Case Report

Case Report: Pulmonary Interstitial Fibrosis Associated with Inhalation Exposure to Aviation Fuels

Charles A. McKay MD, Katherine Hart MD, Munawar Siddiqi MBBS,
Mary A. McCormick PharmD, Marc J. Bayer MD
Division of Medical Toxicology, Department of Traumatology and Emergency Medicine
University of Connecticut School of Medicine a

Int J Med Toxicol 2001; 4(3): 20



This case report is supported by an unrestricted educational grant from
Orphan Medical, Inc.   For more information, please call 1-888-8ORPHAN.

Presented in part at the European Association of Poison Centres and Clinical Toxicologists (EAPCCT) meeting, Dublin, Ireland, 1999.

Address for Correspondence
Charles A. McKay, MD
Director, Medical Toxicology
Hartford Hospital
80 Seymour St
Hartford, CT 06102-5037
E-mail: cmckay@harthosp.org

ABSTRACT

Inhalation exposure to jet fuels causes pulmonary interstitial fibrosis in rats. Pulmonary fibrosis following exposures to petroleum distillates has also been demonstrated in humans. We report a case of a 46-year-old man exposed to aviation fuel (JP-4 and JP-8) by inhalation during 21 years of employment. He developed pulmonary interstitial fibrosis documented by lung biopsy. We review diagnostic criteria for causation in this example of association of pulmonary interstitial fibrosis with chronic jet fuel inhalation.

(Key words: pulmonary interstitial fibrosis, hydrocarbons, jet fuel, JP-4, JP-8, causation).

INTRODUCTION

A number of jet fuels are used by the military, including JP-4, JP-5, JP-7, and JP-8 (jet propellant 4, 5, 7 and 8, respectively). JP-4 is refined from either crude petroleum or shale oil. JP-7 and JP-8 are refined kerosene, a product of refined crude petroleum. These fuels are complex mixtures of aromatic and aliphatic hydrocarbons, and various additives. Both military and commercial aircraft personnel involved with refueling, testing and handling of the jet fuel are at risk for exposure to vapors withfrom both known and postulated health hazards. Neuropsychiatric effects, hepatotoxicity and renal damage are well recognized, as are respiratory irritant effects. Evidence for structural pulmonary change is provided by animal models, which highlight some of the functional and histologic changes resulting from inhalation exposure to jet fuels.

CASE REPORT

A 46-year-old white male presented to the Medical Toxicology Clinic with a biopsy proven diagnosis of idiopathic pulmonary fibrosis. He sought our opinion as to the relationship of his pulmonary disease to a 21-year workplace exposure to fumes and vapors from aviation fuels. His chief complaint was dyspnea on exertion, such as playing basketball or climbing a flight of stairs. He had been in excellent health until approximately nine months previously, when his wife and friends noted him to be short of breath on mild exertion. Six months prior to his clinic visit, he presented to an ambulatory care facility with symptoms of shortness of breath, cough, and fever to 103o F. He was diagnosed with bilateral pneumonia, admitted to the hospital for one week and treated with oxygen and intravenous antibiotics. Diagnostic testing done as an outpatient during the next several weeks included a repeat chest radiograph, pulmonary function tests (PFTs) and echocardiography. Chest radiographs showed persistent opacities, described as "bilateral peripheral, mid and lower lungs, predominant interstitial parenchymal disease" (Figure 1). The results of his PFTs revealed "evidence of a restrictive defect with altered gas exchange...consistent with interstitial lung disease." He was started on prednisone, which he continued to take. Four months prior to the clinic visit, a lung biopsy was performed. Two specimens collected from the right middle lobe and right lower lobe revealed "chronic interstitial pneumonitis and fibrosis, with honeycombing consistent with usual interstitial pneumonia." (Figure 2).

Five weeks after the biopsy (and three months prior to his clinic visit), his job was changed on medical advice to a new position in which he was not exposed to jet fuel vapors. He noted some improvement of his dyspnea over the ensuing months, although he continued to have dyspnea on exertion.

At the time of his clinic visit, review of systems was notable only for dyspnea and urinary frequency (which the patient attributed to excessive fluid intake). He had no significant past medical history or chronic illness prior to his presenting problem, took no medications on a regular basis other than the prednisone begun six months earlier, and had no known allergies. He had occasionally smoked over a period of five years as a teenager, but had quit more than twenty years ago. Alcohol consumption was two glasses of wine weekly, and he used no recreational drugs. His hobbies did not involve exposure to chemicals. He had traveled within the United States and Europe, his most recent travel abroad being to Germany two years previously. He denied any travel to Africa or Asia. He was married and lived with his wife and three children; his wife was a current smoker. There is a family history of carcinoma of the colon but no history of early onset arthritis, connective tissue disorders or pulmonary disease.

The patient worked as a fuel distribution system worker and foreman for twenty years and six months. His duties included distribution and quality control testing of a variety of jet and other aviation fuel products, including JP-4, JP-8, diesel fuel and mid-grade unleaded gasoline. For seven years of this period, he tested these fuels in a fuel pump house that lacked adequate ventilation. This 1300 square foot facility was documented to be out of compliance with Air Force Office of Safety and Health (AFOSH) standard 127-47 for a fuel testing laboratory. The patient estimated that he monitored up to 500 fuel samples monthly, handling some 3 million gallons of aviation fuel annually. There were ten documented spills with showering of fuel onto his face and body. He did not use respiratory or eye protection during his employment. The patient and two other individuals who were less involved with the work needed frequent fresh air breaks to recover from symptoms of headache, nausea and dizziness associated with this work. No measurements of ambient conditions or biologic monitoring of personnel for excretion of metabolites were done during the period of exposure.

Physical examination in the clinic was remarkable only for pulmonary findings of harsh vesicular breath sounds with occasional rhonchi and fine crackles at both bases. Cardiac examination revealed no gallop, and there was no cyanosis, clubbing or lymphadenopathy.

DISCUSSION

Pulmonary interstitial fibrosis is a chronic lung disease known by a variety of names, including idiopathic pulmonary fibrosis, interstitial pneumonia, chronic interstitial pneumonitis, Hamman-Rich syndrome, honeycomb lung and usual interstitial pneumonitis. The two commonly used terms are cryptogenic fibrosing alveolitis and idiopathic pulmonary fibrosis. It develops after an injury to the alveolar capillary basement membrane that results in increased permeability. This causes intracellular edema and inflammation, followed by fibroblast proliferation and excessive collagen deposition. The incidence of disease is approximately 3 to 5 cases per 100,000 persons. It is usually a disease of middle age. Patients typically present with insidious onset of breathlessness on exertion and a non-productive cough. Constitutional symptoms may be present. Physical findings may include bibasilar fine late inspiratory crackles on chest examination. Clubbing of the fingers is a late manifestation, found among 40-75% of the patients. Pulmonary hypertension and cor pulmonale are also late complications of the disease. Cyanosis is also a reflection of advanced disease. Exertional dyspnea with hypoxia is characteristic, although not specific.

There is no diagnostic laboratory test for this condition, although many abnormalities have been noted, including an elevated erythrocyte sedimentation rate, hypergammaglobulinemia, low titers for antinuclear antibodies, rheumatoid factor, circulating immune complexes and cryoimmunoglobulins. Chest radiography shows a reticular to reticulonodular pattern usually appearing as diffuse infiltrates with predilection for the lower lung zones. As the disease advances, a coarse reticular pattern or multiple cystic, honeycomb areas can be seen. Chest computerized axial tomography and gallium scans may show evidence of disease in the setting of normal chest radiographs.

Pulmonary function tests reveal a reduction in lung volumes, including total lung capacity (TLC), functional residual capacity (FRC) and residual volume (RV). Expiratory flow rates (one second forced expiratory volume, FEV1, and forced vital capacity, FVC) may be decreased because of the reduction in lung volume, but the FEV1 / FVC ratio is maintained. The diffusing capacity of carbon monoxide (DLCO) is reduced due to contraction of pulmonary capillary volume and the presence of ventilation perfusion abnormalities. The resting arterial blood gases are usually abnormal, revealing hypoxemia and respiratory alkalosis.

Associations have been made between many diseases or environmental exposures and the occurrence of pulmonary interstitial fibrosis in humans; these are listed in Appendix A. Of the numerous conditions listed, the only significant confounding exposure for our patient was an episode diagnosed as pneumonia several months before he presented to the clinic. However, the fact that his symptoms began months earlier makes this an unlikely etiologic source; it more likely represented an intercurrent illness developing in the setting of his pulmonary disease. History and review of the patient’s medical records suggested no other systemic illness or exposure to account for his condition.

ANIMAL STUDIES

Animal studies demonstrate pulmonary injury, including the development of pulmonary fibrosis, after exposure to jet fuel. Rats exposed to nebulized JP-8 fuel one hour daily for 7 and 28 days at aerosol concentrations of 495-520 mg per cubic meter developed pulmonary function changes suggesting disruption of epithelial cell integrity. This was demonstrated by differences in resistance, compliance and alveolar clearance of [Tc-99m]-diethylenetriamine pentaacetate. Rats inhaling JP-8 demonstrated depletion of substance P as well as decreased neutral endopeptidase (NEP)., These studies used an aerosol/vapor mixture to simulate military flightline exposure conditions. Another long-term inhalation exposure study in rats demonstrated progressive focal interstitial pulmonary fibrosis associated with irregular alveolar collapse after 6-12 weeks of exposure. In this study 40 rats were enclosed for 8 hours daily, five days per week in a box through which gasoline vapor was circulated at an average concentration of 100 parts per million. Pathologic changes were identified in 50% of the rats. ,

ANALAGOUS HUMAN EXPOSURES

Skyberg et al report seven cases of diffuse basal lung fibrosis among 25 cable workers exposed to the vapors of kerosene and oils. This kerosene contained 18-19% aromatic hydrocarbons, similar to the structure of JP-8. There was one case of fibrosis in their control group.

ASSOCIATION AND CAUSATION

It is often difficult to prove causation for associated events. Sir Austin Bradford Hill discussed a set of criteria to provide a reasonable framework to propose a causative relationship. Briefly, the nine characteristics include; (1) consistency of the association across different investigators, times or settings; (2) the strength of association as indicated by relative risk assessments in epidemiologic studies; (3) the specificity of the association; (4) the appropriateness of analogy to other similar chemicals or conditions; (5) the presence of temporality (in other words, the condition must occur after the exposure); (6) the presence of biological gradient (or dose response); and (7) the ability to experimentally produce the findings; finally, the association should not contravene any known biologic principles and should make sense. These last two criteria have been dubbed (8) coherence and (9) plausibility. As Hill stated, "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental question -- is there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect?"

Although Sir Bradford Hill proposed his criteria for the evaluation of association and causation on a population level, many of these principles can also be applied to the evaluation of a single case. Is a contention of causality between jet fuel inhalation and pulmonary fibrosis supported by Hill’s criteria? As mentioned earlier, pulmonary injury and fibrosis have been documented in several animal models of JP-8 inhalation and observed in a case control fashion with workers using other petroleum distillates. These features would satisfy criteria for consistency and analogy and demonstrate experimental production of the condition. The time course certainly seems to satisfy a temporality criterion. Extension of this observed association to the level of causation is both plausible and coherent in the context of pulmonary fibrosis initiated by alveolar capillary injury, which has been demonstrated experimentally at ambient concentrations approximating workplace exposures. The Occupational Safety and Health Administration (OSHA) lists an exposure limit for petroleum distillates of 400 parts per million (ppm), for an 8-hour workday, 40-hour workweek and 500 ppm for 15 minute exposures (short-term exposure limit – STEL). Reported measurements of JP-4 and JP-8 in various closed aircraft shelters during refueling or burning have ranged between 533-1150 mg/m3 (130-280 ppm) and 12-22 mg/m3 (3-5 ppm), respectively. , Dose dependence or dose response relationships (the biological gradient criterion) has been suggested in some of the animal studies above; however, no quantitative documentation of the patient’s exposure is available. The lack of previous reports of these symptoms in surveys documenting neurotoxic effects and hepatic injury would seem to detract from the strength of association and the absence of a true epidemiologic study precludes calculation of relative risk. Finally, if there is a causal relationship between jet fuel and pulmonary fibrosis, we cannot identify the specific jet fuel component(s) that is responsible from the current data.

CONCLUSION

We describe a patient with long-term exposure to volatilized aviation fuel with subsequent pulmonary interstitial fibrosis that meets many of the criteria for causation. We publish this in the hope that others will look for this association and be aware of this possible relationship. In the absence of strong evidence to the contrary, it is reasonable to minimize inhalation exposure or provide adequate respiratory protection to those working in an environment of jet fuel vapor.

REFERENCES:

  1. Crystal, RG, Bitterman, PB, Rennard, SI, et al. Interstitial lung diseases of unknown cause, disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 1984;310:154-166.
  2. Hays, AM, Parlimen, G, Pfaff, JK, Lantz, RC, Tinajero, J, Tollinger, B, and Hall, JN, Witten, ML. Changes in lung permeability correlate with lung histology in a chronic exposure model. Toxicol Ind Health 1995;11:325-336.
  3. Pfaff, J, Parton, K, Lantz, RC, Chen, H, Hays, AM, Witten, ML. Inhalation exposure to JP-8 jet fuel alters pulmonary function and substance P levels in Fischer 344 rats. J Appl Toxicol 1995;15:249-256.
  4. Pfaff, J, Tolinger, BJ, Lantz, RC, Chen, H, Hays, AM, Witten, ML. Neutral endopeptidase (NEP) and its role in pathologic pulmonary change with inhalation exposure to JP-8 jet fuel. Toxicol Ind Health 1996;12:93-103.>
  5. Lykke, AW, Stewart, BW. Fibrosing alveolitis (pulmonary interstitial fibrosis) evoked by experimental inhalation of gasoline vapours. Experientia 1978;34:498.
  6. Lykke, AW, Stewart, BW, O’Connell, PJ, Lemesurier, SM. Pulmonary responses to atmosphere pollutants, 1: An ultrastructural study of fibrosing alveolitis evoked by petrol vapour. Pathology 1979;11:71-80.
  7. Skyberg, K, Ronneberg, A, Kamoy, JL, Dale, K, Borgersen, A. Pulmonary fibrosis in cable plant workers exposed to mist and vapor of petroleum distillates. Environ Res 1986; 40:261-273.
  8. Hill, AB. The environment and disease: association or causation? Proc R Soc Med 1965:295-300.
  9. Agency for Toxic Substances and Disease Registry (ATSDR). 1995. Toxicological profile for jet fuels JP-4 and JP-7. Atlanta, GA:U.S. Department of Health and Human Services, Public Health Service.
  10. Agency for Toxic Substances and Disease Registry (ATSDR). 1996. Toxicological profile for jet fuels JP-5 and JP-8. Atlanta, GA:U.S. Department of Health and Human Services, Public Health Service. (draft)

Appendix A: Conditions or Factors Implicated in Human Pulmonary Interstitial Fibrosis

Primary Pulmonary Diseases

Idiopathic Pulmonary Fibrosis
  Sarcoidosis
  Bronchiolitis Obliterans – Organizing Pneumonia
  Lymphocytic Interstitial Pneumonia:
  - associated with hypogammaglobulinemic state
  - associated with hypergammaglobulinemic state
  - associated with Acquired Immunodeficiency Syndrome
  - associated with bone marrow transplantation
  Histiocytosis X:
  - Eosinophilic Granuloma
  - Letterer-Siwe Disease
  - Hand-Schuller-Christian Disease
  Lymphangioleiomyomatosis

Collagen-Vascular Diseases

Rheumatoid Arthritis
  Systemic Lupus Erythematosus
  Scleroderma
  Polymyositis – Dermatomyositis
  Sjögren’s Syndrome
  Mixed Connective Tissue Disease
  Ankylosing Spondylitis
  Systemic Sclerosis

Drugs and Therapeutic Interventions

Antibiotics (furantoin, sulfasalazine)
  Antiarrhythmic agents (amiodarone, tocainide, propranolol)
  Antiinflammatory drugs (gold, penicillamine)
  Anticonvulsants (phenytoin)
  Chemotherapeutic Agents
  Dietary Supplements (L-tryptophan)
  Therapeutic Radiation
  Oxygen
  Paraquat
  Crack Cocaine Inhalation
Occupational and Environmental Exposures Organic Dusts / Hypersensitivity Pneumonitis:
  - Farmer’s Lung
  - Air Conditioner / Humidifier Lung
  - Bird Breeder’s Lung
  - Bagassosis
  Inorganic Dusts:
  - Silicosis
  - Asbestosis
  - Coal Workers’ Pneumoconiosis
  - Berylliosis
  Gases / Fumes / Vapors:
  - Oxides of Nitrogen
  - Sulfur Dioxide
  - Toluene Diisocyanate
  - Oxides of Metals
  - Hydrocarbons
  - Thermosetting Resins

Alveolar Filling Disorders

Diffuse Alveolar Hemorrhage Syndrome
  Goodpasture’s Syndrome
  Idiopathic Pulmonary Hemosiderosis
  Pulmonary Alveolar Proteinosis
  Chronic Eosinophilic Pneumonia

Pulmonary Vasculitis

Wegener’s Granulomatosis
  Churg-Strauss Syndrome
  Hypersensitivity Vasculitis
  Necrotizing Sarcoid Granulomatosis

Inherited Disorders

Familial Idiopathic Pulmonary Fibrosis
  Neurofibromatosis
  Tuberous Sclerosis
  Gaucher’s Disease
  Neimann-Pick Disease
  Hermansky-Pudlak Syndrome

FIGURES

FIGURE 1: Chest X-Ray (PA and Lateral views) demonstrating increased interstitial markings

FIGURE 2: Photomicrographs of lung biopsy demonstrating thickened pulmonary septa with increased collagen deposition and inflammatory infiltration. a) 40X b) 100X



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