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?