Forensic Medicine
Solvents and Kidney Disease:

Scientific Methodology Between Solvents
& Kidney Disease Symptoms

By Nachman Brautbar, M.D.

Dr. Brautbar specializes in Internal Medicine, Nephrology, Toxicology, Pharmacology, and Occupational Medicine. He is a Clinical Professor of Medicine at the University of Southern California, School of Medicine, teaching medicine, and actively engaged in the practice of medicine. Dr. Brautbar is a member of the American Society of Toxicology, American College of Toxicology, and American Society of Internal Medicine. He has published over 240 scientific peer reviewed papers and book chapters in the fields of Toxicology, Pharmacology, Internal Medicine, Immunology and Nephrology. Dr. Brautbar is a Treating Physician, QME, AME, and a Fellow of the Collegium Ramazzini. Dr. Brautbar has testified as an expert in some major toxic torts nationally. He has served as Chairman of the Department of Medicine, Utilization Review, and Quality of Care committees. He has recently testified in the California State Senate and House on water contamination issues, and lectured at the National Judicial College to State Judges from across the country on the issues of causation and scientific evidence.

Introduction
Industrial solvents constitute an indispensable ingredient of modern living. The principal class of components are the chlorinated and non-chlorinated hydrocarbons. In recent years case reports, case studies and experimental animals studies demonstrated that solvents are causing a variety of kidney disorders including acute and chronic kidney failure. The major routes of absorption of these compounds are through the lungs and the skin. Once in circulation, these compounds are concentrated in the kidney by mechanism remains uncertain but may be related to a solvent-induced disruption of the structural and functional integrity of the limited membranes of the kidney cells. A number of studies have demonstrated that solvent exposure is associated with an increased risk in the development of chronic kidney disease (glomerular disease) through immune mediated mechanisms. Epidemiological studies have shown that, in the United States, 3,373,000 patients are exposed to solvents and among those exposed are patients who have underlying conditions such as diabetes, immunological abnormalities, and hypertension.(1)

This article will discuss the scientific data in relation to solvents and kidney disease symptoms. The effects of industrial solvents on the kidneys is divided into acute (immediate) and chronic kidney disease.

Case Reports
The earlier documentation of renal disease and hydrocarbon exposure consists of case reports. Churchill,(2) et al, recently summarized this data describing 15 adults (12 males) with Goodpasture's syndrome or anti-glomerular basement membrane (GMB) disease. There were five cases of epimembranous glomerulonephritis and 1 adult with subacute glomerulonephritis. The ages ranged from 17-59 years. The hydrocarbon exposure included gasoline, gasoline-based paint spray, jet fuel, mineral turpentine. These case reports describe an observed association between hydrocarbon exposure and renal disorder.

Case Controls Studies
Case control studies are studies involving analysis of a group of subjects with the disease under study (cases) and a comparable group without the disease (controls) and then looking back retrospectively to determine whether there has been a differential exposure to an etiologic factor some point/period in the past. Several good case control studies have examined the role of organic solvent exposure in a population of patients with glomerulonephritis. Seven of these studies demonstrated a significant association between hydrocarbon exposure and the development of glomerulonephritis. Daniel,(3) et al, in a recent review, was able to demonstrate a 2.8 to 8.9 fold increase in the estimated risk of developing glomerulonephritis with hydrocarbon exposure. This study by Daniel showed a dose-response relationship and variations in the disease severity in relation to exposure intensity and the absence of alternative explanations for the association providing support for the conclusion from this study.

Askergren(4) has examined kidney functions in subjects exposed to organic solvents. He has studied the excretion of red blood cells in the urine in 101 professionals exposed to solvents such as styrene or toluene or to a combination of xylene and toluene, and compared them to 39 non-exposed controls. The men exposed to organic solvents excreted significantly more cells than the controls. These findings clearly indicate the role of organic solvents exposure in the development of glomerular kidney disease since the excretion of red blood cells in these patients came only from one source and this is the glomerulus of the kidneys.

The study by Bell,(5) et al, has examined exposure to organic solvents in 50 patients with biopsy proven proliferative glomerulonephritis in whom there was no evidence of systemic disease or preceding infection with that of 100 control subjects matched the age, sex and social class. Exposure scores were derived from the results of questionnaires which were significantly greater in the patients with glomerulonephritis compared to the control subjects, statistical significance of P < 0.01. The degree of exposure was higher in those patients with more severe glomerulonephritis than in those with less severe glomerulonephritis. In the glomerulonephritis patients, solvent exposure was mainly occupational in origin and involved fuels, paints, and degreasing agents in most cases. This occupational exposure was significantly greater that in the control subject groups. This study not only showed a significant statistical association but also showed a dose response which is one of the important determinants of risk analysis and causation in forensic medicine. The study by Churchill,(2) et al, is comparable to the study by Bell,(5) et al, and shows not only a strong statistical association between exposure to solvents and kidney disease, but also a dose-response relationship.

Harrison,(6) et al, in a retrospective analysis of a general population divided the patients into two groups: one with high exposure to organic solvents and heavy metals, and the other group with low exposure. There was a statistically significant increase (8.9-fold) in the number of cases of kidney disease (membranous glomerulonephropathy) in the high-exposure group.

The most recent elegant analysis of the scientific literature, De Broe,(7), et al, have concluded that the relation between hydrocarbon exposure and glomerulonephritis seems to be well-defined from an epidemiological point of view. They also showed, in a controlled study, that patient's who have underlying diabetes with diabetic nephropathy and exposure to hydrocarbons showed a significantly increased incidence of deterioration of the renal failure as compared those with diabetes and without exposure to solvents. The following table summarizes the scientific literature to date, addressing solvents and chronic kidney disease.

Epidemiological Analysis
Landrigan, et. al(1), studied the epidemiology of chronic renal failure and stated that the current annual incidence in the United States is 60/million for males and 40/million for females. They further analyzed the epidemiological diagnostic criteria and concluded that for most cases with end-stage renal failure no etiologic information is available. Fewer than 10% of the end-stage renal disease cases are characterized etiologically (such as lead toxicity, diabetic nephropathy, analgesic nephropathy, ect.) In many instances patients are classified histologically such as glomerulonephritis but little attempt is made in most cases to seek possible toxic contributory factors. Many patients are listed as hypertensive nephrosclerosis and are presumed to be idiopathic in origin, however these cases may very well be the result of other industrial factors. Dr. Landrigan goes further to state that in large part the explanation for this lack of etiology in the majority of the end-stage renal failure patients is that exposure to nephrotoxics typically goes unnoticed.

The studies by Stengl,(20) et al, examined organic solvent exposure and the risk of IgA nephropathy. These investigators have shown that the risk of IgA nephropathy is highest among the most exposed group to oxygenated solvents. The studies by Yaqoob,(21) et al, showed an increased risk factor of 15.5 for development of glomerulonephritis in patients exposed to aliphatic hydrocarbons and a risk factor of 5.3 for patients exposed to halogenated hydrocarbons.

Lagrue(22) has studied 108 patients with nonsystemic chronic glomerulonephritis, 56 hypertensives without kidney involvement, and has shown significant correlation with the exposure to solvents. Zimmerman,(8) et al, have shown that patients with biopsy confirmed primary proliferative glomerulonephritis had a three fold greater average solvent exposure than either control group used. This is a fine epidemiological study showing an increased risk and incidence of glomerulonephritis in solvent exposed populations as compared to non-exposed populations. Ravnskov,(11) et al, compared solvent exposure in 50 patients with biopsy confirmed glomerulonephritis and 2 control groups with 15 individuals with non-glomerular renal disease and 50 patients with appendicitis. Organic solvent exposure was estimated by interview and was measured using weekly hours of exposure, years of duration, and a weighing factor for intensity level. They have found a 3.9 fold increase in the odds of exposure for cases with glomerulonephritis and history of exposure to solvents on an industrial basis.

The epidemiological studies by Steenland,(23) et al, have looked at risks and causes of end-stage renal disease and concluded that regular exposure to industrial solvents played a significant role in the development of chronic endstage kidney disease. They have done a very nice analysis of the various occupations exposed to solvents and their risk analysis utilizing odd ratio factor and showed that solvents used in paints and in glues, and solvents used as cleaning and degreasing agents, play a significant role from a risk factor, epidemiologically and statistically.

In summary, based on the case reports, case control studies and epidemiological studies the basic required scientific criteria for causal link between solvent exposure and chronic kidney disease is established, namely: 1) statistical association, 2) temporal relationship, 3) biological plausibility, 4) coherence of the observation, 5) dose response.(24)

Practical Points
Workers with a history of exposure to paints, glues, degreasing solvents, and cleaning solvents must be evaluated for renal and kidney effects. Such patients may not know of the risks of their exposure and may actually not understand the relationship between an exposure to kidney toxic solvent and the development of high blood pressure or in the worse case scenario the development of end-stage kidney failure Over and above, those patients who are seen for industrial orthopedic injuries and are treated with nonsteroidal antiinflammatory medications and have a occupational history of exposure to nephrotoxic solvents must be evaluated for any potential damage from the synergistic nephrotoxic effects of nonsteroidal antiinflammatory medications given to treat the orthopedic injury and the history of industrial exposure to solvents. In other words, the history of industrial exposure to solvents may have produced a situation where the nonsteroidal antiinflammatory medications will be the final blow to the already compromised kidney or injured kidney by the solvents. Finally, those of us who see patients with asymptomatic kidney disease, hypertension, and early renal disease must perform an evaluation to begin with by taking an outstanding occupational history, thorough performance of renal functions including but not limited to urinalysis, creatinine clearance and a renal ultrasound on a given case.

Case Report
I thought that giving an actual case would demonstrate how real this situation is.

A 30-year old patient who was employed at a metallurgic factory for 15 years was seen for evaluation of end-stage kidney disease. The patient gave a history of daily exposure over the period of employment to paint thinners utilized in spray guns, glues, and degreasing agents, without the provision of protective devices such as a respirator and gloves. He described daily exposure, anywhere from 4-8 hours per day. He described the symptomatology of dizziness, headaches, and feeling like "drunk" when inhaling these vapors from the spray painting, (something typically and classically described by painters exposed to these solvents).

Some 5 years prior to his evaluation, he was found to have borderline hypertension and 1 year later developed difficulty breathing and was diagnosed as having kidney disease. The kidney disease deteriorated and the patient ended with end-stage renal failure on dialysis. His past medical history is essentially unremarkable, there is no evidence of preexisting hypertension, cardiovascular disease, diabetes mellitus, and there is no preexisting history of drug abuse, alcoholism or medication abuse. His family history is essentially unremarkable. Prior to the 15 years of employment with the company, the patient worked at a cable company but was outside and was not exposed to solvents or other known kidney toxic agents.

A differential diagnosis was performed and systemic diseases such as collagen vascular disease, diabetes mellitus, vascular disease, amyloidosis, lead toxicity, and silica toxicity have essentially been ruled out. A kidney biopsy proved chronic glomerulonephritis, most likely membranoproliferative glomerulonephritis. Based on the absence of preexisting renal disease, absence of systemic diseases, absence of diabetes mellitus, absence of drug abuse, absence of lead exposure, and the strong history of solvent exposure with solvents known to be toxic to the kidney such as xylene, toluene, trichloroethene, hexane, and poly aromatic hydrocarbons, it was the opinion that the patient's glomerulonephritis was industrial.

His dialysis treatment, hospitalization, and future medical care, including renal transplantation are industrial and he is totally and permanently disabled. No apportionment was indicated. The prognosis is fair. Patients at this age stand a good chance of undergoing renal transplantation and being able to go on for anywhere between 15 to 25 years depending on any intercurrent complications which may occur. On some occasions more than one renal transplant may be required, something which must be taken into account by counsel and, personally, I commonly recommend an estimated cost for rendering the care prior to renal transplantation, during and post-transplantation, and the cost of future renal transplantation.

Conclusion
The data presented above supports the concept of industrial solvent exposure and the development of chronic kidney disease in the form of a specific glomerulonephritis. The evaluating physician must have a knowledge of kidney pathology and physiology to be able to differentiate between the many common non-solvent-related kidney diseases such as hypertensive kidney disease, diabetic kidney disease and others. A kidney biopsy, if available, is helpful in the diagnosis. Finally, an accurate detailed history of exposure, exposure description by either measurement or inference from symptoms, and detailed material safety data sheets (MSDS) must be available before any opinion can be provided. Finally, the issue of AOE/COE must be addressed carefully after the examining physician has reviewed the above mentioned data and ruled out all other probable causes of glomerulonephritis.

Acknowledgement
The author wishes to thank Michael Wu for his help with this manuscript.

References

1. Landrigan P, Goyer RA, Clarkson TW, Sandler DP, Smith, JH, Thun MJ, Wedeen RP, The Work-Relatedness of Renal Disease, Archives of Environmental Health, May/June, 39(3):225-230, 1984).
2. Churchill DN, Fina A, Gault MH, Association Between Hydrocarbon Exposure and Glomerulonephritis: An Appraisal of the Evidence, Nephron 33:169-172, 1983.
3. Daniell WE, Couser WG, Rosenstock L, Occupational Solvent Exposure and Glomerulonephritis: A Case Report and Review of the Literature, JAMA, April 15, 259(15):2280-2283, 1988.
4. Askergren A, Studies on Kidney Function in Subjects Exposed to Organic Solvents, III: Excretion of Cells in the Urine, Acta Med Scand, 210:103-106, 1981.
5. Bell GM, Gordon ACH, Lee P, Doig A, MacDonald MK, Thomson D, Anderton JL, Robson JS, Proliferative Glomerulonephritis and Exposure to Organic Solvents, Nephron, 40:161-165,1985.
6. Harrison DJ, Thomson D, MacDonald MK, Membranous Glomerulonephritis, J Clin Pathol, 39:167-171, 1986.
7. De Broe ME, D'Haese PC, Nuyts GD, Elseviers MM, Occupational Renal Diseases, Current Opinion in Nephrology and Hypertension, 5:114-121, 1996.
8. Zimmerman SW, Groehler K, Beirne GJ, Hydrocarbon Exposure and Chronic Glomerulonephritis, Lancet, ii:199-201, 1975.
9. Lagrue G, Kamalodine T, Guerro J, Hirbec G, Zhepova F, Bernaudin JF, Nephropathies glomerulaires primitives et inhalation de substances toxiques. J Urol Nephol, 4-5:323-329, 1977.
10. Ravnskov U, Exposure to organic solvents — a missing link in post-streptococcal glomerulonephritis. Acta Med Scan, 203:351-356, 1978.
11. Ravnskov U, Forsbergg B, Skerfving S, Glomerulonephritis and exposure to organic solvents: A case control study. Acta Med Scand, 205:575-579, 1979.
12. Finn R, Fennerty RG, Ahmad R, Hydrocarbon exposure and glomerulonephritis. Clin Nephrol, 14:173-175, 1980.
13. Van der Laan G, Chronic glomerulonephritis and organic solvents, Int Arch Occup Environ Health, 47:1-8, 1980.
14. Ravnskov U, Lundstrom S, Norden A, Hydrocarbon exposure and glomerulonephritis: Evidence from patients occupations, Lancet, ii:1214-1216, 1983.
15. Lague G, Kamalodine T, Hirbec G, Bernaudin JF, Guerro J, Zhepova F, Role of inhalation of toxic substances in the pathogenesis of glomerulonephritis. Nouv Press Med, 6:3609:3613, 1977.
16. Porro A, Lomonte C, Coratelli P, Passavanti G, Maria Ferri G, Assenato G, Chronic glomerulonephritis and exposure to solvents: A case referent study. Brit J Ind Med, 49:738-742, 1992.
17. Yaqoob M, Bell GM, Percy D, Finn R, Primary Glomerulonephritis and Hydrocarbon Exposure: A Case Control Study and Literature Review, Quart J Med, 301:409-418, 1992.
18. Yaqoob M, Patrick AW, McClelland P, Stevenson A, Mason H, Percy DF, White MC, Bell GM, Occupational hydrocarbon exposure in diabetic nephropathy, Diabet Med, 11:789-793, 1994.
19. Nuyts GD, Van Viem E, Thys J, De Leersnijder D, D'Haase PC, Elseiviers MM, De Broe ME, New occupational risk factors for chronic renal failure, Lancet, 346:7-11, 1995.
20. Stengel B, Canee S, Linasset JC, Protois JC, Marceli A, Brochard P, Haomon D, Organic Solvent Exposure may increase the risk of glomerular nephropathies with chronic renal failure. Int J Epidem, 24:427-434, 1995.
21. Yaqoob M, Bell GM, Percy D, Finn R, Primary Glomerulonephritis and Hydrocarbon Exposure: A Case Control Study and Literature Review, Quart J Med, 301:409-418, 1992.
22. Lagrue G, Hydrocarbon Exposure and Chronic Glomerulonephritis, Lancet, i:1191, 1976.
23. Steenland, NK, Thun MJ, Ferguson BA, Port FK, Occupational and Other Exposures Associated with Male End-Stage Renal Disease: A Case Control Study, AJPH, 80(2):153-156, 1990.
24. Hill AB. The Environment and Disease: Association or Causation? President's Address. Proceedings Royal Soc Med., 9:295-300, 1965.

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