VOLUME 114 | NUMBER 12 | December 2006 • Environmental Health Perspectives
Fonofos (O-ethyl S-phenyl ethylphospho-
nodithioate), first registered for use with the
U.S. Environmental Protection Agency (EPA)
in 1967, is an organophosphate insecticide
applied to soil to protect mainly corn but also
sugarcane, peanuts, tobacco, and several other
crops from various types of worms (U.S. EPA
1999). Fonofos has no residential uses. In
1998, the registrant of fonofos voluntarily
cancelled its registration (U.S. EPA 1999).
The current state of knowledge regarding
the health effects of fonofos is limited. The few
studies examining the genotoxicity and muta-
genicity of fonofos have had inconsistent
results. Gentile et al. (1982) found fonofos to
be mutagenic both directly and after metabolic
activation in assays using both Saccharomyces
cerevisiae and Salmonella typhimurium, but
Simmons et al. (1979) found it to be negative
in both assays.
To our knowledge, there have been no
studies of fonofos in whole animals published
in the peer-reviewed literature. However, sev-
eral proprietary 2-year feeding studies con-
ducted for regulatory evaluation found no
tumors in rats and mice from the administra-
tion of fonofos (California Department of
Pesticide Regulation 1997).
The epidemiologic evidence linking fono-
fos with cancer is suggestive, but insufficient
to establish a causal relationship. Early
case–control studies of non-Hodgkin lym-
phoma (NHL) and leukemia risk factors
among farmers pointed toward the class of
organophosphates (Brown et al. 1990; Cantor
et al. 1992; Clavel et al. 1996; Zahm et al.
1993). Later, to evaluate specific pesticides as
risk factors for NHL, Waddell et al. (2001)
and De Roos et al. (2003) pooled three popu-
lation-based case–control studies conducted
in the midwestern United States and found
odds ratios (ORs) for fonofos exposure of 1.7
[95% confidence interval (CI), 1.1–2.6] and
1.8 (95% CI, 0.9–3.5), respectively. Further,
because NHL is associated with a compro-
mised immune system, Lee et al. (2004)
pooled two of the studies to evaluate risk
from pesticide exposure and asthma, a marker
of immune alteration, and observed an ele-
vated main effect for fonofos use (OR = 1.6;
95% CI, 1.0–2.4) as well as an elevated joint
effect of fonofos use and asthma (OR = 3.7;
95% CI, 1.3–10.9).
In addition, in a tumor-specific analysis of
the Agricultural Health Study (AHS), fonofos
has been significantly associated with prostate
cancer among applicators with a family history
of prostate cancer (OR = 1.80; 95% CI,
1.14–2.84) (Alavanja et al. 2003). Moreover,
other chemically similar pesticides of the
organothiophosphate subclass have also been
associated with prostate cancer and lung cancer
in tumor-specific analyses (Alavanja et al.
In light of the evidence linking fonofos to
prostate cancer in the previous tumor-specific
analysis and the literature linking fonofos to
leukemia and NHL, our primary aim was to
study fonofos use with respect to incident
cancer of all types in a chemical specific
analysis among 45,372 participants of the
AHS. Our secondary aim was to use more
detailed exposure information along with an
additional 3.2 years of follow-up since the
previous prostate cancer analysis, which pro-
vided 87 new prostate cancer cases with
prostate cancer family history information, to
see if the prostate cancer finding held.
Materials and Methods
Enrollment and follow-up. The AHS has
been described previously (Alavanja et al.
1996). Briefly, it is a prospective cohort of
52,395 private applicators (farmers) from
Iowa and North Carolina and 4,916 com-
mercial applicators (employees of pest control
companies or businesses whose primary func-
tion is not pesticide application) from Iowa
licensed to apply restricted use pesticides.
This cohort represents 82% of eligible appli-
cators from both states during the enrollment
period of the study (13 December 1993 to 31
December 1997). Population-based cancer
registries of both states were used to identify
subjects with incident cancer diagnoses
between enrollment and 31 December 2002.
Subjects who died or moved out of the state
were censored in the year of occurrence of
either event. Vital status was ascertained using
state death registries and the National Death
Address correspondence to M.C.R. Alavanja, 6120
Executive Blvd., EPS 8000, MSC 7240, Occupa-
tional Epidemiology Branch, Division of Cancer
Epidemiology and Genetics, National Cancer
Institute, Rockville, MD 20852 USA. Telephone:
(301) 435-4720. Fax: (301) 402-1819. E-mail:
We acknowledge the assistance and expertise of
E. Hodgson and R. Rose.
This research was supported by the Intramural
Research Program of the National Cancer Institute
and the National Institute of Environmental Health
Sciences, National Institutes of Health.
The authors declare they have no competing
Received 28 April 2006; accepted 17 August 2006.
Fonofos Exposure and Cancer Incidence in the Agricultural Health Study
Rajeev Mahajan,1Aaron Blair,1Charles F. Lynch,2Paul Schroeder,3Jane A. Hoppin,4Dale P. Sandler,4
and Michael C.R. Alavanja1
1Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute,
National Institutes of Health, Department of Health and Human Services, Rockville, Maryland, USA; 2Department of Epidemiology,
University of Iowa, Iowa City, Iowa, USA; 3Westat, Rockville, Maryland, USA;4Epidemiology Branch, National Institute of Environmental
Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
BACKGROUND: The Agricultural Health Study (AHS) is a prospective cohort study of licensed pesticide
applicators from Iowa and North Carolina enrolled 1993–1997 and followed for incident cancer
through 2002. A previous investigation in this cohort linked exposure to the organophosphate fonofos
with incident prostate cancer in subjects with family history of prostate cancer.
OBJECTIVES: This finding along with findings of associations between organophosphate pesticides
and cancer more broadly led to this study of fonofos and risk of any cancers among 45,372 pesticide
applicators enrolled in the AHS.
METHODS: Pesticide exposure and other data were collected using self-administered questionnaires.
Poisson regression was used to calculate rate ratios (RRs) and 95% confidence intervals (CIs) while
controlling for potential confounders.
RESULTS: Relative to the unexposed, leukemia risk was elevated in the highest category of lifetime
(RR = 2.24; 95% CI, 0.94-5.34, ptrend= 0.07) and intensity-weighted exposure-days (RR = 2.67;
95% CI, 1.06–6.70, ptrend = 0.04), a measure that takes into account factors that modify pesticide
exposure. Although prostate cancer risk was unrelated to fonofos use overall, among applicators
with a family history of prostate cancer, we observed a significant dose–response trend for lifetime
exposure-days (ptrend= 0.02, RR highest tertile vs. unexposed = 1.77, 95% CI, 1.03–3.05;
RRinteraction= 1.28, 95% CI, 1.07–1.54). Intensity-weighted results were similar. No associations
were observed with other examined cancer sites.
CONCLUSIONS: Further study is warranted to confirm findings with respect to leukemia and deter-
mine whether genetic susceptibility modifies prostate cancer risk from pesticide exposure.
KEY WORDS: agriculture, fonofos, insecticides, neoplasms, occupational exposure, organophosphorus
compounds, organothiophosphorus compounds, pesticides. Environ Health Perspect 114:1838–1842
(2006). doi:10.1289/ehp.9301 available via http://dx.doi.org/ [Online 18 August 2006]
Index. Residence information was obtained
through motor vehicle records, pesticide regis-
tration records, and address files of the Internal
Revenue Service. To date, average follow-up
time is 7.5 years and follow-up is > 98% com-
plete. All participants provided informed con-
sent, and the research protocol was approved
by all appropriate institutional review boards.
Exposure assessment. On enrollment, pesti-
cide applicators seeking a restricted-use pesti-
cide license completed a self-administered
questionnaire. The questionnaire obtained
detailed exposure information (days of use per
year, years of use, and decade of first use) for 22
pesticides (including fonofos) and ever/never
use information for 28 additional pesticides, as
well as information on application methods,
pesticide mixing status, personal protective
equipment use, personal equipment repair,
smoking, current alcohol use, cancer history in
first-degree relatives, and basic demographic
data. For some analyses, we used information
on solvent exposure that was collected using a
self-administered take-home questionnaire
completed by 44% of those enrolled [both
questionnaires available at http://www.aghealth.
org/questionnaires.html (AHS 2006)].
We estimated fonofos exposure in terms
of cumulative fonofos lifetime exposure-days
and intensity-weighted exposure-days. We
calculated lifetime exposure-days as the cross-
product of the questionnaire categories for
frequency of fonofos use in an average year
and the number of years of fonofos use, using
the midpoints of the questionnaire categories.
We assessed intensity of exposure using an
algorithm developed by Dosemeci et al.
(2002). This algorithm calculates an intensity
score that takes into account the effect of
modifying factors, such as how often an
applicator personally mixed or prepared the
pesticide, the type of application methods
used, whether an applicator personally
repaired pesticide application equipment, and
the type of personal protective equipment
used. By multiplying the intensity score with
fonofos lifetime exposure-days, we obtained
fonofos intensity-weighted exposure-days.
Statistical analysis. All pesticide applica-
tors who returned an enrollment question-
naire were eligible for analysis. We excluded
applicators if they did not provide information
on fonofos exposure duration (n = 5,987); if
their first primary cancer occurred before
enrollment (n = 937), if they did not live in
either state on enrollment (n = 295); or if they
did not provide information on birth year
(n = 2), smoking (n = 1,664), or use of corre-
lated pesticides (n = 3,054). After exclusions,
45,372 subjects were available for the lifetime
exposure-days analysis. The intensity-weighted
exposure-days analysis contained four fewer
cancer cases and 55 fewer cancer-free subjects
because of missing data on intensity metric
covariates. Compared with retained subjects,
excluded subjects were generally older and
more likely to be from North Carolina.
We categorized fonofos lifetime exposure-
days and intensity-weighted exposure-days into
tertiles based on the distribution of exposure
among all cancer cases. Because the tertiles of
intensity-weighted exposure-days based on the
exposure distribution among all cancer cases
resulted in categories inadequate for analyzing
leukemia (one case in the lowest exposed
group), we created more uniform tertiles for
leukemia based on the exposure distribution
among leukemia cases. We used two different
reference groups—the unexposed and the low-
est exposed groups—to analyze all cancer sites
for which there were at least 15 exposed cases
and 4 cases per lifetime exposure-days category.
Specifically, we examined all cancers com-
bined; cancers of the prostate, lung, and colon;
melanoma skin cancer; leukemia; and lympho-
hematopoietic cancer consisting of Hodgkin
lymphoma, NHL, leukemia, and multiple
Statistical analyses were conducted in
AHS data release 0412.01 using Stata version
8 (StataCorp 2003). We used Poisson regres-
sion to calculate rate ratios (RRs) and 95%
CIs while adjusting for multiple covariates.
Covariates included category of age at enroll-
ment (< 40, 40–49, 50–59, ≥ 60 years of
age), state of residence, pack-years of smoking
categorized at the median (0, ≤ 12, > 12), and
use of the four most correlated pesticides
[trichlorofon, carbofuran, imazethapyr, and
S-ethyl dipropylthiocarbamate (EPTC)].
Pearson correlation coefficients ranged between
0.43 and 0.50. Use of each correlated pesti-
cide was classified as never, low, and high,
with the median lifetime exposure-days cate-
gorizing low and high usage. As an alternative
strategy to account for use of other pesticides,
we also replaced use of the most correlated
pesticides with lifetime exposure-days to all
pesticides. Further adjustment for education,
sex, alcohol consumption in the previous
12 months, applicator type, cancer history in
first-degree relatives, and enrollment year did
not affect point estimates by > 10%. We per-
formed linear trend tests to assess the overall
dose–response trend by entering exposure cate-
gories ordinally in the models after assigning
them median exposure value in that category.
All statistical tests were two-sided.
Selected characteristics of the study popula-
tion are displayed in Table 1 according to life-
time exposure-days category. In this table,
“lowest exposed” refers to those in the lowest
exposure tertile (> 0–20 lifetime exposure-
days), whereas “other exposed” refers to those
in the middle and highest tertiles (> 20 life-
time exposure-days). Overall, two-thirds of
the study participants were from Iowa. More
than two-thirds of the cohort reported corn
farming. Study subjects were also predomi-
nantly white and male. Just over half reported
being never smokers. Close to 55% reported
that the highest level of schooling attained
was no more than a high school diploma.
Approximately 40% reported a history of can-
cer in first-degree relatives.
The unexposed group was generally
younger, less likely to use alcohol, and slightly
less likely to report a family history of cancer,
used fewer pesticides in general, and planted
fewer acres than either exposed group. Both
Iowa participants and corn farmers were over-
represented in the exposed categories. Based
on these differences between the unexposed
group and either exposed group, the lowest
exposed group may represent the exposed
group more closely.
With the intensity-weighted metric, risk
estimates for all cancers combined were not
different from the null, regardless of the refer-
ence group used (Table 2). Colon cancer risk
estimates were elevated, but only when using
the unexposed as the reference, and the rela-
tionship was not monotonic. Leukemia risk
estimates were elevated regardless of the refer-
ence group used. When the unexposed group
was the reference, the RR was 2.67 (95% CI,
1.06–6.70) in the highest exposure category,
and the test for linear trend was significant
(ptrend= 0.04). When the lowest exposed
group was the reference, the corresponding
RR was 2.03 (95% CI, 0.58–7.05). The linear
trend test was not significant. Fonofos inten-
sity-weighted exposure-days were not related
to the risk of any other examined cancer.
Results were similar using the lifetime
exposure-days metric (not shown). For exam-
ple, using the unexposed group as the refer-
ence, leukemia RRs increased monotonically
to 2.24 (95% CI, 0.94–5.34) in the highest
tertile (ptrend= 0.07). When the lowest
exposed tertile was used as the reference, the
risk estimates increased monotonically with
increasing exposure category to 2.18 (95%
CI, 0.57–8.40) in the highest tertile. The test
for linear trend was not significant.
To account for the effect of misclassifica-
tion due to the inclusion of exposure that
occurred too recently to affect cancer risk, we
repeated the analyses excluding 39 cancer cases
and 1,389 cancer-free subjects who either
reported first using fonofos during the 1990s
or did not provide this information. The
results were similar to those presented here
(not shown). The results were also similar after
repeating the analyses among Iowa participants
only (not shown). Additionally, to control for
pesticide use in general, we repeated the analy-
ses adjusting for lifetime exposure-days to all
pesticides instead of the most correlated pesti-
cides, and the results did not differ from those
Occupational fonofos exposure and incident cancer
Environmental Health Perspectives • VOLUME 114 | NUMBER 12 | December 2006
presented here (not shown). To evaluate the
effect of missing information, we repeated the
analyses while allowing subjects with missing
information on covariates to influence the out-
come by assigning them an unspecified cate-
gory. Once again, the results were largely the
same (not shown). Finally, the results were
similar when we separately examined fonofos
days of use and years of use after categorizing
each into none, low, and high categories for
exposure, using the median to distinguish
between low and high (not shown).
We further investigated leukemia by sepa-
rately examining chronic lymphocytic (eight
exposed cases), chronic myelogenous (two
exposed cases), acute myelogenous (five
exposed cases), and all other leukemias (three
exposed cases) (not shown). Acute lympho-
cytic leukemia could not be evaluated (no
exposed cases). Although the CIs were wide
and the point estimates were not significant,
relative to the unexposed, the age-adjusted risk
estimates in low- and high-exposure categories
were elevated for all examined subtypes. In the
high-exposure category, point estimates
ranged from 1.75 for acute myelogenous to
3.65 for chronic myelogenous leukemia.
We also adjusted leukemia risk estimates
using data on use of gasoline, solvents, and
paint, which were collected among private
applicators using the take-home questionnaire
(not shown). Although the subset of other-
wise eligible applicators who provided the
aforementioned information was small (eight
exposed cases), adjusting for these exposures
did not weaken the leukemia risk estimates.
Finally, controlling for animal exposures
using information on the number of livestock
(other than poultry) or whether applicators
butchered animals, provided veterinary ser-
vices to livestock, or worked in swine or poul-
try containing areas, did not affect risk
estimates (not shown).
Table 3 shows prostate cancer risk relative
to the unexposed using both metrics and strat-
ified by family history of prostate cancer in
first-degree relatives. We generated uniform
exposure categories based on the exposure dis-
tribution among prostate cancer cases. In the
group with no prostate cancer family history,
risk was not associated with exposure regard-
less of the metric. In those with a family his-
tory of prostate cancer, the risk estimates
increased, and significant linear trends were
observed using either metric. Using the life-
time exposure-days metric, we observed a sig-
nificant dose–response relationship (ptrend=
0.02), which resulted in a RR of 1.77 (95% CI,
1.03–3.05) in the highest exposure category.
The interaction term, defined as the cross-prod-
uct of family history of cancer and category of
lifetime exposure-days (treated as a continuous
variable), was significant (RR = 1.28; 95% CI,
1.07–1.54). With the intensity-weighted expo-
sure-days metric, risk in the highest category
was 1.83 (95% CI, 1.12–3.00). The test for
linear trend was significant (ptrend= < 0.01), as
was the interaction RR of 1.27 (95% CI,
When the analysis in Table 3 was repeated
using the lowest exposed group as the reference,
the results were similar but less pronounced due
to decreased statistical power (not shown). Risk
was related to fonofos use only in those with a
family history of prostate cancer. Point esti-
mates increased monotonically with lifetime
exposure-days to 1.24 (95% CI, 0.61–2.51) in
the highest category. The interaction RR was
1.25 (95% CI, 0.83–1.89). Point estimates
generally increased with intensity-weighted
exposure-days to 1.68 (95% CI, 0.83–3.39) in
the highest category. The interaction RR was
1.27 (95% CI, 0.85–1.89). Linear trend tests
were not significant using either metric.
When the risk of the other examined can-
cers (all cancers combined, melanoma,
leukemia, lymphohematopoietic cancers, lung
cancer, and colon cancer) was similarly strati-
fied, no discrepancies were observed compar-
ing those with and without a family history of
the specific cancer (not shown).
When we did further analyses to disentan-
gle the effects of prostate cancer family history
and fonofos exposure, we observed that the
age-adjusted main effect for ever compared
with never fonofos exposure was 0.97 (95%
CI, 0.80–1.17), whereas for family history
of prostate cancer, it was 1.67 (95% CI,
Mahajan et al.
VOLUME 114 | NUMBER 12 | December 2006 • Environmental Health Perspectives
Table 1. Characteristics of applicators by fonofos exposure in the AHS (1993–1997) [no. (%)].
(n = 36,313)
(n = 3,496)
(n = 5,563) Characteristic
State of residence
Light (≤ 12 pack-years)
High (≥ 12 pack-years)
≤ High school
> High school
Family history of cancera
Use of correlated pesticides
Acres planted previous yeara
No. of livestock (other than poultry) on farma
None/did not farm
No. of pesticides used (mean ± SD)
11.7 ± 6.7
17.0 ± 6.7
18.4 ± 7.2
aNumbers of applicators do not sum to total because of missing information. bBased on reported alcohol consumption in
the previous 12 months.
1.35–2.07). The observed joint effect of the
two exposures was 2.63 (95% CI, 1.96–3.53).
In this study we evaluated cumulative lifetime
fonofos exposure until enrollment as a risk
factor for incident cancer occurring between
the end of enrollment through 2002. Almost
40% of exposed applicators first used fonofos
before 1980. Thus, although the period of can-
cer incidence follow-up is 7.5 years on average,
the actual time from first use to the end of the
follow-up period is longer. We did not observe
an association between fonofos exposure and
the incidence of all cancers combined. We did
not have enough cases to evaluate NHL. There
was, however, evidence of an association
between fonofos and leukemia. There was also
an observed association between fonofos and
prostate cancer among those with a family his-
tory of prostate cancer.
Organophosphates have been associated
with leukemia and other immunologically
related cancers in the epidemiologic literature
(Brown et al. 1990; Cantor et al. 1992; Clavel
et al. 1996; De Roos et al. 2003; Lee et al.
2004; Waddell et al. 2001; Zahm et al. 1993).
The leukemogenic effects of organophosphates
may be related to immune function perturba-
tion. Organophosphates irreversibly inhibit
acetylcholine esterase, an enzyme that breaks
down the neurotransmitter acetylcholine into
inactive metabolites. Lymphocytes contain
essential components of a cholinergic system,
and studies suggest that prolonged acetyl-
choline esterase receptor stimulation, which
could result from irreversible acetylcholine
esterase inhibition, can alter lymphocytic
activity (Kawashima and Fujii 2003).
Prostate cancer risk was not related to
fonofos exposure overall. We did, however,
find increased prostate cancer risk associated
with fonofos use for those with a family his-
tory of prostate cancer. This result was previ-
ously reported in a case–control analysis of
prostate cancer in the AHS, albeit with 87
fewer cases and 3.2 years shorter follow-up
(Alavanja et al. 2003). Here we extend this
result by also reporting a dose response with
lifetime exposure-days and intensity-weighted
The statistical interaction that we observed
here between fonofos exposure and family his-
tory of prostate cancer could have several
explanations. One explanation may be that
positive prostate cancer family history may
serve as a surrogate for an inherited genetic
trait, such as a polymorphism in a metabolic
enzyme. There are known polymorphic vari-
ants of several cytochrome P450 isoforms that
vary considerably in their ratio of chlorpyrifos
bioactivation to detoxification (Dai et al.
2001; Tang et al. 2001). As organothiophos-
phates, fonofos and chlorpyrifos are similar in
that they must be metabolized to their bio-
active neurotoxic oxon forms (Maroni et al.
2000), and if fonofos shares some of the same
metabolic enzymes as chlorpyrifos, such a
polymorphism may account for the inter-
action. Alternatively, fonofos, phorate, and
chlorpyrifos significantly inhibit testosterone
metabolism in human liver microsomes, most
Occupational fonofos exposure and incident cancer
Environmental Health Perspectives • VOLUME 114 | NUMBER 12 | December 2006
Table 3. Prostate cancer RRs (95% CIs) among AHS (1993–1997) participants by family history of prostate
cancer using fonofos lifetime and intensity-weighted exposure-days metrics.
No family history
CategoryCases (n)RRa(95% CI)
0 534 1.00 (Referent)
> 0–20 58 1.08 (0.82–1.41)
> 20–56 510.93 (0.70–1.25)
> 56 30 0.86 (0.60–1.24)
0 5341.00 (Referent)
> 0–9650 0.93 (0.69–1.24)
> 97–31445 1.03 (0.76–1.39)
> 315 42 0.96 (0.70–1.31)
RRb(95% CI)Cases (n)RRa(95% CI)
aAdjusted for age (< 40, 40–49, 50–59, ≥ 60 years). bAdjusted for age (< 40, 40–49, 50–59, ≥ 60 years) and family history of
prostate cancer. cFor lifetime exposure-days, the categories generated based on the exposure distribution among prostate
cancer cases happened to be the same as the categories generated from the exposure distribution of all cancer cases.
Table 2. RRsa(95% CIs) for selected cancers by fonofos intensity-weighted exposure-days among AHS
(1993–1997) applicators, using unexposed and lowest-exposed applicators as the reference groups.
Melanoma skin cancer
Cases (n)Unexposed reference Lowest exposed reference
61 1.00 (Referent)
aAdjusted for age (< 40, 40–49, 50–59, ≥ 60 years), state of residence, pack-years of smoking (0, ≤ 12, > 12), and use of the
four most correlated pesticides (trichlorofon, carbofuran, imazethapyr, and EPTC).
Mahajan et al. Download full-text
VOLUME 114 | NUMBER 12 | December 2006 • Environmental Health Perspectives
likely as a result of their noncompetitive inhi-
bition of cytochrome P450 3A4 testosterone
metabolism (Usmani et al. 2003).
As with any study, some exposure misclas-
sification is likely (Acquavella et al. 2006), but
because exposure information was collected
prospectively we have no reason to believe that
it occurred differentially between cancer cases
and cancer-free subjects. In addition, some of
the exposure considered here may have
occurred too recently to contribute to cancer
occurrence. However, we repeated several
analyses restricted to those whose year of first
use occurred before 1990, and the results did
not appreciably differ from the unrestricted
Pesticide applicators come into contact
with multiple farm chemicals, including pesti-
cides, and other agents. A previous AHS
examination determined that a relationship
between pesticide exposure and disease is not
likely confounded by farming or nonfarming
activities (Coble et al. 2002). In this study, we
attempted to control for exposures to other
pesticides using two approaches. First, we
adjusted the risk estimates for use of the four
pesticides that were most correlated with fono-
fos. Alternatively, to control for the effects of
exposure to all pesticides, we adjusted for life-
time exposure-days to all pesticides. The meas-
ured differences between exposed and
unexposed applicators in age and family his-
tory of cancer would normally raise concerns
that these groups also differed with respect to
other unmeasured cancer risk factors, but the
overall conclusions did not differ when the
unexposed and lowest exposed groups were
used as the reference.
The main strengths of this study include
its large prospective design, complete recruit-
ment and follow-up, and the use of semi-
quantitative exposure measures that improve
on the qualitative measures used in previous
studies of pesticide exposure. In addition, our
results are internally consistent, as further
adjustment and subgroup analyses did not
result in different conclusions.
This is, to our knowledge, the largest
examination of any group occupationally
exposed to fonofos. Our strategy for evaluat-
ing the carcinogenic potential of pesticides in
the cohort is to examine each pesticide with
respect to cancer outcomes, to examine each
cancer outcome with respect to pesticide expo-
sures, and to examine the consistency of the
relationship across time, state, and license
type. Our conclusions are limited because of
the small number of exposed cases, especially
for leukemia. As follow-up of the cohort con-
tinues, more cancer cases will develop as the
cohort ages, at which point the relationship
between cancer and exposure to fonofos and
other pesticides needs to be confirmed.
Acquavella JF, Alexander BH, Mandel JS, Burns CJ, Gustin C.
2006. Exposure misclassification in studies of agricultural
pesticides: insights from biomonitoring. Epidemiology
AHS (Agricultural Health Study). 2006. AHS Questionnaires.
[accessed 12 June 2006].
Alavanja MC, Dosemeci M, Samanic C, Lubin J, Lynch CF, Knott
C, et al. 2004. Pesticides and lung cancer risk in the agri-
cultural health study cohort. Am J Epidemiol 160:876–885.
Alavanja MC, Samanic C, Dosemeci M, Lubin J, Tarone R,
Lynch CF, et al. 2003. Use of agricultural pesticides and
prostate cancer risk in the Agricultural Health Study
cohort. Am J Epidemiol 157:800–814.
Alavanja MC, Sandler DP, McMaster SB, Zahm SH, McDonnell
CJ, Lynch CF, et al. 1996. The Agricultural Health Study.
Environ Health Perspect 104:362–369.
Brown LM, Blair A, Gibson R, Everett GD, Cantor KP, Schuman
LM, et al. 1990. Pesticide exposures and other agricultural
risk factors for leukemia among men in Iowa and Minnesota.
Cancer Res 50:6585–6591.
California Department of Pesticide Regulation. 1997. Summary
of Toxicology Data: Fonofos. Sacramento, CA:Department
of Pesticide Regulation, California Environmental
Protection Agency. Available: http://www.cdpr.ca.gov/
docs/toxsums/pdfs/254.pdf [accessed 27 February 2006].
Cantor KP, Blair A, Everett G, Gibson R, Burmeister LF, Brown
LM, et al. 1992. Pesticides and other agricultural risk fac-
tors for non-Hodgkin’s lymphoma among men in Iowa and
Minnesota. Cancer Res 52:2447–2455.
Clavel J, Hemon D, Mandereau L, Delemotte B, Severin F,
Flandrin G. 1996. Farming, pesticide use and hairy-cell
leukemia. Scand J Work Environ Health 22:285–293.
Coble J, Hoppin JA, Engel L, Elci OC, Dosemeci M, Lynch CF, etal.
2002. Prevalence of exposure to solvents, metals, grain dust,
and other hazards among farmers in the Agricultural Health
Study. J Expo Anal Environ Epidemiol 12:418–426.
Dai D, Tang J, Rose R, Hodgson E, Bienstock RJ, Mohrenweiser
HW, et al. 2001. Identification of variants of CYP3A4 and
characterization of their abilities to metabolize testosterone
and chlorpyrifos. J Pharmacol Exp Ther 299:825–831.
De Roos AJ, Zahm SH, Cantor KP, Weisenburger DD, Holmes
FF, Burmeister LF, et al. 2003. Integrative assessment of
multiple pesticides as risk factors for non-Hodgkin’s lym-
phoma among men. Occup Environ Med 60:E11.
Dosemeci M, Alavanja MC, Rowland AS, Mage D, Zahm SH,
Rothman N, et al. 2002. A quantitative approach for esti-
mating exposure to pesticides in the Agricultural Health
Study. Ann Occup Hyg 46:245–260.
Gentile JM, Gentile GJ, Bultman J, Sechriest R, Wagner ED,
Plewa MJ. 1982. An evaluation of the genotoxic properties
of insecticides following plant and animal activation. Mutat
Kawashima K, Fujii T. 2003. The lymphocytic cholinergic system
and its contribution to the regulation of immune activity.
Life Sci 74:675–696.
Lee WJ, Cantor KP, Berzofsky JA, Zahm SH, Blair A. 2004. Non-
Hodgkin’s lymphoma among asthmatics exposed to pesti-
cides. Int J Cancer 111:298–302.
Maroni M, Colosio C, Ferioli A, Fait A. 2000. Biological monitoring
of pesticide exposure: a review. Introduction. Toxicology
Simmons VF, Poole DC, Riccio ES, Robinson DE, Mitchell AD,
Waters MD. 1979. In vitro mutagenicity and genotoxicity
assays of 38 pesticides. Environ Mutagen 1:142–143.
StataCorp. 2003. Stata Reference Manual: Release 8. College
Station, TX:Stata Press.
Tang J, Cao Y, Rose RL, Brimfield AA, Dai D, Goldstein JA, et al.
2001. Metabolism of chlorpyrifos by human cytochrome
P450 isoforms and human, mouse, and rat liver microsomes.
Drug Metab Dispos 29:1201–1204.
U.S. EPA. 1999. Fonofos Registration Eligibility Document Facts.
Washington, DC:US Environmental Protection Agency.
0105fact.pdf [accessed 27 February 2006].
Usmani KA, Rose RL, Hodgson E. 2003. Inhibition and activation
of the human liver microsomal and human cytochrome
P450 3A4 metabolism of testosterone by deployment-
related chemicals. Drug Metab Dispos 31:384–391.
Waddell BL, Zahm SH, Baris D, Weisenburger DD, Holmes F,
Burmeister LF, et al. 2001. Agricultural use of organophos-
phate pesticides and the risk of non-Hodgkin’s lymphoma
among male farmers (United States). Cancer Causes
Zahm SH, Weisenburger DD, Saal RC, Vaught JB, Babbitt PA,
Blair A. 1993. The role of agricultural pesticide use in the
development of non-Hodgkin’s lymphoma in women. Arch
Environ Health 48:353–358.