11 Three Pre-Rule Studies of Chlorpyrifos: Nolan et al. (1982) Honeycutt & DeGeare (1993) Kisicki et al. (1999) Human Studies Review Board June 24, 2009.

11

Three Pre-Rule Studies of Chlorpyrifos:

Nolan et al. (1982)Honeycutt & DeGeare (1993)

Kisicki et al. (1999)

Human Studies Review BoardJune 24, 2009

2

Sequence of Presentations

Introduction and Context• Anna Lowit, Ph.D.

Science Assessments Nolan and Kisicki Studies

• John Doherty, Ph.D., DABT

Honeycutt & Degeare Study

• Wade Britton, MPH

Ethics Assessments• John Carley

33

Chlorpyrifos

Introduction and Context

Anna Lowit, Ph.D.Senior Scientist

Health Effects DivisionOffice of Pesticide Programs

4

Introduction Chlorpyrifos:

Organophosphate pesticide which was first registered in 1965

In June 2000:

• The technical registrants entered into an agreement with the Agency to eliminate and phase out nearly all uses that result in residential exposures.

• Human health risk assessment developed for the Interim Registration Eligibility Decision (IRED) relied on adult ChE data from rodents & dogs

– Human studies were not used to inform point of departure or uncertainty factors

– Honeycutt study used in the worker exposure assessment

5

Introduction

Current regulatory activities leading to new risk assessment:

Registration review: 15-year review cycle under FIFRA for registered pesticides

• Update human health & ecological risk assessments

Petition by Natural Resources Defense Council (NRDC) and Pesticide Action Network, North America (PANNA) to revoke all tolerances and cancel all registered uses

6

Introduction Draft Science Issue Paper reviewed by the

FIFRA SAP in 2008

Review the new science from animal & humans under the context of human health risk assessment

Focus on effects in pregnant women, fetuses, and juveniles as these groups are thought to be more susceptible to chlorpyrifos

• Age-dependant metabolism

• Epidemiology studies in mothers & children

• Rodent studies evaluating non-cholinergic toxicities (i.e., behavior, learning, biochemical responses)

• AChE studies in pregnant rats, fetuses, post-natal pups

7

Human Experimental StudiesHuman Experimental Studies

7

Nolan Honeycutt Kisicki

PurposeAbsorption, distribution,

excretionAgricultural re-entry

worker exposureNOEL for RBC AChEI

Date 1981-82 1991-92 1998

LocationDow Chemical

Midland MICitrus Groves in Kern &

Tulare Counties, CAMDS-Harris Labs

Lincon NE

Subjects 6 M 15 M 30 M 30 F

ExposureSingle oral dose

Single dermal doseUncontrolled

occupational exposureSingle oral dose

Endpoints of primary concern

RBC ChEI Plasma ChEI Blood TCP Urine TCP

RBC ChEI Plasma ChEI

Urine TCP

RBC ChEI Blood TCP Urine TCP

8

Proposed Uses of the Human Proposed Uses of the Human StudiesStudies For “Bounding” Analyses

Comparing blood & urine data from the human experimental studies with data from animal studies & human epidemiology studies

Comparing levels of AChE/ChE inhibition in humans and animals

To Develop & Refine PBPK models

Physiologically-based pharmacokinetic models

Current models include Nolan et al data

• Kisicki et al or Honeycutt & DeGeare not used in current model parameterization

8

9

EPA does NOT propose to use data from the human experimental studies for a point of departure (PoD) or to directly inform the inter-species uncertainty factor Animal studies provide high-quality dose-response data for

ChEI across many doses & multiple life stages

Human studies lack dose-response information

• Nolan et al used only one dose level for each route of administration

• Kisicki et al showed ChEI in only one subject

• Honeycutt & DeGeare was not designed for dose response

Human studies do not address non-cholinergic toxicities

• Animal data indicate susceptibility of the developing nervous system to chlorpyrifos

• Epidemiology studies in children generally support the animal studies

9

10

Using Human Biomarker Data:Using Human Biomarker Data:Bounding EstimatesBounding Estimates

10

Rodent Administered Dose, Known & Controlled

Blood &/or Urine Measures

Human Deliberate DosingAdministered Dose, Known & Controlled

Human EpidemiologyExposure,

Limited & Uncertain

Blood &/or Urine Measures

Blood &/or Urine Measures

11

Physiologically-Based Physiologically-Based Pharmacokinetic (PBPK) ModelsPharmacokinetic (PBPK) Models

Represent the anatomy & physiology of the rodent/human

Provide simulations of biological processes such as absorption, distribution, metabolism & elimination

Widely recognized as the “gold standard” in human health risk assessment

Particularly helpful in extrapolations: Route to route

Inter-species

Across dose range11

12

SAP ResponseSAP Response SAP was generally supportive of EPA’s preliminary

conclusions, and identified areas for revision & additional analysis “Overall, the Panel agreed that the human deliberate dosing

studies contain scientifically useful information for risk assessment, but not for directly establishing PoD or uncertainty factors.”

“The Panel appreciated the Agency’s scientific analysis to compare the blood levels in the deliberate dosing and epidemiological studies, and considered it critically important to maximally use the information from these studies . . . as a basis to “bound” the reference doses/concentrations . . .”

“The Panel encouraged the Agency to consider the use of a PBPK model to widen the application of these bounding data for current or potential human exposures and for the final reference dose or reference concentrations.”

12

13

Human Experimental Studies

Nolan et al (1984)

Historically used to interpret biomonitoring studies (e.g., NHANES & worker)

Provides estimate of dermal absorption

Used in current PBPK models for inter-species scaling

14

Kisicki et al (1999)

Lack of plasma ChE is a critical omission from study design decreases its utility

Possible reduced absorption of chlorpyrifos from capsule

Used in 2002 Timchalk et al PBPK paper

• For purposes of model evaluation

• Not used in current parameterization

Human Experimental StudiesHuman Experimental Studies

15

Human Experimental StudiesHuman Experimental Studies

Honeycutt & DeGeare

Will be used in combination with other available worker biomonitoring studies to evaluate range of urinary TCP concentrations for workers

16

Human Experimental StudiesHuman Experimental Studies

16

Nolan Honeycutt Kisicki

PurposeAbsorption, distribution,

excretionAgricultural re-entry

worker exposureNOEL for RBC AChEI

Date 1981-82 1991-92 1998

LocationDow Chemical

Midland MICitrus Groves in Kern &

Tulare Counties, CAMDS-Harris Labs

Lincon NE

Subjects 6 M 15 M 30 M 30 F

ExposureSingle oral dose

Single dermal doseUncontrolled

occupational exposureSingle oral dose

Endpoints of primary concern

RBC ChEI Plasma ChEI Blood TCP Urine TCP

RBC ChEI Plasma ChEI

Urine TCP

RBC ChEI Blood TCP Urine TCP

17

The Nolan The Nolan et al.et al. (1982) and (1982) and Kisicki Kisicki et al.et al. (1999) (1999)

Chlorpyrifos Single Dose Chlorpyrifos Single Dose Studies in Human Studies in Human

Volunteers:Volunteers:

Science Assessment Science Assessment John Doherty, PhD, DABT

Health Effects DivisionOffice of Pesticide Programs

18

Scope of Presentation

The reliability of the analytical data for chlorpyrifos and TCP* and the assessment for ChE and its inhibition with some emphasis on individual variability will be presented.

*TCP = 3,5,6-trichloro-2-pyridinol – the principal metabolite of chlorpyrifos.

19

Study Information - Basic Protocols

Nolan (1984) Kisicki (1999)

Location DOW Chemical Co. Midland, Michigan

MDC Harris Laboratory Lincoln, Nebraska

Number of Subjects

6 males 12/sex for controls 6/sex/dose group

Oral Doses 0.5 mg/kg on tablet

0, 0.5, 1 and 2 mg/kg in capsules

Dermal Doses 5 mg/kg None

20

Study InformationChE activity and analysis for chlorpyrifos and TCP

Nolan (1984) Kisicki (1999)

ChE Assessment Michel pH stat (1961) ∆ pH/hour

Automated Ellman (1961) IU/L

Plasma ChE Consistent with original method (CV 3-12%)

Not assessed.

RBC AChE Consistent with original method (CV 8.5 to

20.2%)

Consistent with other labs (CV 6-13%)

Analytical Method for chlorpyrifos and TCP

GC with FP and EC GC/MS

Levels of Quantization:

Chlorpyrifos TCP

~ 5 ng/mL

~ 2.5 – 5 ng/mL

~ 1 – 1.2 ng/gm

~2 – 10 ng/mL

21

Results –Analysis for ChlorpyrifosLevels are near the LOQ- Reliability fair.

Nolan Kisicki Oral: 22 of 48 samples (5-30 ng/mL)

9 ng/mL in one 0 time.

Dermal: 9 of 36 samplings (5-10 ng/mL). 7 and 10 ng/mL in two 0 time.

0.5 mg/kg: Not detected.

1 mg/kg : 6 of 156 samples (maximum 5.6 ng/gm).

2 mg/kg: 12 of 150 samples (maximum 18 ng/gm).

Poor temporal association with inhibition.

Not present when the only subject with inhibition starts to show inhibition.

Not in urine Not in urine

22

Results: Analysis for TCPRanges show individual variation

Nolan (0.5 mg/kg,

male)

Kisicki (1 mg/kg,

male)

Time to peak in blood (peak level)

2-24 hours (715 to 1430

ng/mL)

4-48 hours (300-610 ng/ml)

Time to peak in urine (peak level)

3-9 hours (268 to 510

µg/hr)

12-48 hours (935-2642

ng/mL)

Half life based on urinary TCP

27.7±5.2 hours (21.3-33.9)

28.5±6.9 (21.6-37.6)

Percent recovered in urine

70±11% (49-81%)

32.1±9.7 (23.4-50.8%)

Internal Dose 0.35±0.06 mg/kg (0.245 –

0.405)

0.32±0.09 mg/kg (0.237-

0.490)

23

Results – Plasma ChE Inhibition and TCPNolan Oral Study

Basal values 0.87±0.09 to 1.42±0.17 are reasonable.

All six subjects maximum 71 to 89% inhibition (good agreement) but time to peak varies (i.e. 6-24 hours).

Maximum blood TCP (715 to 1430 ng/mL) usually before maximum inhibition.

Approximately 700 – 800 ng/mL TCP in blood needed for about 57 to 63% inhibition for two subjects.

But 996 ng/mL associated with only 30% inhibition in another subject.

Correlation of urine (µg/hour) TCP with blood (µg/mL) and with inhibition confounded because of units and times of collection and ChE assessment.

24

RBC AChE inhibition in the Kisicki Study. Basal values (i.e. ♀ group means) of 8576±556 to

9165±709 are reasonable.

1.7 to 5.6 ng/mL chlorpyrifos - no inhibition.

Blood TCP up to 1300 ng/mL not associated with inhibition.

Urine TCP up to 15,323 ng/mL in one subject did not show inhibition.

Only one subject displayed RBC AChE inhibition.

This subject had highest gastro-intestinal absorption.

Inhibition starts to peak before chlorpyrifos and TCP in the blood and urine peak (next slide).

25

Kisicki Study : RBC AChE inhibition – correlation with chlorpyrifos in blood (ng/mL) and TCP in blood and urine).

Hour Subject # 56 (QQ ♀ )

% Inhibition Chlorpyrifos TCP

| Blood | Blood Urine

2

4

8

12

24

36

48

NDa ND ND ND

2% ND 71 ND

23% ← ND 120 1246(6 hr)

28% 18 ← 1600 ← 7966

26% 2.5 1500 8148 ←

19% ND 1300 6270

21% ND 1100 7068

No assessments after 48 hours.

(Subject left study)aND – Not detected R = 8148/1600 = 5.1

26

Chlorpyrifos and ChE inhibition

Chlorpyrifos

↓

[Chlorpyrifos Oxon]

(Rapid irreversible inhibition of ChE/AChE)

↓

TCP

(Also from other pathways)

27

Blood and urine levels of TCP in females dosed with 2 mg/kg.

Subject 49 QQ 51 OR 55 RR 58 QQ 59 QQ

Blood (hour)

Urine (hour)

R

490 (8)

2183 (12)

4.5←

1300 (8)

6064 (24)

4.7

600 (24)

5275 (24)

8.8

480 (8)

2458 (48)

5.12

610 (8)

6622 (36)

10.9←

28

Dermal dosing (Nolan study only)

Borderline inhibition effect on plasma ChE in 3 of 5 subjects, maximum 26% decrease. RBC AChE not inhibited.

Blood TCP at 122 ng/mL with 21% decrease but 36 ng/mL with 26% decrease. No correlation.

Recovery in urine as TCP:

5 mg/kg (five subjects): 1.02±0.57% 0.5 mg/kg (one subject): 2.6%.

29

Some Applications of the Nolan and/or Kisicki Studies

Supports Agency use of low dermal absorption factor (Nolan).

Demonstrates BuChE is more sensitive than RBC AChE in humans (Nolan and Kisicki).

May support PBPK models.

May support “bounding”

Demonstrates variability of humans to absorb chlorpyrifos from the g-i tract.

30

Summary - Strengths

Technical Assessment for ChE/AChE should be reliable in both studies (agree with literature and reasonable CV).

Technical analysis for TCP in blood and urine should be reliable (temporal response in both studies and reasonable dose response in Kisicki).

31

Summary – Limitations: Both Studies

Analytical methods (nano range) are much less sensitive than the epi studies (pico range)*.

Variability in TCP analysis – humans are not equal*.

*Provides challenge for interpreting epi studies.

Comparison between Nolan and Kisicki studies confounded because of tablet vs. capsule dosing.

Chlorpyrifos present near LOQ and in some 0 time samples (Nolan). Reliability only fair.

32

Summary – Limitations: Nolan Study

Only one dose resulting in ~70-89% inhibition.

Does not establish NOEL.

Difficult to establish minimal levels of TCP associated with inhibition.

TCP is in units/hour, epi and Kisicki report units/mL. Do not easily compare.

33

Summary –Limitations: Kisicki Study

Does not include plasma ChE assessment.

Only one subject with RBC AChE inhibition limits usefulness.

34

Honeycutt & DeGeare (1993)

Science Assessment

Wade Britton, MPHHealth Effects Division

Office of Pesticide Programs

35

Study Information

Agricultural postapplication workers monitored during pruning and picking activities in California citrus

Chlorpyrifos (Lorsban 4E) applied once at each of 3 study locations (5-6 lb ai/acre)

Study conducted between 1991/1992

36

Sampling Strategy

15 individuals monitored

Actual workers and typical durations

Picking

5 individuals (5 at 1 site)

Exposure occurred 43 days after application

Pruning

10 individuals (5 at each of 2 sites)

Exposure occurred 2 days after application

37

Multi-faceted Approach

Biological Monitoring*

Urine collected for 4 days after exposure

Blood sampled 1 day after exposure

Pre-exposure samples collected for each

Passive Dosimetry

Dermal

Inhalation

Leaf surface residues

38

Biological Monitoring - Analysis

Blood analyzed for plasma and red blood cell (RBC) cholinesterase (ChE) levels

Urine analyzed for TCP and creatinine

TCP used to calculate chlorpyrifos body burden

Creatinine used to evaluate completeness of sample collection

39

Blood ChE - ActivityPlasma RBC

Pickers

Avg. (SD)

-0.02 % (± 0.05)

Avg. (SD)

- 0.01 % (± 0.05)

Range -7.1 to 5.2 % Range - 5.1 to 6.6 %

Pruners (wet)

Avg. (SD)

- 1.0 % (± 2.9)Avg. (SD)

- 11 % (± 5.3)

Range -4.4 to 3.0 % Range -14 to -3.5 %

Pruners (dry)

Avg. (SD)

- 3.4 % (± 12)Avg. (SD)

30 % (± 16)

Range -14 to 16 % Range 14 to 50 %

40

Urine Measurements

Urine measures

(ug/L)

Absorbed Dose

(ug/person)

Absorbed Dose (ug/kg,

assume 70 kg BW)

Picker4.5 (± 2.6)

32 (± 4.9)

0.45 (± 0.071)

Pruner (wet)

29 (± 28) 204 (± 38) 2.9 (± 0.54)

Pruner (dry)

15 (± 13) 103 (± 20) 1.5 (± 0.28)

•TCP corrected for pre-study levels•Creatinine corrected based upon literature standard (1.8 g/24 hours)

41

Study Strengths

Monitored both urine and blood (plasma and RBC ChE) in all workers

Actual workers monitored while performing activities in production fields

42

Study Limitations

Not statistically designed to define the relationship between TCP and ChE

TCP exposure can occur from many sources

Dosimetry possibly limited absorption of chlorpyrifos

Potential to underestimate TCP & blood ChE activity

43

Conclusions

Represents the best source for occupational worker chlorpyrifos biological monitoring

Provides urine measures and blood plasma and RBC ChE in the same individuals

Actual workers, activities and duration

4444

John M. CarleyHuman Research Ethics Review Officer

Office of Pesticide Programs

Ethics Assessments ofThree Pre-Rule Studies of

Chlorpyrifos

4545

Nolan, et al. (1982)Nolan, et al. (1982)

Nolan, R.; Rick, D.; Freshour, N.; and Saunders, J. (1982) Chlorpyrifos: Pharmacokinetics in Human Volunteers Following Single Oral and Dermal Doses. Unpublished study prepared by the Dow Chemical Company under Protocol HEB-DR-0043-4946-4. 28 p. (MRID 124144)

Dow AgroSciences (2009) Supplemental Documentation of Ethical Conduct of Nolan et al. Study. E-mail correspondence April 29 through May 8, 2009, between Kenneth Racke and Tom Myers, with attachments. 22 p.

4646

Value to SocietyValue to Society

Defines absorption, distribution, and elimination of oral and dermal doses of chlorpyrifos

Contributes to weight of evidence linking animal data and human epidemiological data

4747

Subject SelectionSubject Selection

Subject Selection

Subjects were all salaried Dow employees, recruited through in-house advertisements

6 healthy adult males, screened by a physician not otherwise involved in the research

Women of child-bearing age excluded by IRB

Nature of endpoints and measures ruled out subject bias in reporting

4848

Risks and Benefits Risks and Benefits

Risks Doses based on earlier studies and pilot pre-

test, with adequate margins of safety

Expected effects • Inhibition of plasma ChE but not of RBC ChE

• No clinical signs

• Effects reversible—followed until full return to baseline

Benefits No benefits to subjects

4949

Ethics OversightEthics Oversight

Approved by Dow Human Health Research Review Committee

Approved by University of Michigan Committee to Review Grants for Clinical Research and Investigation Involving Human Beings

Approvals documented; gaps typical for research from this period

5050

Informed ConsentInformed Consent Subjects were given a copy of protocol to review

Subjects were briefed on Study objectives Chlorpyrifos properties Pilot phase results, and study procedures Benefits, including free meals Confidential handling of data Voluntary participation and freedom to withdraw

Subjects signed consent forms reporting that they’d read the protocol and been briefed on the research

Subjects were not paid

5151

Applicable StandardsApplicable Standards

Standards of Conduct

Declaration of Helsinki (1975)

FIFRA §12(a)(2)(P)

Standards of Acceptability

40 CFR §26.1703

40 CFR §26.1704

5252

Compliance with StandardsCompliance with Standards

No evidence to suggest research conduct was inconsistent with DoH (1975)

Evidence indicates compliance with FIFRA §12(a)(2)(P)

No intentional exposure of pregnant or nursing women or of children

No clear and convincing evidence of significant deficiency relative to prevailing standards of research conduct

5353

ConclusionConclusion

If it is deemed scientifically valid and relevant, there are no barriers in FIFRA or in 40 CFR §26.1703 or §26.1704 to EPA’s reliance on the Nolan et al. study in actions taken under FIFRA or §408 of FFDCA

5454

Honeycutt & DeGeare (1993)Honeycutt & DeGeare (1993)

Honeycutt, R., and M. DeGeare (1993) Worker Reentry Exposure to Chlorpyrifos in Citrus Treated with Lorsban® 4E Insecticide. Unpublished study prepared by H.E.R.A.C., Inc. under study numbers 91-102HE and DECO-HEH2.2-1-182(125)B. 950 p. (MRID 43062701)

Dow AgroSciences (2009) Supplemental Documenta-tion of Ethical Conduct of Honeycutt and DeGeare Study. E-mail submission of May 22, 2009 from Kenneth Racke to Tom Myers. 27 p.

5555

Value to SocietyValue to Society

Conducted in response to EPA requirement

Part of larger project to monitor agricultural worker exposure to chlorpyrifos

Determined ChE activity and TCP residues for workers re-entering treated citrus groves Orange pickers re-entering 43 days after treatment

Lemon pruners re-entering 2 days after treatment

Contributes to weight of evidence linking animal data and human epidemiological data

5656

Subject SelectionSubject Selection

Subjects were experienced citrus workers

Recruitment was through labor contractor, who may have influenced subject choice to participate

Difficulty reported in finding qualified and willing subjects

Mingling of subjects in this and companion study of chlorpyrifos handlers

5757

Risks and BenefitsRisks and Benefits Risks

“No increased health risk as I will be doing my job wearing normal protective clothing”

Unaddressed risks:• Heat stress from wearing WBD

• Differential risks for pickers and pruners

Benefits No benefits to subjects

Benefits likely to Dow, EPA, and CDFA

5858

Ethics OversightEthics Oversight Protocol review by UCSF Committee on Human

Research, brokered by CDFA/CDPR, as was then-standard practice in California

Revised CF approved by IRB before use

Some amendments affecting subjects may not have been reviewed by IRB

Ethics oversight was closer and is better documented than is typical for worker exposure studies from this period

5959

Informed ConsentInformed Consent Subjects were briefed in Spanish or

English

Consent forms used were approved by IRB, included all required elements, but retained erroneous content from companion handler study

CF discussion of MOE should have been revised for pruners

Process and form were above average for exposure studies in 1991-92

6060

Applicable StandardsApplicable Standards Standards of Conduct

CCR Title 3 §6710 (26 Sep 1988)• Health of subjects will not be endangered• Participants informed of potential risks• Medical supervision

• Incorporation of recommendations by Human Study Committee of California Health and Welfare Agency

FIFRA §12(a)(2)(P)

Standards of Acceptability 40 CFR §26.1703 40 CFR §26.1704

6161

Compliance with Standards of Compliance with Standards of ConductConduct

Evidence indicates substantial compliance with California rule and with FIFRA §12(a)(2)(P)

Active CDPR oversight and approval

IRB review and approval

Voluntary and informed consent

Some protocol amendments should have led to further revisions to the consent form

6262

Compliance with Acceptance Compliance with Acceptance StandardsStandards

40 CFR §26.1703

No intentional exposure of pregnant or nursing women or of children

40 CFR §26.1704

Not fundamentally unethical

No clear and convincing evidence of significant deficiency relative to prevailing standards

6363

ConclusionConclusion

If it is deemed scientifically valid and relevant, there are no barriers in FIFRA or in 40 CFR §26.1703 or §26.1704 to EPA’s reliance on the Honeycutt & DeGeare study in actions taken under FIFRA or §408 of FFDCA

6464

Kisicki, et al. (1999)Kisicki, et al. (1999)Kisicki, J.; Seip, C.; Combs, M. (1999) A Rising Dose

Toxicological Study to Determine the No-Observable-Effect-Levels (NOEL) For Erythrocyte Acetylcholinesterase (AChE) Inhibition and Cholinergic Signs and Symptoms of Chlorpyrifos at Three Dose Levels. Unpublished study prepared by MDS Harris Laboratories under Project No. 21438 and Dow AgroSciences Study No. DR K-0044793-284. 578 p. (MRID 44811002)

Juberg, D.; Mattsson, J. (2008) Dow AgroSciences Response to EPA Query Regarding Two Toxicology Reports. Unpublished document prepared by Dow AgroSciences LLC under Study ID DRJ05142008. 20 p. (MRID 47429401)

Juberg, D.; Mattsson, J. (2008) Updated Dow AgroSciences Response to EPA Query Regarding Two Toxicology Reports. Unpublished document prepared by Dow AgroSciences LLC under Study ID DRJ05282008. 27 p. (MRID 47436401)

6565

Value to SocietyValue to Society

Objective was NOEL for RBC ChEI following single oral dose

Research undertaken by Dow at their own initiative

Determined RBC ChEI and chlorpyrifos and TCP residues in blood and urine

May contribute to weight of evidence linking animal data and human epidemiological data

6666

Subject SelectionSubject Selection Subjects were “non-institutionalized subjects

consisting of college students and members of the community at large”

More than the reported 60 were involved 140 candidates who responded to a “standard

advertisement” were screened

60 candidates were enrolled as primary subjects and 22 more as alternates

After extensive substitution at the time of “check-in”, 30 males and 30 females served as treated or control subjects

An alternate replacing a primary subject was identified by the same subject number as the person replaced

6767

Subject Selection—2 Subject Selection—2

Age range 19-54, mean age 31

Inclusion criteria few; exclusion criteria extensive

Candidates rejected in screening mainly for drugs or blood chemistry

Enrollees were replaced by alternates mainly because of not showing up at check-in

6868

Dose SelectionDose Selection

Low dose (0.5 mg/kg) for overlap with Nolan, et al.

Because 0.5 mg/kg showed no RBC ChEI in Nolan and no signs, low- and mid-doses (0.5 and 1.0 mg/kg) were administered concurrently in Phase 1

Pause to confirm no effects at 1.0 mg/kg before escalating dose to 2.0 mg/kg in Phase 2

6969

Risks to SubjectsRisks to Subjects Not discussed in protocol Consent Form:

“Potential side effects include . . . improved performance on numerous tests of mental function”

“No adverse effects are anticipated”

“Animal studies indicate little or no risk in humans”

“There are specific and effective antidotes available”

“In all but exceptional cases, persons seriously poisoned . . . recover rapidly leaving no long term effects”

“It may be very unsafe for me to leave the clinic . . .”

“Risks involved in drawing blood . . .”

7070

Risks to Subjects—2 Risks to Subjects—2

“This procedure may be associated with undesirable effects, some of which are not predictable. However, I understand that in the opinion of MDS Harris’ medical consultants, those risks are not great enough to keep me from participating”

7171

Risk MinimizationRisk Minimization

Vital signs taken periodically

Subjects were asked open-ended questions about how they felt

Physicians were on call during subject confinement

Antidotes described were not required by protocol to be available during test

7272

Risk:Benefit RelationRisk:Benefit Relation

Consent Form states subjects would receive “no direct medical benefit”, but that the information developed “may provide potential benefit to others”

Protocol is silent concerning societal value of information expected to be gained

Relation of risks and benefits not addressed in protocol or by IRB

7373

Ethics OversightEthics Oversight Protocol, MSDS, Consent Form, payment, and

recruiting advertisement were reviewed and approved by MDS-Harris in-house IRB

“Additional changes” were reported to have been submitted to IRB direct from sponsor

Amendment 1 and revised CF also approved by IRB

MDS-Harris IRB holds a Federal-Wide Assurance from OHRP

7474

Informed Consent ProcessInformed Consent Process Explanation of research and signature of

consent form occurred during “check-in” the evening before treatment

Hectic circumstances at check-in are unlikely to have provided the prospective subject sufficient opportunity to consider whether or not to participate

All enrolled primary and alternate subjects had provided blood and urine samples for screening and baseline before receiving an explanation of the research or signing the consent form

7575

Informed Consent FormInformed Consent Form

Inappropriate technical language in CF—reading grade level for first full paragraph was 17.7

Poor organization, pronoun shifts, mix of dire warnings and soothing reassurance made it difficult to follow or understand

Discussion of risks incomplete and misleading

Escalation rule was not explained to subjects, nor were results of Phase 1 incorporated into Consent Form for Phase 2

7676

Respect for SubjectsRespect for Subjects

Subjects were free to withdraw

Subject privacy was not compromised in reports

Subjects were compensated for participation

Recruiting and screening processes were needlessly intrusive

7777

Unreported Protocol DeviationUnreported Protocol Deviation

Protocol:

Adverse events, whether serious or non-serious, will be followed to resolution regardless of whether the subject is still participating in the study

The only subject with significant ChEI was lost to follow-up 48 h post treatment

This was not acknowledged to be a deviation from the protocol

7878

Applicable StandardsApplicable Standards

Standards of Conduct 21 CFR parts 50, 56, and 321 Declaration of Helsinki (1996) FIFRA §12(a)(2)(P)

Standards of Acceptability 40 CFR §26.1703 40 CFR §26.1704

7979

Compliance with StandardsCompliance with Standards 21 CFR 50 and 56, like the Common Rule, require

IRB oversight and prior approval

Risk minimization

Favorable risk:benefit balance

Acceptable informed consent process and consent form

Equitable subject selection

Fully voluntary participation by subjects

Review and approval by the MDS-Harris IRB did not show concern for or ensure compliance with these standards

Deficiencies in consent process made conduct non-compliant with FIFRA §12(a)(2)(P)

8080

ConclusionsConclusions No intentional exposure of pregnant or nursing

women or of children

No clear and convincing evidence that research was fundamentally unethical

In spite of some gaps in the record, there is clear and convincing evidence that conduct of the Kisicki study was significantly deficient relative to the standards of 21 CFR parts 50 and 56, cited by investigators as governing this work

Except under the provisions of 40 CFR §26.1706, EPA is forbidden to rely on this study in actions under FIFRA or FFDCA

81

Charge Questions to the HSRB:

Three Pre-Rule Studies of Chlorpyrifos

82

Nolan et al. (1982)

1 Are the blood and urine measurements of chlorpyrifos and/or TCP from the Nolan et al. oral and dermal studies reliable?

2 Are the measurements of cholinesterase activity/inhibition from the Nolan et al. oral and dermal studies reliable?

3 Is there clear and convincing evidence that the conduct of the Nolan et al. study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted?

83

Honeycutt & DeGeare (1993)1 Are the blood and urine measurements of

chlorpyrifos and/or TCP from the Honeycutt & DeGeare worker biomonitoring study reliable?

2 Are the measurements of cholinesterase activity/inhibition from the Honeycutt & DeGeare worker biomonitoring study reliable?

3 Is there clear and convincing evidence that the conduct of the Honeycutt & DeGeare study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted?

84

Kisicki et al. (1999)1 Are the blood and urine measurements of

chlorpyrifos and/or TCP from the Kisicki et al. oral study reliable?

2 Are the measurements of cholinesterase activity/inhibition from the Kisicki et al. oral study reliable?

3 Is there clear and convincing evidence that the conduct of the Kisicki et al. study was fundamentally unethical, or significantly deficient relative to the standards of ethical research conduct prevailing when it was conducted?