11

Two Pre-Rule Studies of Pyrethrins/Pyrethroids:

Newton, J.; Breslin, A. (1983) Asthmatic reactions to a commonly used aerosol insect killer. Medical Journal of Australia 1:378-380.

Lisi, P. (1992) Short Communication: Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349-350.

Human Studies Review BoardOctober 20, 2009

2

Sequence of Presentations

Introduction and Context• Sarah Winfield

Science Assessments• Carol Christensen, MPH

Ethics Assessments• Kelly Sherman, JD, MPH

33

Pyrethrins/Pyrethroids and

Asthma/Allergies

Introduction and Context

Sarah WinfieldHealth Effects Division

Office of Pesticide Programs

4

Pyrethrum, Pyrethrins and Pyrethrum, Pyrethrins and PyrethroidsPyrethroids Crude pyrethrum, made from the chrysanthemum

flower, has insecticidal properties, and is a known allergen

Refined pyrethrum is called pyrethrins, contains six insecticidally active components

Synthetic pyrethroids were developed to modify the structure of natural pyrethrins in order to increase photo-stability and to enhance insecticidal activity

In general, pyrethrins/pyrethroids are less toxic to mammals than organophosphates, and are replacing organophosphate insecticides in the residential market

5

Pyrethrins/Pyrethroids and Asthma/Allergy

Allegations of risk

Center for Public Integrity

Public comments

Relationship to pyrethrum

Registration Review

6

Previous ReviewsPrevious Reviews EPA/ORIA NAS/IOM (indoor air asthma triggers,

2000)“Inadequate or insufficient evidence to determine whether or not an association exists”

FDA (over-the-counter lice-control products, 2003)“Ask a doctor before use if you are allergic to ragweed. May cause breathing difficulty or an asthmatic attack.”

EPA/OPP (Reregistration Eligibility Decisions, 2006)

“Do not allow adults, children, or pets to enter until vapors, mists, and aerosols have dispersed, and the treated area has been thoroughly ventilated”

7

2009 White Paper2009 White Paper “A Review of the Relationship between

Pyrethrins, Pyrethroid Exposure and Asthma and Allergies”

Integrates across animal, human incident and epidemiological information

Found no clear and consistent pattern of effects to indicate conclusively whether there is an association between pyrethrins/pyrethroid exposure and asthma and allergies

Human studies involving intentional exposure not included

8

Proposed use of Human StudiesProposed use of Human Studies

Add these studies to the body of evidence considered in the 2009 analysis

Newton, J.; Breslin, A. (1983) Asthmatic reactions to a commonly used aerosol insect killer. Medical Journal of Australia 1:378-380.

Lisi, P. (1992) Short Communication: Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26:349-350.

9

Newton & Breslin (1983):An experimental,

intentional exposure study

Science Assessment

Carol Christensen, MPHHealth Effects Division

Office of Pesticide Programs

10

Study Information

Newton & Breslin (1983)

Chest Unit, Concord Hospital, Concord, NSW, Australia

Study Objectives:

Study response of asthmatics to pyrethrin and tetramethrin containing insecticide end-use products;

Study time-course of exacerbation of asthma following insecticide exposure

Characterize potential mechanism of asthmatic reaction (immune response v. local irritant effect)

11

Study Methods

Eligible Participants:

Age 18-75

Well-controlled, mild or moderate asthma

Self-report history chest tightness upon exposure to aerosol fly-killer insecticide

Not pregnant, or report history of cardiovascular disease

12

Test Substance

Exposure to aerosol insecticide containing pyrethrins and tetramethrin in enclosed, testing chamber

Test substance well characterized

Participants “blinded” to specific insecticidal products (investigators not “blinded”)

told could be one of several different insecticides

13

Intentional Exposure Regimen: Day 1

Obtain medical history and preliminary measurements of lung function

Provocation with insecticide began:

5 sec. duration of exposure

Remained in chamber 5 min. post-exposure

Lung function measurements repeated upon immediate exit from chamber

14

Intentional Exposure Regimen: Day 1 (cont.)

If no asthmatic reaction occurred, participants asked to return to provocation chamber for an additional 10, 20 or 30 sec. exposure duration

Investigators ceased testing if evidence of asthmatic response observed

After last exposure interval, participants followed up to three hours for signs of asthmatic response, returned home

15

Intentional Exposure Regimen: Day 2

Upon return to the test site,

Histamine challenge repeated in all participants

• Change in immune response after Day 1 exposure measured

All participants challenged with placebo (water)

• Determine if stress due to testing regimen, e.g., enclosed testing chamber

16

Intentional Exposure Regimen: Day 3

One subject (Table 1; #1) who displayed a significant change in lung function (FEV1), returned

Administered bronchodilator before insecticide exposure

Provocation with insecticide repeated using same regimen as Day 1

• Determine if repeat response

17

Study Analysis and Results

No formal statistical analysis performed

Simple counts and proportions provided in table

Selected participants included 7 individuals:

Age 24-71

5 female; 2 male

18

Study Analysis and Results

Asthmatic response self-reported by all 7 participants

No significant changes in histamine response after provocation with insecticide

However, only measured in 4/7 participants

3/7 evidence of airway narrowing

1/7 significant fall in FEV1 (-35%) on both Days 1 and 3 in a similar time sequence (according to authors)

19

Author’s Conclusions

Although all participants self-reported asthma-like response, little quantitative evidence of asthmatic response

1/7 change in lung function (FEV1)

3/7 small airway narrowing (MMFEV)

Further work needed

Mechanism of reaction

Component of end-use product

20

Study Limitations

Quantitative change in lung function observed in 1/7 participants while self-report asthmatic reaction reported by all

Apparent inconsistency in results not fully addressed;

Asthmatic response after bronchodilator unexpected observation

21

Study Limitations (cont.)

Other limitations

Small sample size does not capture variability in population

Smoking, occupation history and age not directly addressed in study

Time period of study (1983) lends doubt to the accuracy and precision of the measurement of lung function

• outdated methods utilized

22

Conclusions

Assuming the study as performed did not deviate from the published report,

Appears scientifically valid

Appropriate to utilize in qualitative WOE

Not appropriate to consider in quantitative risk assessment

23

Lisi (1992):An experimental,

intentional exposure study

Science Assessment

Carol Christensen, MPHHealth Effects Division

Office of Pesticide Programs

24

Study Information Lisi (1992) Brief Communication

Institute of Clinical Dermatology, University of Perugia, Perugia, Italy

Published Study Objectives:

Establish irritation and sensitization potential of pyrethroid end-use products among sensitive sub-group

• Pre-existing dermatological conditions (allergic and non-allergic)

Seven Pyrethroids tested:

• Allethrin, cypermethrin, deltamethrin, fenothrin, fenvalerate, permethrin, resmethrin

25

Study Methods

Exposure Regimen:

Patch tests using 3 different concentrations (1%, 2%, 5%) applied on upper back for each pesticide, each participant

Test substance not well characterized

Patches read 2- and 3-days post-application

26

Study Analysis and Results

No formal statistical analysis performed

Simple counts provided in tables

Selected participants included: (n=230)

162 male, 68 female

Age 19-78

3 groups:

Ag workers (n=82), Former ag workers (n=28), Others (n=120)

27

Study Analysis and Results

Among the 230 participants, 5 cases of irritation and/or allergic reaction observed:

2 – resmethrin, irritant

• Non-atopic participants

1 – cypermethrin, allergic reaction

• Author concludes “not clinically relevant”

2 – fenvalerate, allergic reaction

Both has chronic dermatitis of hands

1 participant previous sensitization observed (non-pyrethroids)

1 participant gardening hobbyist (implication possible exposure to pesticide-not stated)

28

Author’s conclusions

“Pyrethroids only very slightly cutaneous irritants or sensitizers”

29

Study Limitations

Study lacks information concerning:

Purpose for evaluating effects among pre-existing skin conditions

• No background provided; assuming “most sensitize”

• Study population not well characterized

Selection criteria not defined

• Difficult to determine to which sub-groups these results could be applied

30

Study Limitations

Purpose of three sub-groups not specified:

Ag and non-ag groups presumably differ in prior exposure to pyrethroids

Description of “other” study group not provided

Delineation of other pesticide exposed not provided

31

Study Limitations

Actual dosages not identified

* Outcome definition not clarified

Definition of sensitization or irritation not provided

Protocol used to evaluate outcome not specified

Differentiate irritant and sensitization type effects?

Relative adherence to protocol among participants (i.e., testing patches remained for 3 days?)

32

Conclusions

Study suggests little evidence of irritation or sensitization effects among those with various (unspecified) pre-existing dermatological conditions

Given limitations, considered minimally adequate for qualitative WOE

3333

Kelly ShermanHuman Research Ethics Reviewer

Office of Pesticide Programs

Ethics Assessments ofTwo Pre-Rule Studies of Pyrethrins/Pyrethroids

Newton and Breslin (1983)

3535

Value to SocietyValue to Society

Evaluated asthmatic subjects for airway narrowing and chest tightening following exposure to an aerosol pyrethrins spray

Contributes to weight of evidence concerning a potential relationship between exposure to pesticides containing pyrethrins or pyrethroids and asthma or allergic responses

3636

Participant SelectionParticipant Selection

2 men, 5 women; aged 24-71

History of proven bronchial asthma

History of chest tightness on exposure to aerosol insecticides

Not “pregnant or liable to be pregnant”

No cardiac disease

3737

Risks & Risk MinimizationRisks & Risk Minimization Risks

Risks to participants not discussed in article

Unaddressed risk of significant respiratory reaction to the test substance

Risk minimization

Challenge stopped in the event of a significant asthmatic reaction

“Most patients were followed up for 3 hours after challenge”

Participants were asked to report any asthmatic reaction developing over the 24 hours following challenge

38

Benefits & Risk:Benefit Balance Benefits

Not discussed in article

No direct benefits to participants

Societal benefit limited by small sample size and other design issues

Risk:Benefit Balance Unknown whether investigators assessed

risk:benefit balance before conducting research

Limited benefit of information gained may not have outweighed small but non-zero risk of a catastrophic outcome

3939

Ethics OversightEthics Oversight None reported

Informed ConsentInformed Consent

“Informed written consent was obtained before commencement of the trial”

No further details are provided

4040

Applicable StandardsApplicable Standards

Standard of Conduct

Declaration of Helsinki (1975)

Standards of Acceptability

40 CFR §26.1703

40 CFR §26.1704

4141

Compliance with Standards of Compliance with Standards of ConductConduct

Research was consensual, and was not intended to harm participants

No information to assess whether research conduct was consistent with three of the basic principles in the Declaration of Helsinki

No evidence that research conduct was inconsistent with these principles

42

Compliance with Acceptance Standards

40 CFR §26.1703 No intentional exposure of pregnant or

nursing women or of children

40 CFR §26.1704 No clear and convincing evidence that

• Research was fundamentally unethical

• Conduct was significantly deficient relative to prevailing standards

4343

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 Newton and Breslin study in actions taken under FIFRA or §408 of FFDCA

Lisi (1992)

4545

Value to SocietyValue to Society

Tested the dermal irritation and sensitization potential of seven pyrethroids

Contributes to weight of evidence concerning a potential relationship between exposure to pesticides containing pyrethroids and dermal irritation or sensitization responses

4646

Participant SelectionParticipant Selection 230 subjects

162 men, 68 women; aged 19-78

All were patients at the dermatological clinic where the research occurred

82 were current agricultural workers; 28 were former agricultural workers

54 subjects had been admitted or treated for irritant or allergic contact dermatitis of the hands; remaining 176 had been admitted for non-allergic skin disorders

47

Participant Selection—2 Participant Selection—2

No information provided about recruitment

No evidence suggesting that any participants were from an especially vulnerable group

Participants were patients at the clinic where the research occurred

No evidence that subjects were coerced or otherwise improperly influenced to participate

4848

Risks and Benefits Risks and Benefits

Risks No discussion of risks to participants

Unaddressed risk of reaction to the test compounds

Benefits No discussion of benefits or their distribution

No direct benefits to subjects

Potential societal benefit from knowledge gained through the research

49

Risk:Benefit Balance

No information to assess whether investigators assessed risk:benefit balance before conducting research

Potential value of the research outweighs the risks to participants

5050

Ethics OversightEthics Oversight

Not reported

Informed ConsentInformed Consent

Article does not mention “informed consent”

Subjects are referred to as “volunteers”

5151

Applicable StandardsApplicable Standards

Standards of Conduct

Declaration of Helsinki (1989)

Standards of Acceptability

40 CFR §26.1703

40 CFR §26.1704

5252

Compliance with Standards of Compliance with Standards of ConductConduct

Research was apparently consensual; not intended to harm participants

No information to assess whether the conduct was consistent with two of the basic principles in the Declaration of Helsinki

No evidence that research conduct was inconsistent with these principles

53

Compliance with Acceptance Standards

40 CFR §26.1703

No intentional exposure of pregnant or nursing women or of children

40 CFR §26.1704

No clear and convincing evidence that• Research was fundamentally unethical

• Conduct was significantly deficient relative to prevailing standards

5454

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 Lisi study in actions taken under FIFRA or §408 of FFDCA

55

Charge Questions to the HSRB:

Two Pre-Rule Studies of Pyrethroids and

Pyrethrins

56

Newton and Breslin (1983)1. Is the Newton & Breslin study scientifically

sound, providing reliable data?

2. If so, is the Newton & Breslin study relevant to an assessment of the proposition that exposures to pyrethrins/pyrethroids may be associated with asthmatic or allergic respiratory responses?

3. If so, what limitations of the Newton & Breslin study should be taken into account by EPA in assessing the proposition that exposures to pyrethrins/ pyrethroids may be associated with asthmatic or allergic respiratory responses?

57

Newton and Breslin (1983)

4. Is there clear and convincing evidence that the conduct of the Newton & Breslin study was fundamentally unethical, or that its conduct was significantly deficient relative to standards prevailing when it was conducted?

58

Lisi (1992)1. Is the Lisi study scientifically sound,

providing reliable data?

2. If so, is the Lisi study relevant to an assessment of the proposition that exposures to pyrethrins/pyrethroids may be associated with allergic contact dermatitis or sensitization responses?

3. If so, what limitations of the Lisi study should be taken into account by EPA in assessing the proposition that exposures to pyrethrins/pyrethroids may be associated with allergic contact dermatitis or sensitization responses?

59

Lisi (1992)

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