We found no association between permethrin and all cancers combined; cancers of the colon, rectum, lung, prostate, and bladder; melanoma; and non-Hodgkin lymphoma. Some RR estimates for all lymphohematopoietic cancers and for leukemia were elevated (lifetime days), but findings were not consistent across exposure metrics. We found an elevated risk for multiple myeloma among applicators in the highest tertile (n = 10) of lifetime exposure-days (RR = 5.72; 95% CI, 2.76–11.87; p-trend < 0.01) and in the highest tertile of intensity-weighted lifetime exposure-days (RR = 5.01; 95% CI, 2.41–10.42; p-trend < 0.01) compared with nonexposed applicators. We also found consistently elevated and statistically significant risks for multiple myeloma for both exposure metrics and when using applicators in the lowest tertile of exposure as the reference group. However, there were only 15 exposed cases; small numbers indicate this could be a chance finding.
To further evaluate the multiple myeloma association, we carried out a series of additional analyses using different categorizations of lifetime exposure-days and intensity-weighted lifetime exposure-days, as well as other exposure metrics available to us in the AHS: years applied permethrin, average days per year applied permethrin, and intensity score for permethrin. We found consistently elevated RRs in the top exposure categories and highly significant tests for trend (data not shown). An analysis stratifying by state of residence showed statistically significant elevations in the upper tertile for both Iowa and North Carolina (data not shown).
Human data on cancer and permethrin exposure are limited. The only epidemiologic findings available, based on earlier analyses in the AHS cohort, showed an elevated risk for prostate cancer among applicators with a family history of prostate cancer who ever applied permethrin to animals (RR = 2.38; 95% CI, 1.34–4.25), compared with those who never applied it, but no elevation among applicators who had no family history of prostate cancer (Alavanja et al. 2003
). Our results for prostate cancer were weaker. The reasons for this difference are not clear. Our cohort analysis consisted of five additional years of cancer incidence data and was based on a combined use of permethrin on animals and on crops, whereas the analysis by Alavanja et al. (2003)
was a case–control analysis based on the use of permethrin on animals. However, in an analysis for animal permethrin alone, we found no strong association. Other case–control analyses in the AHS found no evidence of elevated risk for cancer of the lung (Alavanja et al. 2004
), colon (Lee et al. 2007
), or breast (Engel et al. 2005
) with permethrin exposure; we also found no evidence of elevated risk for these cancers in this analysis. Chemical-specific analyses from the AHS have shown non-statistically significant increases in multiple myeloma with glyphosate use (De Roos et al. 2005
) and atrazine use (Rusiecki et al. 2004
). However, adjustment for atrazine, glyphosate, and other highly correlated pesticides did not affect the results, so the association between multiple myeloma and permethrin observed here is unlikely to be due to confounding by other pesticide exposures.
Before introducing permethrin-impregnated BDUs for military personnel, the U.S. Army asked the National Research Council (NRC) to review the toxicologic and exposure data on permethrin and perform a quantitative risk assessment to evaluate health risks to deployed U.S. military personnel from vector management tactics. The NRC risk assessment was used to determine whether wearing BDUs impregnated with permethrin (at a concentration of 0.125 mg/cm2
of fabric) 18 hr/day, 7 days/week, for up to 10 years is safe for soldiers, and whether handling permethrin-impregnated fabric is safe for garment workers. The aggregate cancer risk for permethrin, based on estimated exposures for various scenarios and pathways, was found to be low (Macedo et al. 2007
). The NRC concluded that, based on the review of toxicity data on permethrin, soldiers who wear permethrin-impregnated BDUs are unlikely to experience adverse health effects (NRC 1994
There are no previous human data on a potential link between permethrin exposure and multiple myeloma. Multiple myeloma is an incurable B-cell malignancy morphologically characterized by a proliferation of plasma cells in the bone marrow (Kyle and Rajkumar 2004
). It is often preceded by a clinically benign and typically asymptomatic precursor condition, monoclonal gammopathy of undetermined significance (MGUS) (Kyle et al. 2002
; Landgren et al. 2006
). However, it remains unclear whether MGUS precedes all cases of multiple myeloma, or if multiple myeloma can arise de novo
without preceding MGUS (Hideshima et al. 2007
). To date, there are no established lifestyle, occupational, or environmental risk factors for MGUS and multiple myeloma (Landgren and Kyle 2007
). Because the risk of progression from MGUS to multiple myeloma in the general population has been reported to be very stable regardless of the duration of antecedent MGUS (Kyle et al. 2002
; Landgren et al. 2006
), it has been proposed to reflect the second hit in a random, two-hit genetic model of malignancy (Rajkumar 2005
). The specific second hit that initiates the cascade of events associated with progression is unknown but may include gene–environment interactions. Permethrin might play a role as an immune modulatory factor (via immune stimulation, immune dysregulation, or both) involved in multiple myeloma progression. Alternatively, permethrin might act in a similar fashion and trigger the development of MGUS, which in turn is reflected in an excess risk of multiple myeloma, or the observed elevated risk of multiple myeloma could simply be a chance finding.
A hypothesis proposed for the potential carcinogenicity of permethrin involves the breakdown of an amino acid, tryptophan, which can in turn lead to buildup of carcinogenic tryptophan breakdown products (el-Toukhy et al. 1989
) and inhibition of gap-junctional intercellular communication (Tateno et al. 1993
). Mechanisms of action, however, are often dose dependent, and because the AHS does not include dose information, our discussion of mechanisms and biological plausibility must be limited at this time. In experimental studies, permethrin has been evaluated for carcinogenic activity in both rats and mice and for mutagenic activity in vitro
. Results of cancer bioassays in laboratory animals are mixed, and none have indicated an increased risk for multiple myeloma or other hematopoietic cancers (el-Toukhy et al. 1989
; Gabbianelli et al. 2004
; Hakoi et al. 1992
; IARC 1991
; Ishmael and Lithfield 1988
; Tisch et al. 2002
Certain limitations of our data hinder the inferences we can make regarding cancer risks from permethrin use. Although the AHS cohort is large, and 11,688 participants reported permethrin use, the small numbers of certain cancers occurring during the 9.14-year average follow-up period resulted in relatively imprecise risk estimates. In addition, most permethrin applicators were male (98%), precluding our ability to assess the association between permethrin exposure and female cancers. Another limitation is that almost all applicators identified themselves as white (99%). Our analysis provides limited information on the timing of pesticide use in relation to disease. Additionally, with only 9.14 years of follow-up, we are limited in our conclusions concerning latency and temporal changes in PPE. We will better address these issues with increased follow-up and exposure data from subsequent phases of the AHS. Although our study used more detailed exposure estimates than did earlier studies, the hours per day applicators engaged in pesticide application could vary considerably. Finally, although the exposure scale in this study is more sophisticated than that employed in most epidemiologic studies of pesticides, undoubtedly considerable exposure misclassification still occurs, which would tend to bias risk estimates in a prospective study such as this toward the null.
The AHS has several important strengths. It is the largest study of pesticide applicators exposed to permethrin to date. Exposure information was gathered before cancer diagnosis, thereby minimizing recall bias. In general, farmers provide reliable information and considerable detail regarding their pesticide application history (Blair and Zahm 1993
; Blair et al. 1997
; Coble et al. 2002
). The AHS cohort consists of licensed pesticide applicators who are responsible for a thorough understanding of pesticide regulations and for the purchase and application of chemicals (Hoppin et al. 2002
). Recall of pesticide use by the AHS cohort has been shown to be consistent with the dates these pesticides came onto the market (Hoppin et al. 2002
). Comprehensive questionnaire data was used to quantify permethrin exposure levels, providing discrimination between high and low exposures, rather than defining exposure as “ever used” permethrin. In addition, detailed information on the use of many common pesticides and lifestyle characteristics allowed us to adjust for potential confounding factors.
Despite the limitations noted above, our prospective study of cancer incidence among permethrin-exposed pesticide applicators provided an opportunity afforded in few other studies to evaluate cancer risks associated with exposure to this very widely used pesticide, while adjusting for lifestyle factors. We found no evidence of increased risk of cancer for most of the sites we investigated. There was a suggestion of an increased risk for multiple myeloma with increased lifetime exposure-days and intensity-weighted lifetime exposure-days and other exposure metrics (average days per year, total years, intensity level). However, the number of exposed multiple myeloma cases was small, and we cannot rule out that these findings may have occurred by chance. We intend to follow up these results in the future, focusing specifically on multiple myeloma as more cases develop in the cohort.