Document ID: EPA-HQ-OPP-2014-0262-0023
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2021-10-29T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                         WASHINGTON, D.C. 20460      

                                                	OFFICE OF CHEMICAL SAFETY AND 
                                                           POLLUTION PREVENTION
	

MEMORANDUM

Date: 	May 3, 2021

SUBJECT:	Spirodiclofen: Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment

PC Code: 124871
DP Barcode: D461604
Decision No.: 571861
Registration No.: NA
Petition No.: NA
Regulatory Action: NA
Risk Assessment Type: NA
Case No.: NA
TXR No.: NA
CAS No.: 148477-71-8
MRID No.: NA
40 CFR: NA
		              									Ver.Apr.08
	          	
FROM:	Shanna Recore, Industrial Hygienist	
		Elizabeth Evans, Environmental Protection Specialist
		Erin Jones, Epidemiologist 
		Toxicology and Epidemiology Branch
		Health Effects Division (7509P)
						
THROUGH:	David J. Miller, Branch Chief 
		Chemistry and Exposure Branch
		Health Effects Division (7509P)
			
TO: 		Abiy Mohammed, Risk Assessor
		Risk Assessment Branch I
		Health Effects Division (7509P)
			and				
            Veronica Dutch, Chemical Review Manager
		Risk Management & Implementation Branch 5
		Pesticide Re-evaluation Division (7508P)

Summary and Conclusions

Spirodiclofen incidents were previously reviewed in 2014 (E. Evans and S. Recore, D422435, 10/23/14).  At that time, based on the low frequency and severity of spirodiclofen incident cases reported to Incident Data System (IDS) and NIOSH Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides further investigation was not warranted.

In the current IDS analysis from January 1, 2014 to April 19, 2021, one spirodiclofen incident was reported to Main IDS. This incident involved multiple active ingredients.  There were five spirodiclofen incidents reported to Aggregate IDS.  A query of SENSOR-Pesticides 1998-2017 identified 31 cases involving spirodiclofen.  

The Agricultural Health Study (AHS) is a federally-funded study that evaluates associations between pesticide exposures and cancer and other health outcomes and represents a collaborative effort between the US National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), CDC's National Institute of Occupational Safety and Health (NIOSH), and the US EPA. The Agency conducted a search of the AHS publications and the available open literature (PubMED, PubMED Central, and Science Direct) and identified one epidemiological publication that reported on the potential association between spirodiclofen exposure and health effects, specifically childhood leukemia.

Based on the continued low frequency of spirodiclofen incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time. There is insufficient evidence to conclude that a clear associative or causal relationship exists between spirodiclofen and childhood leukemia. 
 
Detailed Review 

 ACTION REQUESTED

Spirodiclofen is being considered under the FQPA-mandated Registration Review program established to review, on a 15-year cycle, pesticides for which a Re-registration Eligibility Decision has been made.  HED's RAB I has requested that CEB conduct a Tier I Update review summary of recent incident data from IDS and SENSOR and any available epidemiological literature as per standard protocol under the Agency's Registration Review Program. One component of the Agency's Registration Review Program is consideration of human incident and epidemiological data.  In conjunction with a human health risk assessment based on other data sources, such human incident and epidemiological data can assist the Agency in better defining and characterizing the risk of pesticides/pesticide products.  

It is important to remember that 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, and such data should be interpreted with caution.  Nonetheless, incident information can be an important source of feedback to the Agency:  incidents of severe outcome, or a suggested pattern or trend among less severe incidents, can signal the Agency to further investigate a particular chemical or product. Epidemiology studies can also be useful and relate the risk of disease, e.g., cancer, and exposure to an agent such as a pesticide product in the general population or specific sub-groups like pesticide applicators.  

 BACKGROUND		

Spirodiclofen is an insecticide/miticide in the tetronic acid chemical class.  The mode of action is inhibition of lipid synthesis.  It controls mites and San Jose scale in citrus, grapes, pome fruit, stone fruit, and tree nut crops.  The method of application is ground boom.  

For this evaluation, both OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredient spirodiclofen (PC Code: 124871).  The purpose of the database search is to identify potential patterns in the frequency and severity of the health effects attributed to spirodiclofen exposure. In addition, a search for available epidemiological publications was also conducted.  

 RESULTS/DISCUSSION
 IDS (Incident Data System)

OPP's IDS includes reports of alleged human health incidents from various sources, including mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports from registrants, other federal and state health and environmental agencies, and individual consumers. Since 1992, OPP has compiled these reports in IDS.  IDS contains reports from across the U.S. and most incidents have all relevant product information recorded. Reports submitted to the IDS represent anecdotal reports or allegations only, unless otherwise stated in the report.  

IDS records incidents in one of two modules: Main IDS and Aggregate IDS:
  
 Main IDS generally contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics.  This system stores incident data for death, major and moderate incidents, and it includes information 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. 
            
 Aggregate IDS contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes). These are reported by registrants only as counts in what are aggregate summaries. 
For the Main IDS for the seven years from January 1, 2014 to April 19, 2021, there was one incident reported that involved the active ingredient spirodiclofen.  This incident involved multiple active ingredients and was classified as minor severity.   
For Aggregate IDS for the five years from January 1, 2014 to April 19, 2021, there were five incidents reported involving spirodiclofen.  These incidents were classified as minor severity. 

 SENSOR-Pesticides

The Center for Disease Control's National Institute for Occupational Safety and Health (CDC/NIOSH) manages a pesticide surveillance program and database entitled the Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides.  All cases must report at least two adverse health effects.  Evidence for each case is evaluated for its causal relationship between exposure and illness based on the NIOSH case classification index.  Using standardized protocol and case definitions, SENSOR-Pesticides state coordinators, operating out of the state's department of health, receive state pesticide incident reports from local sources, then follow up with case sources to get incident scenario to obtain medical records and verify exposure scenario information.  This database includes pesticide illness case reports from multiple states from 1998-2017.   

A query of SENSOR-Pesticides 2010-2017 identified 31 cases involving spirodiclofen.  All 31 cases involved multiple pesticide active ingredients, including spirodiclofen.  Five cases were moderate in severity and 26 cases were low in severity.  All cases were occupational.  
One event led to the exposure and illness of 25 of the 31 cases.  The (single) event that lead to 25 case reports occurred in Washington State in 2013.  The 25 cases were all agricultural workers who were thinning apples in an orchard when they were exposed to off-target spray drift from a nearby application of azinphos methyl and spirodiclofen.  Depending upon their location in the orchard, several workers only smelled the pesticide, several workers however felt the pesticide mist on their face and skin, and they also saw the application underway; which continued for more than 30 minutes while the workers remained in the orchard.  The Washington State Department of Agriculture investigated this event (WSDA Case CJS-0021-13) and violations against the applicator were issued.  Three of these cases from this event were moderate in severity and 22 cases were low in severity.  The three moderate severity cases in this event were treated in a doctor's office for adverse health effects including: headache, chest pain, abdominal pain, nausea, and ocular irritation.

The two other moderate severity cases also involved apple orchard workers.  One case was applying pesticides and he removed his PPE at the end of the row and became ill.  The other case was thinning apples in an orchard and saw the spray applicator about 50 to 80 meters away from him. He smelled the pesticide and could see the mist from the top of the trees and the wind pushed the mist toward him.  

The symptoms most frequently reported among the 31 cases were primarily nausea and headache, followed by dizziness, eye pain, abdominal pain, vomiting, upper respiratory pain/irritation, and cough.   

 Agricultural Health Study (AHS)
            
The AHS is a federally-funded study that evaluates associations between pesticide exposures and cancer and other health outcomes and represents a collaborative effort between the US National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), CDC's National Institute of Occupational Safety and Health (NIOSH), and the US EPA. The AHS participant cohort includes more than 89,000 licensed commercial and private pesticide applicators and their spouses from Iowa and North Carolina. Enrollment occurred from 1993  -  1997, and data collection is ongoing. The AHS maintains a list of publications resulting from AHS studies. If there are AHS findings in the published literature relevant to a pesticide undergoing registration review, the Agency will ensure these findings are considered during the registration review process and, if appropriate, fully reviewed in the risk assessment phase of the process. For this Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment, EPA reviewed the AHS publications listed on the AHS publication website. As of 
April 2021, four AHS epidemiological studies included the word "spirodiclofen" however no epidemiological studies on the AHS prospective cohort population that included effect size measures for the association between spirodiclofen and health outcomes were listed.

 Open Literature Search (PubMed, PubMed Central, ScienceDirect)

In creating the Tier I Update memorandum, a search of the available literature completed on April 15, 2021 returned a total of 216 publications, with 69, 57, 90 publications from each PubMed, PubMed Central, and Science Direct, respectively. Upon further review of the retrieved publications, one publication (Park et al., 2020) contained an effect size measure for the association between spirodiclofen and the health outcome of childhood leukemia. No other publications retrieved contained effect size measures for the association between spirodiclofen and other health outcomes.  

Park et al. (2020) conducted a records-based case-control study to examine the association between prenatal pesticide exposure, including spirodiclofen, and childhood leukemia. Cases were identified via the California Cancer Registry and included all cases of childhood acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) diagnosed between 1986 and 2011 in children <6 years of age, born in California. Controls were identified via LinkPlus (CDC), a probabilistic linkage program, by linking cases to California birth certificates and were randomly selected from California birth records for the same time period and frequency-matched to cases by birth year (1998-2011). Authors state the controls had no record of cancer diagnosis in California before age 6 years, however authors did not specify the method they used to determine this information. Pesticide exposure was measured using statewide pesticide use reporting records from the California Department of Pesticide Regulation (CDPR) Pesticide Use Reporting (PUR) data and land use information from California's Public Land Survey System (PLSS) to align pesticide use data to crop cover data based on location using GIS. For each case/control, pesticide exposure (monthly and annual application rates- total pounds applied/acre over a time period) was assigned based on residential proximity to agricultural pesticide applications using a 4,000 meter buffer around the residential address. The residential address was obtained from the address at time of birth listed on the child's birth certificate. Demographic information on parents and children, including gestational age, was obtained from birth certificates and the year 2000 census. Children were excluded if: their residential address was outside of California (n = 632); were controls who died before 6 years old (n = 1,202);  data were missing for gestation length (n = 12,786); displayed implausibly long gestations (determined based on last reported menses, >45 weeks, n = 2,729); or were likely non-viable births (birth weight <500g or gestational age < 20 weeks, n = 32). Cases and controls were further restricted to rural residents using rural-urban commuting area codes (RUCA) determined through Census Tract information. The final study population included 162 childhood leukemia cases (132 ALL, 30 AML) and 9,805 controls. Of these, 10 ALL cases, 0 AML cases, and 787 matched controls reported exposure to spirodiclofen. Unconditional logistic regression was used to assess the relationship between ever exposure to pesticides during pregnancy and ALL and AML in children, adjusted for birth year, mother's race (Black, White non-Hispanic, Other race/refused to report), any other carcinogenic pesticide exposure, and neighborhood socioeconomic index. Variables were selected based on literature review and 10% change in estimate criterion. Crude ORs were adjusted for birth year. Adjusted ORs were adjusted for birth year, mother's race, and SES-index variable. HLM OR was adjusted for birth year, mother's race, SES-index variable, and overall pesticide effect in the hierarchical model. No evidence of a significant positive association was reported between spirodiclofen exposure during pregnancy and childhood ALL (Crude  -  OR = 1.36; 95% CI: not reported; n = 10 exposed cases; Adjusted  -  OR = 1.28; 95% CI: 0.62, 2.62; n = 10 exposed cases; HLM  -  OR = 1.35; 95% CI: 0.63, 2.89; with n = 10 exposed cases). We note the very small number of exposed cases. No risk estimates were reported by the study authors for spirodiclofen and AML in children.

 CONCLUSION

Based on the continued low frequency of spirodiclofen incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time. In creating the Tier I Update memorandum, EPA reviewed the AHS publications listed on the AHS publication website and searched the open literature. As of April 2021, one publication reporting on the potential association between spirodiclofen exposure and health outcomes was identified and reviewed: the single identified study (Park et al, 2020) found no evidence of a significant positive relationship between spirodiclofen exposure and the health outcome of childhood leukemia. The Agency will continue to monitor the incident and epidemiological information through Registration Review.  

 Citations

Park, A. S., Ritz, B., Yu, F., Cockburn, M., & Heck, J. E. (2020). Prenatal pesticide exposure and childhood leukemia  -  A California statewide case-control study. International Journal of Hygiene and Environmental Health, 226, 113486. https://doi.org/10.1016/j.ijheh.2020.113486

RDI: 4/25/2021