Agricultural Respiratory Diseases

Key words: dusts, gases, pesticides, fertilizers, solvents
Agricultural areas have potentially significant sources of exposure to respiratory irritants and allergens associated with respiratory diseases. From an occupa- tional and environmental perspective on a global scale, exposures to organic and inorganic dusts, biological material such as endotoxin and mold, pesticides, and chemicals are prevalent in agriculture and associated with a wide variety of res- piratory symptoms and diseases. Agricultural activities such as fieldwork, plant- ing and harvesting, grain handling, and work in silos, animal stalls, and dairy barns can generate significant amounts of respirable dust. Many respiratory exposures, like total dust concentration in fields, can be higher in agriculture than in other industries, and exposure levels may often exceed general industry standards for nuisance dusts. Despite generally lower rates of cigarette smoking in agriculture and farm workers, they have an increased prevalence of respira- tory illnesses compared to the general population (Table 19.1) (1–10).
In developed countries, recent technological advances in agriculture have improved working conditions, yet paradoxically have increased other expo- sures such as concentrated indoor exposures to organic dust in confined ani- mal feeding operations. In addition, engineering controls are often insufficient, and respiratory protection is needed but often underutilized by agricultural workers. In developing countries, significant overall exposures remain more widespread as agricultural practices and regulations are not standardized, although the majority of the working population participates in some type of agricultural work. Information regarding disease burden and prevalence is not easily available; statistics may underestimate disease prevalence because of underreporting or unavailability of reliable data. This chapter reviews respiratory illnesses associated with specific agricultural exposures, outlines the medical evaluation for respiratory diseases, highlights evolving research areas, and discusses strategies for prevention (1–3,7,8).
Several specific respiratory illnesses and syndromes are related to occupa- tional and environmental exposures to agricultural areas. For those uniniti- ated in farm medicine, the atypical sources of toxic gas inhalation may come
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as a surprise. Even grain storage and manure can produce toxic substances in the right circumstances.
Toxic Gas Inhalation
Silo Filler’s Disease Farms with large numbers of livestock typically rely on a large storage con- tainer called a silo to store animal feed. A variety of relatively airtight struc- tures can serve for animal feed storage, including upright metal tower silos, in-ground pits, and even huge plastic bags. In the silo, recently harvested grains are tightly compressed to squeeze out most of the air. The remaining oxygen is consumed rapidly by actively metabolizing plant cells. As the silo becomes anaerobic, rising amounts of organic acids are formed, resulting in
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Organic dusts Grain, hay, Animal confinement Asthma, asthma-like endotoxin, areas, barns, silos, syndrome, ODTS,1
silage, cotton, harvesting and HP, chronic animal feed, processing bronchitis microorganisms operations
Inorganic dusts Silicates Field work, harvesting Pulmonary fibrosis, /tiling of soil chronic bronchitis
Gases Ammonia, hydrogen Animal confinement Asthma-like sulfide, nitrogen facilities, manure syndrome, oxides, methane, CO pits, silos, fertilizers tracheobronchitis,
silo-filler’s disease, pulmonary edema
Chemicals: Organophosphates, Applicators, field Bronchospasm, Pesticides paraquat, fumigants work pulmonary edema,
pulmonary fibrosis Fertilizers Anhydrous ammonia Application in Mucous membrane
fields, storage irritation, containers tracheobronchitis
Disinfectants Chlorine, quaternary Dairy barns, hog Respiratory irritant, compounds confinement areas bronchospasm
Solvents Diesel fuel, pesticide Farm vehicle Mucous membrane solutions exhaust, storage irritation, chronic
containers effects Welding fumes Ozone, metals Welding operations Bronchitis, metal fume
fever, emphysema Zoonotic infections Microorganisms Animal husbandry, Q fever, psittacosis,
veterinary services, hantavirus animal droppings pulmonary
syndrome, anthrax
1HP, hypersensitivity pneumonitis; 2 ODTS, organic dust toxic syndrome. Source: From Kirkhorn and Garry (7), with permission from Environmental Health Perspectives.
lowering of the pH (acidification) with suppression of microbial overgrowth and prevention of spoilage. As a result, nitrogen oxides (nitric oxide, NO, or nitrogen dioxide, NO2) are generated during fermentation of silage. Nitrogen oxides (NOx) are dangerous chemical gases released from reactions between nitric acid and organic materials. They are severe respiratory irritants of low solubility that penetrate to the lower respiratory tract. When levels of NOx rise in a closed tower silo, the levels of NO2/NOx may rise progressively in the following 1 to 4 days. During this period, the silo becomes a major hazard for any worker without respiratory protection who enters the silo or works in buildings connected to the base of the silo. Fatal exposures by inhalation of silo gas can occur in this setting. Acute high-level exposure can be a cause of acute hemorrhagic pulmonary edema and death. In addition to the potential for exposure to fatal asphyxia secondary to NO2 and other oxides of nitro- gen, less severe exposure to nitrogen oxides produces transient pulmonary decompensation, cough, dyspnea, and headaches. Long-term pulmonary consequences can occur secondary to fibrotic scarring (7,8,11,12).
The generation of toxic silo gases can occur unpredictably despite adherence to usual work practices. Although the potential for silo gas formation exists with any type of ensiled feed, the risk appears to be highest with corn silage (8,13).
Animal Confinement Gases and Other Gases Animal confinement areas and larger confinement animal facility operations (CAFOs) consist of indoor areas that confine and feed animals and do not grow or store grain. Animals are typically gathered in large numbers to maxi- mize efficiency of space and labor. This practice first became widespread in poultry farms but eventually has been used in other animal confinement areas, such as for raising swine, sheep, and young beef cattle. Animals typically receive all required care in the confinement areas, including feeding, washing, and veterinary services, and may spend their entire lives in these areas. The density of animals in these areas can vary, but generally they are very crowded. A concentrated animal feeding operation can house over 1000 animals (1).
Toxic inhalation exposures in animal confinement facilities are possible with exposures to gases produced from the manure pit. High levels of gases are generated as a by-product of animal waste, especially in high-density con- finement facilities such as with swine. The major gases include ammonia, hydrogen sulfide (H2S), carbon dioxide, and methane, which are all produced in manure pits (14,15).
Ammonia
Ammonia is highly water-soluble and associated with upper airway irritation producing immediate symptoms of burning of eyes, nose, and throat, accom- panied by coughing. The odor of ammonia is detectable at 3 to 5 ppm and respiratory irritation at 50 ppm. Sinusitis, mucous membrane inflammation
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syndrome, with massive inhalation exposures, and noncardiogenic pulmonary edema can result from exposure. Tolerance to ammonia can occur over time, leading to less irritant symptomatology with greater exposure. Possible effects of long-term exposure (i.e., greater than 2 hours per day for up to 6 years) include sinusitis, mucous membrane inflammation syndrome, chronic bron- chitis, and asthma-like syndrome (7,16,17).
Anhydrous Ammonia
Anhydrous ammonia (NH3) is also common in agriculture and is stored as a liquid and then injected into soil to add nitrogen as fertilizer. It is a highly irritating gas that is very water-soluble. Exposures have resulted in severe burns, laryngeal edema, as well as pulmonary effects including bronchiolitis obliterans and reactive airways dysfunction syndrome (18,19).
Hydrogen Sulfide
Hydrogen sulfide (H2S) gas is produced from sulfur-containing compounds in manure contained within an anaerobic environment. It is a respiratory irri- tant at low concentrations and a chemical asphyxiant at high concentration. A concentration of 20 ppm produces mucous membrane irritation; levels of 100 ppm can cause lung injury and bronchiolitis. Higher concentrations may cause asphyxia via inhibition of cytochrome oxidase, similar to the effects of cyanide. Levels of 250 ppm can cause pulmonary edema, and unconscious- ness and death can occur at 500 ppm. However, at levels of 150 ppm or higher, olfactory fatigue and paralysis occur. Exposed persons are not able to detect the presence of the gas, leading to fatal exposures. Agitation of manure during emptying of manure pits can generate concentrations of H2S as high as 1000 ppm into breathing zones of humans and animals. Open-storage manure pits and lagoons are less dangerous than deep pits that are enclosed. Accidental death due to H2S asphyxiation or cardiogenic pulmonary edema, although rare, can occur with exposures in swine or dairy confinement build- ings with under-building manure pits (7,20,21).
Treatment of acute H2S exposures is with nitrites, which facilitates removal of sulfides by inducing methemoglobinemia. However, nitrates may not be helpful after the acute injury period. Complete recovery may occur after exposure to H2S although some have suggested the possibility of residual central nervous system toxicity (14,22,23).
Carbon Monoxide
Carbon monoxide (CO) is generated from the operation of gas-powered equip- ment such as kerosene heaters in insufficiently ventilated buildings. As the gas is invisible and odorless, toxic levels may develop in as little time as 3 to 5 minutes, resulting in poisoning. Higher-level exposures can result in coma, cardiac toxic- ity, respiratory arrest, and long-term neurologic sequelae and death (20,24).
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Carbon Dioxide and Methane
Carbon dioxide (CO2) and methane (NH4), also generated from animal wastes, are simple asphyxiants. Unlike H2S, they are generally not primary causes of adverse health effects. However, methane and carbon dioxide are hazardous when they displace enough oxygen to cause asphyxiation. At lev- els above 5%, methane can be a potential explosive hazard. CO2 is also pro- duced by animal respiration. Co2 levels serve as an indicator of ventilation with acceptable levels typically below 5000 ppm (7,17).
Fumigants
Fumigants are chemicals used to eliminate pests and are applied to crops, grain, or grain storage facilities. Since they are volatile, rapid dissipation occurs and little or no trace is left on the crops or grains. Methyl bromide and phosphine are two common fumigants. Methyl bromide is very toxic and may cause pulmonary edema and hemorrhage after acute exposures. Phosphine is produced from aluminum phosphide pellets that are added to grain and is very reactive, unstable, and toxic. Some have suggested that fumigant expo- sures may lead to chronic lung disease (14,25,26).
Exposure to Dusts
Inorganic Dusts Agricultural work is generally performed outdoors. Major outdoor work activities leading to dust and chemical exposure by farm workers include preparation of soil for field crops, growing, harvesting, transport, storage of agricultural products, and fieldwork activities such as plowing, tilling, and haying. Fieldwork also has the potential to expose agricultural workers to inorganic dusts as well as various pesticides and chemicals. Exposures may be particularly significant in dry, semiarid, and desert climates and under windy conditions. The bulk of inorganic dusts are composed of silicates. These include crystalline silica (quartz) and noncrystalline amorphous silica (diatomite). Dust samples from outdoor agricultural environments may be composed of approximately 10% to 20% or greater concentrations of crys- talline silica. Workers performing fieldwork may develop clinically significant exposures to various silicates including respirable fibrous minerals and to nonfibrous silicate materials, including mica and clay silicates, known to cause pulmonary fibrosis (27–30).
Airborne mineral dust concentrations and exposure potential may vary with many environmental variables, such as regional geological and climate condi- tions, amount of rainfall, type of crops grown, and the specific agricultural practices employed. Aerosolized dusts with a median diameter of 4 to 5µm or less can penetrate deep into the respiratory system and have pathophysiological
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effects after deposition in the gas-exchange areas of the terminal bronchioles and alveoli (12,17).
In general, inorganic dusts do not contribute to agricultural respiratory disease to the same degree as organic dusts. However, occupational exposures to mineral particles from inorganic dusts and crystalline silica may stimulate release of reactive oxygen species (ROS) in the lung. Reactive oxygen species may play a key role in the mechanisms of disease initiation and progression subsequent to inhalational exposures to these particles. In fact, multiple path- ways may be facilitated to produce ROS, which may lead to inflammation, resulting in production of diseases such as pneumoconiosis and carcinogen- esis (31).
Organic Dusts Several work environments have the potential for organic dust exposure including agricultural fields, grain handling and storage areas, animal con- finement areas, and dairy barns. Grain handling and storage has been asso- ciated with respiratory symptoms and illnesses (such as chronic cough, sputum production, chronic bronchitis, grain fever (organic dust toxic syn- drome), and nasal and skin irritation in exposed workers. Similar findings were found in several global areas. Grain elevator workers frequently report symptoms such as cough, sputum production, wheezing, and dyspnea, and have obstructive or restrictive impairments on pulmonary function testing. Respiratory symptoms and worsening of ventilatory function have also been reported with workers exposed to dusts from soybeans and burned rice husk in rice farmers. Growing crops such as rice, soybeans, and flowers has been associated with lung disease (32–43).
Work in dairy barns is also related to respiratory illness. Hay and preserved grasses or corn (silage) are generally used to feed cows in dairy barns and may be a significant source of organic dust exposure to varying degrees based on the mechanism of preparation and storage. Rates of allergic alveolitis were found to be high in workers exposed to hay in small, tightly closed barns. Increased respiratory symptoms have been observed in workers in Finland who shake out hay to feed cows in dairy barns. Another source of exposure in the barn is the bedding chopper, which uses a series of rotating blades to cut bales of hay into smaller lengths, which are then blown into animals’ stalls to serve as bedding. This practice can aerosolize hay and create signifi- cant amounts of respirable dust (44,45).
In addition, possible additive and/or synergistic toxic exposures and respi- ratory health effects may occur with dust exposure with coexistent toxic gases, especially in confined work spaces (12,19).
Major components of organic dusts include substances derived from bac- terial and fungal organisms such as endotoxin from gram-negative bacteria, peptidoglycans from gram-positive bacteria, glucans, and mold and myco- toxins from fungi. Biologically active proteins of organic dusts may be aller-
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genic and proinflammatory. Endotoxin from gram-negative bacteria has been particularly found to be an important causative agent in producing respira- tory illness. Recent insights into the innate immune system from genetic research may help elucidate the biological mechanism(s) related to respira- tory health effects from endotoxin and other inhaled toxins. The Toll-like group of receptors (TLRs) are receptors for specific components of pathogens such as lipopolysaccharide (LPS), peptidoglycan, and others. It appears that genetic variation in TLRs influences the response to inhaled endotoxin. Thus, variable pulmonary responses in individuals exposed to organic dusts may be due to polymorphisms in the TLR genes. For example, it has been demonstrated that common missense mutations in the Toll-like receptor 4 (TLR4) are associated with a blunted response to inhaled LPS (endotoxin). Consequently, some individuals may be more susceptible than others when exposed to organic dusts. Some authors have also suggested that grain dusts and extracts of grain dusts may play a role in activating inflam- mation in the lung independent of endotoxin, and that this mechanism may also involve the TLR receptors (46–50).
Mucous Membrane Inflammation Syndrome
Nasal, eye, and throat symptoms commonly found in animal confinement workers and other workers exposed to dusts and gases have been given the name mucous membrane inflammation syndrome. Nasal symptoms occur in up to 50% and sinusitis in 25% of swine confinement workers. Nasal lavages have demonstrated increased levels of interleukin-1α, interleukin-1β, and interleukin-6 (7,17)
Organic Dust Toxic Syndrome
Organic dust toxic syndrome (ODTS) describes a self-limiting noninfectious, febrile illness accompanied by malaise, chills, myalgia, nonproductive cough, dyspnea, headache, and nausea, which occurs approximately 4 to 12 hours after heavy exposure to organic dust with a high attack rate. Prior sensitiza- tion is not required as in hypersensitivity pneumonitis. Organic dust toxic syndrome is also known as silo-filler’s disease, grain fever, precipitin-negative farmer’s lung, toxic alveolitis, and pulmonary mycotoxicosis. Organic dust toxic syndrome is highly prevalent in swine confinement operations, with a prevalence of approximately 30% to 35%. However, ODTS has also been observed after unloading silos, removing grain from storage bins (especially with grain sorghum), and on mushroom farms. Estimates indicate that up to one third of farmers will experience an episode of ODTS at some time in their work lives. Other surveys indicate an incidence of 6% to 36% in farmers and agricultural workers at any given time (47–60).
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Etiology As organic dust is composed of a variety of respirable organic materials, it is not clear what specific entity is responsible for OTDS. Endotoxin has been suggested to be the primary cause of inflammation in ODTS. Inhalation of endotoxin can reproduce the symptoms of ODTS, and acute ODTS episodes occur in areas of high endotoxin levels. However, endotoxin-free grain extract also appears capable of inducing pulmonary inflammation. Others have sug- gested that other microbial sources, such as spores and glucan, are important in the pathogenesis (14,50,61–68).
Pathogenesis Although it is unclear, ODTS does not appear to elicit a specific immune response to a specific antigen as may occur during an allergic response. Fur- thermore, sensitization does not occur in ODTS, and the condition is non- progressive and resolves within several days. However, some individuals have developed respiratory failure secondary to having ODTS.
Clinical Presentation and Diagnosis Approximately 4 to 12 hours after heavy exposure to organic dust, ODTS presents with fever, chills, malaise, nonproductive cough, dyspnea, myalgias, and headache. Leukocytosis may be found on a laboratory exam. Chest x-ray findings may be normal. Severe cases may present with infiltrates on chest x- ray and respiratory failure. Some authors have suggested an association of a history of ODTS symptoms with chronic bronchitis (43,69,70).
Management Most cases of ODTS are treated with antipyretics and supportive care, although hospitalization may be required for severe cases. Preventive strate- gies such as use of respirators would help in work-practice situations where exposure to high levels of dust may occur (69).
Hypersensitivity Pneumonitis
Etiology Also known as “farmer’s lung” and “extrinsic allergic alveolitis”, hypersensi- tivity pneumonitis (HP) is caused by exposures to specific fungi found in moldy hay, straw, and feed. In addition to moldy feed, exposure to moldy compost, wood chips, sugar cane (bagasse), composting in mushroom grow- ing, and turkey farming can lead to HP. Hypersensitivity pneumonitis is
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much less likely to occur in settings with organic dust exposure compared to ODTS. The overall prevalence of HP is variable and varies with climate.
Studies cite an incidence range from 2 to 3 cases per 10,000 farmers in Swe- den, to 4.2 per 10,000 in Wisconsin, to 43.7 per 10,000 in France (45,71,72).
Pathogenesis Hypersensitivity pneumonitis is a complex disease that has elements of an immunological and cell-mediated allergic response that develops in response to exposure to antigens produced by some species of thermophilic actino- mycetes, such as Micropolyspora faeni, Aspergillus, and other common fungi found as contaminants of grain or hay (73–75).
Ongoing exposure to antigen in sensitized individuals may lead to either a production of antigen-antibody complex (suggesting a type III reaction), or a late-phase cell-mediated response with granuloma formation compatible with a type IV reaction. The immunological response in HP requires prior sensitization and involves recruitment and activation of alveolar neutrophils and macrophages and T-lymphocyte cells. It appears that genetic and envi- ronmental interaction plays an important role in HP.
Risk factors for HP appear to be a –308 polymorphism of the tumor necrosis factor-α (TNF-α) promoter gene and polymorphisms of the major histocompatibility complex (74).
Clinical Presentation The acute presentation of HP occurs after a single large exposure to antigen. Acute symptoms commence typically after 4 to 6 hours of exposure and con- sist of fever, chills, malaise, chest tightness, cough, and dyspnea. Physical exam findings are nonspecific but may include inspiratory crackles on aus- cultation. Hypoxia may be…