Private pesticide applicators and their spouses experience a significant deficit for cancer overall compared with the general population, while the cancer experience of commercial applicators appears to be more similar to the general population. This is consistent with previous observations among farmers tending to have lower overall cancer incidence and mortality rates than the general population. Nonetheless, significant excesses for some cancers are evident including several new excess risks in this update of cancer incidence in the AHS.
Although the numbers are small, a newly identified significant excess of lip cancer is observed among NC applicators. Several studies have identified significant excess risks of lip cancer among farmers.(2
) Ultraviolet light is a well-accepted cause of lip cancer and suggests that increased sun exposure from farming may account for the observed excess. However, since melanoma, a cancer known to be related to ultraviolet radiation was not elevated among applicators in NC, other factors may also contribute to the lip cancer excess. For example, smoking is an important risk factor for lip cancer.(19
) Survey data show that rates of smoking in NC are observed to be higher than in IA(20
) and this pattern is consistent among AHS participants with higher rates of smoking in NC. Given that smoking rates in the AHS are generally lower than the general population, smoking may only explain part of the excess of lip cancer. However, the use of other tobacco products may also be important for the development of lip cancer.(21
) AHS applicators from NC also report a higher prevalence of other tobacco products compared to their counterparts in IA, including: chewing tobacco (19.7% in NC vs. 11.7% in IA), cigars (9.7% in NC vs 6.5% in IA), and cigarillos (7.8% in NC vs. 5.4% in IA). Pesticides, viral infection, and immune suppression have all been hypothesized to additionally influence lip cancer risk. (18
) All of these exposures may vary according to the different agricultural settings in each state though all are relevant risk factors that need to be explored in these populations.
An additional new finding that was not evident in the previous follow-up is the significant excess of MM among private applicators from NC. Meta-analyses of several cohort and case-control studies have suggested a significant association between MM and farming.(2
) Furthermore, several studies have directly implicated pesticides for this excess, including the AHS.(24
) We also recently reported the prevalence of the MM precursor entity, monoclonal gammopathy of undetermined significance, among pesticide applicators in the AHS was twice that of a population-based sample (27
) suggesting a role for farming in the etiology of MM in the AHS. The MM difference by state could be chance, or due to the different exposures, including crop/pesticide profiles and requires further examination.
With the additional follow-up time and more accrued cases, we were able to evaluate risk of NHL overall and by NHL subtype to investigate possible etiologic heterogeneity among the various subtypes. We observed no significant excesses for NHL overall. Although the numbers are small, a significant excess of MZL among spouses in IA is apparent. Evidence suggests that MZL is associated with chronic antigen-driven immune stimulation by autoantigens and/or microbial pathogens. For example, three autoimmune conditions (i.e., lupus, Sjogren syndrome, hemolytic anemia) have been associated with MZL.(28
) We had information on these conditions for 10 of the 12 IA spouses diagnosed with MZL; none reported a history of these autoimmune conditions suggesting that other factors may be etiologically relevant in this population. No data were available for hemolytic anemia. Five distinct microbial pathogens have been identified to be related to MZL; Helicobacter pylori
), Borrelia burgdorferi
), Campylobacter jejuni
), Chlamydia psittaci
), and hepatitis C virus.(34
) Campylobacter jejuni
and Chlamydia psittaci
are bacteria commonly found in birds and animals including cattle (Campylobacter jejuni
) and poultry (Campylobacter jejuni
and Chlamydia psittaci)
. Evidence suggests that occupational exposure to animals increases the risk of developing NHL.(36
) We have previously reported that Iowa farmers raise more livestock compared with NC farmers.(38
) While no specific infections were ascertained in the AHS, these and other infections associated with exposure to animals on the farm may contribute to MZL among IA spouses. Pesticide exposure has been linked to NHL in many studies (39
) and specifically to MZL in one study (41
); thus an exploration of several farm-related exposures among spouses is needed to elucidate the observed MZL excess.
Elevated SIRs were also apparent for some other NHL subtypes. CLL/SLL/MCL was elevated in private applicators from IA, while DLBCL was elevated in private applicators from NC, although these elevations were not statistically significant. This may be a chance occurrence or this difference by NHL subtype may reflect actual differences in farm or other occupational exposures in IA and NC. In our analysis, the RSIRs suggest that the risk is limited to B-cell lymphomas, which were elevated among both private applicators and spouses. Studies have generally, but not uniformly, reported positive associations between NHL and phenoxyacetic acid herbicides. (42
) Associations with other pesticide classes have been studied less, but positive associations have also been observed for carbamate, organochlorine, and organophosphate insecticides. (44
) Few studies of pesticides have been able to evaluate NHL risk by subtype. While spouses may also be exposed to pesticides and other agricultural exposures, on average spousal exposure is less than among applicators. The timing of spousal exposure may also differ from that of applicators. Adequate immune stimulation early in life has been hypothesized to protect from allergy and illness later in life.(46
) Thus, the risk of NHL among spouses who often marry into farm life at a later age may be greater due to a less robust immune response to various agricultural inflammatory triggers compared with applicators that are more likely to have grown up on farms and been exposed at a young age.(49
Aside from these new observations, several previously reported associations were updated. The previously reported excess of prostate cancer among private and commercial applicators (13
) persisted in this extended follow up. This excess is also observed in both states. Excesses in prostate cancer linked to pesticide use among other agricultural populations have been previously reported.(2
) The role of specific chemicals has not been established, although other studies have implicated associations with organochlorine (53
) or organophosphate (51
) insecticides. Increasing evidence from the AHS has also linked these pesticides with prostate cancer. (55
) We also previously reported an excess of ovarian cancer among female applicators.(13
) While this excess persisted, no additional ovarian cancers were accrued since the previous analysis. Exposure to triazine herbicides has been linked to ovarian cancer although not in all studies.(60
) Because some pesticides have been shown to have estrogenic and antiestrogenic properties, increased attention has been paid to the role of endocrine disrupting chemicals in the etiology of both prostate and ovarian cancers.(62
) The suggested relative excess for two other hormonal cancers, breast and uterine cancer among spouses, could also be due to hormonal properties of some pesticides. Aside from pesticides, other agricultural exposures may also contribute to the observed excesses.
The previously reported significant excess of melanoma among AHS spouses did not clearly persist. An elevated SIR among IA and NC spouses was observed but was not statistically significant. A significant relative excess of melanoma (RSIR) among spouses suggests, however, that farm-related activities may contribute to melanoma incidence. In a case-control analysis of cutaneous melanoma in the AHS, Dennis et al. found significant associations between several pesticides and melanoma risk.(64
) Another hypothesized explanation for the observed relative excess is increased exposure to sunlight among spouses who engage in active farm work. Ultraviolet light exposure is the key established environmental risk factor for melanoma (65
). No excess risks, however, were observed among applicators that, presumably, have the highest exposure to sunlight. Thus, it is unclear what other agricultural exposures may be responsible for the elevated melanoma risk among spouses.
Overall, AHS subjects are at a lower risk of cancer than the general population with several cancer sites showing significant deficits. This provides evidence that the farm lifestyle reduced the risk of many cancers. In particular, there is a consistent deficit among smoking-related cancers including, oral, esophageal, pancreatic, lung, and bladder cancer. Except for commercial applicators, the rates of smoking among AHS participants appear to be much lower than rates in comparable gender/state groups as reported by the Behavioral Risk Factor Surveillance System.(20
) The relative deficit of lung cancer could also be due to other factors associated with participation in the AHS, such as high levels of occupational physical activity on the farm, which has been associated with decreased lung cancer risk in several studies.(66
) Farmers are also potentially exposed to endotoxin from animals, grains, and dusts from hay and straw. (70
) Endotoxin exposure has been associated with decreased lung cancer risk.(71
) Thus, the lung cancer deficit observed among farmers compared to the general population, may be also be due in part, to endotoxin exposure.
In summary, cancer incidence overall in the AHS continues to be lower than expected compared to the general populations of IA and NC, although excesses for some cancers are apparent. These patterns are likely influenced by lifestyle and occupational factors. Occupational agricultural exposures are varied and can influence cancer risk in different ways. We have hypothesized several explanations for the observed trends. More detailed exploration of the causes of cancers that show both deficits and excesses are important in furthering our understanding of the contribution of agricultural exposures to these cancer risks.