So, when it comes to the brain weight concern, I agree with Dr. Cory-Slechta that a reduction in brain weight is serious, but, in this case, a reduction in brain weight was proportional to body weight; therefore, I'm skeptical that it has significant independent meaning in this case.  In fact, most treatments that reduce body weight to a significant degree will reduce brain weight at the same proportion or less because of brain sparing.  So, if there was a brain weight reduction that was greater -- not proportional or out of proportion to -- body weight, I would think that would be highly significant, but that's not what is seen here.
                  For the neurotoxicity, they cite a study by Honma and another study by Ichihara.  The Honma study effect, which is reported as key, is a reduction in hang time at postnatal Day 21, and, although it results in a very low calculated benchmark dose, I'm not sure that it's a very reliable measure.  At 21 days of age, hang time is not a very reliable index of neurotoxicity.  And what's of greater concern to me is this is in a study where there are only five animals per group.  So this study is not a very strong study, and it's using a fairly unreliable measure of neurotoxicity using hang time.
                  I think the better study is the Ichihara study which uses hind limb grip strength and finds effects after testing at several different exposure and post-exposure intervals.  And there they use nine animals per group, and they find a consistent pattern of effects that persists both at the end of the exposure period and several weeks after exposure.   And moreover, the effect is basically dose dependent in that, at the first exposure point at the end of exposure, they get an effect at 200 parts per million.  At 400 parts per million, they get an effect at the end of exposure and then four weeks later.  Then, in the high dose, 800, they get an effect at the end of exposure four weeks later and 14 weeks later.  So it really looks dose dependent; the greater the dose, the longer the effect persists.  So I think those are the stronger data and the data that would be best used for the benchmark MBCL.  So those are my comments.
                  DR. KENNETH PORTIER:  Try Dr. Pessah again.  I'll open it up to the panel.  Does anybody else want to comment on?
                  DR. DEBORAH CORY-SLECHTA:  This is Dr. Cory-Slechta.
                  DR. KENNETH PORTIER:  Yes.
                  DR. DEBORAH CORY-SLECHTA:  I used both of these measures -- the hang and the grip strength -- and in young and developing animals.  I disagree with Dr. Vorhees about grip strength.  I think it's actually easier to get standardized data than it is with grip strength.  Grip strength requires a lot of training, if you will, of the investigator, whereas, grip strength is more of a do or die kind of phenomenon and animals simply do it.  So I disagree with that.  I also felt that the grip strength was an interesting parallel to see effects that are seen in humans.  Thank you.
                  DR. KENNETH PORTIER:  Just to be clear, you're disagreeing with Dr. Vorhees.  Is that right?  Dr. Vorhees.
                  DR. CHARLES VORHEES:  Yeah, let me ask you, Debbie, if I can say that, are you not concerned about the five animals per group in that study?
                  DR. DEBORAH CORY-SLECHTA:  I am concerned about that.  I would love to see nine or ten animals in that group.  On the other hand, I feel like grip strength has a lot more variability built into it than does the hanging time.  So, yeah, I am concerned about that.  I would like to see that, but I'm less concerned about hanging time is a measure than grip strength.
                  DR. CHARLES VORHEES:  Well, the grip strength, I will say, that I mentioned the hind limb, they also found forelimb grip strength differences.  They just found more effects on hind limb than on forelimb, but they measured both and they found effects on both.
                  DR. DEBORAH CORY-SLECHTA:  Yeah.  Right.  I understand that.  I'm just responding in my experience to different individuals doing the measurement and sort of the learning curve of being able to do that assay.
                  DR. KENNETH PORTIER:  Any additional comments?
                  DR. CHARLES VORHEES:  I can't resolve that.  I mean, we see that.  We both use those tests, and we both have our concerns about one versus the other.  But I've had some concerns about hang time tests and other early developmental tests in the assessment of neurotoxicity because, not only do I have questions about the consistency of measuring them, but also because a lot of them don't predict adult effects very well.  So, for those reasons, I have concerns about them.
                  DR. KENNETH PORTIER:  Dr. Willett.
                  DR. CATHERINE WILLETT:  I think this conversation also points to some other comments that will come up in the later section about being more transparent about the weight of evidence decisions that went into selecting which endpoints for the dose-response point of departure calculations because, I mean, if you go on a straight weight of evidence, you would do all of the things that you consider.  But I think they chose the other endpoint also because it's protective.  I mean, it results in a more protective estimate but those things -- the factors that went into how they chose them should be more transparently described, I think -- I mean, specifically described maybe in an additional table in the document.
                  DR. KENNETH PORTIER:  Ms. Rudel.
                  MS. RUTHANN RUDEL:  I just have a question for the neurotox folks or, actually, just maybe more broadly, but has there been a developmental neurotox study for this compound?  Or, based on what you've seen, what's the study that you think would show -- would be the design and the endpoint that you would look at to find the sensitive measure and reliable measure of the effect?  And has that study been done or not done?
                  DR. CHARLES VORHEES:  Is this study the best that could be designed to determine developmental neurotoxicity?  No, I don't think so.  I think any of the neuro people could design a better study, but the better study doesn't exist in this area.
                  MS. RUTHANN RUDEL:  So what would that be?  Like, what would you be looking for?
                  DR. CHARLES VORHEES:  Well, it would be interesting to hear what Debbie would say.  From my point of view, I would say that to put less emphasis on these early developmental parameters -- the emergence of various reflexes and things like that -- and put more emphasis on adult assessment to see whether there are long-term consequences of a developmental exposure.  Actually, the study by Honma does that.  There are a number of other later behaviors that were assessed, and they didn't really show much.  So, to me, that indicates that the hang time may not really be telling you anything about the ultimate neurotoxicity of this compound.  They did learning tests and activity tests, and really they only found effects at the higher concentrations.  In some of the tests, they didn't find much of anything at any concentration.
                  There's also some issues around -- there's statistical analysis.  I tried to make sense of the degrees of freedom that they show for their ANOVAs, and they don't appear to match the design.  And so I'm not really sure, in some cases, how they even analyzed their data.
                  DR. KENNETH PORTIER:  That was Dr. Vorhees.  Dr. Pessah, have you joined us?  I'm still trying.  Yeah.  And just reminding the panel to use your name and speak into the microphone because the people on the phone are having a little hard time hearing us.  Dr. Barton, did you capture all of that including this disagreement on the --
                  DR. CHARLES BARTON:  I will have to follow up with the speakers.
                  DR. KENNETH PORTIER:  Good.  Dr. Davies.
                  DR. HOLLY DAVIES:  I have a question.  Since you're talking about Honma, I would like to go back to the data quality evaluation within the systematic review because they hadn't looked at the paper in depth because I wasn't assigned to Question 5, so I was looking forward to this.
                  So I want to go back to the fact that it was unacceptable for the chronic when it was ranked in the systematic review and, if any of you, who clearly delved into this paper and know this to the extent you can disagree about it, looked at the data quality evaluation.  So, for instance, I'm looking at it now, and it got high for statistical methods that you just said you had trouble understanding what they did.  And also it was evaluated both for short-term and for chronic.  Had you looked at that?  I don't know if anyone's looked at that.
                  DR. CHARLES VORHEES:  No, I just looked at the study, and I had questions about it because I thought that the sample size was small and some of the statistical analyses are unclear and I expressed my concern about the hang time test.  And so I, personally, didn't think that the study was a particularly strong one for use in determining the benchmark dose.
                  DR. HOLLY DAVIES:  Okay.  Because I did have that question about the unacceptable and then using it for the point of departure.  Anyone wants to follow up, please tell me.
                  DR. DEBORAH CORY-SLECHTA:  Could you repeat what your question was?  It's a little hard to hear on the phone.
                  DR. HOLLY DAVIES:  Sorry.  The question was in the Data Quality Evaluation, the Honma paper had two ratings, and it was rated high for the acute and unacceptable for the chronic.  And I was hoping that when we got to this point and with people who had dug into the paper would be able to shed some more light on that if you'd looked at the Data Quality Evaluation.
                  DR. DEBORAH CORY-SLECHTA:  Yeah, I hadn't looked at that though.
                  DR. HOLLY DAVIES:  Because that's really the question is how good the papers are as we're using them for the risk assessment.
                  DR. KENNETH PORTIER:  But didn't I hear Dr. Vorhees say that he thought it was better for acute and not acceptable for chronic?  Was that right?
                  DR. CHARLES VORHEES:  No, I wasn't saying that.  No, no, no.
                  DR. KENNETH PORTIER:  Just checking.
                  DR. CHARLES VORHEES:  No, I think the study has serious concerns whether it's for acute or chronic.
                  DR. HOLLY DAVIES:  So I'm just muttering, and I shouldn't mutter to my partner -- not partner, my neighbor -- that sometimes we define chronic and acute differently, and that's why I wasn't sure how people were defining chronic and acute.
                  DR. KENNETH PORTIER:  I think I'm going to look to the EPA and say, did this raise more issues than it answered the question?
                  DR. STAN BARONE, Jr.:  I think it raises some important issues.  I do have some concerns in, at least, some of this dialogue.  There seems to be some misunderstandings with regard to the neurotoxicity risk assessment guidelines, and I want to call out a couple of things and, again, we had provided guidelines to you in our orientation session.
                  BMRs, the issues of BMRs, and I think, we need to be more clear about why we chose the BMR of one percent for brain weight.  Again, it's because of several factors: One is the adversity of the endpoint.  It is an adverse endpoint called out specifically in our neurotox guidelines.  We do not correct for body weight, and it's because of a very large literature on brain sparing.  It is a pathology.  It is adverse.  Second, with regard to the BMR, brain weight is very well conserved.  The variation in brain weight is very tight, so, from both a biological and statistical sense, the BMR is low.  And I think I've already made my point about adversity.
                  The comments about having a DNT guideline-like test for 1-BP, we don't have that.  We have the data that we have, and we tried to evaluate it in the most comprehensive way.  Your input on the weaknesses and the strengths of the findings is important.  I would also ask you to consider having a lower number of animals, would that lead us to a false positive or a false negative?  Which direction would you expect?  Again, those considerations will also be helpful to us in revising our evaluation.  Thank you.
                  MS. RUTHANN RUDEL:  Can I just --
                  DR. KENNETH PORTIER:  Ms. Rudel.
                  MS. RUTHANN RUDEL:  This is Ruthann Rudel.  Thank you.  I thought that the write up of that section was very good, actually.  So I didn't have some of the issues that were brought up here with it.  And, on the developmental neurotox, I'm maybe only suggesting that in that section, there would be a sentence that says, there is not a modern developmental neurotox for this compound.  Just being clear about data gaps throughout, I think it's helpful.
                  DR. KENNETH PORTIER:  Dr. Vorhees, something you said about fitting the curve and dropping the highest dose, was that dropping justified?
                  DR. CHARLES VORHEES:  It wasn't me.
                  DR. KENNETH PORTIER:  Oh, Mark.
                  DR. MARK JOHNSON:  That was me, yeah.  Well, I mean, you do that to get a good fit for your model.  And sometimes, if you have a bell-shaped curve --
                  DR. KENNETH PORTIER:  Yeah, but the guidelines usually say that's not the excuse for dropping the highest dose.  The excuse is usually that's it's above minimum tolerated dose, and, if that wasn't the discussion, then I think we need to point that out.  Just because dropping that highest improves your fit is not an allowed excuse as far as at least from the cancer guidelines.  I don't know about the non-cancer kind of fits.
                  But, if you read the cancer guidelines, it says usually the argument is that it exceeds some minimum tolerated dose and/or is producing an adverse effect that is clearly toxic, kind of an overwhelming toxicity, not just because it doesn't follow the nice curve.  I know because I just looked at this recently.
                  DR. MARK JOHNSON:  My primary concern has to do with the variability and just three data points.
                  DR. KENNETH PORTIER:  But three data points is --
                  DR. MARK JOHNSON:  You can draw a line.
                  DR. KENNETH PORTIER:  That's usually what you have.  You can draw a line and then assess on nonlinearity.  Did you want to add something?
                  DR. STAN BARONE, JR.:  So part of the issue with the highest dose is the animals weren't getting pregnant, and so, again, they're different.  And so we need to be clearer about the rationale for dropping the highest dose.
                  And the second aspect in the dose-response analysis, which I believe we captured, was we're interested in what's happening in the low-dose region and the shape of the curve in the low-dose region versus what's happening at the high-dose region, which may be a totally different mode of action.  So, again, we need to be more clear about the rational definitely from your read and your input.
                  DR. MARK JOHNSON:  I just also want to add, what gives me comfort is that reduction in litter size corresponds very well with those responses done with post implantation.  But they are sort of the same thing, aren't they?  They're related.
                  DR. STAN BARONE, JR.:  The measures what we're looking at, they're related, but the data that are going into it aren't exactly the same thing so biological relationship?  Yes.  But the data aren't exactly the same, and what's reported we're actually looking at different reporting measures to do those calculations.
                  DR. KENNETH PORTIER:  Dr. Davies, your flag is still up?  No.
                  DR. KENNETH PORTIER:  Any additional comments from the panel?  Dr. Vorhees.
                  DR. CHARLES VORHEES:  Can I ask Dr. Barone a question.  So you say that the data aren't identical, but they're not orthogonal either?
                  DR. STAN BARONE, JR.:  True, and that is why we are reporting them separately.  They're not exactly different biologically.  They are related.
                  DR. KENNETH PORTIER:  But, in a weight of evidence, that just means it doesn't add one plus one.  It's like 1 plus 1.25 or something.  They go together.  I understand that.  I wasn't challenging -- I remember reading that section and coming to the same conclusion and saying, oh, that's an acceptable justification for dropping that dose.  I just wanted to make sure we were reading the same thing.
                  Any additional comments on this question?  Good.  Let's move on to 5.2.
                  DR. KATHERINE ANITOLE:  Please comment on the weight of evidence analysis for the choices of non-cancer endpoints for the acute and chronic risk scenarios.  Please provide additional data, data interpretation, or information that would have informed the weight of evidence analysis and selection of critical studies for PODs.
                  DR. KENNETH PORTIER:  Dr. Cory-Slechta, you have the lead.
                  DR. DEBORAH CORY-SLECHTA:  Okay.  I wasn't aware.  I thought we were -- these were together.  I think we already actually discussed this topic under 5.1.  We went through a lot of these considerations already.  I am not personally aware of any other data that would add to or modify this weight of evidence at this point.
                  DR. KENNETH PORTIER:  I tend to agree that Dr. Barton had a lot of weight of evidence discussion in his comments, but let's move on through the group.  Dr. Sheela, I think you're next.
                  DR. SHEELA SATHYANARAYANA:  Well, I thought that these sections were really well written, and, given the data that was there and for the studies that I reviewed, I thought it was appropriate.
                  DR. KENNETH PORTIER:  Dr. Willett.
                  DR. CATHERINE WILLETT:  I agree mostly, entirely.  I just wanted to reiterate what I said a little bit earlier which is it might be helpful to follow the weight of evidence decision-making process at EPA if there was -- this might be a lot of work but -- if there was an additional table that just had the studies and endpoints that were chosen and went through the argumentation for choosing them, or the high-quality studies and why one was chosen over the over, just with the argumentation listed out because it would just make it easier to understand.
                  DR. KENNETH PORTIER:  So that's kind of a presentation recommendation because I think those arguments are in the document.  You're just saying kind of consolidate them into some kind of table that facilitates that, and that's a good recommendation.  Dr. Johnson.
                  DR. MARK JOHNSON:  Yeah, I would like to echo Catherine's comment for the same reason, possibly in Table 3.7 where we could just track it a little bit better.  Personally, I'd like to see the weight of evidence scores, and I think the scores are there as well too that help us understand the relative difference but actually why some were selected, and some were not.
                  And this is my soapbox and I apologize to you if you've heard this before, but, statistically, 1 out of 20 times, we're going to be wrong.  And it just helps me to see those relative differences in the weight of evidence to be able to determine which is more likely to be a positive response than not.
                  DR. KENNETH PORTIER:  Mr. Kaufman.
                  MR. ALAN KAUFMAN:  Sorry.  Al Kaufman.  Nothing to add.  Thanks.
                  DR. KENNETH PORTIER:  Dr. Pessah?  Dr. Vorhees.
                  DR. CHARLES VORHEES:  Under weight of evidence, I would just say that I think more weight should be put on the Ichihara study because it's a longer exposure.  It's a 12-week exposure, and then they also measure the grip strength at various intervals at the end and various weeks afterward.  Whereas, the Honma study is only a three-week exposure with more limited sort of follow-up in the very small sample size.  So, in terms of weight of evidence considerations, I think the Ichihara study should be given greater weight than the Honma study.
                  DR. KENNETH PORTIER:  Anyone else on the panel want to weigh in on weight of evidence for non-cancer endpoints?  No?  Dr. Gilbert.
                  DR. KATHLEEN GILBERT:  Thank you.  Well, when we're talking about non-cancer endpoints, I have to ask why the immunotox was not considered.  They mention it several times that there was data showing immunotox and they talk a little bit about the Lee and Anderson papers, but then it sort of gets dropped.  So I was just curious why the EPA decided not to use that as an endpoint.
                  DR. KENNETH PORTIER:  So you're saying there's basically an incomplete conclusion on immuno in the discussion.
                  DR. KATHLEEN GILBERT:  Well, there were several of the other endpoints that were chosen that didn't have really more papers backing them up, so I was just curious as to why it was kind of dropped.
                  DR. KENNETH PORTIER:  Yeah, kind of goes to Dr. Willett's suggestion that being able to kind of see a bigger picture.  It might have been that the scores on the immuno papers were much weaker.
                  I think Dr. Barone is searching through to see an answer for that.  While he's doing that, any additional comments?
                  DR. SHEELA SATHYANARAYANA:  This is Sheela Sathyanarayana.  I was just going to say that I think a lot of these comments go back to the systematic review and relates to some of the things that Holly said yesterday that, if you really trust your systematic review, then you wouldn't have these kinds of comments and issues coming up now.  And so not all of us could read all of the studies, you know.  I focused on the reproductive developmental tox and, of course, Kathleen's going to focus on immunotox.
                  At some level for the readers, they have to trust that Data Quality Evaluation.  And I went through that document for my studies and I tended to agree, but I think that there's been comments for other studies where people did not agree.  And so, if you're going to go through that exercise of systematic review, it really needs to be done thoroughly.  And I know that that keeps being brought up again and again.  It's a very difficult process and I appreciate that, but I think that there's still some holes here.
                  DR. KENNETH PORTIER:  Dr. Barone.
                  DR. STAN BARONE, JR.:  So, if you look at the systematic review table and the point of departures, at least the NOAELs and LOAELs that are listed for the immune section, there are on the data quality evaluation quite a number of high-quality immune studies, at least according to our evaluation, in several mediums.  I think the issue that -- and this might be an issue of completeness in our description of what we choose for the point of departure -- in general, the point of departure for the immune effects is in the higher dose range.  There are a couple of studies that show points of departure in the lower dose range, and I'm talking about a hundred ppm range.  And the issue is those studies, whether they were suitable for dose response?  Were they modelable?  Those kinds of issues.  We need to be a little clearer about that.
                  We are calling immune effects out as an important domain, and I think on the hazard ID, if you look at the table on page 361 of the assessment, you can see the whole sequence of immune studies.  So your comments are valid.  We'll look at that more closely and provide additional justification and look back at the modeling work because there was a lot of things that we tried to model, not everything was modelable and not everything could be carried forward for dose response, and we may have lost some explanation there.
                  DR. KENNETH PORTIER:  Dr. Davies.
                  DR. HOLLY DAVIES:  Just to go back to the Data Quality Evaluation, I did like the explanation.  I did think it was well written since we're talking about the weight of evidence.  But a lot of the studies in the weight of evidence didn't go through the data quality evaluation, so, if you look through -- if you say as I did -- go through and look at all of them and write down the references and which ones went for data quality evaluations and which ones didn't, you'll see that a lot of them weren't.  And so it wasn't -- so that's why as Sheela said, why we're all evaluating them ourselves, it's because we couldn't just rely on that document.  But it was a well-written document.
                  DR. KENNETH PORTIER:  Dr. Willett.
                  DR. CATHERINE WILLETT:  I just wanted to add a thought about the immunotox.  So I looked at the immunotox too and decided that they didn't use it because it was a higher.  But also there was a lot of high-quality studies in there.  And the other thing I wanted to point is those funny studies I found about the proteomic studies in humans.  Immunotox related proteins came up a lot, so that's mechanistic evidence that immune might be an important thing to consider, and those references are in the comments.  So that's just supporting evidence that immuno might be a good thing to reconsider.
                  DR. KENNETH PORTIER:  Dr. Anderson or Dr. Cory-Slechta, do you want to add anything?
                  DR. HENRY ANDERSON:  I don't have any.
                  DR. DEBORAH CORY-SLECHTA:  I don't have any.  Nothing to add.
                  DR. KENNETH PORTIER:  Anyone else?  Good?  Let's see.  Dr. Slechta, did you capture all of this for the minutes.
                  DR. DEBORAH CORY-SLECHTA:  I hope that I'll be back in touch with everyone.
                  DR. KENNETH PORTIER:  Good.  Let's go onto 5.3.
                  DR. KATHERINE ANITOLE:  While the majority of exposures are occurring via inhalation, and inhalation exposure is the most important, dermal exposures might be an important contributor to aggregate exposure.  Given the limited toxicological data available by the oral route, human equivalent dose or HEDs for dermal exposures were derived by extrapolating from the inhalation PODs.
                  Question 5.3.  Please comment on the assumptions, strengths, and weaknesses of this approach including using an inhalation study instead of a limited oral study for route-to-route extrapolation for determining dermal PODs in the non-cancer assessment.
                  DR. KENNETH PORTIER:  Dr. Gilbert.
                  DR. KATHLEEN GILBERT:  Okay.  I'm going to start with a couple of caveats: (A) I'm not a modeler, so I'm going to defer to my other discussants on a lot of these points; and (B) I just got this question two days ago, so I'm going to be mostly talking about what Dr. Bruckner sent in his notes because he was supposed to be the lead the discussant on this.
                  As we know, the reviewers of the 2016 Draft Risk Assessment recommended the inclusion of dermal exposure.  The EPA assessed the dermal exposure to workers using the dermal exposure to volatile liquids model.  This model estimates .16 dermal exposure for nonoccluded exposers based on a 2011 in vitro dermal penetration study.
                  The report presents several occupation dermal exposure scenarios that take into account the potential for evaporation and glove use.  The potentially exposed workers were primarily confined to two companies that manufactured 1-BP in the U.S.  Dr. Bruckner agrees that dermal exposures may be an important contributor to systemic exposures to BOCs in the workplace and that an estimate of dermal exposure to 1-BP should be included.  The PBPK model of Garner et al. cannot be used for route-to-route extrapolation as it has not been validated with actual TK data and its model structure does not provide for skin exposure.  Unfortunately, there are apparently no published TK data from animal or human studies other than an IV experiment.  The approach described in Section <IP_ADDRESS> for calculating dermal exposures seems quite reasonable as does its assumption of .16 for the fraction absorbed.
                  Dermal absorption of 1-BP depends on the type and duration to the exposure.  Significant dermal exposure may occur in cases of occluded exposure, repeated contact, or dermal immersion.  Work activities with a high degree of splash potential may result in 1-BP being trapped inside the gloves.  It should also be noted that 1-BP easily travels through most glove materials with the exception of certain polyvinyl alcohol or multiple-layer laminates.  So one thing that was not clear to me is why the underlying EPA dermal model assumes only one exposure event per day which seems likely to underestimate exposure as workers come into contact with 1-BP several times during the day.  Based on these uncertainties, the EPA has expressed only a medium level of confidence in the access baseline exposure.
                  My major concerns were why they only used one exposure per day and the information about the glove use being important.  That's all I have.
                  MS. TAMUE GIBSON:  Okay.  Thank you.  I'm the chair for a couple of minutes.  Okay.  Dr. Sheela, do have a response to that?
                  DR. DEBORAH CORY-SLECHTA:  I can't really comment on the calculations for the dermal exposures, and I'll leave that to my dermal colleagues to do.  But, in terms of the oral studies, for the two oral studies that are listed in the Data Quality Evaluation, I feel that they were evaluated appropriately.  One of them was listed as unacceptable because it didn't meet an OECD guideline, and I thought that was an appropriate determination for that specific study.  And I did feel that they were limited, so for that piece of the question, I agreed.  For the dermal piece, I'm just not the right person to address that.
                  MS. TAMUE GIBSON:  Okay.  Thank you.  Dr. Johnson.
                  DR. MARK JOHNSON:  Briefly, I agree.  I'm not a modeler either, but I think using inhalation data may likely be more accurate than using oral data considering first-pass hepatic transformation implications.  But you don't have a refined PBPK model, I agree.
                  But some strength comes from comparing a human experience and human equivalent concentrations with the human experience data.  This is qualitatively done but not as a data integration step in the primary document.  So I would encourage the EPA to consider providing a data integration step within the hazard assessment section; integrating controlled animal data, human experience information, relevant mechanistic and in vitro, and potentially a read across for even in silico information helps to support the refined human equivalent concentrations.
                  DR. KENNETH PORTIER:  Dr. Vorhees.
                  DR. CHARLES VORHEES:  Yeah, I have nothing to add to this section.
                  DR. KENNETH PORTIER:  Dr. Pessah.
                  DR. ISAAC PESSAH:  I have nothing to add.
                  DR. KENNETH PORTIER:  Thank you.  Good to hear that you've joined us this morning.
                  DR. ISAAC PESSAH:  Yeah.  It's a little early here.
                  DR. KENNETH PORTIER:  Ms. Rudel.
                  MS. RUTHANN RUDEL:  I don't know if this is useful at all, but one of the intermediates, I guess, there's the bromopropanol like in the metabolite chains and the compound might be too different but NTP does have a dermal long-term study for 2,3-Dibromo-1-propenal, so it has an extra bromine.  Otherwise, it's pretty much the same.  So I don't know if anything that could be useful from a read across from that compound, but it is there.
                  DR. KATHLEEN GILBERT:  Can you send me that so I can put it in the notes?  Thanks.
                  DR. KENNETH PORTIER:  That was Dr. Gilbert.  Dr. Willett, did you want to comment?
                  DR. CATHERINE WILLETT:  No, I didn't realize I was on this part of this question.
                  DR. KENNETH PORTIER:  Put your flag down.
                  DR. CATHERINE WILLETT:  Oh.  Oh.
                  DR. KENNETH PORTIER:  Does anyone else want to chime in on this?  Dr. Gilbert, did you get what you needed from this?
                  DR. KATHLEEN GILBERT:  Well, I hope the other discussants will send me comments that they have.  Thanks.
                  DR. KENNETH PORTIER:  I'll turn to EPA; do you have any questions?  Nope.  Sorry, I missed part of that discussion.  Okay.  From my agenda, it seems that we have a 15-minute break scheduled at this point, and it's probably needed.  I have 10:17 so let's reconvene at 10 -- what will it be?  35, 10:35.
                  MS. TAMUE GIBSON:  Yes.
                  DR. KENNETH PORTIER:  Okay.  Take a break.

                                    [BREAK]

                  DR. KENNETH PORTIER:  Okay.  The panel is caffeinated and hydrated, and we're ready to keep going.  Are there any additional comments on 5.3 before we move on to Question 5.4?  Let's go ahead and move onto 5.4.
                  DR. KATHERINE ANITOLE:  Decreased live litter size, that is reduced number of live pups per litter, was the endpoint selected as most relevant for calculating risks associated with developmental toxicity following chronic exposures.  EPA selected the BMDS nested dichotomous model, or NCTR, for this developmental endpoint to account for intra-litter correlations and litter-specific covariates.  However, this model can only be applied to increases in effects, therefore, increases in post-implantation loss was the endpoint selected as the most relevant for calculating risks associated with the developmental toxicity following chronic exposures using nested modeling.
                  Question 5.4. Please comment on the nested modeling approach and the selection of endpoints and whether the Draft Risk Evaluation has adequately described the use of this model.
                  DR. KENNETH PORTIER:  We've asked Dr. Gilbert to start.
                  DR. KATHLEEN GILBERT:  Okay.  Once again as a non-modeler, part of this was confusing to me.  They talk about the BMCL and it's my understanding that in terms of the 2019 Draft Risk Assessment, the POD derived from the WIL Research was described as a BMCL not a BMDL as exposure was inhalation, not ingestion.  And they talk about the POD being from -- increased post-implantation loss was a BMCL of 24 ppm that assuming that is just an editorial error.
                  We need to talk about the nested modeling approach and its endpoints.  For dose-response analysis of developmental toxicity studies, data from individual litters are generally considered as an N of 1.  And that was certainly what I was taught when I started doing developmental toxicity.  This is because fetuses from the same dam are not statically independent.  Pups of the same litter tend to respond more alike than do pups from different litter due to similarity in genetics and environment.  However, in a nested study, the endpoint examination is conducted in a subset of subjects from each treated individual, the pups of the treated mother for example.  Because each mother may produce 15 to 20 pups.  If you have 20 treated mothers, you would have 20 observations from each mother.  Obviously, this generates an observational sample size that is larger than that of the originally treated animals.  Since all the observations are made in pups, but not in the mothers, these data should be considered nested data.
                  It says by using litter-specific data, intra-litter correlations can be accounted for through modeling methods as nested dichotomous method models that rely on a binomial model of variability.  Now, I still think that the N of one is the method that is most commonly used, so I would be interested in hearing from the other discussants what they think about using this nested approach.  And the rationale for using it not clear to me anyway.  So, in the Draft Risk Assessment, the supplemental information on human health benchmark dose modeling, it states the application of nested dichotomous models to these data was possible because the incidence data for post-implantation loss was available for every litter and preferable because they can account for intra-litter correlation and litter specific covariates.  At least as far as I'm concerned that needs to be clarified.  I didn't really understand what that meant.
                  However, the endpoints of decreased live litter size and increased post-implantation loss to develop a POD for chronic exposures based on the developmental effects seems appropriate.  A BMR of five percent, which represents a combination of reproductive effects, when a BMR of ten percent would be used and developmental effects for post-implantation loss, which is considered a severe effect like mortality, when a BMR of one percent would seem appropriate.  So the PODs calculated for post-implantation loss using the nested dichotomous model were similar to those calculated for the related decreased live litter size when using BMD modeling.  So that seemed appropriate to me.  I would just like to have seen a better explanation for the rationale for using the nested modeling versus the more traditional N equals one for litters.  And that's all I have.
                  DR. KENNETH PORTIER:  Dr. Sheela.
                  DR. SHEELA SATHYANARAYANA:  So I think that, for my understanding, this was the nested model was done in response to reviews of the 2016 Draft Risk Assessment.  From my reading -- and I admit that I don't do a lot of nested models but -- in terms of doing nested models, it seemed appropriate and also the results did not seem to vary significantly from the non-nested models.  So I didn't find it to be of significance regardless.  So overall, I was okay with it.
                  DR. KENNETH PORTIER:  Dr. Johnson.
                  DR. MARK JOHNSON:  I don't have anything further to add.  Thank you.
                  DR. KENNETH PORTIER:  Mr. Kaufman.
                  MR. ALAN KAUFMAN:  Hi.  Al Kaufman.  Yeah, I think it was adequately explained and described.  Beyond that, I really don't have any comment because it's sort of out of my area of expertise.
                  DR. KENNETH PORTIER:  Dr. Pessah.
                  DR. ISAAC PESSAH:  I have nothing to add.
                  DR. KENNETH PORTIER:  Dr. Vorhees.
                  DR. CHARLES VORHEES:  Yeah, it seemed appropriate to me.
                  DR. KENNETH PORTIER:  So this is Ken Portier.  I probably made that recommendation back in 2016.  Yeah, he's shaking his head, yeah, you did.  I remember that.  And I can explain to you why it's slightly better.  They're not going to be that different: the nested incidence model versus the N equal one traditional proportional model.  It's going to be a slightly different estimate for underlying uncertainty, so the tests are going to be slightly different p-values.  But I think in this case, because of the way the data are, it's not going to change things that much.
                  Statistically, what they did is the appropriate model, okay, but not the traditional model.  Anyone else want to add?  Gosh we're flying through these which is not what I -- I mean, this is what I expected.  Like you said, this is the second round, so this has been polished from the 2016 report.  I'll look to EPA; do you have any clarifying questions or comments?  No.  Then let's move on to Question 5.4 [sic].
                  DR. KATHERINE ANITOLE:  For the cancer risk assessment, EPA derived the inhalation unit risk, or IUR, based on lung tumors in female mice.  While the precise mechanisms/modes of action of 1-BP carcinogenesis are not clearly understood, overall, reasonably available information and the weight of evidence analysis for the cancer endpoint was sufficient to support a mutagenic mode of action for 1-BP carcinogenesis.
                  Question 5.5.  EPA concluded in the human health risk assessment that 1-BP carcinogenesis occurs through a mutagenic mode of action based on reasonably available information and the weight of evidence.  Please comment whether the cancer hazard assessment has adequately described the weight of evidence regarding the mutagenic mode of action.
                  DR. KENNETH PORTIER:  Dr. Eastmond.
                  DR. DAVID EASTMOND:  Okay.  I'll slow you down a bit.  So let me address this in a couple of ways.  First of all, I'd like to get in some technical details that are important because it weighs into sort of the weight of evidence, and then I'll get into my sort of evaluation of this.
                  So the first thing -- and I mentioned this briefly but -- there's a little bit of concern I had about the literature search.  And, essentially, the way that I do this -- and I assume EPA did this as well -- it's described as, when you start this off, you go to sort of standard lists of genetic toxicity testing or other reports and look at them.  And so one of the first things I did is I went to the ECHA documentation database, and there were significantly more studies in the ECHA database than there were in the EPA document.  So then I'm saying, how come they're missing these?  What's going on?  So then I start digging more into sort of what's happening?  For example, there are six different mutation studies in salmonella listed in the ECHA study, but only two really discussed in the EPA document and two briefly mentioned.  So I said, what about these other?  Why were they missed and et cetera?  And part of this is the EPA focused very, almost exclusively, on this difference between open system and closed systems and put their energy into that.  And I'll come back to that in just a minute.
                  But I also did a couple of reviews looking at literature search, are new studies that have been published?  And there are three studies that, I think, are particularly relevant: Two of them which one describes the formation of DNA adducts in vitro and (inaudible) DNA.  And the other one actually reports the formation of DNA adducts, 1-bromopropane in vivo, these N7 guanine adducts.  We'll talk about that briefly in a minute.
                  And then one recent one which is essentially a publication of one of the unpublished studies which is referred to in the report.  I'm pretty sure it's the Weinburg 2016 study, which has just recently been published and was mentioned, I believe, in the ACC comments; they call attention to that paper.
                  In addition, in looking at sort of reviewing some of the data, there's a document PDF called BioReliance 2015 in the references.  The PDF has two studies in it: the first part of the study is the salmonella study, which is referred to; and then there's a second study on the end of it which is by Roy et al.  So the first one's a Wagner et al. as the study director of the second one is by Roy who just happens to have been a former postdoc of mine.  But anyway, it's a study which shows positive effects in human peripheral blood lymphocytes for 1-bromopropane for causing structural chromosomal aberrations.  And so that probably ought to be carried out because it refers to sort of a positive in vitro study.  So that's the first thing.
                  The second thing is that, in my opinion, the sort of mode of action decision is so important that the key studies involved in mode of action determination really need to go through this sort of data quality review and critique.  And so, when I started looking up one of them, one of the studies referred to that 1-bromopropane caused DNA adducts.  And so I said, I want to see this paper.  So I went and clicked and followed the link.  HERO doesn't work for me.  I'll just tell you.  I mean I get there, but I don't find what I want, but I was able to find this particular study.  And I'm looking at it as, is this in the study of DNA adducts?  And then I go through it, where'd they come from?  And buried in the discussion is a sentence saying it causes DNA adducts.
                  And the reference it refers to is an abstract which was presented at the SOT three or four years earlier.  Now whether that would be considered sufficient evidence to base kind of key decision in this document, I'm not certain.  And it ends up being it's not critically important because these are new papers and they'll replace that, provided information for it.  But it triggered in me that maybe some of these studies weren't as evaluated as thorough as they should be, at least the papers themselves.
                  And then one of the other ones, one by Kim et al., the link is a bad link.  It doesn't refer to any -- the study it links to doesn't describe anything about genotoxicity.  So there's just a few of those sorts of things that flag up for me.
                  Now there's a discussion that plays a heavy influence in this determination as a study that took place in 1981 where 1-bromopropane was, along with a number of other halogenoalkanes, were studied in the AMES test in a closed system and an open system.  And they were non-mutagenic in the open system, but when you carefully close the system to prevent evaporation, then they saw a significant increase in mutation.  And this is with and without metabolic activation which indicates it's probably a direct-acting agent.
                  So the shift has been basically to sort of disregard in and the open system studies and focus only on those with closed systems.  I'm not sure that's totally warranted because, for example, the studies that were done by the NTP did as part of their cancer bioassay, they tested 1-bromopropane all the way till toxicity, so at ten thousand micrograms per plate, and it was totally toxic; it killed all the bacteria.  And so those studies should have been valid at the lower concentrations because you're seeing biological effects of the compound, and those studies were particularly negative.
                  So the pattern is a little more messy, and you kind of have to look at each of these studies and look at them individually.  So, in addition, there's a comet assay which was positive in an open system.  There's this structural chromosomal aberration assay which is positive in an open system, and I believe the mouse lymphoma assay was positive in an open system, which I can get the original study too.  But it appears that was the case.
                  In essence, once you break down this, there's quite a bit.  There's mixed results seen in the in vitro test, but there are quite a few positives in in vitro.  And so that's one of the reasons for this focus on the actual mutagenic mode of action.  There's other arguments as well.
                  The contrast on this -- and I'll jump to that -- is that it's negative in virtually every in vivo study.  So you've got -- originally there are two dominant lethal mutation assays.  It was negative in both of those.  There are three micronucleus assays: two in, basically, in mouse and one in the rat, negative in those.  And then there are two fairly recent studies which are looking for mutations in transgenes in transgenic mice and basically it was negative.  So these were looking at change in mutations in the lung, which is one of the target organs; in the colon, which is another target organ; and the liver.  Actually, two of them did the first two tissues, and one of them did one tissue.
                  So you've got kind of a very unusual situation where your in vitros giving you lots of positives.  The class of compounds is one that you think would be mutagenic.  The sort of the profile of tumors that are seen would suggest maybe it's muted; it's a mutagenic carcinogen.  It tends to be that mutagenic carcinogens tend to be active in multiple species and multiple target tissues, and so that's just kind of crude estimate on this.  But, in fact, the data here isn't very supportive of that, so it becomes a difficult sort of call.
                  One of the things they did was they did review in detail the Data Quality Evaluation of these two transgenic mouse studies for mutation and sort of a mix -- they came through this sort of formal evaluation as high quality.  They're both high quality, and one of them was moved to moderate quality for someone's professional judgment, which I can't quite understand why.  But, anyway, then they went through a very detailed -- and what I would consider being an extremely critical evaluation of these studies with expectations that are outside of a normal realm of an evaluation.
                  So, for example, they criticized them because they had not measured respiratory rates, or they had not measured body temperature on these animals during the 28-day studies.  I have never seen a genotox study that has ever done that.  There was a series of things, and they criticized one of them because it wasn't done -- they treated five days a week rather than seven days a week, which the guidelines recommendation seven days a week for 28 days.  Well, the study was designed to mimic the MTB bioassay, which was given five days a week.  So I would not dismiss this study because of these sorts of reasons.  The bottom line is I'm sure you can find some criticism with any study, but they looked to be reasonably sort of very acceptable quality studies.
                  So you're kind of looking at a very strange situation in here where you're -- usually you think of your in vitro study as sort of screening studies, then you follow up with in vivo studies for confirmation.  But, in fact, the follow-up studies in confirmation aren't confirming directly what you're seeing in in vitro studies, but knowing how this chemical works, knowing this sort of pattern of tumors that are caused and, as I've said, I might mention that all the tumors appear to be site of action.  They're direct site of exposure or site of absorption, so you're looking at tumors in the lungs of the female mice.  You're looking at tumors in the large intestine of the rats, and the other tumor was on the skin, so you're looking at skin tumors.  So, again, that was maybe consistent with sort of a direct-acting agent where you're having effects at the site.
                  So, for me, it comes down to the -- this is really a judgment call.  I mean, there's one or two other errors I'll pass on to some things, little mistakes here and there.  I think if I've got anything else, I need to -- oh, well, while I've got the stand, I might as well comment -- a little bit of a thing.
                  For me, there's some sort of consistent ways of citing studies and particularly in published studies where you use the study director's name, the organization that published it, and then the sponsor is given there.  In some cases, the study is attributed to the sponsor.  In other cases, it's to the organization that did the study, and sometimes it's the study director, study author.  So it becomes really confusing when you're comparing across this document with like the ECHA document versus other ones because they all have different study names.  You have to try and say, okay, which study is this?  Fortunately, there aren't so many of them you can kind of piece it together.  But it would be useful, for me, just their sort of a study.  For me, it's always valuable to go to the primary study and look at it and verify.  Now there may be some rare occasions where you can't do that, but then you should have the reference and then say, "as cited by" where you got the information.  Because, well, I think what happened with the DNA adduct thing, I don't think anyone went to the original study.  I think they were using "as cited by" sort of thing.
                  So there's some other things about metabolites.  1-Bromopropane is metabolized to a whole range of metabolites.  Some of those are mutagenic, but some of them are sort of putative metabolites and never have recovered.  They're sort of thought to be in the metabolites.  And so I'm not sure they play a role.  Some will be because they are very minor metabolite, presumably.
                  The other thing I would recommend is if you're going to talk about these metabolites as being important, they should be in the metabolic pathways because they're glycidol and the propylene oxide aren't in your metabolic pathways.  They're in the IARC pathway, which might be useful to adapt, but because these show up numerous times in the document, it'll be helpful to have them there where you can see them.
                  So, as I indicated, I was involved with the World Health Organization, while they're an actual program for chemical safety, and we did an update in their mutagenic testing scheme.  And, if you plug this into the mutagenic testing screen where you screen in vitro and you follow up in vivo, this would come out as being non-mutagenic.  But, given all this other information we know, that's independent of animal cancer data.  Once you now know what causes cancer and you know it's in vocal tissues in this sort of pattern, it makes this really a judgment call.  What do you call it?  And my sort of inclination on this is rather than -- and I've been vacillating and agonizing on this, and I think it's something the EPA will probably discuss some more.  The one in vivo study I mentioned, you now have in vivo DNA adduct evidence, which wasn't there before, but the adducts are N7-guanine adducts which aren't closely related to mutations.  They tend to -- they're clearly associated with exposure.  They're indirectly associated with mutations, so it helps but it also complicates things a little bit.
                  Anyway, so that my sort of inclination is, even if you say, there's not a viable alternative mode of action in my opinion for the other ones, there's some other ones that are possibles.  There's a possibility of cell proliferation, although the evidence for that I found to be very, very limited.  There's some inflammation, so potentially immunomodulatory effects, but I don't know it's that convincing.  There's also reactive oxygen species was bringing oxidative stress.  But, for me, lots of toxicants cause oxidative stress, and they're not necessarily carcinogenic.  So it contributes, but I'm not sure it's a driving mechanism in many cases.
                  So maybe you've been through these discussions, Stan, but, I mean, my might take on this is probably better.  I would lean toward saying the mechanism is not known which I've already stated.  And in the EPA, I know part of it defaults to a linear extrapolation, so essentially you end up with the same outcome, but it doesn't put as much -- you're putting a lot of weight on in vitro studies and all the in vivo studies and genotox really don't support that.  So, for me, I think, the unknown is an easier response than a clear mutagenic mode of action.  But I will say, if you go back and look at IARC, basically, the evidence for genotoxicity is moderate.  If you go to ECHA, they think it's non-mutagenic.  If you go to NTP and the report on carcinogens, they think it is a reasonably anticipated carcinogen, and I think it's through a mutagenic mode of action.  So, obviously, informed scientists can disagree on this opinion and you may disagree with me, but that's sort of my assessment of it.  Any questions?  I'm open to --
                  DR. KENNETH PORTIER:  Let's see if Dr. Willett agrees or disagrees.
                  DR. CATHERINE WILLETT:  Well, I don't have much to add to all of that detailed analysis.  I was thinking more of whether EPA had substantiated their decision-making process, and I think they've clearly articulated why they went one way versus the other.  And I think in the interest in being protective that if there's significant doubt about the mode of action and it could possibly include a mutagenic element to it, that it's best to err on the side of including the mutagenic possibility.  So that was sort of where I came down on it.
                  But I agree there's a lot of uncertainty and a lot of conflicting data.  It doesn't bother me as much because there's a lot of conflicting data everywhere where you have to make really complicated choices.  So I think erring on the side of protectivity, that was a good choice.  But given the fact that that was this sort of weight of evidence decision, I do also agree with the comments from EDF and Earthjustice that maybe that indicates a need to consider the consequence of acute exposure in terms of carcinogenicity potential.
                  DR. KENNETH PORTIER:  Dr. Johnson.  Mark, did you want to add anything.
                  DR. MARK JOHNSON:  I have nothing to add.  Thanks.
                  DR. KENNETH PORTIER:  Mr. Kaufman.
                  MR. ALAN KAUFMAN:  Yeah, I similarly looked at the data and, when you look at the structure, you would sort of expect that you might see a mutagenic mode of action.  On the other hand, the data's sort of conflicting.  It doesn't point to one direction or another very strongly.  However, I think you probably made the best call that you could which is to err on the side of a mutagenic mode of action and just going in that direction, so I'm comfortable.  I think it would just -- you may want to beef up the section where you talk about some of the uncertainties.
                  DR. KENNETH PORTIER:  Dr. Pessah.
                  DR. ISAAC PESSAH:  One of the things that hasn't been said which -- and, again, I'm not a cancer biologist or toxicologist -- is that along with this sort of discussion about DNA adducts, nobody has really mentioned the data that seems to be consistent across studies about a change in redox balance in various tissues.  Both immune tissues, hemopoietic tissues, and in this most recent study that shows glutathione adducts, again, exposure is intraperitoneal, but the doses, I thought, were reasonable certainly in line with what's been done and considered by EPA.
                  So carcinogenesis isn't just one hit, one mechanism, and so why aren't we integrating it or why isn't EPA integrating these two what I -- are sort of consistent observations across studies which is that you're challenging the antioxidant and defense mechanisms.  You're reducing glutathione.  You're producing increased ROS.  And, in addition, there is some evidence that you're producing DNA adducts.  It may not be as strong to identify a mode of action, but it seems like you have to look at these things in an integrated way, but that's just something that came to mind as I was reading the literature.
                  DR. KENNETH PORTIER:  Thank you.  Dr. Vorhees.
                  DR. CHARLES VORHEES:  No, I have nothing to add.
                  DR. KENNETH PORTIER:  Does anyone else want to comment?
                  DR. CHARLES BARTON:  I do.
                  MS. TAMUE GIBSON:  It's Dr. Barton.
                  DR. KENNETH PORTIER:  Who is it?  Oh, Dr. Barton.
                  DR. CHARLES BARTON:  Thank you.  The cancer hazard assessment has not adequately described the weight of evidence regarding the mutagenic mechanism of action.  Also, not all available studies were viewed in the draft document.  There's been seven in vitro studies conducted to examine mutagenicity.  One Huang's assay was positive, and five Huang's assays were negative including two from the NIH.  An in vitro mouse lymphoma study was positive.
                  When in vitro data are equivocal, in vivo studies are usually relied upon.  Six in vivo studies have been conducted.  Three in vivo mouse micronuclei studies, including one from the NIH, were negative.  Two in vivo dominant lethal assays were also negative and one in vivo transgenic rodent somatic cell mutation assay, aka Big Blue, was negative.  Thus, two in vitro studies were positive, but five in vitro and six in vivo studies were negative.  All studies need to be discussed.  While some studies were not used for evaluation need to be discussed for transparency and avoid the perception of cherry-picking data.  The weight of evidence from mutagenicity appears to be negative.  As written, it appears the mutagenicity mechanism of action was concluded, and it could be interpreted that it was included and then studies picked to support that conclusion and that needs to be avoided.
                  For example, chromosomal aberrations in exposed Chinese workers were discussed to support a mutagenic mechanism of action while the study found the non-statistically significant correlation and exposure had a small number of subjects and lack of a control group, not just a nonsignificant trend from high exposures to medium exposures.
                  As previously mentioned, even secondary references to abstracts were used to support mutagenicity while well-conducted studies of high quality demonstrating that it was not mutagenic were ignored.  Several papers have concluded that 1-BP has a non-mutagenic mechanism of action for carcinogenicity such as Stelljes (2019) and Rossman and Duel (2002).  This would mean that there's a threshold for carcinogenicity.  The weight of evidence suggests that the mechanism of action for carcinogenicity is a nonlinear threshold model.  This should be thoroughly explored and discussed.
                  Furthermore, a linear no-threshold one molecule one-hit model of carcinogenicity would warrant a cancer risk assessment for acute exposures.  This would suggest that most fruits and vegetables, as well as grain products, cause unreasonable cancer risk since these contain known carcinogens.  These natural things we eat contain known carcinogens as explored by the carcinogenic potency database at UC Berkeley where 55 percent of the carcinogens are naturally occurring.  This includes constituent natural chemicals in coffee and pastry which many here today had for breakfast.  Thank you.
                  DR. KENNETH PORTIER:  I'm looking at Dr. Eastmond to see if he wanted to comment on this.
                  DR. DAVID EASTMOND:  The only real substantive comment -- there are actually two transgenic mutation studies, both negative.  So the in vivo studies are two negative in vivo studies.  Basically, it's a mixed pattern as I indicated.  The in vitro gives -- there's multiple positive in vitro studies, and there's negative in vitro studies, and they have their limitations.  The in vivo studies -- a number of them -- so that the dominant lethal studies usually aren't very sensitive for picking up mutational effects; point mutation is what we're talking about.  So there's something useful there.
                  The micronucleus studies for the most part, if you're looking at point mutations caused by AMES test, they may or may not be picked up in a micronucleus study, so you wouldn't expect it.  And that's why the transgenic mutation studies become important, but they're not perfect.  They said the in vivo stuff, if you look at it, you come across, it looks pretty negative.  But you do have all this other supportive evidence that makes it difficult to want to dismiss it totally, and that's why I kind of went with the unknown mode of action that still triggers your sort of linear approach.  But it's a little more conservative in how you interpret all these negatives because you do have multiple negative studies.
                  DR. KENNETH PORTIER:  Dr. Blystone.
                  DR. SHERI BLYSTONE:  As the non-toxicologist in the room, I like that approach.  Given everything that I've seen and heard from all of you guys that do know this stuff, to unequivocally say it's a mutagenic mode of action is not appropriate but being protective and using a linear model seems appropriate based on the equivalent, so I like Dr. Eastmond's approach.
                  DR. KENNETH PORTIER:  Dr. Johnson.
                  DR. MARK JOHNSON:  Yeah, I have a quick question for Dr. Eastmond.  Does not assays like AMES and mouse lymphoma have a relatively high false-positive rate?
                  DR. DAVID EASTMOND:  Actually, the reason AMES is so well liked is it has a very low false-positive rate.  So its sensitivity in your sort of classic is about 55 percent; its specificity is like 85 percent which means it has very few false negatives.  So that's one of the reasons, like, it doesn't flag too often for false positives.  So, when you have an AMES test that's positive, usually your -- it's more likely than not that this will be carcinogenic.
                  A lot of the other -- the AMES test is not as prone to the false positives which happen with a lot of the other in vitro assays.  So, like the comet assay, the chromosomal aberration assay, the micronucleus assay, they tend to have a higher false-positive rate, and that's heavily influenced by toxicity.  Because, as you go to high concentrations, DNA strand breakage is a consequence of cell death, and so that can be picked up in these assays.  And so you're always -- cytotoxicity causes DNA breaks but DNA breaks cause cytotoxicity, so in this circle, where are you at in the circle?  And so it's sort of judgment call.  The AMES test usually isn't affected by that.
                  The trick on it is, from my take, is the two tester strains which were positive -- and this is brought out by the NTP, and I think it was mentioned in the EPA document -- is that they have, I guess, they have endogenous glutathione transferase activity, so they think it may be this glutathione mechanism, which is involved, that may have contributed to the positives in those but who knows.
                  The other thing I was going to mention is in the scheme of things, this is mentioned in the document is that these alcoholates, I guess, are thought to be more of the sort of the soft electrophiles rather than hard electrophiles.  And so they tend to be more targeting the soft nucleophiles like the sulfhydryl groups, and that's why you get a whole lot of these reactions and the adducts and the biomarkers.
                  As evidenced in this most recent paper -- and it really ought to be evaluated for quality control because it's one of these adduct papers I don't like because they don't do their adducts in the controls -- they mention the controls are negative, and they show an example.  But they do have adducts in their low dose and their high dose, and their high dose is so much higher than their low dose that you can say, even if the low dose is controlled, you still have an increase.  But the EPA will need to look through that for quality assurance.  But that's in evidence of formation of DNA adducts in vivo which is an important piece of evidence at least.
                  DR. KENNETH PORTIER:  Dr. Blando.
                  DR. JAMES BLANDO:  This is Jim Blando.  I just wanted to support what Dr. Blystone said.  It sounds like, to me, that there's a fair bit of uncertainty about some of this, and I think in light of that, it makes sense to use a linear extrapolation.
                  DR. KENNETH PORTIER:  Dr. Barton.
                  DR. CHARLES BARTON:  Yes, using a linear no-threshold model, just because it is more conservative instead of relying upon the best available science is not appropriate for EPA in my opinion.  Thank you.
                  DR. KENNETH PORTIER:  Ms. Rudel.
                  MS. RUTHANN RUDEL:  This is Ruthann Rudel.  I'm just curious, Dr. Eastmond, what you think about the Toraason paper so the comet assay damage in leucocytes in exposed workers, and how does that sort of relate?
                  DR. DAVID EASTMOND:  Actually, it was pretty negative.  The difference was pre-exposure/ post-exposure in the low dose, and nothing seen in the high dose of the workers.  The Toraason has the in vitro comet assay data and that looks to be real.  That was the DNA strand breakage.  But my take is the Toraason one has, at most, sort of equivocal suggested but this was a pre and post and the high dose -- I think the high dose, the post-exposure was lower than the pre-exposure, so it's certainly wasn't consistent with the clastogenic effect as I thought about that study.  Somebody's who more familiar with it can weight in but that was -- there's some suggestive stuff but we have effects at the low dose and the comet assay and not at the high dose and it's pre and post.  The comet assay's fairly prone to artifacts that you have to be cautious in interpretation of comet assay data.
                  DR. KENNETH PORTIER:  I see a number of flags up.  I just wanted to make sure they're still up for questions.  Dr. Blystone.
                  DR. SHERI BLYSTONE:  Did you want to go first?
                  DR. JAMES BLANDO:  Sure, I was just going to say that Dr. Barton mentioned the best available science, and it sounds like, to me, the best available science produced uncertainty.  So, from a public health perspective since our role is to be concerned about public health is the best available science has produced uncertainty and, therefore, we should be conservative linear in that threshold.
                  DR. SHERI BLYSTONE:  And I was echoing that same thing, best available science.  There's good quality studies that have conflicting data, so you can't say one is better than the other.
                  DR. CHARLES BARTON:  Are we mandated?  I have a question.  Are we being requested to determine what's best for public health?  Or are we being requested on, is there a mutagenic mechanism of action?  I don't think we're being asked.
                  DR. KENNETH PORTIER:  I think the question is on the mutagenic mechanism of action.
                  DR. CHARLES BARTON:  Right and not policy on what is best on public health.
                  DR. KENNETH PORTIER:  You're right.
                  DR. CHARLES BARTON:  Okay.  Thank you.
                  DR. KENNETH PORTIER:  The question of threshold model versus linear model is one that panels -- I've lost count of how many panels we've had that discussion on and some of it becomes an EPA policy.  What's the default when you say unknown mechanism of action?  And Charles, you're aware of this as well as the rest of you are.  Sheri, did you want to say something else?
                  DR. SHERI BLYSTONE:  Just a fair point, Dr. Barton, but I think again, from everything that I'm hearing, it's not really appropriate to conclude a mutagenic mode of action based on the best available science.
                  DR. KENNETH PORTIER:  Dr. Davies.
                  DR. HOLLY DAVIES:  Since EPA's current practice is to default to the linear when it's unclear, I was -- it's a question for EPA -- about the update on what they're doing for that because I thought they were updating their guidance on cancer and how they're dealing with that.  And I was wondering if those updates were coming any time soon if there's going to be a change to that?
                  DR. KENNETH PORTIER:  I know that the Science Advisory Board recently provided a whole bunch of comments on the cancer guidance, and I, myself, put in some comments on mode of action and then modeling.  Dr. Barone.
                  DR. STAN BARONE, JR.:  There's no answer yet.  That particular issue, the guidance, there are discussions about the guidance.  That's a process and, again, we'll take public comment, and there will be peer review by the SAB.  So we're operating under the assumptions of the current 2005 guidance for cancer evaluation including the mode of action analysis.
                  So, while I've got the mic open, I do want to -- and this is sort of a clarification -- to the degree possible that the committee can provide additional data or evidence or emphasis to the interpretation for the mode of action analysis, we would find that very valuable for a revision or our mode of action analysis.
                  In our mode of action analysis, we did, as Dr. Eastmond also pointed out, followed the mode of action framework.  We did consider the evidence for urinary metabolites actual reactive species and epoxide in mouse and in rodent urine as another point of evidence for our mode of action analysis for a mutagenic mode of action.  So, again, by inference and read-across, that was a significant part of our determination.  But, for alternative modes of action, again, we are trying to describe alternative modes of action to the degree possible that we can.  If there's any additional evidence that you've found in your reading and in your review that we should incorporate, please let us know.
                  DR. KENNETH PORTIER:  I'm just letting it sink in here and see if something floats to the top.  I'm watching Dr. Eastmond.  I can see the neurons flying, but I'm not sure anything's going to come out.
                  DR. DAVID EASTMOND:  That's okay.  I was just curious.  The challenge for me, if I recall, and I'm not so familiar with glycidol, but the propylene oxide, generally, I put that in my brain as being a pretty high dose sort of carcinogens site of exposure.  So you go through the metabolic pathways, propylene oxide's got to be a pretty minor metabolite within 1-bromopropane.  So that's why I thought I can't see how this would be -- I mean, I haven't compared the potency, and that's the critical thing.  And maybe you've done that, but for me, I thought, well, this is relevant that there are mutagenic metabolites formed.  It seems to me that they aren't formed at such a level that we would expect to see much of an effect there, but that's just the kind of a seat of the pants guess.
                  DR. STAN BARONE, JR.:  So, in our metabolism section, we did look at that.  It's in the appendix page 338.  We did not include any kind of potency evaluation, and, if you think that might be helpful, we can -- if that's a recommendation, we can, again, look at that.  We didn't do that because we don't have a PBPK model, and that's, again, one of the drawbacks in the tools that we had for this evaluation.
                  DR. DAVID EASTMOND:  I mean, for me, I don't think it's critical as you clearly have tumors, and even if you can work it out, you've got multiple metabolites.  You don't know which one's going to be contributing specifically, so I wouldn't spend a lot of time on it.  That was just sort of my impression.
                  DR. KENNETH PORTIER:  Dr. Pessah, you wanted to comment?
                  DR. ISAAC PESSAH:  Well, again, I just want to ask whether if the data that shows the lowering of glutathione due to formation of glutathione adducts and changes in some of the antioxidant defense enzymes is at all considered as part of an indirect sort of susceptibility or factor in a cancer modeling?  Again, I'm not an expert in this, but it seems like no one's really talked about that.
                  DR. KENNETH PORTIER:  Dr. Barone.
                  DR. STAN BARONE, JR.:  We can add additional text, but the glutathione depletion is a mechanism mode of action that is talked about for both the cancer and the non-cancer.  And that may be more prominent for the peripheral neuropathies and the non-cancer effects for the neurological deficits, and we speak to that in the assessment.  So we can definitely bolster that hypothesis, and there is evidence to support that hypothesis as a mode.  Whether it's definitive for the cancers, we are very clear that it's not definitive for the cancer.
                  DR. KENNETH PORTIER:  Dr. Pessah, was that an adequate -- do you want to follow up?
                  DR. ISAAC PESSAH:  Yes, just that I'm not sure how you would determine that it's not an important factor in the cancer risk evaluation in the sense that there's quite a bit of literature now, not on 1-BP, but in several other areas of toxicology as well as just cancer biology that the depletion of antioxidant defenses is really a factor.  It's been considered a peripheral factor but, nevertheless, as someone mentioned, quite a number of fruits and vegetables we eat are, in fact, contributing to the depletion of antioxidant defenses.  And here's now a solvent as antibiotic which is contributing to that, and I don't see that, again, from a lay perspective being incorporated into an overall risk model or integrated into another risk model.  The answer that Dr. Barone said satisfies me for now.
                  DR. KENNETH PORTIER:  Dr. Johnson.
                  DR. MARK JOHNSON:  Yeah, I have a question for my colleagues too, and maybe Dr. Barone as well.  What kind of bothers me about some of the in vitro mutagenic assays is they didn't really consider, I guess, the spatial differences within the liver.  And, I guess, it's my understanding that the glutathione processes occur first.  Then, they're depleted then you move onto the CYP2E processes where you get the oxidative metabolites where you produced more CO2.  And, I guess, then you have liberation of bromine through the inhalation pathway.  But the Geiger et al. study suggests just the opposite, doesn't it?  It suggests that you get the oxidative metabolites first and then you get the glutathiones.  So it contradicts it in my mind and maybe I just don't know enough about it.  Maybe Dr. Pessah could add a little bit more to that.  So I'm curious in why, I guess, glutathione depletion isn't a more important thing or at least the mid-primary metabolite for low exposures.
                  DR. KENNETH PORTIER:  Dr. Pessah.
                  DR. ISAAC PESSAH:  Well, that's a question that came to my mind.  That it seems that, at lower doses, glutathione is impacted, and I can't tell you why that would be.  But it just seems like a pattern that I picked up from reading.  And I didn't get a real sense that that was a major input into the modeling that they were kind of done separately.  Well, you had the classic mutagenesis assays in the model, but the glutathione and, in general, the antioxidant defense wasn't really -- was that an input into the modeling?  Or was it just considered and then put aside and not a factor?
                  DR. KENNETH PORTIER:  Dr. Eastmond.
                  DR. DAVID EASTMOND:  Let me try to address a couple of things.  1-Bromopropane will react directly with glutathione nonenzymatically, so you're going to see a reduction in glutathione levels, so that would support an oxidative stress mechanism.  As far as zonation in the liver, that is generally the case for things via oral route of exposure where you're going through the hepatic portal vein and then you go in.  But, in this case, we're looking at inhalation or effects at site of exposure.
                  Because of the direct reaction with the compound with glutathione to form a conjugate, it doesn't surprise me at all you'd see glutathione levels drop, and it's very likely that oxidative stress or additional sorts of things because this taxes the pentose phosphate shunt and other things.  There's going to be other physiological changes that will take place, and I would agree it very likely could be involved in the neurotoxicity that Dr. Barone mentioned.
                  I mean, I think it is happening, but there are a lot of chemicals.  In fact, the very reason we have glutathione is to protect us against many, many different types of chemicals: Some are carcinogenic.  Some are noncarcinogenic.  So Tylenol, acetaminophen is sort of classic examples.  When you get to higher doses, it starts conjugating with glutathione.  That doesn't necessarily mean that that compound is carcinogenic.  It's activated as something that reacts with glutathione.
                  DR. KENNETH PORTIER:  Dr. Barone.
                  DR. STAN BARONE, JR.:  Just one clarification for the committee, just to make this hopefully clearer, we're doing our best to qualitatively describe the mode of action and the evidence for a mode of action.  The evidence for mode of action, or lack thereof, informs our choice of dose-response models.  We are not doing dose response on glutathione conjugation.  We're doing dose response on the tumor incidence data.  So there's a distinction there.  Until we have a full quantitative AOP, it's very difficult for us and, even as much as we know about cancer biology, we are not to a point where we have a dose-response model or a quantitative AOP that incorporates multiple mechanisms of action which many of these chemicals have into a dose-response tumor model.
                  That's where we are so I just want to be clear what we have and what we don't have, and the more evidence or more that you can provide critical input to the mode of action qualitative analysis, the better our assessment will be at informing the uncertainty for our cancer evaluation.
                  DR. KENNETH PORTIER:  Dr. Schlenk.
                  DR. DANIEL SCHLENK:  This is kind of just to throw out.  Glutathiones in really, really high concentrations in most tissues, particularly the liver, maybe in some of the other tissues, it's not in such high concentrations like the central nervous system which is probably qualitatively why you actually see those effects.  But, from a carcinogenicity perspective, to get to oxidative stress, the depletion that you need for glutathione's got to be fairly extreme because you also have other oxidative stress mechanisms that protect.  That glutathione tends to be the primary one, but there are other mechanisms that protect.  So the dose has to be extremely high, I think, to get to an oxidative stress capacity to where that makes a difference at least in the liver anyway.  But maybe some of the other tissues, it's a little -- it's possible, but I don't see it as being a primary mode of action at least for the carcinogenicity.
                  DR. KENNETH PORTIER:  So Dr. Eastmond, as we write this up -- I mean, I think this has been an excellent discussion of weight of evidence and how you're kind of weighing all these things, and Dr. Barton's thrown in a little cite issue that we probably should acknowledge as well.  But you think you've got enough to -- once you Dr. Barton's notes and maybe Dr. Johnson's comment.
                  DR. DAVID EASTMOND:  Certainly, I mean, I've written a bunch of stuff, and I can add to it and try to reflect sort of the discussion and the considerations and certainly put Martin's comments as well there.  Certainly, we would reflect the valid point of view.
                  One of the things is the challenge, as you know, is that scientists can differ on the interpretation of some of these things.  This is one of these areas where there's mixed data, and it's reasonable to interpret it differently in how you do it, and decisions you make in the face of uncertainty, that's usually not a scientific thing.  It's sort of comes back to sort of core values.  Anyway, we'll see what we can do on that.
                  DR. KENNETH PORTIER:   So I like the way you kind of laid out this signal for a mutagenic mode of action in your discussion, and, as I was listening to Dr. Barton, I was thinking, what's the signal for a threshold kind of model, and I guess I don't know that one as well.
                  DR. DAVID EASTMOND:  I mean, certainly, you can lay out the signal.  There's evidence pro and con, and my sort of bottom line was evidence in favor tends to be all in vitro, and the evidence opposed is in vivo and that usually trumps the in vitro.  One's a screening and one's the sort of definitive test.  But given there's all this peripheral evidence around that makes you want to be cautious because structural analogs cause cancer.  You've got no reactivity of the chemical.  Now we know it causes adducts in vivo.  So it's a mixed bag.
                  So, for me, I go back to saying, if I'm going to do this in a systematic sort of approach, I might end up with saying, we just don't know the mode of action which then would trigger the same sort of outcome of linear dose response, so they don't have to change everything basically.  But, for me, it's sort of a fair thing.  You can go either way.  There's arguments pro and con on it.  And I'm sure they'll have additional discussions on this as well at least with some of the new information.  But we'll give them our point of view.
                  DR. KENNETH PORTIER:  EPA, does that -- any follow-up?
                  DR. STAN BARONE, JR.:  We appreciate this robust discussion and the divergence of views.  Hopefully, that will be captured and the evidence to support the divergence of views on this particular topic.  Again, as Dr. Eastmond's pointed out, and we did too, there are similar views to our assessment by other assessment bodies and there are differences.
                  DR. KENNETH PORTIER:  Okay.  On my agenda, I had that we were going to break for lunch around 11:45.  I have 11:40.  We're way ahead of our agenda, so I'm suggesting that we meet back from lunch at 1:00.  It gives you an hour and twenty minutes for lunch, a little bit more relaxed lunch than we normally have.  I'm informed by members of the panel that we're not so unprepared, but we'd like the time this evening to fully prepare for Question 7.  So we're going to complete Question 5 and Question 6 this afternoon, and then, when we're done, we're done for the day.  And tomorrow we'll take Question 7 and 8.  So that's kind of thinking about you prepare your time and effort.  I'll see you guys at 1:00.  Thank you.

                                    (BREAK)

                  DR. TODD PETERSON:  Okay.  The public is showing up, so that's good.  Dr. Gilbert has asked that 5.6 and 5.7 be read in, and they're going to address it as a combined question.  We'll go ahead and read both of those.
                  DR. KATHERINE ANITOLE:  Question 5.6; typically, EPA uses the benchmark dose modeling software, BMDS, with a BMR of 10 percent and the models are restricted to multistage models or the broader suite of dichotomous models in BMDS and a single best model is chosen for the POD.  EPA used an alternative approach to calculate the cancer POD versus the standard approach of choosing the best fit model and to assess the impact of model uncertainty.
                  Briefly, EPA used two model averaging approaches -- frequentist and Bayesian -- considering multiple benchmark dose models to calculate the POD at benchmark response levels of 0.1 percent and 10 percent for added and extra risk.  Please comment on the assumptions, strengths, and weaknesses of the model averaging approach for determining the POD in the cancer assessment.
                  DR. KENNETH PORTIER:  Dr. Gilbert.
                  DR. KATHERINE ANITOLE:  Oh, I'm sorry.  Did you want me to read 5.7 as well?
                  DR. KENNETH PORTIER:  Yes, please.  Read 5.7 in as well.
                  DR. KATHERINE ANITOLE:  Question 5.7; in agreement with EPA's long-standing approach, all three tumor types from the NTP study -- NTP, 2011 -- were dose-response modeled with multistage models using the typical constrained model coefficients greater than or equal to zero from U.S. EPA, 2012.  Under the U.S. EPA's 2005 cancer guidelines, quantitative risk assessments from cancer bioassay data were calculated by modeling the data in the observed range to estimate a BMCL for a BMR of 10 percent extra risk, which is generally near the low end of the observable range for standard cancer bioassay data.
                  The BMCs and BMCLs are shown for each of the three cancer datasets.  The results for a BMR of 0.1 percent added risk are presented for comparison.  Please comment on the assumptions, strengths, and weaknesses of the multistage modeling approach for determining the POD in the cancer assessment.
                  DR. KATHLEEN GILBERT:  Okay.  Cancer modeling is not my forte, so I'm really hoping I can get some help from other folks here.  EPA did benchmark dose response modeling of the NTP's 2011 study for all three significantly increased tumor types -- skin tumor in male rats, intestinal tumors in female rates, and lung tumors in female rats.
                  The dose response modeling section on page 175 of the draft risk assessment describes the rationale for the cancer modeling, the details of which were available in the supplemental file entitled "Information on Human Health Benchmark Dose Modeling," which I could not access in HERO.  But I'm not sure I would have the expertise to evaluate it anyway.
                  The usual multistage model was used with both a 0.1 percent added risk and a 10 percent extra risk to calculate the BMC and the 95 percent lower confidence limits of the MCL ppm.  In addition, to assess the impact of model uncertainty, BMCs and BMCLs were also calculated using two model averaging models, namely the frequentist and the Bayesian.  The results calculated by the three models were similar; less than one log difference.  For example, BMCs with a BMR 0.1 percent AR for male rats; squamous cell carcinoma with 2.96, 3.73, and 9.81, using those three different methods.  And the BMCL was even closer; 1.78, 2.25, and 1.47.
                  This kind of consistency using the three models, lent support to the accuracy of the BMC calculated for the cancer risk.  Consistent with the case law and 2017 NIOSH Guidance, the EPA uses one times ten the mice as a benchmark for the purposes of this risk determination for individuals, and industrial and commercial work environment.  I will have to defer to the other discussants whether they think this benchmark is stringent enough.
                  They also calculated the inhalation unit risk for humans using the three different methods based on respiratory carcinomas in mice.  The IUR determined by the multistage modeling, 8 times 10 to the minus 7th, was pretty similar to that determined by the Bayesian model, which is 1 times 10 to the minus 6th.  Once again, this provides support for the multistage modeling approach.  However, it didn't seem to me that the details assessing the rationale for the multistage approach were sufficient.
                  Limitations include, as we've heard before, the lack of an estimate of cancer risk for short term 1-BP exposure.  However, as EPA mentions, the uncertainties involved in extrapolating from continuous studies in animals to a case of a once in a lifetime human exposure with their potentially divergent biological mechanisms make such an assessment problematic.
                  As a result, there are no U.S. federal agency regulatory standards applicable to less than a lifetime exposure to carcinogens.  So, I would just ask some of the other discussants how they felt about that rationale too.  That's all I have.
                  DR. KENNETH PORTIER:  Dr. Johnson.
                  DR. MARK JOHNSON:  I personally prefer the use of Bayesian methods because it implies, as I understand it, the use of prior information distributions for developing your BMR.  So, I applaud the EPA for using that.  I would go further and suggest that maybe you should think about looking at the Bayesian BMR approaches for the non-cancer data and to think about using Bayesian methods for extrapolation development of uncertainty factors.  And I provide a reference, Simon et al. (phonetic), if you care to follow that.  That's all I have.
                  DR. KENNETH PORTIER:  Mr. Kaufman?
                  MR. ALAN KAUFMAN:  Yeah, this is outside my area of expertise.  I'm going to pass.  Thank you.
                  DR. KENNETH PORTIER:  Dr. Pessah?
                  DR. ISAAC PESSAH:  No comment.
                  DR. KENNETH PORTIER:  Dr. Vorhees.
                  DR. CHARLES VORHEES:  I have nothing to add.
                  DR. KENNETH PORTIER:  I am going to help Dr. Gilbert out at this point.  I did look through the section and I looked through the supplement.  I scanned through all of it.  The only thing -- and it looks pretty standard.  It's kind of what was recommended in 2016 that EPA do with these data because, at that time, model averaging was kind of an emerging technology that a lot of people were using.  And I think the panel, at that point, wanted to see that become a bigger part of the risk assessment protocol.
                  What surprised me is you used it only on the cancer, not with the non-cancer ones.  With the non-cancer ones, you fit the models.  Part of that, I can understand, is because you used the multi -- what is it called again?  The model that was used for the non-cancer effects, the NCTR, nested dichotomous model, doesn't really lend itself to the model averaging approach.  I don't think that the science is there yet for handling multistage models and a weighted averaging approach.
                  On the cancer point though, I think, if I read correctly, the document recommends the point of departure from the best-fitting model even after you fit the frequentist and the Bayesian.  And I guess my choice would have been, kind of like Dr. Johnson, to use the Bayesian weighted averaging value.  Now, that said, in almost every case, it doesn't change the point of departure but by maybe a point one way or the other.  So, it's probably not enough to argue from my point of view.
                  The models fit in the weighted averaging are very close to each other surprisingly, until you realize, as Dr. Johnson pointed out to me right before lunch, that in most cases, you're only dealing with three -- at most, four -- dose levels.  So, these models are pretty much fitting a very linear line through.
                  And they're all fitting the best linear line that they can, which means that the BMD and the BMDL estimates are going to be very close to each other as well.  So, while it was a nice exercise, it probably doesn't produce a point of departure that would be that different than fitting the best-fitting model.  Good exercise, nice write-up; I enjoyed it.  But I didn't see anything that I felt needed to be changed.
                  One of the other things I looked through is I like to see BMDs and BMDLs that are close to the dose.  Right?  The minute they start extrapolating way below the lowest dose level, you start to get nervous.  One of the things that happened is the uncertainty around the BMD gets big, which means the BMDL starts going towards zero.  And I worry that there's an extrapolation effect going on.
                  In this case, most of the BMDLs, the BMDs are close to the lowest dose.  So, even if they threw all this out the window and used the NOAEL or the LOAEL, they'd get almost the same result.  So, in this case, I think this is the best that they could do.  I didn't see anything that I needed to see changed here.
                  Anybody else want to join in on that?  Weighted through that supplement?  No?  We all have our preferred supplements.  EPA has provided enough supplemental files for each of us to have our own, right?  That took care of 5.6.  5.7, did you have some additional comments on the tumor types from the NTP study?
                  DR. KATHLEEN GILBERT:  Not really.
                  DR. KENNETH PORTIER:  Does anybody else want to comment on that?  All right.  I felt that EPA did a pretty good justification of why they chose a BMR at 10 percent, why they threw in the 0.1 percent for comparison purposes.  All of that was pretty well explained.
                  MS. RUTHANN RUDEL:  I have one clarifying question.
                  DR. KENNETH PORTIER:  What was that, Ms. Rudel?
                  MS. RUTHANN RUDEL:  Oh, it's Ruthann Rudel.  I have a clarifying question.  If a question's about the age-dependent adjustment factors decision, is that part of this question or a different question?
                  DR. KENNETH PORTIER:  That's a good question.  Maybe I'll look to EPA and say, is this where you want to see us discuss that?
                  MS. RUTHANN RUDEL:  Page 178.
                  DR. KENNETH PORTIER:  I don't see another place where that would come up, unfortunately, unless you wait until Question 8 then bring it in and say, I think you should have asked us the question.  You might wait for that one on Question 6.1, although the 6.1 is MOE.
                  Let's go ahead and take that question.  Maybe that's a good question.  Because it does relate to the calculation of the point of departure, and I think this is the one question where we're talking about rats.  So, what was the comment, Ms. Rudel?
                  MS. RUTHANN RUDEL:  My comment is just that an age-dependent adjustment factor is included in the cancer risk assessment if children under the age of 15 are going to be exposed.  And I thought that's not that realistic to think that there aren't going to be children under the age of 15 exposed to this compound either through consumer uses or through indoor air.  Because it's daycare or a home that's sharing a building with a dry cleaner, or some other user of this chemical which is used a lot.
                  I know that there's one scenario that has children in a dry cleaner.  But here it says ADAFs will not be applied for younger-aged children spending time in the workplace, like a family-owned business, because it's unlikely their exposures are chronic in nature.  I didn't find that persuasive.
                  DR. KENNETH PORTIER:  Does anyone else want to comment on that, on the adjustment factors?  The risk assessors?  I'm looking at Dr. Blystone.  Did you guys feel that what EPA did was -- I don't know.  When I read it, I felt this was kind of the standard thing they would do.
                  But the question about the younger than 15-year-old children in dry cleaners did come up in the public comment, and that's what you're reacting to.  So, I guess my question, looking at the panel, does EPA need to go back and address that better?  Dr. Gilbert?
                  DR. KATHLEEN GILBERT:  Well, it sort of comes back to the question we were talking about before in terms of internal exposure levels.  We don't seem to really have a handle on that, so it's hard to know how relevant that age adjustment is.
                  DR. KENNETH PORTIER:  Dr. Cobb.
                  DR. GEORGE COBB:  Just to layer on top of that comment I made briefly yesterday, I didn't see anywhere any indoor air considerations in schools that weren't related to direct use in machine shops and those kinds of things, and any off-gassing that you might be experiencing from the insulation materials or computer cleaning could very easily increase these exposures to people of this age class.
                  DR. KENNETH PORTIER:  Dr. Sheela.
                  DR. SHEELA SATHYANARAYANA:  Well, in general, I would agree with Ruthann.  If there's no exposure data, that doesn't negate the fact that there could still be exposures.  There needs to be exposure data that's confirmatory that children are not exposed.
                  I think that, over the course of the past couple of days, several people have brought up scenarios and we also heard it from public comments.  So, I think you need to be really transparent that you are not accounting for that population in these calculations.
                  DR. KENNETH PORTIER:  I was trying to think whether this was discussed in the uncertainties.  Was this discussed in the uncertainties around the point of departure?  I can look to Dr. Barone.  He might be able to answer it quicker than whether I can find it in the document.
                  DR. STAN BARONE, JR.:  So this does get back to a critical conversation we were having before lunch.  Just to remind folks, the 2005 Cancer Guidelines and the Supplemental Guidance specifically call out application of age-dependent adjustment factors for children, again, 0 to 16, for a mutagenic mode of action.  It is not called out in a default in your extrapolation to do age-dependent adjustment factors.  It's only called out in the cases where we observe and declare that a mutagenic mode of action is partially or entirely part of the mode of action for that chemical carcinogenesis.
                  So I'd have to put that in context with our earlier discussion.  We'd also discussed earlier the conditions of use and the scope of the assessment.  The question is -- and the committee can comment on -- whether children in dry cleaners -- after-school care, during the workday -- that would be in the back of the shop or in the shop, whether those would be a vulnerable population.  We, again, because of the chronicity of the exposure, didn't call those out.
                  So, if you think we should do something more about that or supply additional information or analysis, that is where the children and the exposure come together.  Because there are exposures and we've outlined what those exposures are for near-field and far-field.  Again, occupational non-users would be included in that occupational non-user group.  That's the only population where children really exist where there's some degree of repeated exposures.
                  In the consumer products arena, we are looking at the consumer products and the consumer product uses as acute exposures only.  In our Cancer Guidelines, in general, seven years, 10 percent of the lifetime or greater, is what we apply our cancer risks to.  Okay?  Seven years, one-tenth of the lifespan is what generally is recognized as being what we apply the cancer risk models to.  Not one day, not one hit, not one exposure, but repeated exposures in some form or fashion for one-tenth of the lifespan.
                  DR. KENNETH PORTIER:  Dr. Blando?
                  DR. JAMES BLANDO:  As I'm processing, I think you just answered my comment.  But I'm still processing, so I'm not sure.  But I would just confirm that, in fact, when we did our studies in dry cleaners, we did have dry cleaners that had their children doing their homework at the shop with mom and dad.  And in fact, we had the children who, when mom and dad needed an extra hand, would say, hey, come over here and give me a hand with whatever.
                  Not to add a funny anecdote; we even had one dry cleaner ask us if we could do our sampling on their dog because they brought their dog to the shop.  And we were going to try and do it but, of course, we didn't.  But I would just confirm that, in fact, we did observe on our one little study that children would be present.  Obviously, those children are not there for seven years.
                  DR. STAN BARONE, JR.:  But there are children --
                  DR. JAMES BLANDO:  Well, we didn't ask.  I mean, the children we observed were young, elementary school-aged children all the way up to kids that looked like they were freshmen in high school.  So, I think that's reasonable.
                  The other thing to note is -- and I wasn't sure if we were going to discuss this somewhere else -- most of the dry-cleaning shops that we would go to were at all co-located buildings.  For example, we had one dry cleaner who their giant axial exhaust fan in their ceiling above their dry-cleaning machine went out their one-story roof, but it was connected to a building that had an apartment with a window.  And I remember commenting, thank God it's cold today, because the window's closed for the apartment complex.
                  So, I guess there are a numerable number of configurations that you could bring up, but I would just say that I think it doesn't seem uncommon to me based on our anecdotal field experience that these are going to be in co-located buildings, potentially having apartments on the second floor or having kids help mom and dad out in the shop after they get done with school.  Because mom and dad are working 12-hour shifts, so what are they going to do with their kids when they get out of school?  They're going to come to shop and do their homework and everything else.  That was our experience.
                  DR. KENNETH PORTIER:  I'm sitting here having déjà vu, because I heard this conversation in 2016.  And I think, if you read the minutes, you'd hear the same kind of discussion.  Maybe my question to EPA is, in the scoping document, was this discussed?  And the decision made not to include it in scope.  Or was it just not discussed?  That's a good point.  Because I know it was discussed in 2016.  Stan?
                  DR. STAN BARONE, JR.:  Déjà vu.  Yes, it was discussed in 2016.  Yes, it was in scope.  The issue of dry cleaners or the dry-cleaning use was brought in post the 2016 assessment.  That was part of the scope.  The issue of co-located facilities and adjacent facilities and daycares and so on were part of the consideration if we were doing general population exposures.  It was part of the scope that we put out in the previous scoping problem formulation document.
                  Since the declaration that the agency is moving forward with the listing of 1-Bromopropane as a hazardous air pollutant, those will come under the regulatory authority of the air program.  And further work and analysis and restrictions would come from that effort, not from this effort.  So, we're not looking at risk estimation for co-located facilities and the adjacent buildings.
                  DR. BILL DOUCETTE:  Just a quick follow-up -- Bill Doucette -- this is indoor air we're talking about.  Doesn't that regulation deal only with outdoor air?
                  DR. STAN BARONE, JR.:  We'll be looking at the risks in the indoor environment in the workplace.  That's our job.  Not for the adjacent or co-located facilities.  That's under the Office of Airs --
                   DR. BILL DOUCETTE:  Okay.  And a follow-up to that, if I may, other consumer products other than dry cleaning we mentioned that could potentially be a source of indoor air, would that be under your purview?  It doesn't seem like it should fall under the outdoor air.
                  DR. STAN BARONE, JR.:  Again, for the consumer products that are generating or using 1-BP, that comes under our scope.  And that is part of our scope, so that's the reason why we did the market analysis we did.  We've googled and we've searched our own proprietary databases and we've contacted the industry associations to a pretty extensive degree.
                  It doesn't mean we wouldn't appreciate any new information.  But on consumer products, we are looking at that.  There are consumer products included in this assessment, and that is indoor air.  And that's why we're modeling the insulation board as well as the other uses of consumer products that we think are significant sources of 1-BP exposure.
                  DR. HOLLY DAVIES:  Could I just follow up quickly?  Just because, when I think of HAPs, I think of big facilities.  I know you're not the air program -- and this is Holly Davies -- but if you could just give a little information on how the Clean Air Act would regulate the dry cleaners, I think that would just help alleviate some of our concern.
                  DR. STAN BARONE, JR.:  I'm not in a position to give the detailed background on the HAP analysis.  But it is an extensive program.  I think there were comments the other day that the agency is still in the process of deciding about accepting the petition.  That's not true.  The agency has accepted the petition to list 1-BP as a HAP.  Listing 1-BP is where we are now, the actual listing.  And that is an administrator's activity.  The administrator actually has to sign off on the listening.
                  As was mentioned, frankly, the agency hasn't listed a new chemical on the HAP list.  This is the first, so this is a big deal.  It's eminent, we have been told.  But that's a process.  So, when that will happen, I can't say.
                  DR. HOLLY DAVIES:  But would dry cleaners have to have permits?  Like I said, I just think of big facilities, not little facilities.  I guess Sheri knows.  Maybe I'll just ask Sheri later.
                  DR. SHERI BLYSTONE:  Well, just a couple of comments.  I'm not a Clean Air Act person either, but it's all about the sources, right?  So, there's stationary sources, mobile sources, indoor sources; I'm just looking at the EPA's website right now.  They work on all of those and decide, based on the reporting and everything, what needs to be controlled.  So, it would include indoor air as well.  If dry cleaners are a source, then they would be covered under the program, right?
                  DR. HOLLY DAVIES:  And they're not too small a source.  Keeping in mind the decisions have been made, I get that.
                  DR. STAN BARONE, JR.:  Dr. Blystone's correct.  The Office of Air will be taking information that we've gathered and using that in their source characterization.  There's a rulemaking process.  The rulemaking process, the max standard develops a rule and a standard for testing and monitoring for those different source categories.  There's monitoring that follows that rulemaking, that data collection and the actual measurements -- real measurements, not modeling -- and modeling.  But there's actual monitoring measurements that are part of a process.  That's a multi-year effort.
                  Then, following the monitoring, there's an assessment and then there's a residual risk assessment for the different source categories.  So, again, risk mitigation follows that.  Previous efforts go back in time.  You can look at the perc rule and the max standard for perchloroethylene in dry cleaners.  Dry cleaners were assessed for perchloroethylene.  There is a phase out.  There are efforts underway to get perc out of dry cleaners.
                  Again, those kinds of multi-year efforts were significant for the perchloroethylene effort.  Whether that would be applied for 1-BP is somewhat debatable.  The facts on the ground are we're talking about six or seven dry cleaners in the whole country using 1-BP.  Facts on the ground.  This is not 20 thousand dry cleaners.  This is not a broad-spectrum exposure source category today.  So, again, let's put our focus on risks where the risks occur.  Just wanted to make that clear.
                  DR. KENNETH PORTIER:  Mr. Kaufman?
                  MR. ALAN KAUFMAN:  Yeah, hi.  Al Kaufman.  I think you may have just answered my question when you reminded me that there are only 20 dry cleaners using the 1-BP.  But I wanted to go back for a second to children's exposure.
                  Considering that dry cleaning is very often an entry occupation for a lot of immigrant populations where everybody in the family kind of pitches in and works after school, I suspect that for those situations where kids are present, they might not be just in the back doing their homework.  They might actually be working.  And they might have a chronic exposure.  But if we're only talking about 20, we're not talking about a huge risk.
                  DR. KENNETH PORTIER:  Ms. Rudel?
                  MS. RUTHANN RUDEL:  I agree with your point about focusing on risks where risks occur.  I think I commented earlier that it's hard to feel a lot of confidence in knowing how and where the chemical is used.  So, we don't have a lot of great information about that.  I'm concerned about overlooking some exposure pathways and scenarios that could be important.
                  One of them is this family business situation.  And another one I'm interested in for any kind of product that's a consumer use product, if you're a child in a household and there's a hobby room or somebody collects coins or they're doing some arts and crafts and they have these materials in their home, then that seems like a chronic indoor air exposure from consumer product uses.
                  We could consider including that as a susceptible population or something like that.  I'm not exactly sure why it would be not considered chronic if you have a consumer product, because people have them sitting in their houses and might use them regularly and have them in their indoor air as a result.
                  DR. STAN BARONE, JR.:  So, if the panel has information about the periodicity of any of these consumer uses, again, that would apply to a chronic exposure, information we have, at least from consumer products or obvious kinds of uses of these products, they are not used every day.  They're not used repeatedly every day.  So, that's very different than a chronic exposure.
                  Some of the information that was brought forward about the off-gassing could inform some of our approaches and our modeling, but that isn't necessarily a chronic exposure.  That could be a subchronic exposure.  We'll have to look at that.  But again, if you have additional information that would help inform those activities or patterns, that would be really helpful to us.
                  Something that we struggle with, again, there's been some discussion prior about surveys and publications on this particular topic.  For consumers, there is a paucity of data.  There's very few comprehensive studies of consumer products.  And we have, of course, research efforts in our Office of Research and Development on this as well.
                  DR. KENNETH PORTIER:  Ms. Rudel and Dr. Gilbert, it sounds to me like you might want to make a recommendation or a suggestion that this be better discussed in, it looks like, Section 4.4.1 on potentially exposed or susceptible subpopulation, other risk-related considerations.  I don't see discussion of what you just talked about, and you might make a recommendation that there's obviously a data gap.
                  Although we acknowledge the fact that there's not a lot of locations today that are using 1-Bromopropane in a dry cleaner, that's not to say, next year, that shoots up 100-fold.  So, I think it's valid to at least have a suggestion that that uncertainty be discussed in that section.  Maybe the two of you could put that in.  Dr. Gilbert, had you wanted to make another comment?
                  DR. KATHLEEN GILBERT:  I just have a question.  I know this isn't really what we're discussing, but the whole Clean Air Act petition for 1-BP, we said 20 dry cleaners this might be relevant for.  They will actually put a chemical on the Clean Air Act for such a small number of facilities that it might be relevant to?  Or is there some other rationale that I don't understand?
                  DR. STAN BARONE, JR.:  The petition was for 1-BP manufacturing use processing.  Dry cleaners are just one source.  Again, you had heard about the estimates of 24 million pounds production.  Production, processing, other facilities could be sources, and actually, more significant sources of general population exposure.  So, the Clean Air Act would be addressing those kinds of activities/sources to the general population.
                  This is the dissection between TSCA and the Clean Air Act.  We're actually looking at the internal, inside the house.  We're looking at the manufacturing, the facility, the processing facility and the workers there, and the occupational nonusers, whereas the Clean Air Act covers the general population.
                  DR. KENNETH PORTIER:  Hence my recommendation that we put it in there.  Because it doesn't take it off the table; it leaves it there as something that EPA, at some point, will have to consider.
                  Any additional comments on points of BMD modeling and calculation of the points of departure for non-cancer and cancer endpoints?  I don't see any, so I think we'll move on.  Where are we?  Question 6?  Is that where we are?  Yes?
                  MS. RUTHANN RUDEL:  I have a request for that, because I'm lead on 6.1 and 6.3 and they're acute versus chronic.  Could we combine those two?
                  DR. KENNETH PORTIER:  6.1 and 6.3?  I'll tell you what.  Why don't we read 6.1, you make your comments for 6.1 and 6.3, and then when we get to 6.3, say, "I've already made those comments."  And that gives the panel the chance to address both of those separately.  So, let's go ahead and -- yes, Ms. Rudel?
                  MS. RUTHANN RUDEL:  It's Ruthann. Have we passed the question where we talk about uncertainty factors?  Or is that coming?  That's coming?  Okay.
                  DR. HOLLY DAVIES:  Could we just take a quick break between questions?
                  DR. KENNETH PORTIER:  Take a break?
                  DR. HOLLY DAVIES:  Or does no one else want a break?
                  DR. KENNETH PORTIER:  Okay.  Well, let's take a 10-minute break.
                  DR. HOLLY DAVIES:  I feel like a small break between questions.
                  DR. KENNETH PORTIER:  Take a 10-minute break.  What time do I have here?  I've got 1:42, so we'll come back together five minutes before 2:00.
                  (BREAK)
                  DR. KENNETH PORTIER:  Before we move onto Question 6, Dr. Blystone said she had one more comment she wanted to get on the record.
                  DR. SHERI BLYSTONE:  Yeah.  I mean, because at one point, you had pointed to me and asked for my opinion, but I never gave my opinion.  But I wanted to follow up with Ruthann exactly what her concern was.  So, in the break, I did do that.
                  Her concern was that children in dry cleaning operations should be considered for a chronic hazard.  And if you're talking about every day probably, that they're there every day throughout their childhood, seven years is going to be part of that.  So, it seemed reasonable to me as well that that is a pathway that should be considered for chronic hazards.
                  DR. KENNETH PORTIER:  All right.  A chocolate fix is going around the room.  It stopped.  Now, Dr. Anitole, please read in Question 6.1.
                  DR. KATHERINE ANITOLE:  For non-cancer risk estimates, EPA used the margin of exposure, or MOE, approach.  MOEs for acute and chronic exposures were calculated separately based on the appropriate non-cancer POD and the estimated exposure concentrations adjusted for durations.  The endpoint-specific MOEs were compared to the endpoint-specific benchmark MOEs.  If the MOE estimate was less than the benchmark MOE, the exposure scenario for non-cancer endpoints was interpreted as a human health risk.
                  For cancer risk estimates, EPA multiplied the occupational scenario-specific exposure estimates by the cancer IUR to estimate the extra cancer risks.  Extra lifetime cancer risk estimates from 1-BP exposure were compared to the benchmark cancer risk levels.

                               CHARGE QUESTION 6

                  I think I got a little mixed up here.  Question 6.1; please comment on the assumptions, strengths, and weaknesses of the MOE approaches used to estimate the non-cancer risks to workers and occupational non-users -- for example, adults of reproductive age -- following acute inhalation exposures to 1-BP, including the MOEs presented in the document.  Specifically, please suggest alternative data that could be used.  Please comment on the selection of uncertainty factor values in deriving the benchmark MOE for acute inhalation exposures.
                  Did you want me to read 6.3 in combination?
                  DR. KENNETH PORTIER:  I think we'll get to it.  Let's just tackle 6.1, and we'll just fold Dr. Gilbert's comments into 6.3 at the time.  Dr. Gilbert?
                  DR. KATHLEEN GILBERT:  Well, I think I'm supposed to be talking about -- okay, the non-cancer endpoints.  There's an amazing table, 3.1, that describes all of the different organ systems and talks about the uncertainty factors which, as far as I can tell, are perfectly appropriate.  And they also describe obviously the BMCLs which, for a particular target organ system, seem to be fairly consistent across the different studies.
                  So, the main question, I think, has to do with the study that they used which, for many of the endpoints, they used the WIL paper to talk about acute inhalation exposures.  This is somewhat problematic, as they discussed, but I have a rationale for.  They say that support for using this endpoint for acute short-term exposures is the fact that the male and female reproductive effects, that is in the F-zero males and females collectively, contributing to the decreases in live litter size, which is the endpoint they're looking at, all occurred within a short window of exposure between ovulation and implantation.
                  They suggest that other studies have shown, which is absolutely true, that short-term exposure to certain chemicals during this critical window can induce long-term effects.  That's very well documented.  However, showing that chronic exposure, that happened to overlap this crucial short development window, caused long-term effects in the pups is not the same.
                  Because, in the WIL study, yes, they are exposed during that short window of time, the parents.  But they're also exposed for 70 days premating.  And they're making the argument that the effects that they see on the live litter are only due to the short window of time during gestation as opposed to anything that's happening during the 70-day preexposure.  Described by the EPA as a very health protective effect, not necessarily accurate, and that could overestimate the risk to workers and consumers following acute exposure.
                  However, they think it's justified enough because of the studies that have shown that short-term exposure during that time period can cause the long-term effects that they saw in the pups.  So, I am basically okay with that since they're calling it a health protective, even though I don't see the rationale.  I don't think you can actually say that you can guarantee that the effects that they got in the pups had to do with just that narrow window of exposure and, therefore, was a result of the acute exposure.  I'd be interested in what other folks have to say about that.
                  Let's see.  Table 3.1, as I said, describes the endpoints and the ATCs selected for the inhalation non-cancer dose response.  Applied a composite uncertainty factor of 100 for acute and chronic inhalation benchmark MOE based on default intraspecies uncertainty factor of 10, an additional 10 to account for additional toxicokinetic differences, including variability in expression and function of CYP2E1, which is involved in 1-BP metabolism.
                  Since BMD modeling was used to derive at HEC, a NOAEL to LOAEL uncertainty factor of one seemed appropriate.  And the sub-chronic to chronic was not needed because a key study used a chronic exposure protocol.
                  One thing I had a question about.  They talked about the different HECs provided for acute versus chronic exposure; when describing the decreased live litter size and post implantation loss in F0 females, there were different HECs for the acute versus chronic.  Explained by the fact that HECs are calculated by duration adjustment and a human equivalent DAF.
                  The adjusted POD is the POD times duration adjustment.  And the baseline used for the duration adjustment was 8 hours per day for exposure for occupational and 24-hour exposure for consumer.  For acute exposure, the duration adjustment was hours per day exposed divided by 8.  And for chronic, it was hours per day divided by 8 times days per week to reflect a 40-hour work week.
                  To me, this needed a little more explanation.  I think that's basically it.  My main concern was the use of the WIL study, which is a chronic exposure to look at acute endpoints.
                  DR. KENNETH PORTIER:  Thank you.  Dr. Anderson, do you want to add to this?
                  DR. HENRY ANDERSON:  Yeah.  I don't have much to add.  The only thing that I saw is that there's really a lot of studies that are categorized as being high quality.  The one thing here that I thought is, if you look at the human data, what's striking is that at least the short-term or a higher exposure impacts appear to be all neurological.  And there's quite a number rated high quality neurologic studies.
                  The data quality in the neurologic short-term studies, which gets you some fairly low NOAELs,  some of those haven't been evaluated.  There's two rated high that have fairly low levels.  It would seem to me it would be helpful, when you have a plethora of studies and different endpoints, to provide the analysis of what would be the benchmark or the selected study if you were to use different endpoints.  But I just think that neurologic endpoints are more consistent with what actually is on the ground experience in the human category.
                  So, it would seem that it would be helpful to have a better explanation for why they chose to only use a single study when there are multiple choices.  And why they then didn't choose the neurologic endpoints, or at least do the calculation with them.  With the issue of uncertainty factors, when there's pretty good consistency between the animal studies and the human experience, one could reduce the uncertainty factor in the animal to human translation there.
                  So, I think it would be helpful to perhaps add some reliance on what is seen in the human studies, even if those data are not used.  That's one of the issues.  And then, again, the identification of the subpopulations.  Clearly, individuals with neurologic disease, those with diabetes in the workforce, all of those are diseases that have an impact on the neurologic system.  That places them at greater risk to other neurotoxins.
                  So, that would be some recommendations I have.  Perhaps, some greater discussion of alternatives to the cancer risk.  That's diligent in this case to utilize for the acute exposures.  That's it.
                   DR. KENNETH PORTIER:  Thank you, Dr. Anderson.  Does anyone else want to comment on this question?  Maybe somebody else on the line.  Dr. Cory-Slechta?  Dr. Pessah?
                  DR. CORY-SLECHTA:  Yeah, no comment.
                  DR. ISAAC PESSAH:  No additional input.
                  DR. KENNETH PORTIER:  Dr. Gilbert, I have a question.  Using a chronic developmental study to set an acute point of departure, is that conservative or anti-conservative?  Is that going to produce a lower point of departure or a higher one?  I was just trying to think of the implications of doing that on the risk assessment.