Renal and Hepatic Disease 20

20

Renal and Hepatic Disease

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N

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Key words: liver disease, kidney disease, agrochemicals, biological hazards,

organic solvents, infections

Generally speaking, the occurrence of liver or kidney disease is not particu- larly associated with agriculture. Nevertheless, life in rural settings in general, as well as work in agriculture in particular, is associated with a variety of health risks that can affect liver or kidney. These risks are not completely dif- ferent from those in urban life but can be present to a greater or lesser degree.

Environmental exposures on farms are typically characterized by biological hazards, including a higher infectious disease risk; by the use of agricultural chemicals, including fertilizers and biocides; and by exposures to solvents, fuels, paints, and welding fumes associated with maintenance and repair work. On the other hand, pollution by traffic exhausts, industrial emissions, and other effluents of civilization play a comparatively smaller role in a rural environment. Health risks associated with general lifestyle choices, such as smoking, alcohol consumption, and lack of physical exercise, are also pres- ent to a lesser extent on average than in urban settings. This association might not be true under all circumstances as with respect to alcohol consumption in wine-producing areas or to behavioral patterns in migrant farm workers as compared to farmers themselves. Diseases of poverty, such as malnutrition and infectious diseases not only put the farm worker at risk for hepatic and renal injuries, but also can cause diseases in their own right (1,2).

General Epidemiological Liver and Kidney Findings in Farmers

Cohort studies in farmers or agricultural workers have mostly been targeted at cancer outcomes; those focused on other health issues are scarce. The over- all findings suggest that farmers and farm residents experience less cancer and more favorable mortality patterns, except from accidents, than their respective control groups. Liver cirrhosis as a cause of death was significantly

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less than expected in New York farmers, and so was the incidence of liver and kidney cancer in several cohorts of farmers, agricultural workers, and licensed pesticides applicators in other studies (3–7).

One cohort study among farmers and agricultural workers from Italy found a small excess of kidney cancers based on five observations against the background of overall reduced cancer mortality. Studies in female farm resi- dents have shown either insignificant elevations of liver cancer risk or no ele- vations at all, with kidney cancer risk being significantly reduced. In a large case-control study of hepatocellular carcinoma, cholangiocarcinoma, or combined hepatocellular and cholangiocarcinoma, male farmers were the only occupational group with an odds ratio significantly below unity. A few studies suggest that migrant farm workers may differ from farmers by expe- riencing excesses of cancers of the buccal cavity and pharynx, lung, and liver.

This disease pattern, however, appears to be more closely related to lifestyle factors like smoking and alcohol drinking than to occupational exposures typically associated with farming (8–13).

Only few reports describe relevant disease patterns deviating from the above-mentioned findings. One was a cluster of 14 hepatic angiosarcoma cases in Egypt, 10 of which had “a definite history of a direct chronic recur- rent exposure to agricultural pesticides of variable chemical nature.” The authors’ conclusion that “this significant increase . . . among farmers involved in pesticide spraying suggests that agricultural pesticides might play a role in the genesis of hepatic angiosarcoma” does not hold, however, against the lack of evidence in the rest of the available literature (14).

Elevated rates of liver cancer in rural populations in Fiji as compared to Tonga have been attributed to the higher prevalence of food contamination with aflatoxin in the former, reflecting different storage practices. Men who used mainly dichlorodiphenyl-trichloroethane (DDT) in an antimalarial campaign in Sardinia, Italy, during the late 1940s experienced an increased mortality from liver and biliary tract cancers. This increase, however, also occurred in nonexposed subjects and showed no dose response relation. The authors concluded that these cancers probably were unrelated to DDT and that other environmental exposures common to the Sardinian population accounted for the increase in risk (15,16).

In a report on a case series on end-stage renal disease (ESRD) in El Sal-

vador, the authors described a group of patients with known risk factors for

ESRD, basically diabetes mellitus, hypertension, and chronic consumption of

nonsteroidal antiinflammatories. Another group had unusual characteristics

that were not associated with the known risk factors. According to the

authors they “identified an important group of patients with ESRD who

seem to lack a cause for their disease. Their special characteristics make it

possible to suspect a relationship with the occupational exposure to insecti-

cides or pesticides.” While this interpretation contrasts with the lack of simi-

lar findings in other rural populations from other regions, it is a perfect

illustration of a widespread perception bias in parts of the epidemiological

literature on health risks associated with agriculture: health effects are read- ily attributed to agricultural chemicals, notably pesticides, without even try- ing to define what pesticides are, and without adequate consideration of other possible causes (17).

Chemical Exposures

Chemical exposures in agriculture and farming can be manifold and hetero- geneous. This is especially true for the handling of pesticides, an exposure category often used in the occupational medical literature (see Chapter 16).

Although liver and kidney damage from agrochemicals is noted with some regularity both in high-dose animal toxicology testing and in case reports from accidental or suicidal poisoning, these findings are hardly transferable to occupational or environmental human exposure situations. The reason for the findings in animals is that many of these chemicals through their metab- olism may lead to adaptive responses such as enzyme induction, organ enlargement, and, finally, to overload phenomena at the highest doses that are not normally achievable in human workplaces. Consequently, a general risk increase for liver disease caused by agrochemicals is doubtful, and no reports are available regarding the general risk for kidney effects. However, in situations with poor occupational hygiene and lack of personal protective equipment, eventually aggravated by unfavorable climatic conditions, high exposures to agrochemicals with the occurrence of mostly acute adverse health effects are possible. Other chemical exposures in agriculture such as solvents may have well-known liver- or kidney-damaging properties associ- ated with certain uses; however, their relevance for farmers and farm workers has rarely been assessed. Given these limitations, only some generic remarks on chemicals in farming can be made and some specific examples for toxic effects on liver or kidney can be given (18).

Pesticides

Pesticides are a heterogeneous group of chemicals that, by definition, are produced and used to exert biological activity. There are thousands of natu- rally occurring pesticides in all kinds of plants and, currently, some 500 dif- ferent synthetic molecules in more than 5000 formulations. As diverse as their chemistry are their respective biological targets and modes of action. They are used as herbicides, fungicides, insecticides, acaricides, rodenticides, and microbicides. Against this background, it is impossible to give a summary evaluation of liver or kidney effects of these substances in farm workers or residents (see Chapters 13 and 16).

Most insecticides act primarily as neurotoxins, with much lower effective

doses in insects than in mammals. They elicit symptoms in the central and

peripheral nervous system much earlier than in any other organ system. This explains why, except in cases of deliberate poisoning, as in suicide, manifest liver or kidney damage due to insecticide use hardly ever occurs in persons who handle them professionally. One exception to this statement may be lead arsenate, which was used as an insecticide in vineyards in the past and allegedly caused liver cirrhosis and liver cancer in wine growers. Such cases have been acknowledged as an occupational disease in Germany; however, some doubted the relevance of arsenic as the major culprit. Elevated liver enzyme activities in professional pesticide sprayers have occasionally been reported, whereas others did not confirm these findings (19–25).

Some fungicides act via inhibition of the P450 enzyme family and can thus interfere with xenobiotic metabolism in mammals. Although liver damage has been found after administration of fungicides in experimental animals, liver and kidney toxicity of most of these substances is insignificant in humans under normal circumstances. Notable exceptions from this rule hap- pened in the past with the accidental consumption of wheat seedlings treated with hexachlorobenzene (HCB). Several thousand cases of hepatic porphyria occurred after incidences of mass poisoning in Iraq and Turkey. Of course, porphyria was neither the leading nor the most severe symptom of HCB poi- soning (26,27).

Herbicides primarily target plant-specific enzymes and are thus generally of comparatively low toxicity to nontarget organisms. Acute intoxications mainly affect the central nervous system, with kidney effects being reported after long-term exposure to chlorophenoxy derivatives. From this group of substances, 2,4,5-T especially has been found to be contaminated with dioxin in the past, and a variety of health effects in former users have been attrib- uted to it. The most exposed, however, were not farmers but American sol- diers involved in the spraying of Agent Orange in Vietnam, and hepatic or renal disorders were not a major issue in these cases. The herbicide paraquat has become an infamous example of high mortality due to pulmonary fibro- sis together with liver and kidney failure. Although such cases usually relate to either accidental or suicidal oral intake of larger quantities, one case of lethal paraquat poisoning in a Japanese worker with an occupational history of spraying paraquat in a greenhouse has been reported (28,29).

Solvents and Fuels

Although exposures to organic solvents and fuels are not specific for agricul-

tural settings, they represent typical health risks for farmers. Solvents and

fuels not only are used in repair and maintenance work, as in painters or

cleaners, but also are often the basis for the preparation of pesticide solutions

for spraying. Especially for sprayed solvents, exposure through inhalation or

skin contact not only of vapors but also of aerosols is possible. Depending

on the substance used, the hepatotoxic potency of the solvent can be more

relevant than that of the active ingredient pesticide. This aspect is often neglected in the discussion of health findings in pesticide sprayers, not least because of the difficulty of differentiating between the effects of single factors in complex mixtures. To enable an educated guess of the possible solvent-related health risk for farmers, experience from typically solvent- exposed professionals like degreasers, printers, painters, and paint manufac- turers may serve as a model. Here, on average, subclinical effects have been described on liver and kidney function. However, except from some specific agents like N,N ¢-dimethylformamide or several chlorinated hydrocarbons, the hepatotoxicity and nephrotoxicity of organic solvents should not be overrated (30–34).

Many similar studies have not found any demonstrable solvent effect on liver and kidney even in comparatively highly exposed subjects, and liver- related findings often were more closely associated with individual alcohol consumption than with occupational solvent exposure. Taken together, the findings of slight effects on kidney and liver, if any, in heavily solvent- exposed workers other than farmers is consistent with the generally low reported rates of liver or kidney damage in farmers, who have much lower solvent exposure (35–38).

Biological Agents

If ever there is a “typical exposure” in agricultural settings, it is the close con- tact with biological agents, many of which are associated with an enhanced risk for infections. This link is most evident in cases of zoonoses, diseases that can be passed from animals, whether wild or domesticated, to humans.

Although most zoonotic infections do not primarily affect liver or kidneys, some links can be established.

A two- to fivefold prevalence of hepatitis E antibodies, for example, has been found in North Carolina swine workers as well as in Moldavian swine farmers, suggesting that hepatitis E may be a zoonosis and specifically an occupational infection of livestock workers. Being in the vicinity of wildlife, including having close contact with free-roaming farm animals such as dogs, and in some regions also herding of sheep, goats, and cattle are associated with an increased risk for human alveolar echinococcosis, which typically forms hydatid cysts in the liver and caused up to 100% lethality in untreated patients before the 1970s (39–44).

Life in rural areas itself may be associated with lack of sanitation or unhy- gienic work practices, not only in developing but also in developed countries.

One well-described risk factor for infectious disease in general, including liver

or kidney disease, is the use of untreated waste water for irrigation, which

increased the incidence of shigellosis, salmonellosis, typhoid fever, and infec-

tious hepatitis by a factor of two to four in Israeli kibbutzim. In Turkey,

this practice has been identified as a source of hepatitis E infection in farm

workers. Melioidosis is an infection, endemic in Southeast Asia, North Aus- tralia, New Guinea, and in tropical Africa, that primarily affects the lung but can subsequently lead to liver and kidney abscesses. Farmers and stockmen represented predisposed populations in North Queensland, which was attrib- uted to their prolonged soil contact (45–47).

Noninfectious biological hazards through fungal growth on hay, grain, food, and feedstock also have to be taken into account. Again, liver and kid- ney are not the most important targets for associated health effects but can be affected in special cases. A case of acute renal failure (ARF) due to inhala- tion of ochratoxin A produced by a mold of the species Aspergillus ochraceus was reported from Italy. After working 8 hours in a granary closed for sev- eral months, a farmer and his wife suffered respiratory distress; the woman developed nonoliguric ARF, and biopsy revealed tubulonecrosis. A strain of

Conclusion

Living on farms or doing farm work is associated with a number of health risks, some of which may also pertain to liver or kidney. However, apart from some specific but rare diseases or some unusual local clusters, liver or kidney disease in general is not a major cause of concern in rural settings. One cause for this reduced specific illness frequency as compared with urban popula- tions is the reduced presence of some classical behavioral risk factors, notably smoking and alcohol consumption. The highest risks for liver and kidney dis- ease in farming are due to biological hazards. Toxicological health risks, where present, are not primarily targeted at liver or kidney. This does of course not mean that there are no relevant toxicological risks present in agri- culture. Occupational hygiene, including appropriate personal protective equipment, is essential in the handling of toxic chemicals in agriculture, as well as elsewhere.

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