Page 3 of 7

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 u sed in agriculture

.

IV. RESULTS/DISCUSSION

IDS records incidents resulting in high er 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 informati on 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 A ggregate IDS , from January 1, 200 7 to June 13, 2012, there w ere 2202 reported incident s involving 2,4

- D resulting in low severity outcomes. T here 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 nee d for a more in depth Tier II analysis during the Preliminary Risk Assessment phase of Registration Review

.

For the M ain IDS, from January 1, 200 7 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 exposure s classified as resulting in a moderate severity, and 1

exposure classified as major severity), and 4 42 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 Re gistration 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 ar e considered to provide more certain information about the potential effects of the particular pesticide. The one higher severity exposure (major outcomes) that involve s 2,4

- D only is described in Table 1.

Agricultural Health Study

2,4

- D AHS Review
Amo ng 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 equip ment 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 cancerPage 4 of 7

evaluated thus far in the AHS cohort including cancer of the breast, prostate, lung, pa ncreas, 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
includi ng 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 f armers. 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 co hort 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

sev eral 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 t he 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 freque nt 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 o nly, but there is a high absolute number of incidents reported involving 2,4

- D with another active ingredient

. Although vast majority of these incidents w ere 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 i ncident 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 t he 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 co hort. A m 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. I nt J Canc er, 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. E nviron 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. A m J Epidemiol, 161( 2), 12 1

- 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. Am erican Journal o f Respiratory and Critical Care Medicine, 165(5 ), 683

- 689. doi: 10.1164/rccm.2106074Page 6 of 7

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. In ternational 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 applicat ors in the Agricultural Health Study. Oc cupational and Environmental Medicine, 66(1 1), 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). P esticide use and fatal injury among farmers in the Agricultural Health Study. In t Arch Occup Environ Health. doi: 10.1007/s00420

- 012

- 0752

- xPage 7 of 7

Table 1 : M ain IDS high severity incidents involving 2,4

- D

Human Incidents Chemical: 2,4

- D PC Code s : 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 treatm ent, 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 tr aumatic; 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