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pesticide applicators and their spouses. If there are AHS findings relevant to a particular 

pesticide going through registration review, the Agency will ensure they are considered in the 

problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk 

assessment phase of the process. The AHS includes information on use of 50 different pesticide 

active ingredients commonly used in agriculture.

IV. RESULTS/DISCUSSION

IDS records incidents resulting in higher severity outcomes in more detail, in a module called the 

Main IDS module. This system stores incident data for death, major and moderate incidents, and 

it includes more details about the location, date and nature of the incident. Main IDS incidents 

involving only one pesticide are considered to provide more certain information about the 

potential effects of exposure from the pesticide. The less severe human incidents (minor, 

unknown, or no effects outcomes) are reported by registrants as counts called aggregate 

summaries and are recorded in a separate module called Aggregate IDS. 

In Aggregate IDS, from January 1, 2007 to June 13, 2012, there were 2202 reported incidents

involving 2,4-D resulting in low severity outcomes. There are relatively few details provided on 

the incidents in the Aggregate IDS module and these incidents are low severity; regardless, the 

high absolute number of incidents (relative to other pesticides in IDS) reported involving 2,4-D

may suggest the need for a more in depth Tier II analysis during the Preliminary Risk 

Assessment phase of Registration Review.

For the Main IDS, from January 1, 2007 to June 13, 2012, there are 17 exposures, occurring in 

the United States, reported for single chemical only in the database (1 exposure classified as 

resulting in minor severity, 15 exposures classified as resulting in a moderate severity, and 1 

exposure classified as major severity), and 442 additional exposures that involved more than one 

chemical (1 exposure classified as resulting in unspecified severity, 3 exposures classified as 

resulting in minor severity, 403 exposures classified as resulting in a moderate severity, 29 

exposures classified as major severity, and 6 deaths). During the scoping phase of Registration 

Review, the higher severity exposures (those resulting in fatal or major outcomes) are considered 

in more detail. Additionally, as described above, incidents involving one pesticide are those 

upon which focus is typically placed because they are considered to provide more certain 

information about the potential effects of the particular pesticide. The one higher severity 

exposure (major outcomes) that involves 2,4-D only is described in Table 1. 

Agricultural Health Study 

2,4-D AHS Review

Among the 100+ publications from the Agricultural Health Study (AHS), there are only two 

which report an association of note with regard to 2,4-D exposure: risk of upper respiratory 

effect (rhinitis), and risk of fatal injury (Slager et al., 2009; Waggoner et al., 2012). Authors 

caution strongly that the positive exposure-response relation noted for 2,4-D in relation to fatal 

injury was unexpected, may be due to chance, and could not be discerned from risk of use of 

farm machine equipment used to apply the herbicide. However, given the frequency of use of 

2,4-D the results deserve consideration. The herbicide 2,4-D was not associated with any cancer 
Page 4 of 7

evaluated thus far in the AHS cohort including cancer of the breast, prostate, lung, pancreas, 

colon or cutaneous melanoma (Alavanja et al., 2004; Alavanja et al., 2003; Andreotti et al., 

2009; Dennis, Lynch, Sandler, & Alavanja, 2010; Engel et al., 2005; Lee et al., 2007). 

In previous research, AHS authors noted links between several individual pesticides as well as 

pesticide groups and lower respiratory symptoms, including wheeze (Hoppin, Umbach, London, 

Alavanja, & Sandler, 2002). The herbicide 2,4-D was not associated with wheeze in that study. 

However, 2,4-D use was significantly associated with an upper respiratory symptom, rhinitis or 

runny nose, in a study among 2,245 commercial pesticide applicators from Iowa (odds ratio (OR) 

1.34 (95% confidence interval (95% CI) 1.09, 1.64) (Slager 2009). Authors observed a positive 

exposure response relation (p for trend 0.009) between rhinitis and pesticide exposure, but only 

among applicators that reported using BOTH glyphosate and 2,4-D over the lifetime. Allergic 

reaction to grain or hay did not influence (confound) the relation in this study. Authors note 

rhinitis, while generally a non-serious, aggravating condition, is a marker for upper respiratory 

immune reaction to pesticides. Additional research is needed to understand the full import of 

immunological response to pesticides in the overall health burden of agricultural pesticide 

applicators; however, as the authors note, this paper suggests immune response to herbicides 

including 2,4-D may occur among occupationally exposed workers. 

The risk of fatal injury among agricultural workers is among the greatest of all occupational 

groups in the U.S.; the rate of fatal injury in the AHS cohort is comparable to the national rate 

for farmers. In this study, authors examined risk of fatal injury among 51,035 male pesticide 

applicators in Iowa and North Carolina considering cumulative pesticide use of the 15 years prior 

to the time of the study. There were 338 fatal injuries in the AHS cohort during this time period. 

Researchers observed a 20-50% increased risk of fatal injury among those exposed to 2,4-D, and 

significant exposure response relation (p for trend 0.01) (Waggoner et al., 2012). Authors states 

that the associations between herbicides overall as well as specific compounds including 2,4-D 

were not predicted, and may be due to chance. However, the observation of associations with 

several herbicides somewhat undermines the role of chance explanation. Authors further 

comment that given the structure of the data, it was not possible to disentangle to role of 

pesticide application equipment and the frequency of use of the equipment with the risk from 

individual pesticide exposure. Given the seriousness of the outcome and the frequency of use of 

2,4-D and herbicides in general, more research is warranted.

Overall, the AHS database lacks evidence that 2,4-D is related to any cancer outcome evaluated. 

There is some information to suggest an influence of 2,4-D exposure on upper respiratory 

immune response, however only in the presence of other herbicide, glyphosate. The association 

with fatal injury is unexpected and may be explained by frequent use of application equipment, 

or both; further research is needed to disentangle the role of multiple farm-related occupational 

exposures with risk of fatal injury.

Summary 

Overall, the AHS database lacks evidence that 2,4-D is related to any cancer outcome evaluated. 

There is some information to suggest an influence of 2,4-D exposure on upper respiratory 

immune response, however only in the presence of other herbicide, glyphosate. The association 

with fatal injury is unexpected and may be explained by frequent use of application equipment, 
Page 5 of 7

or both; further research is needed to disentangle the role of multiple farm-related occupational 

exposures with risk of fatal injury.

In general, there were few incidents reported for 2,4-D as a single chemical only, but there is a 

high absolute number of incidents reported involving 2,4-D with another active ingredient. 

Although vast majority of these incidents were of low severity, several high severity outcomes 

are reported in the IDS database. It is important to note that since most of these reported 

incidents involve more than one active ingredient (i.e. 2,4-D and another active ingredient), the 

incidents that were reported were not necessarily attributable to 2,4-D. Further, while incident 

information can be an important source of feedback to the Agency, reports of adverse health 

effects allegedly due to a specific pesticide exposure (i.e., an “incident”) are largely self-reported 

and therefore, generally speaking, neither exposure to a pesticide or reported symptom (or the 

connection between the two) is validated or otherwise confirmed. Typically, causation cannot be 

determined based on incident data. Nevertheless, based on the absolute number of incidents and 

the few high severity outcomes that are reported, these incident data warrant further analysis in 

the preliminary risk assessment phase of Registration Review. Obtaining additional information 

on current usage data for 2,4-D would improve future assessments by placing the high number of 

incidents in context with the high volume of use of this chemical. Additionally, follow-up 

studies from the AHS will be evaluated if available at the time of the risk assessment.

 

References

Alavanja, M. C., Dosemeci, M., Samanic, C., Lubin, J., Lynch, C. F., Knott, C., . . . Blair, A. 

(2004). Pesticides and lung cancer risk in the agricultural health study cohort. Am J 

Epidemiol, 160(9), 876-885. doi: 160/9/876 [pii] 10.1093/aje/kwh290.

Alavanja, M. C., Samanic, C., Dosemeci, M., Lubin, J., Tarone, R., Lynch, C. F., . . . Blair, A. 

(2003). Use of agricultural pesticides and prostate cancer risk in the Agricultural Health 

Study cohort. Am J Epidemiol, 157(9), 800-814. 

Andreotti, G., Freeman, L. E., Hou, L., Coble, J., Rusiecki, J., Hoppin, J. A., . . . Alavanja, M. C. 

(2009). Agricultural pesticide use and pancreatic cancer risk in the Agricultural Health 

Study Cohort. Int J Cancer, 124(10), 2495-2500. doi: 10.1002/ijc.24185

Dennis, L. K., Lynch, C. F., Sandler, D. P., & Alavanja, M. C. (2010). Pesticide use and 

cutaneous melanoma in pesticide applicators in the agricultural heath study. Environ 

Health Perspect, 118(6), 812-817. doi: 10.1289/ehp.0901518

Engel, L. S., Hill, D. A., Hoppin, J. A., Lubin, J. H., Lynch, C. F., Pierce, J., . . . Alavanja, M. C. 

(2005). Pesticide use and breast cancer risk among farmers' wives in the agricultural 

health study. Am J Epidemiol, 161(2), 121-135. doi: 161/2/121 [pii] 10.1093/aje/kwi022.

Hoppin, J. A., Umbach, D. M., London, S. J., Alavanja, M. C. R., & Sandler, D. P. (2002). 

Chemical predictors of wheeze among farmer pesticide applicators in the agricultural 

health study. American Journal of Respiratory and Critical Care Medicine, 165(5), 683-

689. doi: 10.1164/rccm.2106074
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Lee, W. J., Sandler, D. P., Blair, A., Samanic, C., Cross, A. J., & Alavanja, M. C. R. (2007). 

Pesticide use and colorectal cancer risk in the Agricultural Health Study. International 

Journal of Cancer, 121(2), 339-346. doi: 10.1002/ijc.22635

Slager, R. E., Poole, J. A., LeVan, T. D., Sandler, D. P., Alavanja, M. C. R., & Hoppin, J. A. 

(2009). Rhinitis associated with pesticide exposure among commercial pesticide 

applicators in the Agricultural Health Study. Occupational and Environmental Medicine, 

66(11), 718-724. doi: 10.1136/oem.2008.041798

Waggoner, J. K., Henneberger, P. K., Kullman, G. J., Umbach, D. M., Kamel, F., Beane 

Freeman, L. E., . . . Hoppin, J. A. (2012). Pesticide use and fatal injury among farmers in 

the Agricultural Health Study. Int Arch Occup Environ Health. doi: 10.1007/s00420-012-

0752-x
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Table 1: Main IDS high severity incidents involving 2,4-D

Human Incidents Chemical: 2,4-D

PC Codes: 030001, 030004, 030016, 030019, 030025, 030035, 030053, 030063,030065, 030066, 

051505

Incident 

Package 

Report

Incident 

Date Location

Registration 

Number Product Name

Exposure 

Severity* Incident Description

018502 -

00008 4/2/2007 ZEBULON, NC 000264-

00002

WEEDAR 64 

BROADLEAF 

HERBICIDE

HB

A 41 year old male sprayed diluted product earlier in 

the day. Later that day he experienced confusion, 

dizziness, conductive disturbance, and hypoglycemic 

shock. He was taken to the ER.

* Severity Categories

H-A Human Fatality Death (if the person died)

H-B Human Major Major (if the person alleged or exhibited symptoms which may have been life-threatening, or resulted in adverse 

reproductive effects or in residual disability)

H-C Human Moderate Moderate (if the person alleged or exhibited symptoms more pronounced, more prolonged or of a more systemic 

nature than minor symptoms; and involved some form of treatment, even though symptoms were not life 

threatening and the person returned to his/her pre-exposure state of health with no additional residual disability)

H-D Human Minor Minor (if the person alleged or exhibited some symptoms, but they were minimally traumatic; the symptoms 

resolved rapidly and usually involve skin, eye or respiratory irritation)

H-E Human Unspecified Unspecified (if symptoms are unknown, unspecified or are alleged to be of a delayed or chronic nature that may 

appear in the future)

H Human Undetermined (an undetermined severity)

from 40 CFR § 159.184