Draft, Do not cite

Diazinon Case Study Page 1 of 27



# Attachment C

Draft Case Study

Integrating Human Incident Data into Regulatory Risk Assessment

Diazinon Human Incident Data

Office of Pesticide Programs

Office of Pollution Prevention and Toxic Substances U.S. Environmental Protection Agency

FIFRA Sc ientific Advisory Panel February 2

- 5 , 2010Draft, Do not cite

Diazinon Case Study Page 2 of 27 C.I. INTRODUCTION

Th is document focuses primarily on human incident data

– and describes the ways

in which th is type of data can be appropriately used to inform the risk assessment of pesticides. I ncident data typ ically contain information on potential acute human

exposure s and the resulting health outcomes that might be associated with them ; Reports vary in quality and level of detailed narratives describing the exposure scenario; they are self reported cases of e xposure and resulting outcomes collected in a systematic way

. Despite these limitations, I ncident data sets are an important resource of health surveillance information on registered pesticides.

Although OPP could have chosen many other pesticides for whic h incident data have impacted our regulatory decision making, OPP selected diazinon for this case study because it has a robust animal toxicology data base, a regulatory history that includes recent, significant changes in allowable exposures , and a high f requency of reported incidents. Additionally, diazinon is a chemical currently being re

- evaluated under OPP‟s registration review program, and thus its effects and exposure assessment is being updated. The main intent of this case study is to illustrate ho w human incident

data can be integrated with current hazard and exposure information, and be considered in light of previous risk mitigation activities. As described below, diazinon human incident data mainly demonstrate the impact of previous regulatory risk mitiga tion decisions, without meriting a recommendation to reconsider the most recent hazard and/or exposure assessment.

Please note that t

his case study has been prepared as an illustrative case study focused on reviewing incident data and acute eff ects . It does not represent a full analysis of all available information concerning incident data, epidemiology and toxicology.

The case study is organized into f our sections:

I. Introduction: OPP‟s use of human incident data

II. Regulatory b ackground : Diazinon

III. Review of human incident data: Diazinon

I V. Overall Conclusion/Summary: overall consideration of human incident data

I. OVERVIEW OF INCIDENT DATABASES

EPA relies primarily on incident data collected u nder the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and implementing regulations

, which require pesticide registrants to notify EPA if and when they become aware of “[i]nformation about incidents affecting humans or other non

- target organisms ... [where] a person or

non

- target orga nism may have been exposed to a pesticide ... [and] that the person orDraft, Do not cite

Diazinon Case Study Page 3 of 27 non

- target organism suffered a toxic or adverse effect, or may suffer a delayed or chronic adverse effect in the future ... [and] [t]he registrant has or could obtain information concerning where the incident occurred, the pesticide or product involved, and the name of a person to contact regarding the incident” (CFR §159.184).

EPA stores information reported under this provision in the Incident Data System (IDS). IDS is maintained by OPP and incorporates data submitted by registrants , as well as other incidents reported directly to EPA. In addition to the IDS, the Agency draws upon additional human incident data collected by other entities : the American

Association of Poison Control Center s (PCC), the National Pesticide Information Center (NPIC), the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health Sentinel Event Notification System for Occupational Risk (NIOSH SENSOR) and the California Pesti cide Illness Surveillance Program (PISP). These additional incident data sources allow the Agency to determine reproducibility and consistency of reported symptoms among the general population

and certain sensitive subpopulations.

A. Human Incident Database s : Strengths and Limitations

In addition to basic demographic information, incident data provide exposure and hazard information on registered pesticides:

Types of exposure information include:

o Occupational (agricultural or residential professional appli cator) versus

non

- occupational (residential)

o Narratives (describing how/why the exposure occurred)

o Product information

o Scope of database (national/non

- national coverage) Types of hazard information include:

o Severity rankings

o Symptoms

When evaluating huma n incident data, it is important to understand not only the strengths but also the limitations of the data . The main limitation of human incident information is the difficulty associated with establish ing a causal determination between exposure and outcome

. Another significant limitation is the lack of information that would provide better context to evaluate the significance of incident data. For example, without data on extent of use in the areas covered by a data source, EPA may be

unable to determine w hether a high frequency of incidents indicates that one pesticide poses a greater problem than other pesticides or whether the increased frequency

reflect s differences in market share of pes ticides sold

.

Additionally, incidents are mainly self

- reported

, and typically neither exposures to a pesticide nor reported symptoms are easily verifiable (although as described in this

section , some databases involve more follow

- up and confirmation than others)

. Finally

, because of the self

- reported nature of most inc idents, these databases are likely toDraft, Do not cite

Diazinon Case Study Page 4 of 27 underestimate the incidence of exposures that actually do occur due to under reporting. Some may be less inclined to report a work related adverse event if it might lead to unemployment. Because of these limitations, t he Agency seldom relies sole ly on one
incident data source to make determinations about whether there is concern for the safe

use of a registered pesticide and/or pesticide product , but draws on several sources in conjunction with other types of hazard inf ormation

.

The following descriptions are intended to provide more detailed information about the strengths and weaknesses of each database.

I ncident D ata S ystem (IDS) : IDS is national in scope and includes reports on both occupational and non

- occupati onal incidents, but like most incident

databases it includes more information about non

- occupational incidents than occupational incidents

. Different from other sources, IDS includes narrative

information about exposure scenarios. Agency reviewers must ana lyze and distill

each narrative to determine potential associations, which is resource intensive. As IDS is populated mostly by registrant

- s ubmitted information , the Agency has relatively high confidence in the product information provided because of the

a ccuracy and verification of the information

.

IDS also includes hazard information and severity of reported effects

. These

s everity categories include:

o H

- A: Human fatality,

o H

- B: Human major incident, symptoms may have been life threatening, or

resulted in adverse effects or in residual disability

o H

- C Human moderate incident, symptoms were not life threatening and the person returned to pre

- exposure state of health with no residual disability

o H

- D Human minor incident, symptoms resolved rapidly and may i nvolve skin, eye, or respiratory irritation

o H

- E symptoms unknown or not specified.

These categories are included for each incident (as specified in 40 CFR §159.184 ) ; however, upon review of narratives, severity categories often appear inflated compared to other databases (and subsequently, the Agency has less

confidence in these classifications than it does in those from other sources of

information ).

Poison Control Center ( PCC ) : PCC is national in scope and provides mainly

non

- occupational incidents. The incident database does not include narrative

information

, which makes it difficult to assess patterns of exposure scenarios.

The information available to PCC often doe s not identify the specific pesticide product in volved , and the Agency relies on an EPA generated table that matches product identification numbers in the PCC to EPA product identification numbers (and subsequently, pesticide specific information). This effort has resulted inDraft, Do not cite

Diazinon Case Study Page 5 of 27 a pproximately 80% of PCC incidents including specific informat ion identifying the pesticide product

.

As for hazard information, PCC provides severity rankings and symptom information that are designated/recorded by trained health care professionals

, and therefore the Agency has relatively high confidence in this in formation. PCC also provides some information about the likelihood of the adverse effect being a result of the reported exposure. Overall, PCC provides good information about national trends, frequency of incidents for pesticides (which is somewhat limite d by PCC‟s product database), as well as the hazard potential for particular pesticides

. O n the other hand, exposure scenario information is difficult to

ascertain.

National Pesticide Information Center ( NPIC ) : Although NPIC also collects pesticide incid ent data, it is primarily intended to provide objective data on pesticide s . Similar to IDS and PCC, the incidents reported in this database are mainly non

- occupational. NPIC incidents include narratives and product information when the caller provides it. The scope is national ; however, there are significantly fewer incidents reported to NPIC than are reported to PCC or IDS.

Hazard information includes severity rankings as well as route s of exposure and
symptoms, which are recorded by trained personnel. N PIC also provides information on how likely is the link between exposure and adverse effect (which they call a certainty index). Because the NPIC operation is not as extensive as

PCC

, and does not involve the same number of incidents as PCC and IDS, the

da ta are less use ful for d etecting trends . The information, particularly in the

incident narratives and/or in the hazard ratings, can, however, help to

corroborate conclusions drawn from other incident data sources . NPIC also publishes annual reports and an alyses in the open literature which are valuable resources to the Agency.

National Institute of Occupational Safety and Health ( NIOSH ) Sentinel Event

Notification System for Occupational Risk ( SENSOR ) : The NIOSH SENSOR

database is not national in scope, but includes 12 participating states

. This
system capture s pesticide

- related acute illness/injury occurring in the se state population s . This database collects info rmation on illness and injuries resulting from both occupational and non

- occupational exposures . U nlike other incident
databases, the majority of the incidents in NIOSH SENSOR involve occupational cases. These include narratives and product information ba sed on input by trained professionals.

Hazard information includes severity rankings, and narrative information can include information on symptoms and treatment. Overall, NIOSH SENSOR provides good information on both occupational and non

- occupational incidents,

and it sometimes provides valuable insights into the hazard and/or exposure potential of a pesticide. NIOSH SENSOR also conducts analyses of its own dataDraft, Do not cite

Diazinon Case Study Page 6 of 27 and publishes these in the Morbidity and Mortality Weekly , which are a valuable

resource t o the Agency.

Pesticide Illness Surveillance Program ( PISP ) : The scope of the database is limited to California, but as a major agricultural state in the U.S. it contains a substantial body of information. PISP is also a resource both for well

characteri zed occupational incidents and for non

- occupational incidents. The database includes narratives and product information that is entered by trained professionals who conduct follow

- up on each reported case. Although there are no severity rankings, there ar e other fields (such as days lost from work and days hospitalized) which can be used as proxies for severity. Symptom and

sometimes treatment information is available in narrative fields. PISP also provides information assessing the strength of the eviden ce of a link between exposure and adverse effects (in the field designated “Relationship”). Overall, PISP provides good information on both occupational and non

- occupational
incidents, and sometimes it provides valuable insights into the hazard and/or

expo sure potential of a pesticide. Additionally, PISP data is publicly available.

B. How does OPP Evaluate Human Incident Data?

Currently, O PP evaluates human incident data on a case

- by

- case, chemical

- specific basis. Incidents from each database are analyzed for the nature and severity of the effects reported ( e.g., deaths, gastrointestional problems, etc

. ), frequency of more
severe incidents, and patterns/trends of reported symptoms

, The exposure potential is also evaluated including the factors affecting exposu re of products (e.g., the frequency of incidents/trends over time, patterns/trends of exposure scenarios ).

Additionally, narratives of more severe incidents are often evaluated with respect to

any temporal association that might exist between the time

- of

- exposure and the effects reported to determine whether an association between the exposure and the effect is supported . For example , if a severe incident occurs at the time of exposure, or if
symptoms and health conditions occur immediately after exposure without prior medical history

, and the sy mptoms progress over time or are reproduced upon re

- exposure,
then EPA would likely regard that severe incident as likely due to pesticide exposure.

When preliminary analyses of one data source indicate a possible hazard/exposure potential of interest, additional databases are consulted for consistency and reproducibility, and the overall potential for a relationship b etween exposure and

adverse out come is considered in light of all other available information (e.g ., animal toxicity profile and mode of action, etc.) using the Bradford Hill causal criteria of consistency, reproducibility, temporal association and biological plausibility.

C. How does OPP use Incident Data?

Human observational data in general provide re al

- world feedback on pesticide products being used by the public. In particular, OPP uses human incident information, on balance, for several purposes. First, the program uses incident data to inform riskDraft, Do not cite

Diazinon Case Study Page 7 of 27 reduction/prevention through risk assessment/risk management activities ( as illustrated by the diazinon case study) . For example, incident information can indicate a need for new risk management measures

, and it can help assess the success of risk mitigation actions after they are implemented. Secondly, a s a risk communication tool, incident data provide insight into the potential nature, extent and severity of illnesses or injuries resulting from exposure to pesticide products to help inform decision makers,

stakehold ers and the public in general about their safe use

. Thirdly, incident information is an integral part of OPP‟s performance accountability system, to ensure that the risk management actions taken by OPP to protect hum an health and the environment are effective

. Lastly, incident information ca n be useful in targeting enforcement activities

, and it can serve as a source for information about compliance with incident reporting regulations.

CASE STUDY ON THE REVIEW OF INCIDENT DATA: DIAZINON

II. REGULATORY BACKGROUN D : DIAZINON

Diazinon, first mark eted in 1956, is a restricted use organophosphate (OP) pesticide currently registered for use on a number of fruits, vegetables, nuts, and ornamentals grown outdoors in nurseries . It is also used in cattle ear tags. Prior to 2000, diazinon

was one of the most widely used insecticides available on the residential market. In 2000, based on potential risks to children identified during the reregistration process (the previous OPP pesticide re

- evaluation program), all residential use diazinon products were can celled. Sales of all indoor residential use products ended in 2002, and sales of all outdoor residential use products ended in 2004. Due to these risk mitigation

efforts outdoor consumer use of diazinon and professional use of diazi n on on turf and

ornament als decreased around 10

- fold from 2000 to 2005/2006

.

During the re

- registration process potential risks to occupational workers were also identified and subsequently mitigated via increased restricted entry intervals (REIs), prohibition of foliar applica tion on most vegetables and elimination of aerial application and granular uses

. E ngineering controls were also required

. Consequently, professional use of diazinon in California in agricultural and non

- agricultural sectors also decreased during the perio d fr om 2000

- 2007 by over half (see A ppendix A for details on
chemical use trends ).

In 2008, EPA conducted a review of diazinon incidents in IDS during the problem formulation phase of the next round of registration review, and found a high number of

incid ents as well as a distinct trend of incidents reported over time. Subsequently, other incident databases were consulted and considered in light of the most recent risk assessment. This case study summarizes those incident data reviews and findings.Draft, Do not cite

Diazinon Case Study Page 8 of 27 III. HUM AN INCIDENT DATA REVIEW : DIAZINON

A. Summary of Animal Toxicology and Mode of Action

Prior to review of human incident data, consideration of the available animal toxicology and mode of toxicological action is an important step towards interpretation of

the se human symptoms. Because human incident data primarily report events from acute exposure, the review of acute a nimal toxicology data is most relevant. From review of the animal toxicity information, diazinon has a low acute toxicity via oral,

dermal or inhalation routes of exposure. It is minimally irritating to the eyes and is not considered a skin sensitizer. Diazinon induces cholinergic signs or symptoms of toxicity typical of an organophosphate (OP) pesticide. Like other OPs

, diazinon inhibits th e enzyme acetylcholinesterase in the central and peripheral nervous systems . This inhibition leads to accumulation of the acetylcholine neurotransmitter at synapses and ultimately to disruption of normal nerve transmission, which results in physiological and behavioral changes

. As with the other OPs, a t extremely high doses, death can occur

from diazinon exposure.

The available animal toxicology database is robust and includes data from multiple species (hens, mice, rats, rabbits, and dogs). Clinical si gns of toxicity observed in laboratory animals include: tremors, convulsions, salivation, and dyspnea (labored breathing). Inhibition of plasma, erythrocyte and/or brain cholinesterase activity occurs by all routes (oral, dermal, and inhalation) and for a ll durations of exposure. In animal
studies, diazinon does not inhibit neurotoxic esterase ( NTE ) and it was not found to

induce organophosphate

- induced delayed neuropathy (OPIDN) . Further, it has not

been shown to cause histopathological lesions of the n ervous system.

The risk assessment conducted by OPP aims to protect public health by regulating

on the most sensitive and biologically plausible adverse effect. Cholinesterase inhibition data from rat studies provide s the basis for risk extrapolation for the diazinon (for additional information about diazinon‟s toxicity, see Appendix C).

. Human Incidents Review of Severity and Symptoms

Taking into account the current toxicological understanding and review of the incident data for diazinon, the inc ident data is consistent with OPP‟ s earlier hazard

assessment. In this particular case study, the diazinon human incidents were identified

from the various incident data sources, PCC, NPIC, NIOSH Sensor and PISP and the severity of the incidents was assess ed . In PCC (using the most recent years of data, 2004 and 2005) diazinon is in the top 10 pesticides regarding total frequency ofDraft, Do not cite

Diazinon Case Study Page 9 of 27 incidents reported, and in the top third regarding the proportion of severe (death, major, moderate) incidents. At the same t ime, about 95% of incidents are low severity; about 5% of reported diazinon incidents involving one substance and one active ingredient resulted in a moderate, major or death classification in 2004 and 2005.

Similar to PCC, the majority of the diazinon i ncidents reported in the IDS received low severity classifications (10% higher severity, no deaths 2004 to 2005). For NIOSH SENSOR, the majority of diazinon incidents fall within the low severity category; about 7% of reported incidents in 2004 and 2005 re sulted in a death or high severity classification. There were two cases that resulted in death, one was attributed to suicide by ingestion and there is no qualitative information available for the second case of death. Of the thirteen high severity illness es reported, four were considered attempted suicides, and other incidents involved misuse. Similarly, in NPIC approximately 10% (3 out of 28) of the incidents reported in the 2004

- 2005 timeframe resulted in a ”high severity illness or injury” classificatio n. No deaths were reported in this database. For PISP, only two cases were reported in the 2004

- 2005 timeframe and both were attempted suicides. PISP does not include a severity category, but it does include the categories “days lost from work” and “days hospitalized” which can serve as proxies for a severity classification. For these two cases, only “days hospitalized” was recorded for one of the incidents: 8 days hospitalized, which is considered severe.Draft, Do not cite

Diazinon Case Study Page 10 of 27 Figure C

- 1

. pr ovides a snapshot of the types of effects reported as related to diazinon exposure

in the 2004

- 2005 timeframe (the most recent two years of data available for all databases). It should be noted that multiple types of effects may occur concurrently within o ne incident.

Frequency of Human Incidents Over Time

In addition to the review of human symptoms and severity of health outcomes,

h uman incident data were also assessed to determine whether there were any trends or patterns over time in regions, prod uct

- types and/or exposure scenarios most likely to

result in incidents. Because of uncertainties related to exposure inherent in incident data ( limited information on overall usage , potential differences in reporting in regions/populations, uncertainty reg arding the product tagged to the incident),

conclusions can not be made based on these analyses (see Appendix B for further information). Nonetheless , all human incident data point to diazinon incidents decreasing over time as demonstrated by Figure C

- 2

. These decreases are in large

measure associated with residential exposures that occurred prior to cancellation of residential uses in 2000, with sales of all indoor residential use products ending in 2002 and sales of all outdoor residential use products e nding in 2004

.Draft, Do not cite

Diazinon Case Study Page 11 of 27 Figure C

- 2 . Diazinon incidents over time

The decline in OP and diazinon incidents has been reported on previously (Blondell 2007; Stone 2009)

IV. CONCLUSION/SUMMARY

Overall, the review of the human incident da ta on diazinon largely confirms OPP‟s earlier hazard assessment. Most of the different types of sy mptoms reported following diazinon exposure are consistent with cholinergic toxicity, and the reports cited represent nearly all of the reported incidents. T he databases do not suggest any new types of hazards.

The high frequency of “ miscellaneous “ effects from PISP data reflects only two cases with 11 reported symptoms between them, and most of the miscellaneous symptoms involved excessive salivation and swe ating which are typical symptoms of cholinergic toxicity

. EPA also thinks that t he reported “ ocular symptoms ” probably reflect

diazinon ‟s cholinesterase inhibitory effects ( e.g. , pinpoint pupils) or local insults from direct exposure to the eye. Further, while dermal symptoms are somewhat unusual,Draft, Do not cite

Diazinon Case Study Page 12 of 27 EPA thinks that they probably reflect local insults from direct exposure to the skin (see Appendix B for further details).

In the review of incident data over time, t he expected impacts of the Agency‟s regula tory decisions are generally reflected in the decrease of diazinon incidents over time across multiple human incident databases. Th is decrease is consistent with chemical use trend data (for residential and agricultural usage), as well as the four

- year ph ase out/cancellation of all indoor and outdoor residential uses and the occu pational risk mitigation actions.

V. WEIGHING AND INTEGRA TING HUMAN INCIDENT DATA INTO RISK

ASSESSMENT AND CHARA CTERIZATION

Human incident data are not collected for the explicit purpose of informing the risk assessment. This information, nevertheless , may serve as an important resource that contributes to characterizing potential risk. It also may be useful in formulating the problem statement

, in suggesting further analyses to clarify the risk potential (e.g

. , further evaluations of the toxicological database and available epidemiology studies) or possibly to identify additional stud y need s . Because each incident data base source considered by OPP and described in this report h as its own strengths and weaknesses, the reliability and the utility of the information must be evaluated with respect to its utility

to inform decisions on a case

- by

- case basis.

Incident data should be described in the context of risk characterization . F or example, i ncident data may confirm experimental toxicological observations and biologic mechanisms , as was in the case f or diazinon. In addition, such incident data may be useful to characteriz e human behavior and practices that contribute to illness

an d injury (e.g., misuse of the product). If incident data are collected for and available over a period of time, it may be useful to help evaluat e the efficacy of previously implemented risk mitigation activities, as illustrated by the diazinon case study.

When incident data are used in risk characterization, it is critical that the strengths and weakness of these data be properly evaluated to determine their influence on any conclusions and decisions regarding potential risk and the need for risk mitiga tion

decisions. In w eighing the evidence available in the human incident databases, a

number of factors must be considered , including whether there is an adequate

characterization of the nature of exposure and of the severity of the effect s

. Emphasis

sho uld be place on information of good quality and o n those cases for which the effects

are consistent or frequently observed both within and across the available databases. Less weight should be given to an isolated observation that is not consistent with

b roader database or to those situations that reflect only occasional obvious gross or

intentional misuse. In the case of diazinon, the incident data base associated with this pesticide is strong

, because the nature and frequency of effects reported were

co nsistent with the broader toxicological effects observed in laboratory studies including its mode of action and its ability to cause cholinergic toxicity.Draft, Do not cite

Diazinon Case Study Page 13 of 27 Incident data may, on occasion, identify a health effect or illness that is not previously observed in the toxicology studies . In some cases, these human incident reports may consist of anecdotal or isolated observations that have limited factual support or firm evidence of connection to exposure. In the case where the incident reports such as these ar e isolate d , anecdotal, or have little or no support, th e s e data should be given little to no weight in the integrative risk assessment process. In those cases where a greater number of reports are seen and there is some biological plausibility connected to the effect or illness, further broader analyses or investigations should be considered to help clarify or confirm the findings.

.Draft, Do not cite

Diazinon Case Study Page 14 of 27 APPENDIX A: CHEMICAL USE TRENDS

The usage data in this report is from two sourc es. The first source reports the chemica l usage for non

- a gricult ur al sites and the data are collected via survey by a private

market research firm. The second data source is the Cali fornia Department of Pesticide

R egulation and the data are gathered under the full use repor ting required of all agricultur al pesticide use s (which includes structural fumigation, pest control, and turf applications) in the state . The available usage data sets are grouped into two categories, consumer and professional usage, in order to provide context to the differe nt

incident data sets.

Consumer (Homeowner) Usage The data reported below provides an estimate of the pounds of diazinon applied by

consumers on outdoor sites.

(EPA Proprietary Data

- approved for public release)

The increase in diazinon usage between 1997 and 2001 is likely due to the phase

- out of another organophosphate, chlorpyrifos. The phase

- out of chlorpyrifos left diazinon as the market leader. In 2000, there was a cancellation of all residential uses of diazinon

and retail sales of the products ended by the end of 2004

. The refore, the decrease in

diazino n usage between 2001 and 2005 is likely a reflection of the product availability.

Professional Usage

Pest Management Professional (PMP) Firms : There are limited data to report for the pounds of diazinon applied by (PMP) firms. PMP applicators primarily treat areas in and around buildings for pests such as: termites, cockroaches, fleas, ants, and other pests. These applications are made to both residential and com mercial establishments and nearly 70 % of the applications are in residential establishments.Draft, Do not cite

Diazinon Case Study Page 15 of 27 The available data from 2001 and 2003 shows a decline in the total number of pounds applied from 430,000 to 110,000 (EPA Proprietary Data

- Approved for public re lease).

While these data are limited, it is likely that the pounds of diazinon applied by PMP firms have been declining since the cancellation of residential use s in 2000.

Professional Turf and Ornamental Pesticide Applicators: The data reported below

p rovide an estimate of the pounds of diazinon applied by professional turf and ornamental applicators. This data set covers the following sectors: golf courses, lawn care operators, horticultural nurseries and greenhouses, institutional turf facilities,

lan dscape contractors, and turf farms. The lawn care operators and landscape contractors apply pesticides to residential and nonresidential areas.

(EPA Proprietary Data

- Approved for public release)

In 1988, there was a cancell ation of outdoor uses on golf courses and sod farms and in

2000 there was a cancellation of residential uses.

Professional Usage of Diazinon in California (Agricultural and Non

- Agricultural) : The

data reported below represents the pounds of Diazinon appl ied on all sites in California except home and garden applications and most industrial and institutional uses.Draft, Do not cite

Diazinon Case Study Page 16 of 27 (CALDPR, 1997

- 2007)

The California data reflect a smoother decline over the years

, likely because this data

set d oes not include home and garden applications which were cancelled in 2000. The decline in 2002, is likely to be due to the agricultural mitigation measures required in the

2002 IRED.

Diazinon usage appears to be decreasing over time in both non

- agricult ural and agricultural sectors. The decline in residential usage accords well with the four

- year phase out/cancellation of all indoor and outdoor residential uses beginning in the year 2002 (e ffective December 31, 2002, retailers could no longer sell indoo r residential products; e ffective December 31, 2004, retailers could no longer se ll outdoor residential products). The decline in agricultural usage (as indicated by California data) also accords well with risk mitigation measures impacting agricultural w orkers (specified in the 2002 IRED). Although as depicted below (and a s expected), agricultural usage is not declining as rapidly as non

- agricultural usage.Draft, Do not cite

Diazinon Case Study Page 17 of 27 APPENDIX B: HUMAN IN CIDENT DATA

– ADDITIONAL ANALYSES/ INFORMATION

More detailed incident analys es are captured in this appendix (as well as details of some of the figures/numbers presented in the body of the document). While n ot all

were considered sufficiently relevant to mention in the body of this case study they are presented here for completen ess and transparency

.

Figure 1 depicts the frequency of reported symptoms across the database s , and the table below provides the information that informed the figure.

Table B.1 Frequency of Reported Symptoms 2004

- 2005

Effect Type PCC IDS NIOSH

SENSOR PIS P NPIC

C ardiovascular 4 % 2 % 10% 9% 7%

D ermal 14 % 35 % 8% 13 %

G astrointestinal 18 % 20 % 21% 9% 18 %

H ematological/Hepatic 0% 9%
Neurological 13% 15 % 31% 9% 27 %

O cular 29% 3 % 15% 9% 18 %

R enal 0% 3% 2%

R espiratory 6% 19 % 8% 18 % 9 %

M uscular 6 %

Miscellaneous 15 % 5% 36% 7% Total Reported Symptoms 854 65 39 11 99

Total Incidents* 2028 52 17 2 28 *involving one substance , one active ingredient Hatched cells indicate these categories were not available in particular databas e, empty cells indicate no symptoms fell into these categories.

One way incidents have been used in post

- market surveillance is to discern whether there are particular products within a similar group of products that stand out as resulting in more and/or more severe incidents than others in the same group or if there is a particular geographic pattern of incidents . The following tables depict initial explorations into these two potential patterns/trends. IDS and PCC are the preferred

databases to look for trends in product frequencies/geography due to the high number of reported incidents and national coverage, with the caveat that the Agency has less confidence in the product information in PCC. If a pattern/trend emerges, other

databases are consulted. F or diazinon

, our analysis was aborted due to lack of discerned pattern/trends upon initial review.Draft, Do not cite

Diazinon Case Study Page 18 of 27 Table B.2 Product Frequency

– Diazinon Incidents

– frequency by product (initial attempt)

PCC Product Name EPA Reg

. Number PCC

1993

- 2005 NPIC

1995

- 2001 NPIC

2002

- 2008 IDS

2000

- 2007 ( EPA Reg.

No .) NIOSH

SENSOR

DIAZINON 20964 (12 %) Diazinon

ORTHO DIAZINON

PLUS INSECT

SPRAY from

CHEVRON (INSECTICIDE) 1081 (5.7%) Ortho

Diazinon

Plus Insect Spray

2390264

3 Diazinon

Ultra Insect Spray Spectracide

Diazinon

4EC

KGRO

Diazinon

Insect Spray

Dexol And

& Roach

Killer

Diazinon

Granules

KGRO

SA

- 50

Diazinon Spray

Concentrate

Diazinon

Lawn &

Garden

Insecticide Super KGRO

Fruit & Vegetable

Insect

SPECTRACIDE FIRE

ANT KILLER

GRANULES from

SPECTRUM GROUP 0088450

0101 964

ORTHO DIAZINON

INSECT SPRAY from

SOLARIS GROUP 0002390

2364 584

(6.2%) Ortho

Diazinon Insect Spray Diazinon

Plus Insect Spray

Concentrate ORTHO

DIAZINON

INSECT

SPRAY *Product name not prov ided in CA PISP databaseDraft, Do not cite

Diazinon Case Study Page 19 of 27 Table B.3 Diazinon Incidents

– frequency by state (‘bold font’ for top states for each database)

PCC IDS NIOSH SENSOR NPIC

State Incident

Count Percent Number Of

Cases Incident

count % top 12

states

AK 8 0%

AL 875 2% 1 Most incidents

AR 964 3% 5

AZ 843 2% 6 90 1% Incidents occurred

CA 4831 14% 65 1134 19% Incidents occurred

CO 591 2% 4 3

CT 270 1% 2

DC 54 0%

DE 47 0% 1

FL 2552 7% 32 816 13% Most incidents

GA 1580 5% 12

HI 35 0%

IA 275 1 % 4 37 1%

ID 455 1% 2 Incidents occurred

IL 472 1% 16 1

IN 763 2% 11

KS 241 1% 2

KY 568 2% 5 1 Most incidents

LA 624 2% 6 851 14% Most incidents

MA 518 1% 8

MD 385 1% 3

ME 4

MI 1258 4% 10 336 5%

MN 249 1% 5

MO 893 3% 18

MS 166 0% 5 1

MT 116 0% 2

NC 929 3% 17 1 Most incidents

ND 18 0%

NE 362 1% 1

NH 180 1% 1

NJ 442 1% 5 1

NM 507 1% 4 18 0%

NV 316 1% 3

NY 911 3% 10 581 9%

OH 891 3% 10 2

OK 625 2% 8

OR 633 2% 7 356 6%

PA 878 3 % 8

RI 91 0% 1

SC 189 1% 6

SD 70 0% 2

TN 692 2% 12

TX 3875 11% 39 1440 24% Most incidents

UT 977 3% 9

VA 785 2% 11 1

VT 19 0%

WA 1298 4% 14 513 8% Incidents occurred

WI 324 1% 5

WV 190 1% 6

WY 82 0% 1Draft, Do not cite

Diazinon Case Study Page 20 of 27 Unknown 5 9 0% 1 Refused to give 11 0% Other US territory 1 0% Overseas US military 1 0%

Mexico 38 0% 4 0% Foreign country (not MX or CN) 3 0% Out Of Country 4

Total 414

PCC

PCC is one of the easier incident databases to wor k with. To assess whether incidents involving children and adults result in different symptom profiles , the data were segregated by age group. AAPCC incident information does not indicate that diazinon is more toxic to children than „adults‟ (people olde r than 12 years old). Additionally, the clinical effects most frequently reported are similar in both age categories, as are the proportion of reported clinical effects.

Figure B.1

DURATION AGE No. of

incident

s SEVERITY Reported CLINICAL EFFECTS

All du rations < 12

years 4032

(12%) 1% high severity (moderate, major,

death) (code) Medical

outcome Count %

(4) Death 1 0%

(3) Major effect 11 0% (2) Moderate

effect 56 1%

(1) Minor effect 312 8% (6) Not followed (judged at most minor) 837 21%

(0) No effect 181 7 45% (5) Not followed (judged nontoxic) 545 14% (7) Unable to

follow (potentially toxic) 91 2% (8) Unrelated

effect 362 9% *Clinical effects for medical outcomes coded
1,2,3,4,6,7,10

*Most frequently reported clinical effects = 1gastrointestinal/vomi ting, 2ocular/irritation,pain; 3miscellaneous/other; 4respiratory/cough,chokeDraft, Do not cite

Diazinon Case Study Page 21 of 27 > 12

years 30998

(88%) 6% high severity (moderate, major,

death)

Medical

outcome Count %

(4) Death 12 0% (10) Death

- indirect report 2 0%

(3) Major effect 179 1% (2) Moderate

effect 1663 5%

(1) Minor effect 6492 21% (6) Not followed (judged at

most minor) 7589 24%

(0) No effect 6314 20% (5) Not followed (judged nontoxic) 2166 7% (7) Unable to

follow (potentially toxic) 1415 5% (8) Unrelated

effect 5166 17% *Clinical effects for medical outcomes coded
1,2,3,4,6,7,10

*Most frequently reported clinical effects = 1ocular/irritation,pain; 2gastrointestinal/nausea; 3gastrointestinal/vomiting

Figure B.2 Adults/People > 12 years old

Exposure Site Number of

associated

incidents P ercentage

Own_residence 27399 88%
Workplace 1606 5%

Other_residence 1221 4%

Public_Area 309 1%

Unknown 231 1%

Other 117 0%

School 66 0%
Health_care_facility 41 0%

Restaurant/food_service 8 0%

Figure B.3 Children/People < 12 years old

Exposure Si te Number of

associated

incidents Percentage

Own_residence 3727 92%

Other_residence 246 6%

Public_Area 29 1%

School 9 0%

Unknown 8 0%

Other 7 0%
Workplace 3 0%
Health_care_facility 2 0%

Restaurant/food_service 1 0%Draft, Do not cite

Diazinon Case Study Page 22 of 27 The sites of exposure are not that different between these two age categories, except the older category includes exposure in the workplace.

Considering the proportion of sever e outcomes in relation to all incidents is a potential metric for classifying the hazard potential for pesti cides. Although diazinon incidents are declining over time, of note is a fairly steady proportion of severe outcomes (~6%). The incidents tallied below may involve more than one substance and/or active ingredient (although over 90% involve just one subst ance and one active ingredient).

Figure B.4

NIOSH SENSOR

The 220 diazinon cases are grouped by severity in Table B.4 below. As can be seen, the majority of these cases fell within the low severity category, and a total of 15 cases

fell within the dea th or high severity category.

Table B.4 Number of Cases by Severity of Outcome

Severity of Outcome Number of Cases

Death 2 High severity illness or injury 13 Moderate severity illness or injury 53 Low severity illness or injury 152

For the two cases resulting in death, one was attributed to suicide by ingestion. For the second case there is no qualitative information available on the behavior surrounding the fatal exposure.

Of the thirteen high severity illnesses reported, four were considered attem pted suicides. Another case was noted as an accidental ingestion. In a sixth case, a womanDraft, Do not cite

Diazinon Case Study Page 23 of 27 applied diazinon on her skin as a treatment for scabies. A seventh case resulted from mixing and spraying the pesticide in bathroom. An eight case resulted from mix ing the chemical with kerosene and spraying it in a home. A ninth case involved exposure in a well ventilated utility room. It was not possible to identify the type of exposure for the remaining cases.

In Table B.5, the type and number of reported sympto ms for each category of outcome severity are shown. In the case of death, respiratory, GI, and neurological symptoms were reported. In those cases classified as high severity, cardiovascular, respiratory, GI, and neurological symptoms were most the frequ ently indicated symptoms. For the moderate and low severity categories, GI, neurological and respiratory symptoms were

the most common.

Table B.5 Types of Symptoms Associated with each Outcome Severity Category

Outcome

Dermal Cardio Resp GI Rena

l Neur

o Ey e Misc

Death 0 0 1 1 0 1 0 0 High severity illness or injury 1 10 9 10 4 11 6 5 Moderate severity illness or injury 10 12 20 33 3 39 8 12 Low severity illness or injury 41 13 59 80 5 90 36 21

For children under the age of six there were eleven total reported incidents. There was a single high severity case where dermal, respiratory, GI, neurological and eye related symptoms were reported. For the remaining cases, GI and neurological symptoms were the most frequently reported symptoms.

Table B.6 Chil dren Under 6, Types of Symptoms Associated with each Outcome Severity Category

Outcome Dermal Cardio Resp GI Rena

l Neur

o Eye Misc High severity illness or injury 1 0 1 1 0 1 1 0 Moderate severity illness or injury 0 1 2 2 0 2 1 1 Low severity illness or injury 2 1 0 4 0 3 0 2

CA PISP

Among the case reports between 1996 and 2006, the majority of the reported symptoms involved systemic effects such as nausea, vomiting, dizziness, diarrhea, tingling, tachycardia, weakness, headache, chest pain, sweating, lightheadedness, numbness and bradycardia. A large number of these exposures occurred from non

- occupational exposure to drift. During school hours, a groundskeeper used a hose

- end sprayer to apply diazinon to shrubbery about 15 feet from the air conditi oner intake. The odor entered the ventilation system in the first floor classrooms. About 15 minutes later, several students reported symptoms including headache and visited the school nurse. Most of the students requested to go home after being evaluat ed.Draft, Do not cite

Diazinon Case Study Page 24 of 27 Figure B.5Draft, Do not cite

Diazinon Case Study Page 25 of 27 APPENDIX C: ADDITION AL TOXICOLOGICAL INF ORMATION

The mechanism of toxicity for diazinon is typical of an anticholinesterase organophosphate that inhibits acetylcholinesterase (AChE) in the central and peripheral nervous system. AChE is re sponsible for terminating the action of the neurotransmitter, acetylcholine in the synapse of the pre

- and postsynaptic nerve endings and in the neuromuscular junction. The action of acetylcholine does not persist long as it is hydrolyzed by AChE and rapid ly removed. As an anticholinesterase organophosphate, diazinon inhibits AChE by reacting with the active site to form a stable phosphorylated complex incapable of deactivating acetylcholine at the synaptic gutter between the pre

and postsynaptic nerve end ings or neuromuscular junctions of skeletal muscles resulting in accumulation of acetylcholine at these sites. This leads to continuous or excessive stimulation of cholinergic fibers in the postganglionic parasympathetic nerve endings, neuromuscular juncti ons of the skeletal muscles, and cells of the central nervous system that results in hyperpolarization and receptor desensitization. These cholinergic actions involving end organs (heart, blood vessels, secretory glands) innervated by fibers in the postgan glionic parasympathetic nerves result in muscarinic effects, which are manifested as miosis, excessive glandular secretions (salivation, lacrimation, rhinitis), nausea, urinary incontinence, vomiting, abdominal pain, diarrhea,

bronchoconstriction or bronch ospasm, increased b ronchosecretion, vasodilation, bradycardia, and hypotension. Nicotinic effects are due to accumulation of acetylcholine at the skeletal muscle junctions and sympathetic p reganglionic nerve endings. Nicotinic

effects are manifested as mu scular fasciculations, weakness, mydriasis, tachycardia, and hypertension. The central nervous system effects are due to accumulation of acetylcholine at various cortical, subcortical, and spinal levels (primarily in the cerebral cortex, hippocampus, and e xtrapyramidal motor system). The central nervous system effects are manifested as respiratory depression, anxiety, insomnia, headache, restlessness, tension, mental confusion, loss of concentration, apathy, drowsiness,
ataxia, tremor, convulsion, and coma (ATSDR, 2008)

.Draft, Do not cite

Diazinon Case Study Page 26 of 27 REFERENCES 1

40 CFR §159.184

Agency for Toxic Substances and Disease Registry (ATSDR). 2008. Toxicological profile for Diazinon. Atlanta, GA: U.S. Department of Health and Human Services,

Public Health Service.

Blondell, JM, 2007. “Decl ine in pesticide poisonings in the United States from 1995 to 2004.” Clinical Toxicology, 45:5, 589

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Calvert, GM, Barnett, M, Blondell JM, Mehler, LN, Sanderson, WT. “Surveillance of

Pesticide

- Related Illness and Injury in Humans” Handbook of Pesticid e Toxicology, 2 nd
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Environmental Protection Agency (EPA), Reigart, JR, Roberts, JR. 1999. Recognition and Management of Pesticide Poisonings, Fifth Edition . EPA 735

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1999. http://www.epa.gov/oppfead1/safety/healthcare/handbook/handbook.htm

Environmental Protection Agency (EPA), 2004. Interim Reregistration Eligibility Decision

for Diazinon

. EPA 738

- R

- 04

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Environmental Protection Agency (EPA), 2008. Diazinon. Revised Human Health Assessment Scoping Do cument in Support of Registration Review. EPA

- HQ

- OPP

2008

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Hoffman, RS, 2007. “ Understanding the limitations of retrospective analyses of poison

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World Health Organization/International Programme on Chemical Safety (WHO/I PCS), 2002. Report of the Meeting on Bridging the Gap Between Clinical and Regulatory Toxicology. January 2002. http://www.who.int/ipcs/methods/en/bridging_gap_report.pdf

1 References have not been consistently cited in the document, and will be amended before the SAP.Draft, Do not cite

Diazinon Case Study Page 27 of 27 World Health Organization/International Programme on Chemical Safety (WHO/IPCS), 2004. Report: Workshop on Poisons Centres and the Use of Human Data in Consumer Product Risk Assessment. May 2005. http://www.who.int/ipcs/methods/en/cardiff_report.pdf