25 June 2008 Final Report of the April 9-10, 20 08 EPA Human Studies Re view Board Meeting: Discussion of AEATF-II Mop and Wipe Scenarios. Pages 16-27.

p. 16 EPA Review of AEATF-II Mop and Wipe Scenarios (due to similarities of the mop and wipe scenarios, both exposure scenar ios were reviewed together)

p. 17 Science

Charge to the Board

If the proposed research described in AEATF’ s proposed mop scenario design, protocol, and supporting documentation is revised as suggested in EPA’s review, does the research appear likely to generate scientifically reliable data, useful for assessing the exposure of handlers who apply an antimicrobial pesticide by mopping?

If the proposed research described in AEATF’s proposed wipe scenario designs, protocol, and supporting documentation is revised as suggested in EPA’s review, does the research appear likely to generate scientifically reliable data, useful for assessing the exposure of handlers who apply an antimicrobial pesticide by wiping?

Board Response to the Charge

The two proposed human studies focus on handlers during floor mopping or surface wiping with a liquid antimicrobial pesticide product to determine potential dermal and inhalation exposures. The studies are (1) AEA03, “A Study for Measurement of Potential Dermal and Inhalation Exposure During Application of a Liquid Antimicrobial Pesticide Product Using Bucket and Mop Equipment for Cleaning I ndoor Surfaces,” and (2) AEA02, “A Study for

Measurement of Potential Dermal and Inhala tion Exposure During App lication of a Liquid Antimicrobial Pesticide Product using Trigger Spray and Wipe or Ready to Use Wipes for Cleaning Indoor Surfaces.” The protocols associated with these studies have many similarities. The Board’s comments were therefore very similar for the two studies. All comments below can be applied to both studies, unless otherwise noted.

Study Objective

AEATF II stated that the primary purpose of the handler studies is to develop more accurate information on worker exposures to antimicrobials. AEATF II also presented

information to indicate that ex isting human exposure data are in adequate. The Board concurred that existing data are inadequate and that the development of more accurate information is an appropriate goal.

Benefits and Risks

The Board concurred with the Agency that th e generation of new data for mop and wipe

activities would be of value in the assessment of risks for antimicrobial products. The Board concurred with the Agency that there are only mini mal risks associated with the application of adilute solution of didecyl dimethyl ammonium chloride (DDAC) as described in the study protocols.

Study Design Criteria

The Board was pleased by the amount of ra ndomization included in the design of these studies. The investigators and the Agency have in dicated that they are interested in knowing the

statistical distribution of the e xposure level, with an acceptable bound for the relative accuracy of p. 18 the estimated mean and 95 per centile. In both AEA03 (mop) and AES02 (wipe) studies, the same

set of three sites will be used as clusters, each representing a random sample of one for three different types of buildings. In order to understa nd the spectrum of exposure, six volunteers will be randomly selected to fill each of six consecuti ve time durations. This configuration of three

clusters of six handlers for each cluster is ba sed on a simulation study under two-stage cluster sampling with an intra-class correlation coeffi cient of 0.3 and a geometric standard deviation (GSD) of 2.86. The sample size justification depends on these design parameters.

In an earlier mop study, conducted by the Ch emical Manufacturers’ Association (CMA), the estimated GSD was 3.53. It therefore appeared to the Board that the proposed AEA03 study design would not ensure three-fold relative accuracy ( K =3) for the resulting estimated mean and the 95 percentile of the exposure distribution. Furthermore, in an earlier CMA wipe study the estimated GSD was 5.00, much larger than 2.86 assu med in the simulation study that was used to derive the sample size justific ation. Again, it appeared unlikely to the Board that the AEA02 study design would produce a three-fold relative accuracy for the resulting estimated mean and the 95 percentile of the exposure distribution.

The Board also noted that the stratified nature of selecting a cluster from each of three types of sites makes it impossible to assess the variabil ity of exposure distribution from site to site. Likewise, because of the stratified natu re of selecting one handler for each of six mopping/wiping durations, one cannot estimate th e exposure distribution. The experimental design can be viewed as consisting of 18 desi gn points with 18 data poi nts, resulting in no degrees of freedom for estimation of variability as there are no re plications at any design point. In light of these concerns, the Board recommende d that the Agency reconsider the design of the study, or develop an explicit statem ent of the limitations on the use of data that will be collected under the proposed design.

Site selection

The studies will take place in Fresno, Californi a, in three buildings: an office building, a retail building, and a building with large meetin g spaces. The way in which the clusters have been defined suggests that they re present a fixed effect factor (i .e., building type) rather than a random effect factor. The proposed study design will not replicate this fixed effect by having more of than one building of each type. The Board acknowledged the prac tical considerations

that led to the decision to have both studies in the same city, us ing the same buildings. However, it must be realized that any gene ralizations to moppers and wipers in other parts of the country and in other kinds of buildings would be based on expert opini on, and that such generalizationswould not be statistical generaliz ations. Nevertheless, the Board c oncurred with the Agency that some generalizations from these data would seem to be reasonable at this point in time.

Sample size

p. 19 The proposed sample size of 18 observations for each scenario did not appear to have a statistical justification, as i ndicated above. The Board was concerned about recommending this sample size and the 3x6 design (three sites, si x workers per site) on which it is based. The

concern is that all that all future scenario de signs for the AEATF- II program are likely to have three clusters and six time durations, with the justification being the Board’s recommending these protocols. The Board has s een this happen with insect repe llency studies repeatedly. That is, a new protocol has justified its sample size by reference to a previously submitted protocol. The adequacy of the proposed sample size for future studies will be informed by the data collection and analysis of this first set of studi es. In general, the Board will not consider a new protocol that has justified its sample size by reference to a previously submitted protocol.

Task duration

AEATF-II’s protocol for mopping proposed that handlers mop for a maximum of 90 minutes. This value was derived from a survey conducted by the Internat ional Sanitary Supply Association (ISSA). AEATF-II cal culated an average mopping duration to 83 minutes from the ISSA study data. The Board understood that this va lue was calculated in the following manner:

• ISSA data indicated that handl ers spend, on average, 12 minutes to mop 1000 square feet.

• It was assumed that a hospital room consists of a 240 square feet (12x20) main room and a 36 square foot (6x6) bathroom fo r a total floor area of 276 sq ft.

• It was assumed that a worker would mop 25 such rooms for a total of 6,900 sq feet.

• Thus, 6900 square feet x 12 minutes pe r 1000 square feet = 82.8 minutes

A similar calculation was made for the wipe scen arios, resulting in an estimated average wiping

time of 212.75 minutes.

The Board concluded that the task duration tim e frame was not adequate to characterize daily exposure. The Board recommended that th e work time frame be expanded to exceed the 95th percentile of the ISSA survey findings.

The Board also noted that the lengths of mopping (or wiping) would be consistently tested from the longest time period to the shortest time period for each site. For this to be a valid approach, one must be willing to assume that th ere is no “carry-over” effect from one testing period to another. One factor th at could lead to a carry-over e ffect would be whether residues from earlier mopping (or wiping) could affect the measurements on la ter study participants, especially respiratory effects. The Board recomm ended that these concerns be reflected in the protocols.The Board found the explanation of potential analyses that the Agency would conduct based on these studies to be very helpful. A ba sic assumption for these analyses is that the distribution of exposure/unit hand led is the same regardless of the number of active ingredient (Ai) units handled or the time spent mopping (or wiping). However, the mean exposure/Ai unit p. 20 and/or variance of the exposure/ unit is likely to incr ease with the number of units due to fatigue. This assumption could be at least partially ch ecked by plotting exposure/Ai unit by Ai unit, though such an analysis might conflict with the s econd analysis identified: the assessment of the assumption of proportionality. A regression would likely be conducted for this second analysis. If the distribution of exposure/unit handled were constant or increased with the number of units handled and proportionality was demonstrated, th en both the mean and the variance would be expected to increase with the num ber of units handled. In simple linear regression, the variance is assumed to be constant for all values of x. Thus, a weighted regression, not a simple linear regression would be needed. Because the protocol does not ensure that there will be replication of exposures for the same number of units, whet her a simple or weight ed regression would be more appropriate could not be fully evaluated. If, instead of time, the number of Ai units handled were the measure that defined each person’s pa rticipation, the data would more likely lend themselves to a proper assessment of the assumption of proportionality.

Participation Criteria

AEATF plans to recruit subjects from among identifiable and willing professional janitors. A rationale for this decision was provided. AEATF also assumes that these professionals would have higher exposures than consumers. One Board member expressed the view that professionals have substantial experience and perhap s training in how to minimize exposure, and that consumers might have highe r exposures per Ai unit handled. AEATF-II plans to recruit subjects through servic e providers. The Board suggested th at unions also be considered in the development of the recruitment procedures.

Measurement Criteria

The Board noted that inhalation exposure fr om vapors would likely be low in these studies due to the relatively low volatility of the active ingredient used in the scenarios. However, the extent to which liquid aerosols gene rated in the mop protocol would contribute to aggregate exposure is not known. It was not clear what particle size range was expected to be generated in these studies, nor was it clear what particle size range w ould be captured by the sampling method. The Board suggest ed that a laborator y study that measured aerosol size under varying environmental conditions would be he lpful in clarifying these uncertainties.

The following are key variables that will ha ve an effect on inhalation exposure:

• Ventilation

• Temperature

• Total area treated

• Duration

• Volume of the enclosed spaceThe protocols state as follows: “light level, air temperature, and re lative humidity of the work area for the duration of exposure mon itoring will be documented with automated instrumentation logging and record ing at intervals appropriate for the duration of the work period. Monitoring equipment will be calibrated or standardized according to the cooperating p. 21 contractors’ SOPs. HVAC will be described in detail and the air turnover rate will be measured

or estimated.” The Board recommen ded that the equipment and pro cedures used to characterize

these environmental factors be desc ribed in greater detail, either in the protocols or in the SOPs. The Board also asked investigators to explain how the effects of such factors as ventilation, temperature and the volume of the enclosed spac e would be used to modify or interpret study

results.

AEATF-II proposed to use dermal exposure assessment methods similar to those used by the Agricultural Handler Exposure Task Force st udies; i.e., cotton garments on most of the body, handwashing, and face/neck wiping. As in its previous reports, the Board noted that these methods have the potential to underestimate e xposure. The Board supported the use of a double layer of socks to capture potential exposure from spill s or splashes.

Laboratory and Field Conditions

The Board considered the quality assuran ce and quality control procedures that accompanied these protocols to be of high quality. The Board appreciated the attention to detail provided by the investigators.

The Board raised several concer ns regarding field conditions.

These studies will use DDAC, contained in the product Sani-Care Lemon QuatTM as the chemical of interest. The Board agreed that the choice of DDAC as the antimicrobial material for these studies was appropriate, give n its wide use, availability, and the existence of a reliable and sensitive analytical method.

The Board encouraged the Agency and the invest igators to ensure that work activities be as realistic as possible. For example, a worker should use a bucket of the disinfectant solution until it becomes dirty; the worker should then empty the bucket and pick up a fresh bucket. All

of this could be done without the involvement of study staff. In general, the Board viewed the activities of the study staff descri bed in the current protocols to be too disruptive of “usual practices”. The Board recommended that the prot ocols be revised to provide a more detailed description of what the workers will actually do, and that the presence of staff during the exposure period be kept to a minimum.

The Board was also concerned with what is sometimes called the “Hawthorne Effect”. That is, workers will change behavior consciou sly or unconsciously when they are aware that they are being observed. The current protocols indicate that there will be constant surveillance of workers, including video recording. The Board urged the Agency and the investigators to

minimize these observations and to train st aff to be as unobtrusive as possible.Finally, the Board requested that the protocol provide more sp ecificity as to where study subjects will be located while waiting to participate in the study. There was a concern that observation of some study subj ects by other study subjec ts could alter behavior.

HSRB Consensus and Rationale

p. 22 The Board considered the AEATF-II study protocols to successfully address many design challenges. The Board appreciated pa rticularly the clarity of the prot ocols, the attention to detail, and the thorough description of quality assuranc e and quality control procedures. The Board concurred with the Agency th at existing data on handler e xposures to antimicrobials are inadequate and that the developm ent of more accurate informati on is an appropriate goal. The Board also concurred with the Agency that th ere are only minimal risks associated with the application of a dilute solution of didecyl dimethyl ammonium chloride as described in the study protocols.

While the Board concluded that the research could produce scientifically reliable data, the Board identified several contextual factors that may limit the generalizability of the findings. The Board recommended that the Agency recons ider the design of the study, or develop an explicit statement of the limitations on the use of data that will be collected under the proposed design. The Board noted that any generalizations to moppers and wipers in other parts of the country and in other kinds of buildings would be based on ex pert opinion, and that such generalizations would not be statistical ge neralizations. The Board cautioned the Agency regarding the 3x6 design in the protocols, suggest ing future scenario designs for the AEATF- II program would likely have three cl usters and six time durations, w ith the justification being the Board’s recommendation of these protocols. Th e Board concluded that the task duration time frame was not adequate to characterize daily exposure. The Board recommended that the work time frame be expanded to exceed the 95th percen tile of the Internati onal Sanitary Supply Association survey findings. The Bo ard noted that if, instead of time, the number of Ai units handled were the measure that defined each person’s participation, the data would more likely lend themselves to a proper assessment of the assumption of proportionality.

In regard to inhalation expos ure assessment, the Board sugge sted that a la boratory study that measured aerosol size under varying enviro nmental conditions would helpful in clarifying uncertainties regarding particle size and sampling methods. The Bo ard raised several concerns regarding the field conditions for these studies: ensure that any ca rry-over effect in buildings is avoided; ensure that work activitie s be as realistic as possible; re vise protocols to provide a more detailed description of what the workers will actua lly do; keep the presence of staff and intrusive observation of workers during the exposure period to a minimum; and, provide more specificity as to where study subjects will be located while waiting to participate in the study..

Finally, the Board encourages modifications of future related protocols based on the

lessons learned from these initial submissions. Su ch adjustments are anticipated to improve the study design and subsequent results, leading to a more accurate charact erization of pesticide handler exposure.

EthicsCharge to the Board

p. 23 If the proposed research described in AEAT F’s proposed mop scenario design, protocol, and supporting documentation is revised as suggested in EPA’s review, does the research appear to meet the applicable requirements of 40 CFR part 26, subparts K and L?

If the proposed research described in AEATF’s proposed wipe scenario designs, protocol, and supporting documentation is revised as suggested in EPA’s review, does the research appear to meet the applicable requirements of 40 CFR part 26, subparts K and L?

Board Response to the Charge

Brief Overview of the Studies

Each of these scenarios (mop and wipe) has be en designed to develop data for a database of exposure monitoring information which will be used by the EPA for making regulatory decisions about future exposur es to a variety of antimicr obial products an d their active ingredients. The sponsor of both scenarios is the Antimicrobial Exposure Assessment Task Force II (AEATF-II) of the American Chemistry Council. The scenarios will be conducted on behalf of that entity by Golden Pacific Laboratories, LLC, of Fresno, California. For each of the scenarios, there will be three field sites in Fresno, California.

According to the protocols, these studies are intended to comply with the ethical standards contained in 40 CFR Part 26, subparts K and L, in addition to the requirements of FIFRA § 12(a)(2)(P), and Title 3, § 6710 of the Ca lifornia Code of Regulations. Both scenarios were reviewed and approved by a commercial IR B, the Independent Investigational Review Board, Inc. (IIRB, Inc.) of Plantation, Florida.

For each scenario, the protocols include detailed explanations of how the buildings in which the scenarios take place will be chosen, how the subjects will be recruited, how the informed consent of those subjects will be obt ained, and what will take place during the conduct

of the scenarios.

Each of the protocols requires that the subjec ts be at least 18 years of age, and they exclude female subjects who ar e pregnant or lactating.

The test substance that will be used in bot h scenarios is diluted Sani-Care Lemon Quat. Its two active ingredie nts are didecyl dimethyl ammoni um chloride (DDAC) and n-Alkyl dimethyl benzyl ammonium chlorides (ADBAC).

Critique of Studies

The Board concurred with the factual obs ervations of the ethical strengths and weaknesses of the studies, as detailed in the EPA’s Science and Ethics Reviews (Carley 2008a and 2008b).In general, the research described in thes e two protocols appears to comport with the applicable requirements of 40 CF R Part 26, subparts K and L. Th e risks to study participants, p. 24 in general, will be minimal and would appear to be justified by the likely societal benefits, specifically the production of data that could be used by the EP A in determining acceptable exposures to antimicrobial products used in certain mopping and wiping activities.

The test compound contains two active ingr edients, DDAC and ADBAC, both of which have been extensively tested in animals. The su bjects will only be exposed to concentrations of the test compound at the label d ilution rates. At thos e dilutions, animal te sting has shown the compound to have low acute toxicity and a lo w chronic hazard profile. Both of the active ingredients have already been approved by the EPA for use in many formulations, and in many janitorial products. In addition, the test co mpound itself, Sani-Care Lemon Quat, has been approved by the EPA, and will only be used in the scenarios in conformity with its approved labeling. All of the subjects will be professional janitors with ex tensive experience in using these products, and thus unlikely to misuse them in a way that might increase their likelihood of being

harmed.

Although the risks to subjects fr om exposure to the test compound appear very low, it should be noted that in terms of the purposes of th ese scenarios, it is not actually necessary that subjects be exposed to an antim icrobial product. The scenarios ar e intended to measure only the amount of skin, clothing and inhalation exposure when someone is engaged in certain activities relating to applying an antimicrobicide. They are not measuring the actual effects to the test subject from that exposure. Thus, it might be possible to design s cenarios in which instead of an antimicrobicide, some less toxic tracer substanc e might be used. It would be appropriate for protocols to discuss this possibili ty for further minimizing risks, a nd to indicate why (if it is true) such an option would not allow the needed information to be collected.

Another possible risk is that of heat-relate d illness, given that the subjects will be required to wear two layers of clothing during the scenario ac tivities. That risk is being minimized by the fact that those activities will take place indoors in temperature-controlled environments. In addition, subjects will be give n appropriate breaks. The breaks will not only minimize the likelihood of heat-related illness, but also reduce the likelihood of cardiovascular

harms.

With regard to subject selection, EPA observe d that “[n]o potential subjects are from a vulnerable population” (Carley 2008a and 2008b). In this regard, it should be noted that 45 CFR § 46.111(b) states that “economically or educa tionally disadvantaged persons” may constitute a vulnerable population. Accordingl y, given that this study is recruiting from a population of individuals who may not have s ubstantial education, who may be relatively disadvantaged from an economic viewpoint, and many of whom ma y not speak or read English, it would be appropriate not to dismiss the possibility that th e subjects in this study might be vulnerable to coercion and undue influence, but ra ther to instead recognize that there are sufficient safeguards in the design of the study to protect the subjects, even if they are vulnerable.The study protocols included several mechan isms designed to minimize coercive recruitment and enrollment, including the fact that subjects were not recrui ted directly from their employers, but instead would themselves resp ond to flyers that have been posted.

p. 25 Compensation was not considered to be so high as to unduly influence participation, and minors and pregnant or lactating women were explicitly excluded from volunteering (pregnancy being confirmed by requiring all female volun teers under the age of 50 to undergo a urine pregnancy test). The potentia l stigmatization resulting from study exclusion was minimized by the use of so-called ‘alternate’ participants, a llowing for volunteers to withdraw or be excluded from participating without unduly compromising their confidentiality.

With regard to the eligibility criteria, the Board believes that the requirement for females under the age of 50 to take a pregnancy test c ould be refined. It woul d be possible to design

criteria that created a better fit between which fe male subjects might be able to get pregnant, and which of them are being asked to take that test. By doing this, the researchers would be showing greater respect for this group of subjects.

The protocol might provide a greater justif ication for why subjects older than 65 are

excluded.

Most of the issues raised by the Board relate to informed consent and recruitment. With regard to the consent forms, as a general matte r, given the population from which subjects are being recruited, it would be appropriate to make su re that the consent forms are at an appropriate level of readability. In at least some places, ther e appears to be room for further simplification.

The consent forms do not appear to describe adequately the procedures discussed in the protocol relating to (a) still phot ography of the subjects, (b) videotaping of the subjects, and (c) observation of the subjects by members of the st udy team. All of these procedures pose possible risks to the privacy and confidentia lity of the subjects. The fact th at each of these procedures will be part of the protocols should be adequately explained in the consent forms. That explanation should include the details relating to who will be observing and w ho will be taking the photographs (e.g., members of the study team, outsid e contractors, other s ubjects). In addition, both the protocol and the consent forms should expl ain what procedures will be in place to make sure that the photographs and videos will be stored in a way that adequately protects both the confidentiality and the privacy of the subjects, an d explains what harms to subjects might result if those protections are not adequate. If subject s will be accorded the right to opt out of being photographed, that should be expl ained in the consent form.

In the Purpose section of the consent form , it should be explained that the underlying purpose of the study will be to collect information that will be provided to the EPA, and that the

EPA would use that information to determine th e appropriate standards for allowable exposures to products such as the test compound.

The consent form in one instance (the pa ragraph numbered 4 under Study Procedures) uses the term “same-sex person.” That confusing term should be replaced with the descriptions used elsewhere in the form, such as “a researcher of your own sex.”p. 26 In the description of risks to subjects from exposure to the test compound, it is merely

stated that the risks ar e low. If there is a known risk from getting the compound in a person’s eyes, for example, that risk should be explained.

The approved version of the consent form, under the Pregnancy Risks heading, begins

with “We don’t know the risks to the unbor n from exposure to SANI-CARE LEMON QUAT and may be hazardous . . .” There is a word or words missi ng in this sentence, and it therefore needs to be revised. More significantly, the “a nd may be hazardous” language differs from the language that appears in the versions of the consent forms submitted to the IRB by the

researchers. The Board was not able to determine how this change in language took place. There

is not documentation that the IRB asked for the ch ange, or that the chan ge was initiated by the researchers themselves, and that they submitted a copy of the consent form with this change to

the IRB. This circumstance raises some concer ns regarding whether the EPA was provided with the full documentation of what went on during th e IRB approval process. The Board believes it would be appropriate for the EPA to determine how this change occurred. In addition, some

members were concerned that this lack of docum entation might relate to the operation of IIRB, Inc., which might reinforce prior Board conc erns about the operation of that IRB.

With regard to the recruitment brochure, it would appear appropriate for that document to mention that the product which will be used in the study is Sani-Care Lemon Quat. At the beginning of that document, it fails to mention that the study will look not only at how much of the product “gets on” the workers, but also how much of it they inhale. Under the eligibility criteria, it states that subjects must be “Mal e or non pregnant, non or nursing female.” This language needs to be corrected. A nd in the last sentence, the broc hure incorrectly states that the

EPA will use this information to reduce risks to workers. The statement should be revised to more accurately state the EPA will use the info rmation to determine how much of the product workers will be exposed to; it is not true that it will necessarily lead to a reduction in risks to

workers.

The phone texts that are used for calls to employers, and for calls to workers making inquiries, fail to mention that the study will be looking at inhalation risk s in addition to risks relating to getting the compound on th e worker’s skin and clothing.

With regard to recruiting and obtaining the informed consent of Spanish-speaking persons, the Board agrees with the changes recommended by the EPA (Carley 2008a and 2008b). It would also be appropriate fo r the protocol to include a more detailed discussion of how the researchers will obtain appropriate community involvement (such as, for example, discussions with unions representing janitorial workers).

With regard to the translations into Spanish of the various documents, the Board believes that it is important to make sure that the appr opriate dialect of Spanis h is being used in the

translations. The translation of the consent fo rm, for example, was provided by someone from Miami, Florida, yet the study will be taking place in California. The Spanish-speaking communities in Miami and California might well use significantly different dialects of Spanish.p. 27 It was also not clear from the docum ents who was producing the Spanish-language version of some of the materials, such as the recruitment brochure.

HSRB Consensus and Rationale

The Board concurred with the initial assessmen t of the Agency that if the proposed mop and wipe scenario design, prot ocol, and supporting documentation is revised as suggested in EPA’s review, the research does appear to meet the applicable requirements of 40 CFR part 26, subparts K and L.