Abstract
Literature suggests that early exposure to the farming environment protects against atopy and asthma; few studies have examined pulmonary function. We evaluated associations between early-life farming exposures and pulmonary function in 3,061 adults (mean age=63) from a US farming population using linear regression. Childhood raw milk consumption was associated with higher forced expiratory volume in the first second (FEV1) (β=49.5ml; 95%CI=2.8,96.1ml; p=0.04) and forced vital capacity (FVC) (β=66.2ml, 95%CI=13.2–119.1ml, p=0.01). We did not find appreciable associations with other early-life farming exposures. We report a novel association between raw milk consumption and higher pulmonary function that lasts into older adulthood.
Introduction
Previous literature suggests that the farming environment protects against childhood asthma and allergy.1 Along with farm animal contact, raw milk consumption has been an exposure of particular interest.2 In adults, atopy and, to a lesser degree, asthma have been associated with the early-life farm environment.3 Studies of early-life farming exposure and adult pulmonary function are few and none have investigated raw milk. 4–6 The two largest studies reported higher forced expiratory volume in the first second (FEV1) or forced vital capacity (FVC) among adults raised on farms.4,5 Here we investigate associations between early-life farm exposures, including raw milk consumption, and pulmonary function in an adult US farming population.
Methods
As described previously,3,7 the Agricultural Lung Health Study (ALHS) is a case-control study of current asthma among farmers and their spouses nested within the prospective Agricultural Health Study (AHS data releases P3REL201209.00, PIREL201209.00 and AHSREL201304.00). Pulmonary function (FEV1, FVC and FEV1/FVC) was measured by trained staff during in-home visits with an EasyOne® Spirometer (NDD Medical Technologies, Chelmsford, MA) based on American Thoracic Society guidelines. Information on early-life exposures was obtained by questionnaire. Raw milk consumption was determined from the following prompt and question: “We are also interested in whether you ever drank raw or unpasteurized milk, also referred to as “farm milk.” Have you ever drank raw milk?” Wording of questions for other early-life exposures, including timing of raw milk consumption, are available in Supplemental Table 1. This analysis includes 3,061 individuals (from 3,301 enrolled in ALHS during 2009–2013) with complete data on early-life exposures and covariates, and whose FVC values had a quality attribute of “C” or better.8
Using linear regression we estimated betas and 95% confidence intervals (CI) for associations between early-life exposures and FEV1 (in ml), FVC (in ml), and FEV1/FVC (as a percent) adjusting for age, age2, height, height2, sex, race (white, non-white), state (Iowa, North Carolina), smoking status (current, former, never), pack-years of cigarette smoking, and current asthma status (case, non-case). FVC models also included weight. Covariates were selected based on previous research on modeling pulmonary function9 and ALHS analyses.3,7 Since we analyzed actual values for FEV1 and FVC, we included all variables from standard prediction equations,9 including race despite the small number of non-white individuals in ALHS.
Results
Approximately half of participants were male farmers and half were female spouses (Supplemental Table 2). Most (98.4%) were white and 71.0% were from Iowa. The mean age was 63 years. Few currently smoked; 66.5% never smoked. Three-fourths (73.8%) reported their family lived on a farm when they were born, 60.9% that their mother worked with farm animals while pregnant with them (in utero exposure), and 75.6% reported contact with farm animals before age 6 years (Table 1).
Table 1.
Associations between Early-life Farm Exposures and Pulmonary Function in the Agricultural Lung Health Study, 2009–2013
| Early-life Exposures | N | FEV1 (ml) | FVC (ml) | FEV1/FVC (%) | |||
|---|---|---|---|---|---|---|---|
|
| |||||||
| β (95%CI)a | Pvalue | β (95%CI)a | Pvalue | β (95%CI)a | Pvalue | ||
| Total | 3061 | ||||||
| Mother Lived On Farm While Pregnant | |||||||
| No | 771 | Referent | Referent | Referent | |||
| Yes | 2250 | −16.6 (−59.1, 26.0) | 0.45 | −11.7 (−60.1, 36.6) | 0.63 | −0.6 (−1.2, 0.1) | 0.11 |
| Missing | 40 | ||||||
| Mother Performed Farm Activities While Pregnant | |||||||
| No | 940 | Referent | Referent | Referent | |||
| Yes | 1962 | 6.0 (−33.8, 45.8) | 0.77 | −6.6 (−51.9, 38.8) | 0.78 | 0.3 (−0.3, 1.0) | 0.32 |
| Missing | 159 | ||||||
| Mother Worked with Farm Animals While Pregnant | |||||||
| No | 957 | Referent | Referent | Referent | |||
| Yes | 1863 | −4.4 (−44.4, 35.7) | 0.83 | −9.5 (−55.2, 36.2) | 0.68 | 0.2 (−0.5, 0.8) | 0.61 |
| Missing | 241 | ||||||
| Family Lived on Farm when Born | |||||||
| No | 767 | Referent | Referent | Referent | |||
| Yes | 2259 | −19.7 (−62.3, 23.0) | 0.37 | −11.8 (−60.2, 36.7) | 0.63 | −0.6 (−1.3, 0.05) | 0.07 |
| Missing | 35 | ||||||
| Farm Animal Exposure Before Age 3 | |||||||
| No | 822 | Referent | Referent | Referent | |||
| Yes | 1958 | −1.8 (−43.4, 39.8) | 0.93 | −9.1 (−56.6, 38.3) | 0.71 | 0.3 (−0.4, 0.9) | 0.46 |
| Missing | 281 | ||||||
| Farm Animal Exposure Before Age 6 | |||||||
| No | 625 | Referent | Referent | Referent | |||
| Yes | 2314 | 3.5 (−42.2, 49.2) | 0.88 | 9.2 (−42.8, 61.3) | 0.73 | 0.01 (−0.7, 0.7) | 0.99 |
| Missing | 122 | ||||||
| Breastfed | |||||||
| No | 1057 | Referent | Referent | Referent | |||
| Yes | 1439 | 20.3 (−21.8, 62.3) | 0.35 | 20.1 (−27.7, 67.9) | 0.41 | −0.2 (−0.8, 0.5) | 0.66 |
| Missing | 565 | ||||||
| Indoor Furry Pets Before Age 6 | |||||||
| No | 2204 | Referent | Referent | Referent | |||
| Yes | 800 | −7.3 (−47.6, 33.1) | 0.72 | −34.7 (−80.6, 11.2) | 0.14 | 0.9 (0.2, 1.5) | 0.01 |
| Missing | 57 | ||||||
| Mother Smoked Cigarettes when Pregnant | |||||||
| No | 2637 | Referent | Referent | Referent | |||
| Yes | 275 | −25.1 (−87.5, 37.3) | 0.43 | −11.6 (−82.8, 59.7) | 0.75 | 0.1 (−0.9, 1.2) | 0.77 |
| Missing | 149 | ||||||
| Parents Smoked Cigarettes in House Before Age 6 | |||||||
| No | 1362 | Referent | Referent | Referent | |||
| Yes | 1611 | −12.4 (−48.9, 24.0) | 0.50 | −21.0 (−62.4, 20.4) | 0.32 | 0.4 (−0.2, 1.0) | 0.16 |
| Missing | 88 | ||||||
| Raw Milk | |||||||
| No | 643 | Referent | Referent | Referent | |||
| Yes | 2246 | 49.5 (2.8, 96.1) | 0.04 | 66.2 (13.2, 119.1) | 0.01 | 0.4 (−0.4, 1.1) | 0.33 |
| Missing | 172 | ||||||
Estimates represent the difference in mean response (FEV1 and FVC in milliliters and FEV1/FVC as a percent) between a subject who experienced the exposure and one who did not, holding all covariates constant. Covariates were selected based on previous research on modeling pulmonary function and ALHS analyses and included: age, age2, gender, race, state (Iowa or North Carolina), height, height2, smoking status, pack-years, asthma status, and for FVC, weight. Confidence intervals (CI) were calculated as the beta coefficient plus or minus 1.96 times the standard error (β±1.96*SE).
Raw milk consumption was common (73.4%), and most who drank it (84.1%) started before age 6 (Tables 1 and 2). Raw milk consumption was associated with higher FEV1 (β=49.5ml; 95%CI=2.8,96.1ml; p=0.04) and FVC (β=66.2ml; 95%CI=13.2,119.1ml; p=0.01; Table 1) but not FEV1/FVC (β=0.4%; 95%CI=−0.4,1.1%; p=0.33). Associations were most notable for raw milk consumption beginning before age 6 years (FEV1: β=51.3ml; 95%CI=2.8,99.8ml; p=0.04; FVC: β=76.7ml; 95%CI=21.7,131.7ml; p=0.006; Table 2) but were also in the positive direction for the smaller group who started after. Estimates for raw milk consumption beginning before and after age 3 years were similar to age 6 estimates (Table 2). Although ability to recall timing of events before age 3 years may be limited, when we examined starting raw milk consumption before age 2 years (1,458 individuals) results were slightly stronger (FEV1: β=61.3ml; 95%CI=10.9,111.8ml; p=0.02; FVC: β=83.3ml; 95%CI=26.1,140.5ml; p=0.004). Consuming raw milk as the main milk source in childhood (79.3% of consumers) was most notably associated with higher FVC (β=53.8ml; 95%CI=7.2,100.5ml), though the association was also in the positive direction for FEV1 (β=28.3ml; 95%CI=−12.7,69.3ml).
Table 2.
Associations between Raw Milk Exposure and Pulmonary Function in the Agricultural Lung Health Study, 2009–2013
| Raw Milk Exposure | N | FEV1 (ml) | FVC (ml) | FEV1/FVC (%) | |||
|---|---|---|---|---|---|---|---|
|
| |||||||
| β (95%CI)a | Pvalue | β (95%CI)a | Pvalue | β (95%CI)a | Pvalue | ||
| Total | 3061 | ||||||
| Raw Milk Started Before or After Age 6 | |||||||
| Never Drank Raw Milk | 643 | Referent | Referent | Referent | |||
| Start Before Age 6 | 1888 | 51.3 (2.8, 99.8) | 0.04 | 76.7 (21.7, 131.7) | 0.006 | 0.3 (−0.5, 1.1) | 0.51 |
| Start Age 6 or After | 336 | 42.7 (−22.3, 107.8) | 0.20 | 35.3 (−38.5, 109.0) | 0.35 | 0.7 (−0.4, 1.7) | 0.23 |
| Missing | 194 | ||||||
| Raw Milk Started Before or After Age 3 | |||||||
| Never Drank Raw Milk | 643 | Referent | Referent | Referent | |||
| Start Before Age 3 | 1688 | 51.1 (1.6, 100.6) | 0.04 | 74.3 (18.2, 130.4) | 0.01 | 0.3 (−0.5, 1.1) | 0.48 |
| Start Age 3 or After | 536 | 46.0 (−11.0, 103.0) | 0.11 | 53.9 (−10.8, 118.5) | 0.10 | 0.5(−0.4, 1.7) | 0.31 |
| Missing | 194 | ||||||
| Was Raw Milk the Main Milk in Childhood | |||||||
| No | 1173 | Referent | Referent | Referent | |||
| Yes | 1781 | 28.3 (−12.7, 69.3) | 0.18 | 53.8 (7.2, 100.5) | 0.02 | −0.1 (−0.8, 0.5) | 0.68 |
| Missing | 107 | ||||||
| Ever Raw Milk/Main Milk in Childhood | |||||||
| Never Drank Raw Milk | 643 | Referent | Referent | Referent | |||
| Drank Raw but not Main Milk | 415 | 56.9 (−3.8, 117.6) | 0.07 | 60.6 (−8.2, 129.5) | 0.08 | 0.7 (−0.3, 1.7) | 0.19 |
| Main Milk was Raw | 1781 | 45.2 (−4.4, 94.8) | 0.07 | 66.4 (10.1, 122.7) | 0.02 | 0.2 (−0.6, 1.0) | 0.56 |
| Missing | 222 | ||||||
Estimates represent the difference in mean response (FEV1 and FVC in milliliters and FEV1/FVC as a percent) between a subject who experienced the exposure and one who did not, holding all covariates constant. Covariates were selected based on previous research on modeling pulmonary function and ALHS analyses and included: age, age2, gender, race, state (Iowa or North Carolina), height, height2, smoking status, pack-years, asthma status, and for FVC, weight. Confidence intervals (CI) were calculated as the beta coefficient plus or minus 1.96 times the standard error (β±1.96*SE).
Among the 2,246 individuals who ever drank raw milk, the majority (n=2,044; 91.0%) no longer drank it (stopped on average 45.0 years prior), while 168 (7.5%) drank it within the last 10 years (stopped on average 3.3 years prior). Raw milk associations did not change when we accounted for consumption within the last 10 years or excluded 197 ever raw milk drinkers for whom we could not be certain that consumption started in childhood (i.e. before age 18 years) (Supplemental Table 3). Among those starting before age 6 we could examine lifetime duration and found no association (Supplemental Table 3). Results for raw milk consumption were also virtually unchanged when we excluded 360 individuals with a FVC quality attribute of “C” (Supplemental Table 3).
Raw milk associations were more apparent in the much larger group of non-asthmatics (n=1,936; FEV1: β=61.0ml; 95%CI=4.9,117.1ml; FVC: β=66.2ml; 95%CI=0.9,131.5ml) than in asthmatics (n=1,125; FEV1: β=23.1ml; 95%CI=−59.3,105.5ml; FVC: β=53.2ml; 95%CI=−36.7,143.0ml), but these differences were not statistically significant (FEV1: Pinteraction=0.07; FVC: Pinteraction=0.30; Supplemental Table 4). In addition, raw milk associations among non-asthmatics were not materially altered by excluding individuals with childhood asthma (N=25), childhood pneumonia (N=166), or either (N=184) suggesting that the associations were not driven by susceptibility to childhood respiratory illnesses. For example, the estimate for raw milk consumption and FEV1 among non-asthmatics was 61.1ml after excluding individuals with either condition. Raw milk associations for FEV1 were more apparent in women (β=58.0ml; 95%CI=9.9,106.0ml) than men (β=36.5ml; 95%CI=−48.4,121.3ml), but this difference was of borderline statistical significance (Pinteraction=0.05; Supplemental Table 4). For FVC, results differed little by gender (females: β=68.1 ml; 95%CI=14.4,121.8ml; males: β=56.4ml; 95%CI=−40.4,153.3ml; Pinteraction=0.19). No material differences by atopy status (defined as specific IgE>0.70 IU/ml to at least one of ten allergens measured in blood3) or number of siblings (dichotomized into 0–2 or 3+, used as an indicator or exposure to infections in early-life10) were noted (Supplemental Table 4).
Childhood indoor furry pet exposure was associated with modestly higher FEV1/FVC (β=0.9%; 95%CI=0.2,1.5%; p=0.01; Table 1). Aside from this, no other early-life farming exposures were associated with adult pulmonary function (Table 1). Given the childhood furry pet association, we examined raw milk models additionally adjusted for that exposure, but found no evidence of confounding (FEV1: β=49.7ml; p=0.04; FVC: β=67.9ml; p=0.01).
Discussion
Childhood raw milk consumption was related to higher FEV1 and FVC in this older adult US farming population. Few previous studies have addressed the relationship between early-life farm exposure and FEV1 or FVC in adults,4–6 and none examined early-life raw milk consumption. The two largest studies – the European Community Respiratory Health Survey II (ECRHS II, N=10,201) and a Finnish study (N=5,666) – both found that being born or raised on a farm was associated with higher FEV1 and/or FVC.4–5 The ECRHS study specifically noted a stronger positive association between living on a farm in childhood and FEV1, but not FEV1/FVC, in women than in men,4 similar to our finding of a slightly stronger raw milk-FEV1 association in women.
Although we found positive associations of raw milk consumption with both FEV1 and FVC, we did not see an association with FEV1/FVC suggesting that the beneficial effect of raw milk is predominantly on lung growth rather than airway caliber. In support of this hypothesis, we did not see an effect of raw milk consumption on either adult non-atopic asthma or atopic asthma (both compared to individuals with neither asthma nor atopy) in a previous publication.3 We also observed a slight increase in FEV1/FVC for indoor furry pets before age 6 years. However, in a previous publication we did not find a protective association between indoor furry pets before age 6 years and either asthma, atopy, or their combination.3
Mechanisms of our observed association are speculative. Differences in the nutrient composition of raw and commercial milk, including total fat content and specific fatty acid composition,2 could theoretically influence rates of growth, including the lungs, in childhood. Raw milk contains micro-organisms absent from pasteurized commercial milk; some may influence the developing immune system in ways that could account for the reported protective effect of early raw milk consumption on allergic disease.2 Several studies have reported that raw milk consumption in pregnancy or childhood leads to greater production of interferon gamma (IFNG) in children.2,11 In a US birth cohort, higher IFNG production by stimulated peripheral blood mononuclear cells (PBMCs) at age one year was related to higher FEV1 and FVC, but not FEV1/FVC, at age 8.12 Elevated IFNG may protect young children against airway infections contributing to better pulmonary function in adulthood.
As described in detail in a previous ALHS paper,3 we sought to enhance the quality of information about early-life exposures by sending participants questionnaires in advance of home visits, encouraging participants to speak with family members (e.g., siblings), and asking about exposures by six years of age when memories are more reliably formed. Although we could not directly assess selective entry into our study based on raw milk consumption and pulmonary function, we performed a quantitative selection-bias analysis13 based on childhood farm animal exposure and asthma in a previous publication;3 we did not find evidence for selection bias from AHS into ALHS. Nevertheless, a biased association could still result if choosing to remain in farming before the initial AHS enrollment period (1993–1997) was jointly related to early-life raw milk consumption and better pulmonary function. Finally, we had limited ability to assess duration of raw milk consumption in the minority who started after age 6 and lacked data on the quantity consumed.
Previous literature examining the hygiene hypothesis in farm environments have identified protective associations with in utero and childhood exposures using several metrics including farm animal contact and farm work performed by mothers while pregnant, residing on a farm at birth or in childhood, and farm animal contact and farm work performed by individuals during childhood.1,2 Our study examined similar metrics which, not surprisingly, were highly correlated. The first six variables in Table 1 had tetrachoric correlations ranging from 0.84 to 0.99 in ALHS.3 However, raw milk consumption - the only farming variable that we found to be related to pulmonary function - was less strongly correlated with the other farm variables; correlations ranging from 0.47 to 0.54.3 In addition, pulmonary function parameters were correlated with each other to varying degrees; partial correlations, adjusted for age, height, gender, and race, were 0.84 for FEV1 with FVC, 0.60 for FEV1 with the FEV1/FVC, and 0.15 for FVC with FEV1/FVC. Given the hypothesis-driven nature of our research14,15 and the correlations of several early-life farming exposures as well as pulmonary function measures, we did not correct for multiple comparisons, thereby increasing the possibility of false positives but reducing the risk of false negatives.
A strength of our study is the large farming population of older adults, allowing us to assess possible persistence of associations across the life course in the US. Our data suggests that raw milk consumption, particularly early in life, is associated with better pulmonary function in adulthood.
Supplementary Material
Acknowledgments
This work was supported by the intramural research program of the NIH, National Institute of Environmental Health Sciences (NIEHS) (Z01-ES049030 and ZO1-ES102385) and National Cancer Institute (Z01-CP010119). This work was also supported in part by American Recovery and Reinvestment Act (ARRA) funds through NIEHS contract number NO1-ES-55546. We thank the numerous study staff at Social & Scientific Systems, Inc. who played a role in the data collection. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the National Institute for Occupational Safety and Health (NIOSH). Mention of any company or product does not constitute endorsement by NIOSH.
Footnotes
Conflict of interest
None. The authors declare no conflict of interest.
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