano, Y., Kawasaki, H., Nakashima, T., Ikezani, H.:

Thorotrast-induced hepatic angiosarcoma, and combined hepatocellu- lar and cholangiocarcinoma in a single patient. Cancer 1982; 49:

2161 ⫺2164

33. Kopelman, H., Robertson, M.H., Sanders, P.G., Esch, I.: The Epping jaundice. Brit. Med. J. 1966/I: 514 ⫺516

34. Kopelman, H.: Epping jaundice after two years. Postgrad. Med. J. 1968;

44: 78 ⫺81

35. Krishnamachari, K.A.V.R., Nagarajan, V., Bhat, R.V., Tilak, T.B.G.:

Hepatitis due to aflatoxicosis. An outbreak in Western India. Lancet 1975/I: 1061 ⫺1063

36. Kuntz, E., Neumann-Mangold, P.: Die akute perorale Trichloraethylen- Vergiftung. Med. Welt 1965: 2872 ⫺2874

37. Kuntz, E., Ordnung, W., Schmidt, U., Wildhirt, E., Engels, Ch.: Leber und Umwelt. Eine anamnestische Praxisstudie. Kassenarzt 1988; 7:

32 ⫺40

38. Kuntz, E.: Lebererkrankungen aus der Sicht der niedergelassenen Ärzte.

(Befragung von 2990 Ärzten). notabene medici 1989; 19: 243 ⫺246 39. Kuntz, H.D., May, B.: Berufsbedingte Lebererkrankungen. Münch.

Med. Wschr. 1980; 122: 1059 ⫺1062

40. Kuntz, H.D., May, B.: Gewerblich-bedingte toxische Leberschäden.

Atemw.-Lungenkrankh. 1984; 10: 477 ⫺483

41. Kurrpa, K., Husman, K.: Car painters exposure to a mixture of organic solvents: serum activities of liver enzymes. Scand. J. Work Environ.

Health 1982; 8: 137 ⫺140

42. Labadie, H., Stoessel, P., Callard, P., Beaugrand, M.: Hepatic venooc- clusive disease and perisinusoidal fibrosis secondary to arsenic poison- ing. Gastroenterology 1990; 99: 1140 ⫺1143

43. Langbein, G., Permanetter, W., Dietz, A.: Hepatozelluläres Karzinom nach Vinylchlorid-Exposition. Dtsch. Med. Wschr. 1983; 108: 741 ⫺745 44. Lange, C.E., Jühe, S., Veltmann, G.: Über das Auftreten von Angiosar- komen bei zwei Arbeitern in der PVC-herstellenden Industrie. Dtsch.

Med. Wschr. 1974; 99: 1598 ⫺1599

45. Lelbach, W.K.: Leber und Umweltgifte. Klin. Wschr. 1985; 63:

1139 ⫺1151

46. Linsell, A.: Incidence of hepato-carcinoma in relation to aflatoxin intake. Arch. Toxicol. 1980; 3: 13 ⫺18

47. Matsumoto, T., Matsumori, H., Kuwabara, N., Fukuda, Y., Ariwa, R.A.:

A histopathological study of the liver in paraquat poisoning. An analy- sis of fourteen autopsy cases with emphasis on bile duct injury. Acta Path. Japon. 1980; 30: 859 ⫺870

48. McGill, D.B., Motto, J.D.: An industrial outbreak of toxic hepatitis due to methylenedianiline. New Engl. J. Med. 1974; 291: 278 ⫺282 49. Morant, R., Rüttner, J.R.: Thorotrast-Spätschäden. Schweiz. Med.

Wschr. 1987; 117: 952 ⫺957

50. Nevens, F., Fevery, J., van Steenbergen, W., Sciot, R., Desmet, V., de Groote, J.: Arsenic and non-cirrhotic portal hypertension. A report of eight cases. J. Hepatol. 1990; 11: 80 ⫺85

51. Olsen, J.H., Dragstedt, L., Autrup, H.: Cancer risk and occupational exposure to aflatoxins in Denmark. Brit. J. Canc. 1988; 58: 392 ⫺396 52. Peters, H.A.: Hexachlorobenzene poisoning in Turkey. Fed. Proc. 1976;

35: 2400 ⫺2403

53. Piontek, M., Hengels, K.J., Borchard, F., Strohmeyer, G.: Nicht-zirrho- tische Leberfibrose nach chronischer Arsenintoxikation. Dtsch. Med.

Wschr. 1989; 114: 1653 ⫺1657

54. Piqueras, J.: Hepatotoxic mushroom poisoning: diagnosis and manage- ment. Mycopathologia 1989; 105: 99 ⫺110

55. Pond, S.M.: Effects on the liver of chemicals encountered in the work- place. West J. Med. 1982; 137: 506 ⫺514

56. Pond, S.M.: Manifestations and management of paraquat poisoning.

Med. J. Aust. 1990; 152: 256 ⫺259

57. Raithel, H.-J., Zober, A., Valentin, H.: Berufsbedingte toxische Leber- schäden. Inn. Med. 1983; 24: 16 ⫺24

58. Redlich, C.A., West, A.B., Fleming, L., True, L.D., Cullen, M.R., Riely, C.A.: Clinical and pathological characteristics of hepatotoxicity associ- ated with occupational exposure to dimethylformamide. Gastroenterol- ogy 1990; 99: 748 ⫺757

59. Reuber, M.D., Glover, E.L.: Carbon tetrachloride-induced cirrhosis.

Effect of age and sex. Arch. Path. 1968; 85: 275 ⫺279

60. Roat, J.W., Wald, A., Mendelow, H., Pataki, K.J.: Hepatic angiosar- coma associated with short-term arsenic ingestion. Amer. J. Med. 1982;

73: 933 ⫺936

61. Ruprah, M., Mant, T.G.K., Flanagan, R.J.: Acute carbon tetrachloride poisoning in 19 patients: implications for diagnosis und treatment. Lan- cet 1985/I: 1027 ⫺1029

62. Scailteur, V., Lauwerys, R.R.: Dimethylformamide (DMF) hepatotoxic- ity. Toxicology 1987; 43: 231 ⫺238

63. Sinniah, D., Baskaran, G., Looi, L.M., Leong, K.L.: Reye-like syndrome due to Margosa oil poisoning: report of a case with post mortem find- ings. Amer. J. Gastroenterol. 1982; 77: 158 ⫺161

64. Solis-Herruzo, J.A., Vidal, J.V., Colina, F., Castellano, G., Munoz- Yagüe, M.T., Morillas, J.D.: Clinico-biochemical evolution and late hepatic lesions in the toxic oil syndrome. Gastroenterology 1987; 93:

558 ⫺568

65. Sotaniemi, E.A., Sutinen, S., Sutinen, S., Arranto, A.J., Pelkonen, R.O.:

Liver injury in subjects occupationally exposed to chemicals in low

doses. Acta Med. Scand. 1982; 212: 207 ⫺215

(13)

66. Stift, A., Friedl, J., Längle, F., Berlakovich, G., Steininger, R., Mühlbacher, F.: Successful treatment of a patient suffering from severe acute potassium dichromate poisoning with liver transplantation.

Transplantation 2000; 69: 2454 ⫺2455

67. Texter, E.C., Grunow, W.A., Zimmermann, H.J.: Massive centrizonal necrosis of the liver due to inhalation of 1,1,1-trichloroethane. Gastro- enterology 1979; 76: 1260 ⫺1268

68. Thiele, D.L., Eigenbrodt, E.H., Ware, A.J.: Cirrhosis after repeated tri- chloroethylene and 1,1,1-trichloroethane exposure. Gastroenterology 1982; 83: 926 ⫺929

69. Thomas, L.B., Popper, H., Berk, P.D., Selikoff, I., Falk, H.: Vinyl-chlo- ride-induced liver disease. From idiopathic portal hypertension (Banti’s syndrome) to angiosarcomas. New Engl. J. Med. 1975; 292: 17 ⫺22 70. Triebig, G., Weltle, D., Schaller, K.-H., Valentin, H.: Chronische Löse-

mittel-Expositionen und Leberenzyme. Fortschr. Med. 1985; 103:

271 ⫺275

71. Underwood, J.C.E., Huck, P.: Thorotrast-associated hepatic angiosar- coma with 36 years latency. Cancer 1978; 2610 ⫺2612

72. Velicia, R., Sanz, C., Martinez-Barredo, F., Sanchez-Tapias, J.M., Bru- guera, M., Rodes, J.: Hepatic disease in the Spanish Toxic Oil Syndrome.

A thirty months follow-up study. J. Hepatol. 1986; 3: 59 ⫺65

73. Ward, E., Boffetta, P., Andersen, A.: Update of the follow-up of mortal- ity and cancer incidence among European workers employed in the vinyl chloride industry. Epidemiology 2001; 12: 710 ⫺718

74. Weller, I.V.D., Cohn, D., Sierralta, A., Mitcheson, M., Ross, M.G.R., Montano, L., Scheuer, P., Thomas, H.C.: Clinical, biochemical, serologi- cal, histological and ultrastructural features of liver disease in drug abusers. Gut 1984; 25: 417 ⫺423