In this analysis of data from the AHS cohort, we found no clear evidence of an association between overall use of OC insecticides and cancer incidence. We observed an excess of leukemia and a deficit of colon cancer among workers who reported ever using any OC chemicals; however, no clear dose-response relationship with increasing level of exposure was apparent for these or other cancers. These findings do not suggest that OC insecticides, as a whole, are carcinogenic in our study population, although it should be noted that this study did not consider all types of OC insecticides, as some chemicals (e.g., endrin, methoxychlor, mirex) were not assessed in the AHS questionnaires.
While we found generally no evidence of a relationship between overall OC use and cancer risk, it is important to recognize that analyses of a class of pesticides are informative only to the extent that the effects of intra-class chemicals are similar. Organochlorine insecticides possess very different chemical structures, and may exert different biologic effects in humans. If OC chemicals differ in carcinogenic potency and mechanism of action, then analyses of overall OC use may dilute or conceal chemical-specific effects. We observed some statistically significant associations with lifetime days of exposure to individual chemicals. Most associations involved elevated cancer risks (rectal cancer and chlordane, lung cancer and dieldrin, NHL and lindane, melanoma and toxaphene, leukemia and chlordane / heptachlor), although reductions in risk were also observed (colon cancer and aldrin; overall cancer and heptachlor). Only two of these associations with cumulative exposure were also observed in analyses of ever use of specific chemicals in the entire cohort (rectal cancer and chlordane, leukemia and chlordane/heptachlor). The chemical-specific analyses involved a large number of comparisons, and, consequently, at least some of these findings may be due to chance. However, some of the observed associations (lindane and NHL, chlordane / heptachlor and leukemia) are supported by previous evidence.
The risk of NHL rose with increasing cumulative exposure to lindane. Though not produced in the U.S. since 1976, imported lindane is still used in this country for seed treatment for a limited number of vegetables, and for the pharmaceutical treatment of scabies and head lice. Oral administration of lindane has been observed to increase the incidence of liver tumors in mice and, less clearly, thyroid tumors in rats (13
). Previous epidemiologic evidence has suggested a relationship between lindane exposure and NHL. A moderate association between lindane use and NHL was observed in a pooled analysis of three population-based case-control studies conducted in the Midwestern U.S., with stronger relative risks observed for greater duration and intensity of use (18
). An increased risk of NHL with lindane use was also found in a Canadian case-control study of NHL (19
). In support of these epidemiologic findings is the observation that lindane induces chromosomal aberrations in human peripheral lymphocytes in vitro
Chlordane and heptachlor are structurally related chemicals. Chlordane is metabolized into heptachlor, and technical-grade products of each contain approximately 10–20% of the other compound (15
). These chemicals were banned from use in agriculture in the U.S. in the late 1970s, and completely banned in 1988. Chlordane and heptachlor are established carcinogens in animal models, with orally administered doses clearly demonstrated to induce liver tumors in mice and rats (15
). Previously published evidence suggests that these chemicals may be leukemogenic. Two reports have been published describing 25 and 11 cases of blood dyscrasias following exposure to chlordane and heptachlor, respectively, usually as a result of pest control treatment in the home or garden (21
). Additionally, heptachlor has been observed to induce tumor promoting mechanisms in human myeloblastic leukemia and lymphoma cells (23
). Findings from a U.S. population-based case-control study of leukemia generally did not suggest an association with chlordane, although a three-fold elevated risk was observed among farmers reporting 10 or more days of use annually on animals (25
). Some case-control studies of NHL have reported associations with chlordane/heptachlor exposure (26
), although later studies found no such relationship (19
). We did not observe a relationship with NHL in our study.
Our finding that lung cancer relative risk increased significantly with increasing dieldrin exposure was previously reported in an earlier AHS analysis by Alavanja et al. (9
). Dieldrin produces liver tumors in mice, though not in other animal models (13
), and has been reported to induce chromosomal damage in a dose-response manner in a human embryonic lung cell line (29
). However, no elevated cancer rates were observed among workers employed in the manufacture of dieldrin, aldrin and endrin (30
We found equivocal evidence of an increase in rectal cancer risk with overall OC use, and stronger evidence for use of chlordane. Pesticide use has generally not been linked with rectal cancer in previous epidemiologic studies, and reports of rectal cancer incidence among farmers are inconsistent, with both increased (33
) and decreased (37
) risks observed. An excess risk of rectal cancer accompanying pesticide use was observed in a small cohort of Icelandic pesticide applicators (40
); however, the association was based on small numbers, and no specific information on OC insecticides was available (33
). A significantly elevated number of deaths due to rectal cancer was observed in a cohort of workers involved in the production of dieldrin and aldrin, although a dose-response relationship with exposure intensity was not present (32
We also observed an increased risk of melanoma accompanying high exposure to toxaphene, although this finding was based on small numbers. Toxaphene, a complex mixture of chlorinated camphenes, which was widely used in North America until 1982 (41
), has been reported to cause liver and thyroid tumors in animal studies and to induce sister chromatid exchanges in vitro
). In one study, an increased frequency of chromosomal aberrations was reported among workers exposed to toxaphene (42
). Otherwise, no previously published epidemiologic evidence suggests carcinogenicity to humans. Case-control studies of NHL and leukemia conducted in Iowa and Minnesota both found no evidence of a relationship with toxaphene use (25
It has been hypothesized that OC insecticides, which demonstrate weak estrogenic and anti-estrogenic properties (4
), may play a role in the pathogenesis of hormone-related cancers such as breast and prostate (43
). However, epidemiologic studies of these agents generally do not support a relationship with breast cancer (7
), and are unclear with respect to prostate cancer (44
). While our analysis of pesticide applicators is not informative with respect to breast cancer and OC use, we did find consistent evidence suggesting no increased prostate cancer risk with exposure to OC insecticides. These findings are consistent with an earlier case-control study of prostate cancer conducted within the AHS cohort (8
). In that study, a variable defined from factor analysis that included age greater than 50 and OC insecticide use was found to be weakly associated with increased prostate cancer risk; however, no relationship between prostate cancer and cumulative exposure to OC chemicals was observed. Our current findings offer further evidence that use of OC insecticides is not associated with prostate cancer risk.
This study has several strengths. First, information on exposure to OC chemicals was conducted prior to disease onset, precluding the possibility of differential recall bias. Second, the extensive information collected in the AHS regarding exposure to each insecticide enabled the development of detailed measures of OC exposure for use in our analysis. Third, unlike previous cohort studies investigating exposure to OC insecticides, we were able to control for a variety of potentially confounding occupational, demographic and lifestyle factors in our analysis. Fourth, our outcome for this study is cancer incidence, using data collected from population-based cancer registries, which eliminates issues of survival bias when cancer mortality is the endpoint of interest.
There are also limitations to this study. First, only 44% of the enrolled study subjects completed the take-home questionnaire, which was the source of detailed information regarding OC insecticide use. This raises the question as to whether selection bias may have influenced our findings and may have limited the generalizability of our sample. However, an earlier analysis found that individuals completing the take-home questionnaire were older on average than non-respondents, but otherwise comparable (48
). Since we adjusted for age in all analyses, it is unlikely that selection bias is a plausible explanation for our findings. Second, study subjects would mostly have been recalling past, not current, use of OC insecticides at the time of data collection since most OC insecticides were banned long before study enrollment. The subjects’ recall of pesticide exposures several years in the past could introduce measurement error. Since information on pesticide use was collected prior to disease diagnosis, the misclassification should be non-differential and would likely lead to an attenuation of observed risk estimates. Although exposure misclassification may have occurred, previous evaluation of this issue has shown that recall of pesticide use in the AHS is comparable to that of other factors commonly obtained by interview in epidemiologic studies, Test-retest percentage agreement ranged from 70% to more than 90% for ever vs. never use of specific pesticides and from 50% to 60% for duration, frequency, or decade of first use of specific pesticides (49
). A majority of subjects reported pesticide use duration information that was plausible (i.e., not an overestimate) in relation to the years that that pesticide had been registered for use (50
). Third, the timing of the AHS (recruitment from 1993–1997, follow-up through 2002) may have been too late to capture cancer risks associated with OC insecticides, many of which were taken off the market in the 1970s and 1980s. However, the OC insecticide body burden among AHS applicators may still be high, given the tendency of these chemicals to accumulate and persist in fatty tissue. When we restricted our analysis to subjects aged 50 or older at enrollment, who were most likely to have applied OC insecticides in large amounts prior to their restriction, our findings did not change. Fourth, the follow-up of this cohort is relatively short, and for some cancers the number of accrued cases is small, particularly for chemical-specific analyses; as a result, analyses of these cancers had limited statistical power to detect associations of moderate size. Additionally, given the large number of comparisons performed in our analyses, we cannot rule out the possibility that some of our observed chemical-specific findings may have arisen due to chance.
In conclusion, our analysis of data from the AHS cohort suggests that, overall, use of OC insecticides was not related to cancer risk. We did, however, observe associations among specific chemicals, some of which (lindane and NHL, chlordane/heptachlor and leukemia) are supported by previously published studies and warrant further investigation. New studies of OC insecticide use in Western countries are probably no longer feasible, given that most chemicals have been off the market for many years. Instead, the most suitable settings for such projects nowadays are likely to be found in India and other developing countries where these chemicals are still in use. A future re-analysis of AHS applicators following additional follow-up may also be informative for clarifying whether these insecticides influence cancer risk.