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1 1
Two Pre-Rule Studies of
Pyrethrins/Pyrethroids:
Newton, J.; Breslin, A. (1983) Asthmatic reactions
to a commonly used ...
2
Sequence of Presentations
 Introduction and Context
• Sarah Winfield
 Science Assessments
• Carol Christensen, MPH
 E...
3 3
Pyrethrins/Pyrethroids
and Asthma/Allergies
Introduction and Context
Sarah Winfield
Health Effects Division
Office of ...
4
Pyrethrum, Pyrethrins andPyrethrum, Pyrethrins and
PyrethroidsPyrethroids Crude pyrethrum, made from the chrysanthemum ...
5
Pyrethrins/Pyrethroids and
Asthma/Allergy
 Allegations of risk
 Center for Public Integrity
 Public comments
 Relati...
6
Previous ReviewsPrevious Reviews
 EPA/ORIA  NAS/IOM (indoor air asthma triggers,
2000)
“Inadequate or insufficient evi...
7
2009 White Paper2009 White Paper
 “A Review of the Relationship between Pyrethrins,
Pyrethroid Exposure and Asthma and ...
8
Proposed use of Human StudiesProposed use of Human Studies
 Add these studies to the body of evidence
considered in the...
9
Newton & Breslin (1983):
An experimental,
intentional exposure study
Science Assessment
Carol Christensen, MPH
Health Ef...
10
Study Information
 Newton & Breslin (1983)
 Chest Unit, Concord Hospital, Concord, NSW, Australia
 Study Objectives:...
11
Study Methods
 Eligible Participants:
 Age 18-75
 Well-controlled, mild or moderate asthma
 Self-report history che...
12
Test Substance
 Exposure to aerosol insecticide containing
pyrethrins and tetramethrin in enclosed,
testing chamber
 ...
13
Intentional Exposure Regimen: Day 1
 Obtain medical history and preliminary
measurements of lung function
 Provocatio...
14
Intentional Exposure Regimen: Day 1 (cont.)
 If no asthmatic reaction occurred,
participants asked to return to provoc...
15
Intentional Exposure Regimen: Day 2
 Upon return to the test site,
 Histamine challenge repeated in all participants
...
16
Intentional Exposure Regimen: Day 3
 One subject (Table 1; #1) who displayed a
significant change in lung function (FE...
17
Study Analysis and Results
 No formal statistical analysis performed
 Simple counts and proportions provided in table...
18
Study Analysis and Results
 Asthmatic response self-reported by all 7 participants
 No significant changes in histami...
19
Author’s Conclusions
 Although all participants self-reported
asthma-like response, little quantitative
evidence of as...
20
Study Limitations
 Quantitative change in lung function observed
in 1/7 participants while self-report asthmatic
react...
21
Study Limitations (cont.)
 Other limitations
 Small sample size does not capture variability in
population
 Smoking,...
22
Conclusions
 Assuming the study as performed did
not deviate from the published report,
 Appears scientifically valid...
23
Lisi (1992):
An experimental,
intentional exposure study
Science Assessment
Carol Christensen, MPH
Health Effects Divis...
24
Study Information
 Lisi (1992) Brief Communication
 Institute of Clinical Dermatology, University of Perugia,
Perugia...
25
Study Methods
 Exposure Regimen:
 Patch tests using 3 different concentrations
(1%, 2%, 5%) applied on upper back for...
26
Study Analysis and Results
 No formal statistical analysis performed
 Simple counts provided in tables
Selected parti...
27
Study Analysis and Results
 Among the 230
participants, 5 cases of
irritation and/or allergic
reaction observed:
 2 –...
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 condit...
30
Study Limitations
 Purpose of three sub-groups not specified:
 Ag and non-ag groups presumably differ in prior
exposu...
31
Study Limitations
 Actual dosages not identified
 * Outcome definition not clarified
 Definition of sensitization or...
32
Conclusions
 Study suggests little evidence of
irritation or sensitization effects among
those with various (unspecifi...
33 33
Kelly Sherman
Human Research Ethics Reviewer
Office of Pesticide Programs
Ethics Assessments of
Two Pre-Rule Studies...
Newton and Breslin (1983)
35 35
Value to SocietyValue to Society
 Evaluated asthmatic subjects for airway
narrowing and chest tightening following
...
36 36
Participant SelectionParticipant Selection
 2 men, 5 women; aged 24-71
 History of proven bronchial asthma
 Histo...
37 37
Risks & Risk MinimizationRisks & Risk Minimization
 Risks
 Risks to participants not discussed in article
 Unaddr...
38
Benefits & Risk:Benefit Balance
 Benefits
 Not discussed in article
 No direct benefits to participants
 Societal b...
39 39
Ethics OversightEthics Oversight
 None reported
Informed ConsentInformed Consent
 “Informed written consent was ob...
40 40
Applicable StandardsApplicable Standards
 Standard of Conduct
 Declaration of Helsinki (1975)
 Standards of Accep...
41 41
Compliance with Standards of ConductCompliance with Standards of Conduct
 Research was consensual, and was not
inte...
42
Compliance with Acceptance Standards
 40 CFR §26.1703
 No intentional exposure of pregnant or nursing
women or of chi...
43 43
ConclusionConclusion
 If it is deemed scientifically valid and relevant,
there are no barriers in FIFRA or in 40 CF...
Lisi (1992)
45 45
Value to SocietyValue to Society
 Tested the dermal irritation and sensitization
potential of seven pyrethroids
 C...
46 46
Participant SelectionParticipant Selection
 230 subjects
 162 men, 68 women; aged 19-78
 All were patients at the...
47
Participant Selection—2Participant Selection—2
 No information provided about recruitment
 No evidence suggesting tha...
48 48
Risks and BenefitsRisks and Benefits
 Risks
 No discussion of risks to participants
 Unaddressed risk of reaction...
49
Risk:Benefit Balance
 No information to assess whether
investigators assessed risk:benefit
balance before conducting r...
50 50
Ethics OversightEthics Oversight
 Not reported
Informed ConsentInformed Consent
 Article does not mention “informe...
51 51
Applicable StandardsApplicable Standards
 Standards of Conduct
 Declaration of Helsinki (1989)
 Standards of Acce...
52 52
Compliance with Standards of ConductCompliance with Standards of Conduct
 Research was apparently consensual; not
i...
53
Compliance with Acceptance Standards
 40 CFR §26.1703
 No intentional exposure of pregnant or
nursing women or of chi...
54 54
ConclusionConclusion
 If it is deemed scientifically valid and relevant,
there are no barriers in FIFRA or in 40 CF...
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 ...
57
Newton and Breslin (1983)
4. Is there clear and convincing evidence that
the conduct of the Newton & Breslin study
was ...
58
Lisi (1992)
1. Is the Lisi study scientifically sound, providing
reliable data?
2. If so, is the Lisi study relevant to...
59
Lisi (1992)
4. Is there clear and convincing evidence that the
conduct of the Lisi study was fundamentally
unethical, o...
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  • Note: 6.7 L = 0.0067 meters cubed
    Respiratory irritation observed in animal studies, repeated exposures of > 30 mg/m3
  • No information was provided about how the subjects were approached or recruited into the study
  • With respect to 40 CFR 26.1704
    1) The research was not fundamentally unethical as that term is interpreted by the Agency because there is no evidence that the research was intended to harm the participants.
    2) And, while the risk-benefit balance is concerning, at the end of the day, our consideration is bound by the evidence presented in the article.
    The Agency’s standard for concluding that the study is not in compliance with 40 cfr 26.1704 requires clear and convincing evidence of a significant deficiency relative to prevailing standards, and we don’t have that type of information here. It can be argued that the risk to the subjects was reasonable in light of the benefits to be gained by the knowledge.
    Therefore, NEXT SLIDE
  • Transcript of "Two Pre-Rule Studies of Pyrethrins/Pyrethroids:"

    1. 1. 1 1 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 Board October 20, 2009
    2. 2. 2 Sequence of Presentations  Introduction and Context • Sarah Winfield  Science Assessments • Carol Christensen, MPH  Ethics Assessments • Kelly Sherman, JD, MPH
    3. 3. 3 3 Pyrethrins/Pyrethroids and Asthma/Allergies Introduction and Context Sarah Winfield Health Effects Division Office of Pesticide Programs
    4. 4. 4 Pyrethrum, Pyrethrins andPyrethrum, 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. 5. 5 Pyrethrins/Pyrethroids and Asthma/Allergy  Allegations of risk  Center for Public Integrity  Public comments  Relationship to pyrethrum  Registration Review
    6. 6. 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. 7. 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. 8. 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. 9. 9 Newton & Breslin (1983): An experimental, intentional exposure study Science Assessment Carol Christensen, MPH Health Effects Division Office of Pesticide Programs
    10. 10. 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. 11. 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. 12. 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. 13. 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. 14. 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. 15. 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. 16. 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. 17. 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. 18. 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. 19. 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. 20. 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. 21. 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. 22. 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. 23. 23 Lisi (1992): An experimental, intentional exposure study Science Assessment Carol Christensen, MPH Health Effects Division Office of Pesticide Programs
    24. 24. 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. 25. 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. 26. 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. 27. 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. 28. 28 Author’s conclusions  “Pyrethroids only very slightly cutaneous irritants or sensitizers”
    29. 29. 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. 30. 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. 31. 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. 32. 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
    33. 33. 33 33 Kelly Sherman Human Research Ethics Reviewer Office of Pesticide Programs Ethics Assessments of Two Pre-Rule Studies of Pyrethrins/Pyrethroids
    34. 34. Newton and Breslin (1983)
    35. 35. 35 35 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
    36. 36. 36 36 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
    37. 37. 37 37 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. 38. 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
    39. 39. 39 39 Ethics OversightEthics Oversight  None reported Informed ConsentInformed Consent  “Informed written consent was obtained before commencement of the trial”  No further details are provided
    40. 40. 40 40 Applicable StandardsApplicable Standards  Standard of Conduct  Declaration of Helsinki (1975)  Standards of Acceptability  40 CFR §26.1703  40 CFR §26.1704
    41. 41. 41 41 Compliance with Standards of ConductCompliance with Standards of Conduct  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. 42. 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
    43. 43. 43 43 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
    44. 44. Lisi (1992)
    45. 45. 45 45 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
    46. 46. 46 46 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. 47. 47 Participant Selection—2Participant 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
    48. 48. 48 48 Risks and BenefitsRisks 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. 49. 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
    50. 50. 50 50 Ethics OversightEthics Oversight  Not reported Informed ConsentInformed Consent  Article does not mention “informed consent”  Subjects are referred to as “volunteers”
    51. 51. 51 51 Applicable StandardsApplicable Standards  Standards of Conduct  Declaration of Helsinki (1989)  Standards of Acceptability  40 CFR §26.1703  40 CFR §26.1704
    52. 52. 52 52 Compliance with Standards of ConductCompliance with Standards of Conduct  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. 53. 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
    54. 54. 54 54 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. 55. 55 Charge Questions to the HSRB: Two Pre-Rule Studies of Pyrethroids and Pyrethrins
    56. 56. 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. 57. 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. 58. 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. 59. 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?
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