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: Lisi, P. (1992) Short Communication: Sensitization risk of pyrethroid insecticides. Contact Dermatitis 26: Human Studies Review Board October 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 Winfield Health Effects Division Office of Pesticide Programs

4 Pyrethrum, Pyrethrins and Pyrethroids 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 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”

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

9 Newton & Breslin (1983): An experimental, intentional exposure study Science Assessment Carol Christensen, MPH Health 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  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 (FEV 1 ), 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  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 FEV 1 (-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 (FEV 1 )  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, MPH Health 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 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

33 Kelly Sherman Human Research Ethics Reviewer Office of Pesticide Programs Ethics Assessments of Two Pre-Rule Studies of Pyrethrins/Pyrethroids

Newton and Breslin (1983)

35 Value 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 Participant Selection 2 men, 5 women; aged 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 Risks & 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

39 Ethics Oversight None reported Informed Consent “Informed written consent was obtained before commencement of the trial” No further details are provided

40 Applicable Standards Standard of Conduct  Declaration of Helsinki (1975) Standards of Acceptability  40 CFR §  40 CFR §

41 Compliance 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 Compliance with Acceptance Standards 40 CFR §  No intentional exposure of pregnant or nursing women or of children 40 CFR §  No clear and convincing evidence that Research was fundamentally unethical Conduct was significantly deficient relative to prevailing standards

43 Conclusion If it is deemed scientifically valid and relevant, there are no barriers in FIFRA or in 40 CFR § or § to EPA’s reliance on the Newton and Breslin study in actions taken under FIFRA or §408 of FFDCA

Lisi (1992)

45 Value 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 Participant Selection 230 subjects  162 men, 68 women; aged  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 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 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

50 Ethics Oversight Not reported Informed Consent Article does not mention “informed consent” Subjects are referred to as “volunteers”

51 Applicable Standards Standards of Conduct  Declaration of Helsinki (1989) Standards of Acceptability  40 CFR §  40 CFR §

52 Compliance 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 Compliance with Acceptance Standards 40 CFR §  No intentional exposure of pregnant or nursing women or of children 40 CFR §  No clear and convincing evidence that Research was fundamentally unethical Conduct was significantly deficient relative to prevailing standards

54 Conclusion If it is deemed scientifically valid and relevant, there are no barriers in FIFRA or in 40 CFR § or § 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?