Send letter to journal:
Re: Will sewage workers with endotoxin-related symptoms have benefit of reduced lung cancer?

Dear Editor

Thorn et al.[1] reports that sewage workers suffer from various symptoms which can be related to bacterial endotoxin (lipopolysaccharide) exposure. Other studies[2-5] have shown that some members of this occupational group are commonly exposed to endotoxin. However, there appears to be a large discrepancy in endotoxin exposure among those categorized within this group.[2] Endotoxin exposure to some of these workers appears to be sufficient to induce a respiratory response characteristically associated with endotoxin.[2] Workers that have the highest exposure in sewage treatment are suggested to be associated with the waste treatment process.[3] Professor Rylander pointed out that endotoxin exposure to this occupational group is low overall [Personal Communication with Professor Rylander]. Rapiti et al.[6] suggested that the lack of an increased lung cancer rate in one study[7] and reduced risk of lung cancer in another[8] for sewage workers may be related to endotoxins in their occupational environment as was originally reported for cotton textile workers.[9] Other studies[10,11] that reported on lung cancer rates for sewage workers support these finding as suggested by Rapiti et al.[6] Rylander[12] and Lange[13] previously reviewed the epidemiological literature on reduced cancer rates in various occupations that are exposed to endotoxin.

A number of epidemiological,[12-16] experimental[17,18] and clinical[19,20] studies have suggested that endotoxin is effective against cancer. A recent study in humans by Palmberg[21] reported that there is a rapid blood response of total leukocytes, monocytes and granulocytes within seven hours followed by a dramatic decline within 24 hours. These findings are supported by a human investigation by O’Grady et al.[22] that instilled endotoxin into a lung segment and found increased tumor necrosis factor (TNF) and IL-1 in the broncho-alveolar lavage fluid 2 to 6 hours afterwards. Cytokine levels returned to normal concentrations within 24 to 48 hours after treatment. An increase of TNF in lung fluids as a result of exposure to endotoxin and dust containing endotoxin has been reported by others conducting human investigations as well,[23-25] including the suggestion of a dose-response relationship.[25] Thus, periodic exposure as would likely be experienced by those in sewage and dusty occupations may afford a continual or pulse stimulation of the immune system. Such stimulation may enhance production of anticancer mediator factors and cells[26] that are suggested to be responsible for observed reduced lung cancer rates.[13]

Experimental studies[27] have suggested that benefit of endotoxin exposure is most effective during initiation of lung cancer with a finding of less benefit for established tumors. This, along with Palmberg,[21] supports the hypothesis[14,27] that endotoxin in an occupational setting is effective against the early formation of lung cancer. Thus, further suggesting endotoxins' mechanism of reduced lung cancer is its stimulation of the immune system in guarding against early lung cancer events.

Additional studies are warranted on the relationship of endotoxin and reduced lung cancer rates. This relationship has been suggested for textile and agricultural workers.[12-16] There is no reason to believe that it will not exist for other occupational groups exposed to endotoxin. Many have explained that the relationship is not one of benefit, but rather methodology and bias, including differences in smoking rates.[6,9] However, this explanation is not supported by experimental and clinical investigations involving endotoxin. The major influence on lung cancer is tobacco use (smoking). Although smoking is identified as one of the reasons for lower than expected rates in some populations, studies[6,9] have shown that smoking is not always an explainable factor or bias for reduced lung cancer. For example, Rapiti et al.[6] reported that the consumption of cigarettes and prevalence of smoking in a population of municipal waste workers was higher than the general population, but cancer deaths (SMR) for lung cancer in this group was 0.55. Epidemiological studies need to not only include and report detrimental outcomes but also potentially beneficial associations as well.

References

(1) Thorn J, Beijer L, Rylander R. Work related symptoms among sewage workers: a nationwide survey in Sweden. Occup Environ Med 2002; 59: 562-6.

(2) Rylander R Health effects among workers in sewage treatment plants. Occup Env Med 1999; 56: 354-7

(3) Lundholm M, Rylander R. Work related symptoms among sewage workers. Br J Ind Med 1983; 19: 325-329.

(4) Thorn T, Kerekes E. Health effects among employees in sewage treatment plants: a literature survey. Am J Ind Med 2001; 40: 170-179.

(5) Laitinen S, Kangas J, Kotimaa M, Liesivuori J, Martikaninen PJ, Nevalainen A, Sarantila R, Husman R. Worker’s exposure to airborne bacteria and endotoxin at industrial wastewater treatment plants. Am J Ind Hyg Assoc 1994; 55: 1005-1060.

(6) Rapiti E, Sperati A, Fano V, Dell’Orco V, Forastiere F. Mortality among workers at municipal waste incinerators in Rome: a retrospective cohort study. Am J Ind Med 1997; 31: 659-661.

(7) Friis L, Edling C, Hagmar L. Mortality and incidence of cancer among sewage workers: a retrospective cohort study. Br J Ind Med 1993; 50: 653-7.

(8). Lafleur J, Vena JE. Retrospective cohort mortality study of cancer among sewage workers. Am J Ind Med 1991; 19: 75-86.

(9) Enterline PE, Sykora JL, Keleti G, Lange JH. Endotoxin, cotton dust and cancer. Lancet 1985; 2: 934-5.

(10) Friis L, Mikoczy L, Hagmar L, Eding C. Cancer incidence in a cohort of Swedish sewage workers: extended follow-up. Occup Environ Med 1999; 56: 672-673.

(11) Betemps EJ, Buncher CR, Clark CS. Proportional mortality analysis of wastewater treatment system workers by birthplace with comments on amyotropic lateral sclerosis. J Occup Med 1994; 36: 31-35.

(12) Rylander R. Environmental exposures with decreased risks for lung cancer. Int J Epidemiol 1990; 19: S67-S72

(13) Lange JH. Reduced cancer rates in agricultural workers: a benefit of environmental and occupational endotoxin exposure. Med Hypotheses 2000; 55: 383-5.

(14) Mastrangelo G, Marzia V, Marcer G. Reduced lung cancer mortality in diary farmers: is endotoxin exposure the key factor? Am J Ind Med 1996; 30: 601-9.

(15) Schroeder JC, Tolbert PE, Eisen EA, Monson RR, Hallock MF, Smith TJ, Woskie SR, Hammond SK, and Milton DK. Mortality studies of machining fluid exposure in the automobile industry IV: a case-control study of lung cancer. Am J Ind Med 1997; 31: 525-533.

(16) Hodgson JT and Jones RD. Mortality of workers in the British cotton industry in 1968-1984. Scan J Work Environ Health 1990; 16: 113- 120.

(17) Lange JH. Anti-cancer properties if inhaled cotton dust: a pilot experimental investigation. J Environ Sci Health 1992; 27A: 505-514.

(18) Lange JH. An experimental study of anti-cancer properties of aerosolized endotoxin: application to human epidemiological studies. J Occup Med Toxicol 1992; 1: 377-382.

(19) Engelhardt R, Mackensen A, Galanos C. Phase 1 trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. Cancer Research 1991; 51: 2524-30.

(20) Pance A, Reisser D, Jeannin JF. Antitumoral effects of lipid A: preclinical and clinical studies. J Investig Med 2002; 50: 173-8.

(21) Palmberg L, Larssson BM, Malmberg P, Larsson K. Airway response of healthy farmers and nonfarmers to exposure in swine confinement building. Scand J Work Environ Health 2002; 28: 256-263.

(22) O’Grady NP, Presa HL, Pugin J, Fiuza C, Tropea M, Reda D, Banks SM, Suffredini AF. Local inflammatory responses following bronchial endotoxin instillation in humans. Am J Respir Crit Care Med 2001; 163: 1591-1598.

(23) Wang Z, Larsson K, Palmberg L, Malmberg P, Larsson P, Larsson L. Inhalation of swine dust induced cytokine release in the upper and lower airways. Eur Respir J 1997; 10: 381-387.

(24) Jagielo PJ, Thorne PS, Watt JL, Frees KL, Quinn TJ, Schwartz DA. Grain dust and endotoxin inhalation challenges produce similar inflammatory responses in normal subjects. Chest 1996; 110: 263-270.

(25) Michel O, Nagy AM, Schroeven M, Duchateau J, Neve J, Fondu P, Sergysels R. Dose-response relationship to inhaled endotoxin in normal subjects. Am J Respir Crit Care Med 1997; 156: 1157-1164

(26) Zhang M and Tracey KJ. Endotoxin and cancer, In: Brade H, Opal SM, Vogel SN, Morrison DC, Eds. Endotoxin in health and diseases. New York: Marcel Dekker .1999: pgs 915-926.

(27) Lange JH, Sykora JL, Weyel DA, Keleti G, Talbott EO. An animal model for evaluating epidemiological evidence of anti-lung cancer activity of aerosolized cotton dust. Proc of the Eleventh Cotton Dust Research Conference, RR Jacobs and PJ Wakelyn, eds., January 7-8, 1987, National Cotton Council, Memphis, TN, pages 93-96.