UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION MEMORANDUM Date: December 12, 2011 SUBJECT: Paraquat dichloride: Review ofHuman Incidents PC C ode: 061601 DP Barcode: D 392273 Decision No.: 452150 Petition No.: NA Risk Assessment Type: NA TXRNo.: NA MRIDNo.: NA Regi st ration No.: NA Regulatory Action: NA Case No.: NA CAS No.: 72963-72-5 40CFR: NA FROM: Khin Swe Oo, Environmental Health Scientist



## ~ -o' Toxicology and Epidemiology Branch :... - Ver.Apr.08
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# {2 THROUGH: David Miller, Acting Branch Chief 

## rc/ // jtf/t{ Toxicology and Epidemiology Bran Health Effects Division (7509P) TO: Becky Dais s , Risk Assessor Risk Assessment Branch IV Health Effects Division (7509P) and Molly Clayton, Chemical Revie w Manager Risk Management & Implementation Branch III Pesticide Re-evaluation Division (7508P) I. CONCLUSION In general, a moderately large number of incidents have been reported involving paraquat di chloride. T here were 46 cases reported for products containing paraquat dichloride present as a single chemic al only ; 73 cases reported for products containing paraquat dichloride as nons ingl e active chemical, and 78 cases reported in Aggregate IDS. Human incident data may warrant further analysis for the risk assessment and /or risk management of paraquat dichloride.
Page 1 of6II. ACTION REQUESTED This review is intended to fulfill our requiremen t to docket summaries of incident data that were reported to the Agency , as well as to ensure human incident data and the Agricultural Health Study (AHS) are p art of the problem formulation phase of regis tra tion review. Rep orts of adverse health effects allegedly due to a specific pest icide 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. Typically , causation cannot be determined based on incident data. H owever, 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 s ignal the Agency to furthe r investiga te a particular chemical or product. Observational epidemiology stud ies r e late the risk of disease, 

### e.g., cancer, and expo sure to an agent such as a pesticide product in the general population or specific sub -groups like pesticide applicators. 

### III. BACKGROUND For thi s evaluation, the OPP Incident Data System ( IDS) was utilized f or pesticide incident data on the active ingredient paraquat dichloride (PC Code 061601). The purpose of the database sea rch is to identify potential patterns on the frequency and severit y of the health effects attributed to paraquat dichloride exposure. The IDS includes reports of alleged human health incidents from various sources, includi ng mandatory Federal Insecticide , Fungicide and Rodenticide Act (FIFRA) Section 6 (a) (2) reports from registrants, other federal and state healt h and environmental agencies and individu al consumers. Since 1992, OPP compi les these reports in ID S. ID S contains reports from across the U.S. and most incidents ha ve all relevant product information recorded . Rep orts submitted to the IDS represent anecdotal reports or allegations only , unless otherwise stated in the report. The AH S is a high quality , prospect ive epidemi o logy study evaluating the link between pesticide us e and various health outcomes including cancer . The AHS include s private and commercial pesticide applicators and their sp o u ses. If there are AHS findin gs relevant to a particular pesticide going through registration review , the Agency will ensure they are considered in the problem formulation/seeping phase of the process and, if appropriate , full y 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 ID S records incidents resulti ng in higher severity outcomes in more detail , in a module called the Main IDS module. This system store s incident data for death, major and mod erate incidents, and it includes more detail s about the location, date and nature ofthe incident. Mai n IDS incidents invo lving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide , and therefore these incidents are li sted in the Table 1 at the end ofthis report. Additionally, since higher severity incidents are generally of greater concern, incidents involving death and major outcomes include a narrative summary in Tab le 1 . The less severe hu man incidents (minor, unknown, or no effects o utcomes ) are reported Page 2 of6by registrants as counts called aggregate summaries and are recorded in a separate module called Aggregate IDS . In Aggregate IDS , from January 1 , 2006 to June 8, 2011, there are 78 incidents involving paraquat dichloride. Because it falls within the categories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides detail s about the incident and single chemical incidents are not distingui shed from multiple chemical incidents ; however, a high frequency of incidents indicates there is a high potential for exposure and vice versa. For paraquat dichloride, there appears to be a moderately high potential for expo sure. For the Main IDS, from January 1, 2006 to June 8, 2011, there are 119 cases reported that involve the pesticide products containing active ingredient paraquat dichloride . Seventy three cases reported for pesticide products containing paraquat dichloride as one of the active ingredients in the product, and 46 cases reporte d for single chemical paraquat dichloride only in the database. There is one HA (human death) , 9 HB (human major) , and 36 H C (human moderate). HA and HB incident descriptions are included in Table I. Among HB cases, 33.3% of cases were intentional ingestion, 22.2% were accidental ingestio n , and 44.5% of cases were accidentally exposed to the product while using it. In the AHS , there have been five evaluations of various ca ncer and non-c ancer endpoints in which authors reported notable associations with the herbic id e paraquat: respi ratory outcomes wheeze and chronic bronchitis (among non- smoking women); thyroid disease ; Parkinson's disease (PD) ; and an evaluation of all cancers in relation to paraquat use over the lifetime. With the exception ofthe research study on Parkinson ' s disease , all investigations were preliminary, and not based upon prior knowledge of a role for paraquat 

### (i.e. , no 

### a priori) hypotheses. Animal studies and limited other epidemiologic evaluations have suggested a possible role for paraquat (and rotenone) in the etiology of Parkinson 's disease. Strengths of this epidemiology study include its large sample size, and prospective nature of the data co llection , as well as high response rate ; limitations included the narrow generalizability of the results (primarily performed among white, male, pesticide applicators), and lack ofknowledge of exposure periodicity and time of cessation of exposure. Results are briefly summarized below. In two AHS st udies, modest associations were observed between paraquat, as well as other pesticides , and both wheeze (OR 1.27 (95% CI 1.04, 1.56), and chronic bronchiti s (among nons moking women) (OR 1.91 (95% CI 1.02 , 3.55)). Overall , these studies are not st rongly supportive of a link between paraquat and respiratory health outcomes measured, exposure measurement error may explain these results; EPA will continue to monitor this literature through the regulatory review process. In addition, while there is limited a priori evidence as to a role for paraquat in thyroid disease, authors reported a statistically-significant elevated odds of hypothyroidism (under-active thyroid gland) among women who reported exposure to paraquat (OR 1.8 95% C I 1.1, 2.8). Alternative explanations may also exist at this time , and have not been completely investigated. Concerning Parkinson's disease, aut hors reported elevated odds ofPD among tho se who used paraquat in comparison to those who did not (OR 2.5 (95% CI 1.4, 4.7)). This result is supportive of the toxicological findings. In addition, AHS authors compared cancer incidence between users and non-users of paraquat, and did not observe strong evidence of an association between paraquat and any cancer outcome evaluated (including all cancers combined, prostate, lung , and colon). Elevated risks were observed with respect to non-Hodgkin Page 3 of6lymphoma (N HL) however, these results could be otherwi se explained. As stated by the authors, "There was some suggestion of a possible link b etween paraquat exposure and NHL risk in humans , but the inconsistency in exposure level trend suggests that tbis could be a chance finding. " In summary , based upon preliminary investigati ons withi n the AHS , authors observed some evidence of a possible role for paraquat in relation to wheeze as well as chronic bronchitis among non-smoking women, and thyroid disease. However, at this time other explanations cannot be excluded, and additional replication is needed. Autho rs did not observe strong evidence of an association with cancer. Concerning Parkins on ' s disease, recent evaluatio ns support observations in experimental toxicology. In general , a moderately large number of incidents have been reported involving paraquat dichloride. There were 46 cases reported for pesticide products containing paraquat dichloride present as a single chemical only; 73 cases reported for pesticide products containing paraquat dichloride as non-single active chemical, and 78 cases rep orted in Aggregate IDS. Human incident data may warrant further analysis for the risk assessment and/or risk management of paraquat dichloride.

Page 4 of6Table 1: Human Incidents (HA and HB) due to Paraquat dichloride. PC code 061601.

Incid ent Page Incident Product Reg Location State Expo Incident Description

Package # Date Name Number sure number Type
017507 - 16 5/18/200 GRAMOXON 000100- NEAR MD HB A 27 year old man , ingested 4 oz of product (43% solution) .

00015 6 E INTEON 01217 PITTSF I ELD He developed burning sensation i n his chest and mouth ; he

' also vomited several times . At the hospital esophagogastroduodenoscopy was done and found ulcerations in the esophagus , stoma c h and proximal duodenum . He was discharged after 24 hours . He returned

to the ER , 4 days later with shortness of breath and

hemoptysis (coughing blood). Chest X-ray showed bilateral

lung infiltrates. A serum and urine paraquat level four days

after the in gestion was 0.08 mcg/ml (normal <0 . 06 mcg/ml),

and 0.76 mcg/ml (asymptomatic sprayers up to 0.3 mcg/ml) respectively. He was given methy l prednisolone , dexamethasone , cyclophosphamide , acetylcysteine, vit C ,

vit.E , Rapamycin and antibiotics . He was put on hemod i alysis for 6 days for kidney failure . He was transfered

to the inpatient psychiatric ward after 39 days with res i dual

lung and kidney symptoms .

017862 - 47 8/1/2005 GRAMOXON NC HB A 56 year old male stated that he developed shortness of

00006 E (NON - b r eath , pain i n chest/shoulders/ n eck , low fever and rapid

SPECIFIC) heart rate after using the product. He was admitted to the

hospital for 18 days . He used the product again this year

and came down with same symptoms ; lab results showed ,
WBC was 15,000 and erythrocyte sedimentation rate was

97 (normal 15-20) . However , physicians were unable to find

the cause of h i s symptoms .

018909 - 49 8 / 24 / 200 PARAQUAT GOLDSBORO NC HA A 59 year old male died of cardiac arrest and mu l ti system

00001 7 ( NON - organ fa i lure in the hospital. It was not clear if he drank the

SPECIFIC) product intentionally or not.

018939 - 78 1/ 1 /2006 GRAMOXON 000100- AR HB Adult (18 - 64) year old ma l e stated that the product

00008 EMAX 01074 accidentally spilled on his hands several times, while using it

at work. He sta ted that he developed dry and flaky skin on hands , and flakey fingernails , Page 5 of6018939 - 86 8/14/200 PARAQUAT sc HB A 52 year old male ingeste d about 60 ml of paraquat (30 ml

00013 7 (UNSPECIFI of 43 . 8% paraquat and 30 ml of water). Gastric lavage was

ED) performed about 1.5 h r post-ingestion . However , he

developed impaired lung, liver and kidney functions . He

was put on hemoperfusion , and l a t er received hemodia l ysis .

He was also give n cyclo p hos p ham i de and methylpredniso l o n e. Se r um paraquat l evel was 0.79 mcg/m l

at about 4 hours after i ngestion. He was transferred to the

psychiatric unit about 2 weeks after the admission.

020720 - 3 1/112009 PARQUA T DOYLESTOW PA HB A 50 year old female was admitted to ICU with multi-organ

00026 (NON - N failure . The doctors wanted to rule out paraquat poisoning .

SPECIFIC) The cause remained unclear .

020720 - 23 3/8/2009 GRAMOXON CA HB A 53 year old female accidentally ingested the product

00027 E (NON - (about 1-2 tea spoon) which was placed in the water bottle .

SPEC I F I C) She deve l oped oral swelling and was admitted to the

intensive care u n it. Para q uat leve l at 22 hours post-inges ti on

was 0.038mcg/ml; li ver enzymes levels were also inc r eased.

Paraquat was not d e t ec t ed in t he urine samp l e collected 4
days post - ingestion. She was intubated and put on dialysis machine for few days . She was discharged from the hospital after 3 weeks.

021194 - 5 8114/200 GRAMOXON 000100- OTHELLO , WA HB A 49 year old male stated that he got the product

00005 9 EMAX 01074 accidentally in his mouth while using it , and developed

(DISCONTIN swollen lips , tongue and ulcers in his mouth . He was

UED) admitted to the ICU; found ulcers also in the esophagus. He

was discharged from the hospita l after few days.

021704 - 15 1/ 1 3/201 GRAMOXON CA HB A 44 year o l d ma l e mistaken l y d r ank the product and

00006 0 E developed difficu l ty in breathing and vomiting of b l ood. He

was admitted to the intensive care unit. No further

information .
022354- 16 8/31/201 GRAMOXON 000100- GA HB Adult (16-64) year old worker , accidentally spill the product

00006 0 E INTEON 01217 (concentration , 50/50) on his stomach and genital areas . He

was admitted to the Burn Center, and he received a skin

transp l ant.

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