In this ecological study, a statistically significant positive association with the extent of viniculture is observed for non-melanoma skin cancer in males and females, prostate cancer, bladder cancer, and non-Hodgkin lymphoma in males, but not in females. Lung cancer risk is significantly reduced in communities with a large area under cultivation. Our main hypothesis that pesticides might play a role for the observed associations will be discussed for specific cancer types in the following.
Non-melanotic skin cancer
Several studies have shown that the lifetime cumulative sun exposure is responsible for the development of non-melanotic skin cancer (for an overview, see [24, 25]). In ecologic studies, squamous cell carcinoma is related more strongly to latitude or measured ultraviolet radiation than is basal cell carcinoma. As more outdoor workers might be occupied in regions with extensive winegrowing, our finding of an increased non-melanotic skin cancer risk in winegrowing communities appears plausible. In fact, in communities with a large area under cultivation, 14.8 percent of male skin cancer patients (C44 ICD-10) with known occupation (as recorded in the cancer registry) had worked as an outdoor worker (farmer, winegrower, gardener, forestry worker or construction worker). In communities with medium and a small area under cultivation, this proportion is 12.2 percent and 7.5 percent, respectively. Comparably, the proportion of outdoor workers among female cancer skin cancer patients (C44 ICD-10) is 7.6 percent, 5.1 percent and 2.6 percent in communities with a large, medium and small area under cultivation, respectively. Previous arsenic exposure has to be considered as an alternative explanation: arsenical pesticides were applied by Moselle wine growers  between 1920 and 1942. The clinical signs of arsenic exposure are arsenical keratoses, which may progress to squamous cell carcinoma or basal cell carcinoma . Moreover, arsenic seems to act as a co-carcinogen with ultraviolet radiation . As the latency period of non-melanotic skin cancer is suspected to be very long, an excess in non-melanotic skin cancers might therefore be partly explained by arsenic exposure, however, this explanation appears rather speculative. Moreover, risk estimators for non-melanotic skin cancer do not markedly increase when our analysis is restricted to persons aged 70 or more. The association between sun exposure and melanoma of the skin seems to be more complex: Intermittent sun exposure and sunburn history rather than lifetime cumulative sun exposure plays a role in the aetiology of melanoma of the skin [28, 29]. This complex relationship might explain why our study does not reveal a clearly increased melanoma incidence in communities with a large area under wine cultivation. Moreover, adjusting for potential confounders as, for example, leisure time UV exposure, was not possible in this study.
While several epidemiological studies point to an increased brain cancer risk among pesticide exposed persons [13, 14], few studies specifically focus on the residential population in winegrowing regions. In their ecological study in the province of Trento, Italy, Ferrari and Lovaste  find the highest incidence rates of intracranial tumours in regions of intensive fruit and wine cultivation. However, the authors do not indicate the significance level of their findings. Another ecological study among French agricultural workers reveals a significant association between pesticide exposure in vineyards and brain cancer mortality . The results of our ecological study do not support an increased brain cancer risk of residents in winegrowing regions (RR in the primary analysis for large vs. a small area under cultivation = 1.06 (95% CI 0.72–1.57) among men; RR = 1.21 (95% CI 0.79–1.86) among women).
Some previous studies point to a potentially elevated rectum cancer risk [32, 33], other studies find reduced colorectal cancer risks among farmers  or farm residents . Altogether, there is very little evidence to date for a possible relationship between pesticide exposure and rectum cancer. Our finding of an increased cancer incidence of the rectosigmoid junction (but not of rectum cancer in all) among males living in winegrowing communities might be alternatively explained by life-style (e.g. dietary) or medical (participation at screening) factors, by inhomogeneous reporting behavior, or by chance.
The increased NHL incidence among male, but not among female inhabitants of communities with a medium or large area under wine cultivation suggests a potential occupational rather than residential aetiology. However, in communities with a medium or a large area under cultivation, only two male NHL patients (=2 percent of male NHL patients with known occupation, missing values 55 percent) and one female NHL patient (=1.3 percent of female NHL patients with known occupation, missing values 44 percent) had worked as wine-growers, making an occupational aetiology improbable.
Our finding of an increased NHL incidence among potentially pesticide-exposed residents of winegrowing communities is in accordance with the literature. However, most previous studies are related to agricultural workers in general, not to winegrowing workers. In a large Italian multicenter case-control study , orchard, vineyard, and related tree and shrub workers appeared to be at increased risk for hematolymphopoietic malignancies. The carcinogenic effects of pesticides may be associated with their genotoxicity and immunotoxicity [37–39], increased cell proliferation , and association with chromosomal aberrations . Because of the lack of a positive association between potential residential pesticide exposure and NHL in females (actually with a significantly decreased rate ratio for follicular NHL in winegrowing communities with a large area under cultivation), our study does not definitely support the hypothesis of an elevated NHL risk among the residential population in Rhineland-Palatinate winegrowing communities.
To date, there is inconclusive evidence for a relationship between pesticide exposure and bladder cancer. In a retrospective cohort study among 32,600 employees of a lawn care company, Zahm  finds a significantly increased bladder cancer mortality. However, bladder cancer numbers are very small; furthermore, two of the three observed deaths had no direct occupational contact with pesticides. Rusiecki et al.  evaluate the cancer incidence in atrazine-exposed pesticide applicators among 53,943 participants in the Agricultural Health Study. In their study, assessing atrazine exposure by lifetime days of exposure, the rate ratio for bladder cancer is non-significantly elevated to 3.06 (95% CI 0.86–10.81). Assessing atrazine exposure by intensity-weighted lifetime days, the rate ratio for bladder cancer decreases to 0.85 (95% CI 0.24–2.94). Viel and Challier  analyze the mortality from bladder cancer among French farmers. While the mortality among farmers is non-significantly lowered (standardized mortality ratio = 0.96; 95% CI 0.85–1.08), there is a significant association with exposure to pesticides in vineyards (risk ratio = 1.14; 95% CI 1.07–1.22). According to the authors, these results could explain the French south-north gradient in bladder cancer, as vineyards are mainly located in Southern France.
Our finding of an increased prostate cancer risk in potentially pesticide-exposed residents of winegrowing communities is in accordance with the literature. In a recently conducted meta-analysis, van Maele-Fabry et al.  include 18 epidemiological studies published between 1984 and 2004. The combined rate ratio for all studies is 1.28 (95% CI 1.05–1.58). According to the authors, no specific pesticide or chemical class is responsible for the increased risk; nevertheless, the strongest evidence consists for phenoxy herbicides possibly in relation with dioxin and furan contamination. Van Maele-Fabry  point to the lack of fundamental understanding of the basic biology of human prostate cancer: hormones (both androgens and estrogens) would likely play a role in the etiology or promotion of prostate cancer. Therefore, the authors regard it as plausible that chemicals able to modulate steroid sex hormones as agonists, antagonists or as mixed agonist-antagonist might contribute to the development of prostate cancer through hormone-mediated effects. Several pesticides might interfere with sexual hormones through direct action on receptors but also through indirect non-receptorial mechanisms.
We applied an ecologic study design which does not allow a differentiation between residential, occupational, and life-style risk factors for cancer. The chief limitation of ecologic studies is the inability to link exposure with disease in particular individuals. A second major limitation of ecologic studies is the lack of ability to control for the effects of potential confounding factors. Thus, observed risk differences between communities with different area under cultivation may be due not to varying levels of pesticide usage, but rather to the independent effect of other confounding variables on cancer risk. Moreover, our "exposure" categories (small, medium, or large area under cultivation) represent very crude indicators of the individual exposure; the actual individual exposure depends on occupation, place of residence at the time of pesticide spraying, wind direction etc. Furthermore, several tests were performed, introducing a multiple comparison problem (altogether, 270 risk ratios were calculated). In general, our study design should therefore be regarded as exploratory rather than hypothesis testing. Due to small numbers, particularly for cancer cases in communities with a large area under cultivation, the power of the study to detect slight increases in incidence is limited. Many other potential risk factors of occupation and lifestyle from living in agricultural area would need to be discussed to explain the findings, but these would have to be collected in a study using individual information. For instance, data on socioeconomic levels or smoking prevalence were not available on a small scale. The use of 1996 data on agricultural characteristics might be criticised, since a lag time of 4–7 years for cancers occurring 2000–2003 is not plausible. It was not possible to obtain older data, but since the political boundaries did not change and agricultural land use stayed constant, their use seems warranted in the current study.
The completeness of reported cancer cases is still relatively low in Rhineland-Palatinate (about 80 percent for all cancers). Therefore, the calculation of standardized incidence ratios for residents of winegrowing communities in comparison with the population of Rhineland-Palatinate might at least partly reflect a higher completeness rather than truly elevated risks. As a probably more reliable approach of calculating cancer risks, we therefore decided to compare the observed cancer cases in communities with a medium or a large area under cultivation with – as a kind of internal reference – the number of cases reported in communities with a small area under cultivation. While we regard the "internal" comparison of winegrowing communities (communities with a medium or large area versus small are under cultivation) as a more reliable approach than the comparison with the Rhineland-Palatinate population, we nevertheless cannot totally exclude a higher (or lower) completeness in communities with a medium or large area under cultivation than in communities with a small area under cultivation.
Increased incidence of endocrine-related tumors with the estimated incidence of cancer in the national population of Germany as reference
In our primary analysis, we compared cancer rates in communities with a large resp. medium area under cultivation with cancer rates in communities with a small area under cultivation. However, in fact even in communities with a small area under cultivation, cancer incidence might be elevated, potentially leading to an underestimation of the results of our primary analysis (concerning rate ratios in communities with medium or large area under cultivation). In a side analysis, we therefore calculated standardized incidence ratios regardless of the incompleteness of the Rhineland-Palatinate cancer. Because of the incompleteness of the Rhineland-Palatinate cancer registry, the results of the calculation of standardized incidence ratios (SIR) tend to underestimate the true cancer risks for incompletely recorded cancer subentities; therefore decreased SIR should not be interpreted. If standardized incidence ratios were calculated with the estimated incidence of cancer in the national population of Germany as reference, among men we found an elevated SIR for prostate cancer and testicular cancer in communities with a large area under wine cultivation. Among women, we found an elevated SIR for endometrial cancer and (in communities with a medium area under cultivation, but not in communities with a large area under cultivation) for breast cancer incidence. Altogether, the results of our additional SIR analysis are compatible with a potential carcinogenic role of pesticides in the etiology of endocrine-related tumors of the breast, testis, prostate, and endometrium.