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Cowboys and Lung Cancer

Jacob Schor, ND FABNO

January 15, 2008

The Stock Show is in town.  Stepping out our front door and sniffing the air here in Park Hill confirmed it.  Cows have a way of making their presence known by the way they change the air around them. Working with cattle may not be the cleanest job but it may protect you against lung cancer.

The Hygiene Theory is now the accepted explanation for the rapid increase in allergies, asthma and other immune related conditions seen in the developed world.  The theory’s premise is that when people live in clean, hygienic environment, their immune systems go unchallenged and are prone to malfunction.  Not having enough germs to deal with, the immune system can over react to little things that don’t really pose a threat to health.  Foods, pollens, animal dander and even odors  trigger immune responses rather than real threats from infectious bacteria, molds, and viruses.

This same Hygiene Theory is being rustled up to explain the increase in certain cancers.  Children who are exposed to the germ warfare in daycare centers have lower odds of getting leukemia.      Having older siblings lowers the odds of getting lymphoma later in life.   The more older siblings, the better off the one is. The more older siblings the more germs and infections the kid gets exposed to. An alternate explanation to this data is that it’s the mother’s exposure to the germs that conveys this cancer immunity.   The more kids she’s raised, the more germs she’s been exposed to and the better the immune system she passes to her later offspring. It is still pretty much the same idea.  Getting sick with little infections provides protection against big things

Our immune systems were designed to be in a constant state of action fighting a daily onslaught of microbes.  In our modern world, infectious attack is a relatively weak and occasional occurrence. Our immune systems have turned into couch potatoes, suffering from delusions that innocuous things are attacking but whimping out if and when real trouble shows.

Giuseppe Mastrangelo, an Italian researcher, (you might have guessed that) and his colleagues have shown that dairy farmers have a way lower risk of lung cancer compared to neighboring farmers who worked in fields or orchards.  The more cows, the greater the protection. This includes dairy farmers who smoked

Mastrangelo first published these observations in 1996.  He and his colleagues looked at 2,283 male farmers ‘who worked either in cattle raising or in crop/orchard cultivation.’  Over a period of 22 years 422 of them died.  There were far fewer deaths due to cancer among the 1,561 dairy farmers, about 35% less than what would have been expected.  The decrease in lung cancer was even more striking, a 51% reduction from predicted numbers.  Nothing is perfect though.  The dairy farmers had almost three times the number of brain tumors.   The farmers who worked in fields or orchards and didn’t care for cattle had the predicted numbers of cancers.  Among the dairy farmers, the longer they had worked with cattle and the more land and cows they owned, the more the decrease in lung cancer risk.

Mastrangelo published again in 2005, confirming his earlier paper. This time they looked at what happens to dairy farmers who quit working on the farm.  The researchers looked at mortality data for 2,561 dairy farmers compared with the general population, from 1970 to 1998.  There were sixty-two lung cancer cases among the farmers. Again, the more cattle on the farm, the lower the odds of dying from lung cancer.  Well, only from 1970 to 1984.  Most of these guys left their farms and from 1985 to 1998 these one time farmers lost their protection against lung cancer.

Cow manure is a mash of various bacteria.  Many of these bacteria produce endotoxins, chemicals excreted that are toxic to other bacteria. Dairy farming involves moving vast amounts of cow waste. The manure when dried often turns to dust which is carried in the air. The dust contains these bacterial endotoxins.  People who work with cattle are constantly breathing in this endotoxin laced air.  Current theory is that it is this constant and continual exposure to these toxins that creates the protective effect. The endotoxin exposure triggers macrophages in the lungs to produce a chemical called tumor necrosis factor and this protects the farmers from lung cancer.

free pdf of the latest dairy farmer study: http://aje.oxfordjournals.org/cgi/content/full/161/11/1037

I know our stock show is more about cowboys than dairy farmers and clearly the Marlboro man is a cowboy not a dairy farmer. Yet how much difference is there between the stuff either get to breath?   Maybe in a sort of sick way, it is ok for the Marlboro Man to smoke.  Maybe real cowboys can smoke and not get lung cancer as easily as the rest of us.  It’s a matter of how much manure you inhale when you are not smoking. 

Some entrepreneur should take this information and invent a protective treatment for smokers.  People who smoke in spite of all the evidence that it triggers lung cancer, could inhale nebulized cow manure between cigarettes.  Or they could add an endotoxin releasing pinch of cow manure to their to their tobacco.  Such solutions may also be helpful at convincing smokers to quit. 

I am not prepared to go down to the stock show and suggest to any cowboys that they consider smoking manure.  Yet this concept of endotoxin exposure is fascinating and will eventually have practical implications. 

  Br J Cancer. 2002 May 6;86(9):1419-24.Links    Daycare attendance and risk of childhood acute lymphoblastic leukaemia.    Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL, Reynolds P.

    Division of Public Health Biology and Epidemiology, University of California-Berkeley, California, CA 94720-7360, USA.

    The relationship between daycare/preschool ("daycare") attendance and the risk of acute lymphoblastic leukaemia was evaluated in the Northern California Childhood Leukaemia Study. Incident cases (age 1-14 years) were rapidly ascertained during 1995-1999. Population-based controls were randomly selected from the California birth registry, individually matched on date of birth, gender, race, Hispanicity, and residence, resulting in a total of 140 case-controls pairs. Fewer cases (n=92, 66%) attended daycare than controls (n=103, 74%). Children who had more total child-hours had a significantly reduced risk of ALL. The odds ratio associated with each thousand child-hours was 0.991 (95% confidence interval (CI): 0.984-0.999), which means that a child with 50 thousand child-hours (who may have, for example, attended a daycare with 15 other children, 25 h per week, for a total duration of 30.65 months) would have an odds ratio of (0.991)(50)=0.64 (95% CI: 0.45, 0.95), compared to children who never attended daycare. Besides, controls started daycare at a younger age, attended daycare for longer duration, remained in daycare for more hours, and were exposed to more children at each daycare. These findings support the hypothesis that delayed exposure to common infections plays an important role in the aetiology of childhood acute lymphoblastic leukaemia, and suggest that extensive contact with other children in a daycare setting is associated with a reduced risk of acute lymphoblastic leukaemia. Copyright 2002 Cancer Research UK

Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1928-34.        Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia.    Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M, Does MB, Wiencke JK.

    Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034, USA. xiaomei.ma@yale.edu

    A role for infectious agents has been proposed in the etiology of childhood acute lymphoblastic leukemia (ALL), particularly for common ALL (c-ALL; ALL diagnosed in children ages 2-5 years and expressing CD10 and CD19 surface antigens). We evaluated the possible etiologic role of daycare attendance (a proxy measure for exposure to infectious agents) and infections during infancy in the Northern California Childhood Leukemia Study. A total of 294 incident ALL cases (ages 1-14 years) and 376 individually matched controls were included in this analysis. In non-Hispanic White children, daycare attendance measured by child-hours was associated with a significantly reduced risk of ALL. Compared with children who did not attend any daycare, the odds ratio (OR) for those who had >5,000 child-hours during infancy was 0.42 [95% confidence interval (95% CI), 0.18-0.99] for ALL and 0.33 (95% CI, 0.11-1.01) for c-ALL. Test for trend is also significant, which supports a dose-response relationship. The magnitude of effect associated with the same number of child-hours was stronger for daycare attendance during infancy than for daycare attendance before diagnosis. In addition, self-reported ear infection during infancy was associated with a significantly reduced risk of c-ALL (OR, 0.32; 95% CI, 0.14-0.74) in non-Hispanic White children. In Hispanic children, no association was observed among daycare attendance, early infections, and risk of childhood ALL or c-ALL. These results offer indirect yet strong support for the infectious disease hypothesis in the etiology of ALL in non-Hispanic White children and highlight an important ethnic difference.

BMJ. 2005 Jun 4;330(7503):1294. Epub 2005 Apr 22. 

    Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study.    Gilham C, Peto J, Simpson J, Roman E, Eden TO, Greaves MF, Alexander FE; UKCCS Investigators.

    Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, Sutton SM2 5NG.

    OBJECTIVE: To test the hypothesis that reduced exposure to common infections in the first year of life increases the risk of developing acute lymphoblastic leukaemia. Design and setting The United Kingdom childhood cancer study (UKCCS) is a large population based case-control study of childhood cancer across 10 regions of the UK. PARTICIPANTS: 6305 children (aged 2-14 years) without cancer; 3140 children with cancer (diagnosed 1991-6), of whom 1286 had acute lymphoblastic leukaemia (ALL). MAIN OUTCOME MEASURE: Day care and social activity during the first year of life were used as proxies for potential exposure to infection in infancy. RESULTS: Increasing levels of social activity were associated with consistent reductions in risk of ALL; a dose-response trend was seen. When children whose mothers reported no regular activity outside the family were used as the reference group, odds ratios for increasing levels of activity were 0.73 (95% confidence interval 0.62 to 0.87) for any social activity, 0.62 (0.51 to 0.75) for regular day care outside the home, and 0.48 (0.37 to 0.62) for formal day care (attendance at facility with at least four children at least twice a week) (P value for trend < 0.001). Although not as striking, results for non-ALL malignancies showed a similar pattern (P value for trend < 0.001). When children with non-ALL malignancies were taken as the reference group, a significant protective effect for ALL was seen only for formal day care (odds ratio = 0.69, 0.51 to 0.93; P = 0.02). Similar results were obtained for B cell precursor common ALL and other subgroups, as well as for cases diagnosed above and below age 5 years. CONCLUSION: These results support the hypothesis that reduced exposure to infection in the first few months of life increases the risk of developing acute lymphoblastic leukaemia.

    PMID: 15849205 [PubMed - indexed for MEDLINE]

Cancer Res. 2007 Nov 15;67(22):11074-82.        Childhood social environment and risk of non-Hodgkin lymphoma in adults.    Smedby KE, Hjalgrim H, Chang ET, Rostgaard K, Glimelius B, Adami HO, Melbye M.

    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    Better hygiene and sanitation and decreasing family size parallel the increasing incidence of non-Hodgkin lymphoma (NHL) in many populations around the world. However, whether sibship size, birth order, and crowding are related to adult NHL risk is not clear. We investigated how family structure and childhood social environment were related to the risk of NHL and NHL subtypes in a large Scandinavian population-based case control study with 6,242 participants aged 18 to 74 years. Detailed exposure information was obtained through telephone interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using logistic regression, and all statistical tests were two-sided. Having four or more siblings was associated with a moderately increased risk of NHL, compared with having no siblings (OR 1.34, 95% CI 1.11-1.62, P(trend) < 0.001). Having four or more older siblings was associated with a similar risk increase (OR 1.33, 95% CI 1.12-1.59, P(trend) = 0.003) compared with being the oldest, whereas number of younger siblings was unrelated overall. The associations were independent of other environmental exposures and did not vary by country, age, or sex. High household crowding was also positively associated with risk of NHL. Results were slightly stronger for diffuse large B-cell and T-cell lymphomas than for other major NHL subtypes. Our findings add to the evidence that large sibship size, late birth order, and childhood crowding are associated with an elevated risk of NHL. Effect mechanisms may be related to early age at onset and high frequency of specific infections or total microbial exposure in childhood.

    PMID: 18006854 [PubMed - indexed for MEDLINE]

Med Hypotheses. 2006;67(4):717-20. Epub 2006 May 22.   

    Comment in:        Med Hypotheses. 2007;68(4):914-5.

    A reformulation of the hygiene hypothesis: maternal infectious diseases confer protection against asthma in the infant.    Hersoug LG.

    Research Centre for Prevention and Health, Glostrup University Hospital, Copenhagen County, 57 Nrd Ringvej, Building 84/85, DK-2600 Glostrup, Denmark. Hersoug@vip.cybercity.dk

    Epidemiological studies have shown an inverse relationship between allergic respiratory diseases and the number of siblings. It was hypothesized that the lower prevalence of allergic respiratory diseases in large sibships was due to cross-infections between siblings. According to this hygiene hypothesis the increase in the prevalence of atopic diseases is caused by a decrease in the exposure to infections. It was believed that early infections were beneficial for health because of their contribution to the maturation of the immune system. However, in this interpretation a possible protective influence of the mother was overlooked. A new hypothesis is therefore proposed. Maternal exposure to infections induces immunological memory, which protects her children against allergic respiratory diseases.

    PMID: 16716534 [PubMed - indexed for MEDLINE]

Am J Ind Med. 1996 Nov;30(5):601-9.Links    Reduced lung cancer mortality in dairy farmers: is endotoxin exposure the key factor?    Mastrangelo G, Marzia V, Marcer G.

    Istituto di Medicina del Lavoro, University of Padova, Italy.

    From two areas in the Province of Padova, we selected 2,283 male farmers who worked either in cattle raising or in crop/orchard cultivation. There were 422 cohort deaths from 1970 to 1992. Using the regional population as a reference, the standardized mortality ratio (SMR) was calculated, with 95% confidence intervals (CI) based on the Poisson distribution. Cancer mortality was significantly reduced among the 1,561 dairy farmers (SMR = 0.65; CI = 0.53-0.81); there was a significant decrease in lung cancer (SMR = 0.49; CI = 0.31-0.74), whereas a significant increase from brain tumors was found (SMR = 2.83; CI = 1.04-6.17). Neither overall cancer mortality nor the lung cancer SMR deviated significantly from unity for the 722 crop/orchard farmers. Among dairy farmers, moreover, lung cancer SMRs showed a significant downward trend across the quartiles of increasing length of work, 0.96 in the first quartile, and 0.48, 0.40, and 0.25 in the second, third, and fourth quartiles, respectively. Moreover, lung cancer risk decreased with increasing farm land area, with SMRs in the quartiles of 0.89, 0.37, 0.41 and 0.19. This decrease cannot be attributed to either a selection (healthy worker effect) or a confounding (lower percentage of smokers) bias. Nor was it due to an artifact introduced by differences in age distribution among the quartiles. Dairy farmers are known to be exposed to higher airborne endotoxin concentrations; reasonably, this cumulative exposure increases further with years of work and area of farm. Endotoxins may have protected the dairy farmers against lung cancer through the tumor necrosis factor produced by alveolar macrophages.

Am J Epidemiol. 2005 Jun 1;161(11):1037-46.        Lung cancer risk: effect of dairy farming and the consequence of removing that occupational exposure.    Mastrangelo G, Grange JM, Fadda E, Fedeli U, Buja A, Lange JH.

    Department of Environmental Medicine and Public Health, University of Padova, Padova, Italy. giuseppe.mastrangelo@unipd.it

    The aim of this study was to confirm the exposure-dependent reduction in lung cancer risk reported for dairy farmers exposed to endotoxin and to evaluate the consequence of leaving dairy farming and taking employment in industry or services, where exposure to microbial agents is lower. Standardized mortality ratios, with 95% confidence intervals, for 2,561 self-employed dairy farmers were estimated, considering the general population of Veneto, Italy, from 1970 to 1998 as the reference. Sixty-two lung cancer cases, whose information was checked against clinical records, were compared with 333 controls in a cohort-nested case-control study. Odds ratios with 95% confidence intervals were estimated by logistic regression analysis. A downward trend of standardized mortality ratios for lung cancer across tertiles of number of dairy cattle on the farm was significant (p < 0.05) from 1970 to 1984 but not from 1985 to 1998, when most subjects were no longer dairy farmers. Age- and smoking-adjusted odds ratios for lung cancer significantly decreased with increasing number of dairy cattle (p for trend = 0.001) for workers for whom < or =15 but not >15 years had elapsed from the end of work to the end of follow-up. In conclusion, increased levels of endotoxin (or other associated environmental factors) might be protective against lung cancer; protection diminishes over time after that exposure is removed.