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Hormesis: Its Scientific Foundations and Biochemical Regulatory Applications — Transcript

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0:00thank you very much it's my pleasure to
0:01be here today I'll be talking about uh
0:05hormesis um its scientific foundations
0:08and
0:09biochemical regulatory
0:12applications in terms of hormesis now um
0:16what we've come to learn is that low
0:19doses of many different types of
0:21stressors um things such as exercising
0:24intermittent fasting hypoxia heat cold
0:28ionization ionizing radiation
0:30non-ionizing radiation electricity
0:33toxins chemicals drugs all of them can
0:37stimulate a wide range of adaptive
0:40responses these induced adaptive
0:44responses by those the plethora of
0:46agents that I just mentioned they have
0:48the potential to profoundly affect the
0:50success of medical interventions for
0:53numerous disorders things like heart
0:55attack stroke um shark brain traumatic
0:58damage organ transplant plant
1:01surgeries stresses that trigger adaptive
1:04responses also offer ways to enhance
1:06healthy aging improve Human Performance
1:09prevent damage to tissues later exposed
1:12to injurious levels of various types of
1:14stressors so in my opinion now at the
1:17center of this adaptive response concept
1:20is the phenomenon of
1:23hormesis hormesis is a basic dose
1:26response relationship it mediates
1:29processes by which human adaptation and
1:32performance may be improved optimizing
1:35the do symmetry while providing the
1:38underlying molecular mechanism so what
1:41is hormesis how can it be used to
1:44achieve these Public Health and Medical
1:48advances well I'll give you a definition
1:51Now hormesis is really a dose response
1:55phenomenon and it's characterized by a
1:57lowd dose stimulation and a high does
2:01inhibition it's a non-monotonic basic
2:04dose response but it's not just a
2:07typical basic dose response it has
2:10specific dose response features which
2:13we'll take a look at now hormesis is
2:17kind of the new kit on the Block even
2:19though it has a long history and by new
2:21kit on the Block means that it's forcing
2:23itself to the table to the dose response
2:27table uh the two dose responses that I
2:30kind of grew up with teaching writing
2:32about were the other two kids in that
2:34slide over there um the threshold dose
2:37response
2:38model uh which is uh this line over here
2:42and you see if we reach a threshold and
2:44Zing we go up and that's a threshold
2:47dose response and the other player um is
2:51the linear dose response the threshold
2:54dose response is typically used by
2:56Regulatory Agencies such as the FDA such
2:59as EPA in their regulation of
3:02non-carcinogenic effects um however both
3:05of these agencies and others uh use the
3:08linear dose response uh when they are
3:11dealing with carcinogenic effects
3:13whether they are um ionizing radiation
3:16or whether it's a chemical carcinogens
3:19typically the the linear dose response
3:22is used the linear dose response very
3:24has very different implications uh than
3:27the
3:28threshold you can see with the threshold
3:31that there is a dose below that
3:34threshold which does not differ in
3:37response from the control group meaning
3:39it's without detectable biological
3:42effect it means that it's exposure is
3:45safe below the threshold in
3:48theory however if you take a look at the
3:51linear dose response the the response is
3:54really directly proportionate to dose
3:56all the way down to zero really means in
4:00the in an absolute extremist sort of
4:02sense that a single molecule brings with
4:04it u a theoretical risk even if you
4:07can't quantify this with your
4:09instrumentation in a radiation sense a
4:12single ionization would do the same
4:15now um so basically um this is the
4:20reality that we are dealing with within
4:22a regulatory sense and if you take a
4:25look now at the new kit on the Block the
4:27hormetic model is really similar to
4:30those two at high
4:32doses but it has profound differences in
4:35the low dose Zone you can see this
4:38little dip below this j-shaped dose
4:41response is actually showing a risk that
4:43is below the control group actually um a
4:47protective or beneficial effect it's
4:50saying that uh when you reach a lowd do
4:53Zone things that are typically viewed as
4:56being harmful dangerous whatever
4:59regulated as such by the Regulatory
5:02Agencies is actually uh showing the
5:04potential here in this model to actually
5:08have a beneficial effect and that when
5:10we have regulations which are pushed
5:12down into this level I will contend here
5:15that and in my writings that in fact it
5:18has a net negative in terms of its U um
5:22its Public Health
5:24implications you have a question
5:26Interruption is the line of the control
5:30group is that yeah it's this is a
5:32normalized control group so it's like of
5:34the 100% value and that's a very helpful
5:38question because uh you'll see
5:40subsequent slides that that will be
5:42normalized to that 100% control value so
5:45thank you very
5:47much okay
5:50now in general um we find when you're
5:53taking a look at hormetic dose
5:56responses uh that they're generally they
5:59have generally similar quantitative
6:01features with respect to the amplitude
6:03and the range of response now this was
6:07uh it's actually very surprising to me
6:10um when I first got revved up on this
6:13probably 30 years ago
6:17um I didn't I really didn't think that
6:20this was true not that I actually even
6:22thought deep enough to even pose the
6:24question whether it was true or not I I
6:27thought that we were dealing with a lowd
6:28do stimulus in a high do inhibition but
6:31I thought that the this lowd dose
6:34stimulatory effect or this j-shaped
6:36we'll talk about why we plot things with
6:40an inverted U or a j- shape in a second
6:42but I but I thought that gee you'd have
6:44really great evidence for hormesis if
6:46this if you had a low dose stimulation
6:48that can go up by three or four or five
6:50or six fold and then at high doses it
6:52would decrease uh but I realized that
6:55you could get a range of at least I
6:57thought a range of potential
7:00stimulations quantitatively differing
7:03however I've actually collected I'm
7:06going to say 45 to
7:0965,000 examples of hormetic dose
7:11responses in the literature over these
7:14years I have about five or so databases
7:18created for different reasons to answer
7:19different questions and um to my
7:23surprise um after looking at probably
7:27four or five thousand of these I found
7:30that the lowd dose
7:32stimulation is actually for the most
7:34part very
7:36modest it doesn't go up by three or four
7:38or fivefold it goes up by in the
7:41percentage range it goes up by usually
7:44not more than twice the control group
7:46and usually not more than 30 to 60% of
7:49the control group and this is um really
7:54made me change my thinking about what
7:57hormesis is what about its implications
8:00are but it also made it as I think
8:04you'll see later on something that was
8:06um um made things much more
8:09understandable for me because my my and
8:12it'll lead to the second comment here
8:14because actually way back when when I
8:16was young um I was an undergraduate um
8:20kind of a junior in college in in
8:231966 and I was taking a a plant
8:26physiology course and one of of our many
8:29experiments that we had to do was to
8:32study something that caused the dose
8:34response relationship so the professor
8:36gave us this
8:38synthetic um plant growth inhibitor and
8:42we treated his favorite plant which was
8:44peppermint and we were to show a dose
8:47dependent decrease in the peppermint
8:50growth over time and so we were doing so
8:53many experiments I'd have to say I had
8:55no focus on this peppermint experiment
8:58at the time
8:59and then in November of 66 towards the
9:02middle of this fall semester he comes in
9:04one day and he says um the group that's
9:07doing this dose response relationship um
9:11something unusual has happened your
9:12plants are being stimulated and he said
9:16he said I don't know why they're being
9:17stimulated we do this exercise every
9:19semester he said it really isn't
9:21research it's to teach you a concept of
9:23dose response relationship and he said
9:26and the plants are being stimulated
9:28they're not supposed to be stimulated if
9:30anybody's interested in trying to figure
9:32out why something aberant is going on
9:34come back and see me at the end of the
9:36semester of course the the story is that
9:38the only one who was interested in going
9:40back and seeing this guy happened to be
9:42me and so um so I go back and see him in
9:45in my notebook which I still retain
9:47today is like the end of January of now
9:501967 and he we go back and we we say
9:54well okay let's let's do it all over
9:56again he said except this time I'm going
9:57to look over your shoulder and see how
9:59what you did pull out your notebook try
10:01to figure it out and um and we'll do it
10:04so actually make up your stock Solutions
10:06new and I'll see if you make them up
10:08correctly and how you did it and so as
10:11it turns out uh it appeared as though
10:14when we made our stock solutions that we
10:16um we had a 10 tenfold delusional error
10:21um in the experiment that we did and so
10:25um which is an insight and so so we did
10:28it the way he said we should do it and
10:31we did it the way my little research
10:33group did it we ended up having a wide
10:34range of concentrations and this time
10:37with him more or less looking over my
10:39shoulder kind of doing it the right way
10:42at high doses we actually saw this dose
10:44dependent decrease like he had seen
10:46every year except our lowd do
10:49stimulation which was that 10-fold
10:51dilutional thing still showed a lowd do
10:55stimulation and so that was my first
10:57introduction to things things biological
11:00that could have a basic dose response
11:02and so after the little experiment was
11:04over I said I I I guess we've answered
11:06the question he says no you haven't
11:07answered the question you've just done
11:09this now twice but now you did it better
11:11than the first time you have to do it
11:13over
11:14again and because that's what scientists
11:17do they have to they have to verify what
11:20they have observed so I went back and I
11:22did it over again and then I did it over
11:24again again and came in and showed them
11:26my findings it was still the same B
11:28phasic those response he said this is
11:30only increasing by about 30 to 60% or so
11:34he said he said statistically he said
11:37this is very tenuous he said it may be
11:40real but it's very tenuous he says you
11:43think you're going
11:44to challenge my reputation by getting
11:46something like this out in the
11:47literature he says you have to actually
11:49have more proof than what you
11:52have so I said okay I'll do it again and
11:55I did this thing eight times I said I'm
11:58done I I don't care what happens I'm
12:00done I'm convinced that I know this is
12:02stimulated at low dose he says okay he
12:04says at that point we had tested around
12:0616 or 1700 different peppermint plants
12:09and all these different things he said
12:11but but we haven't understood why this
12:13actually occurs and so I said
12:17oh so he says I think we should it may
12:20be occurring because there's some
12:22microbial action in the soil that's
12:24changing this compound to something else
12:26and maybe that's what so he said let's
12:28do this experiment in Hydroponics where
12:30the soil is eliminated I said well well
12:32that's a good idea and so so then I went
12:35back and tried to do this thing in
12:37Hydroponics and set up all the doses and
12:40we had lots of doses then we were
12:42actually running around 12
12:44concentrations and a lot of a wide range
12:47of things it was not like two or three
12:48doses it was a lot and and actually uh
12:52following them over time we got this
12:53lowd dose stimulation again high dose
12:55inhibition this time we only actually
12:58verified it um about four or five times
13:01and thank goodness I was done with them
13:04and uh but it took a long time but it
13:06was very useful to me uh and I said I'm
13:09never going to work in Plants anymore I
13:11decided to become an insecticide
13:12toxicologist I said this guy is driving
13:14me crazy he's never satisfied never ever
13:18satisfied and and I came to uh well in
13:22the beginning I just couldn't stand
13:23working with them and uh I'm glad I went
13:26to another area and I came to appreciate
13:29him as they say you might appreciate
13:31that your your parents you know forcing
13:32you to do something so many years I came
13:35to appreciate this guy's insistence on
13:37replication years later when I got
13:40reintroduced to the term hormesis and
13:44and uh a modest increase in the
13:46percentage Zone and a need to replicate
13:49and replicate and replicate your
13:51findings so that you can demonstrate
13:53that it's not a function of background
13:56variability or some other kind of
14:00something that that's uh that's unusual
14:02in the experimental situation so but the
14:05interesting thing is that the lowd do
14:09stimulation can occur uh either as a
14:12result of a compensatory process
14:14following an initial uh disruption in
14:17homeostasis or it could occur with a
14:20direct stimulation now my we published
14:23our work I never knew the term hormesis
14:26I just said we have a lowd dose
14:27stimulation and a high dose inhibition
14:30uh published in the journal a British
14:31Journal called physiologic plantarum and
14:33I was out of there more or less going
14:35into into my PhD work and so um but the
14:40interesting thing is that is that years
14:43later I came
14:44back uh when I was got reintroduced to
14:47this hormesis concept um this this
14:50fellow from England said that you you
14:52need to have a an initial decrease of
14:55some toxicity in and and then you'd have
14:59uh an overcompensation response and and
15:02he' show this lowd does dip and then
15:04this overcompensation response and and
15:06it only would go up by this 30 to 60%
15:09range and so I went back carried all my
15:11data known had my data longer than I've
15:14been married and been married for 42
15:16years and
15:18um still have the the the notebooks and
15:21I went back and I because we measured
15:23things Week 1 2 3 4 5 six and so forth
15:26and I went back and we true as it was
15:29the guy was right our first week was a
15:31dose dependent decrease and if we had
15:33stopped our research after one week I
15:35never would have discovered this
15:36hormesis phenomenon for myself and when
15:38I followed it over week 2 3 four and
15:40five I saw this compensatory growth and
15:42it came out looking like a basic dose
15:45response
15:46relationship um and so and so and I said
15:51this is now looking back over things
15:53then I began to get an insight as to why
15:55the hormetic response was always modest
15:57because if you were trying to to
15:58compensate for damage you wouldn't
16:00grossly overstate or grossly
16:03overcompensate you would compensate to
16:05try to get back to your original Dynamic
16:07set point um as efficiently and as
16:10quickly as possible and and you might
16:12over over it's like I arrived for this
16:15presentation yesterday at about 2:30 in
16:18the afternoon I didn't arrive a week
16:20before um um it's like you you you use
16:25you you act very efficiently because you
16:28things cost TimeWise MoneyWise
16:31resource-wise otherwise biologically we
16:33do the same thing if you want to get
16:34back to the original set point you don't
16:36want to miss it you want to slightly
16:39overstate it and slightly overstating
16:42means that in the well maximum 30 to 60%
16:45range uh you wouldn't want to you know
16:48overstate it by four and fivefold and
16:50began to see why the hormetic response
16:53was modest and then it was also
16:55interesting to me I began to see
16:57examples where there wasn't an initial
16:59toxicity but where there could be a
17:00direct stimulation and then when I
17:03looked at um the the dose and I knew
17:06they had to be acting through different
17:08mechanisms I so when you get a direct
17:10stimulation or if you get an
17:11overcompensation stimulation very
17:13strange to me that them the quantitative
17:17features of their dose responses were
17:18still the same I said H how could that
17:21be the case and so then I my insight or
17:25my hypothesis was actually what the
17:27hormetic response was was really
17:29demonstrating was how much gain there is
17:31in the biological system and was
17:33actually a measure of biological
17:35plasticity and and whether you got there
17:37through a direct stimulation or you got
17:39there through a overcompensation
17:40response you were still capped by this
17:44phenomenon and so so to me it was
17:47beginning to make some biological sense
17:50now in the world of of hormesis we talk
17:52about I never really talk about benefit
17:54I usually talk about this as a
17:56biological phenomenon in whether it's
17:58benefit or or harmful is important but
18:01it shouldn't be part of the definition
18:02of hormesis hormesis is really a
18:04scientific an assessment um because
18:07sometimes you'll find that lowd dose
18:08stimulation is actually harmful
18:11sometimes you'll find that it's going to
18:12be very beneficial um I can tell you
18:14that and from the harmful side I've done
18:16a lot of work with anti-tumor drugs on
18:19on on tumor cell lines and most
18:23anti-tumor drugs they they kill tumor
18:26cells at high doses but in our
18:27experience this is a pretty pretty broad
18:30experience shows that most anti-tumor
18:33drugs actually stimulate or the
18:35proliferation of tumor drugs at low
18:37Doses and so there it's inducing an
18:39Adaptive response in the tumor cells and
18:41they conformed identically to the
18:43hormetic dose response even the the if
18:46you take a look at penicillin and
18:48streptomycin and you look at them with
18:50harmful bacteria at low doses they
18:52actually increase the proliferation of
18:55the bacteria that they kill at high
18:57doses it's very hormetic dose response
19:00relationship um so it may be good for
19:03the bacteria good for the tumor cell but
19:05bad for the patient so you have to see
19:07it within a biological context um okay
19:12this is kind of the example I was just
19:13talking about here we're looking at
19:15chemotherapy and you can have a typical
19:18hormetic dose response with a normalized
19:20control over here at high doses it does
19:22its thing but at low doses you get the
19:25the hormetic stimulation you can take a
19:27look now at a lot of memory drugs memory
19:31drugs actually uh have been studied very
19:33widely um dozens and dozens and dozens
19:35of these drugs in in Hope for this the
19:37magic pill and a lot of them work and
19:40when they work they show an inverted
19:42u-shaped dose response they actually can
19:45increase memory um and at high doses
19:48they actually can decrease uh memory
19:51performance in these animal models
19:53interestingly as you you may not even
19:55think about this this little the rise in
19:57the increase in memory is really the
19:59same increase that you would see in in
20:02how large the proliferation is of of the
20:04tumor cells there why would they
20:07increase to the same degree and and you
20:08can look at this in a whole plethora of
20:10other endpoints and this is to me um why
20:14I developed this this uh um biological
20:18plasticity uh Theory to try to um try to
20:22figure out why the increases is limited
20:25in very good studies to this 30 to 60 %
20:29now I study hormesis today for a number
20:32of years in a lot of different ways um
20:34experimentally uh studying dose response
20:37pattern statistical significance the
20:39replication a lot of work on mechanism
20:41today a lot of work on simulation
20:44studies when you're dealing with large
20:46populations all in a sense to try to
20:48figure out what is going on at this
20:50cellular level based upon my work with
20:54over the last 25 30 years on this with
20:56multiple databases lots of experimental
20:59stuff um basically um we find that that
21:03hormesis is it's very general it's a
21:07very general phenomenon it occurs
21:08independent a biological model we see it
21:10in Plants we see it in microbes we see
21:12it in invertebrates vertebrates humans
21:14we see it in in vitro in Vivo um we see
21:18it for a whole essentially independent
21:20of endpoint we see it independent of
21:23inducing agent chemical class we see it
21:26at different levels of biological
21:28organization which I find really
21:29interesting so we see it at the cell
21:31level we see it at the organ level we
21:32see at the at the individual level we
21:35see it every place I believe it's a very
21:37general phenomenon very basic component
21:39to life as I mentioned before the dose
21:42response is typically modest it's
21:44usually in the 30 to 60% range the the
21:47width can vary um the width is typically
21:50you know
21:51essentially uh 75% of our our um
21:55examples in our database are within 20
21:57fold of the threshold that that Tipping
22:00Point that crossing point that zero
22:02equivalent Point some uh two to 5% are
22:06very very broad very wide and why are
22:09some very wide why are some very much
22:11more narrow and and it and I don't know
22:14the answer to that question I I think it
22:16could have to do with the degree of
22:18homogeneity or heterogeneity in the
22:20cells of the population that you're
22:21study but that's an area to be studied
22:25this is the typical example of a
22:26hormetic dose response you have the the
22:29normalized control group you have the
22:31little lowd dose stimulation high dose
22:34inhibition you have the little threshold
22:36here um and and toxicity or or
22:40inhibition at the at the high dose most
22:42people would say okay you have toxicity
22:44it kind of goes back to the control and
22:46just you have experimental bounce or
22:48noise here but we get to flip over to
22:50the other side and that's where the
22:53hormetic thing is a lot of people in the
22:56good old days would say that's um you're
22:58just deluding yourself calibri that's
23:00just that's just experimental error you
23:03want to believe something that doesn't
23:04exist and I've spent actually quite a
23:07bit of time convincing myself that that
23:09that I'm right and they're wrong and
23:11then after that I have to now
23:14um play by the rules of the game and
23:17their criteria are the criteria set up
23:19by the field to to establish that that
23:23such phenomenon is real and not variable
23:25and you can begin to see why the wisdom
23:27of my old advisor uh you have to
23:30replicate this thing you need lots of
23:33Doses and you have to replicate it
23:35replicate it replicate it and show this
23:37and today in today's with good
23:39statistical activity in today's world
23:41you have to be able to to find
23:44mechanisms that U essentially can
23:47explain and mechanisms that mediate this
23:50uh stimulation and inhibition and um and
23:54in the last 10 years those mechanisms
23:56have come to be and last last year two
23:58years ago we published actually uh
24:01specific hormetic mechanisms for 400
24:04different dose responses with mechanisms
24:06down to the receptor and cell signaling
24:08pathway which were very um definitive
24:10for each of those 400 I have another 600
24:13that I have that will be sent out fairly
24:16soon uh hormesis could occur for
24:19everybody whether you're normal or
24:22whether you're a highrisk group except
24:24if you're a highrisk group it's kind of
24:26shifted uh on the dose to a lower dose
24:29but basically the the the quantitative
24:32features of the dose response for
24:33hormesis are the same I was actually
24:35criticized this has almost never
24:37happened probably to anybody but I wrote
24:39a um an a paper for an annual review of
24:41Public Health on hormesis a number of
24:43years ago and so usually when somebody
24:46writes an annual review you're supposed
24:47to be thought of as knowing something
24:49about about the topic so I I wrote this
24:52paper came out and one of the the
24:53editorial board members decided to
24:55challenge me by saying that um that you
24:58never addressed the concept of high-risk
25:00groups and he wrote a he wrote a
25:02separate paper in the same issue of the
25:05annual review saying what the
25:06limitations of my paper were and
25:08actually I've never seen that done
25:10before in a uh in an annual review but I
25:14tried to take it as a positive and so I
25:17so but it was a good question and I
25:18hadn't addressed that question so I went
25:20back into our database and found that
25:22there was a lot of information on
25:24differential susceptibility and we then
25:26published a subsequent paper 2 years
25:28later addressing his point and showing
25:31um essentially um the the little
25:34schematic that I showed you there so
25:36criticism can be good if you listen to
25:38it um and objective criticism I want to
25:42share with you that that in the
25:44beginning of my my stay with all this I
25:47I have to tell you when I was beginning
25:48to make my move on hormesis getting out
25:51a lot of funding mid90s later 90s uh I'm
25:55a toxicologist and I try to publish my
25:56papers in in our society's journals and
25:59I I had six papers on toxicol on
26:02hormesis that I thought were pretty
26:03substantial I sent them to my journal
26:05which was talk sciences and uh and I got
26:08kind of good reviews on six and I got
26:10rejection rejection rejection rejection
26:12rejection rejection and um and you know
26:16at my stage at that point I mean yeah I
26:18keep getting rejections even today but
26:20you know it kind of consense based on
26:21the reviews what what the editor should
26:24say you know accept with minor revision
26:25major revision this and that I was just
26:27getting
26:28with pretty not bad reviews clobbered
26:30with the final decision so I call up my
26:32grant manager and I say I think I'm
26:35doing really well on this um but I'm
26:38getting rejected by this top journal and
26:40he says Eddie says if you want your
26:43Grant review renewed you have to find a
26:45way to get into those journals or it's
26:48not going to get renewed so at that
26:51stage um I could have just kind of blown
26:53it off because I really didn't need his
26:55grant money anyways um
26:58but um so I said H I said what am I
27:03going to do here I mean because I mean
27:06the sign of idiocy is right doing the
27:07same thing over and over and over again
27:09I guess and getting the same result all
27:10the time I wasn't I mean six times in a
27:12row I still hadn't learned my lesson and
27:15so um so what I did was I said all right
27:18I said I'm going to invite these guys
27:20this editorinchief who thinks he knows
27:21it all I'm going to invite five people
27:23who made their name on lowd do linearity
27:25and I'm going to invite them to a big
27:27debate at at my University invite the
27:30world so to speak to it and I'm going to
27:32pull a Fidel Castro and I'm going to
27:34talk for 6 to8 hours on hormesis on day
27:37one I'll allow them to talk as much as
27:39they want and criticize me on day two
27:41and we'll see who's left standing on day
27:43three and so and so that's what happened
27:46in in the year 2000 I did that 200
27:48people showed up we advertised it widely
27:51my grant manages there I I did my six
27:53hours on eight hours on on uh on
27:56hormesis everything I knew you guys
27:57won't have to you know put up with that
28:00really and so um and so but as it turns
28:03out I came home my wife said how'd you
28:04do and I said I was just awesome today I
28:07just the best six-hour talk I'll ever
28:09give on hores is right the only one I
28:12said I think I convinced the world I
28:13think I convinced them all
28:15that why I'm right so I showed up the
28:18next day and the first talk was by this
28:21leading biostatistician he says because
28:23I had sent them all 150 articles nine
28:26months before the meeting I told him
28:28this is what I want you to look at what
28:29I why I believe what I believe this guy
28:32shows up and says he sent me 150
28:34articles seriously I'm going to read 150
28:36articles this guy sends me I'm pretty
28:38busy skim through it I'm just going to
28:40assume that he's correct but you know he
28:42said I looked at his first database that
28:44he created and that database is actually
28:47seriously flawed and I'm saying uhoh and
28:51cuz this is a really smart guy and he
28:52says you know he says his database his
28:55datab but he said uh
28:57I work consult a lot for the EPA and FDA
29:00and he said and they'll say well Cali's
29:02published a number of studies on this
29:04and and and isn't hormesis real and he
29:06says well it's not so much as real or
29:08not the issue is is it's significant or
29:10not he says his database can show
29:12examples of hormesis because it's based
29:14upon essentially um uh evaluative
29:19criteria and it could be rigorous he
29:21said but calib doesn't actually didn't
29:24actually use our priority entry criteria
29:27and putting this first database together
29:29and so that's like that's like saying um
29:33uh like a baseball player did you have a
29:34good season last year you could say I
29:35got 150 hits well well how many times
29:38did you get up um well you could have
29:40been up 300 times or 600 times in a
29:43season it makes a big difference in your
29:44batting average
29:47caliber what what is hormesis is does it
29:49occur 100% of the time 50% of the time
29:52or 2% of the time his database can't
29:55answer that question and I say oh crap
29:59he's right and so my I said my grant
30:02manager is there and I'm seeing him
30:03writing down things on his paper and
30:05then and then the next guy got up uh so
30:07it was a hit I think I took pretty much
30:09in the stomach and nose and then my then
30:12the next guy got up who was from talk
30:13Sciences the editor and chief he says I
30:15don't even care about this debate over
30:17uh frequency of hormesis he says in talk
30:21sciences and talkx Colley today we
30:23worship at the altar of mechanism and
30:25until he can can explain
30:27he's not getting in my journal and then
30:30the next guy got up and the next guy got
30:31up and the next and at the end I'm not
30:34sure if you ever seen you know Rocky
30:35balore and Apollo
30:38Creed but I kind of felt like Rocky did
30:41after 15 rounds with Apollo Creed and so
30:44I came home after the second day I said
30:46well the second day go better than the
30:47first day and I said I said I'm kind of
30:51I'm still standing like Rocky was but
30:53I'm a big groggy to say the least and so
30:57um nonetheless I scored my points uh
31:00wasn't totally defunct um but I realized
31:03that I wasn't quite ready for the prime
31:06time and so so I went to work really
31:09hard created a database with the help of
31:11this
31:12biostatistician that had good our
31:14priority entry in evaluative criteria
31:17looked through 21,000 papers this and so
31:19forth and so on ultimately came up with
31:21an answer to the frequency question and
31:25and ultimately you know it was
31:26approximately 40% with very rigorous
31:29high priority entry and evaluative
31:31criteria um sent the paper to science
31:34and they didn't want to look at it sent
31:35it to Nature and didn't want to look at
31:36it but we actually got it in talk
31:39sciences and it was highlighted and
31:41profiled and and was given a strong
31:44status there and so as it turns out this
31:47was a a big breakthrough because nature
31:49picked up on it and they wrote a then
31:51they invited me to write a special
31:53article later on that that made it into
31:56their into their press package and the
31:58next thing I knew that there were front
32:00page stories and a number of newspapers
32:02and got my picture in US News and World
32:04Report Wall Street Journal um whole
32:07bunches of things and and became um
32:10famous overnight so to speak on the
32:12hormesis front also developed a lot of
32:14enemies on the on the local front
32:16because I was proclaiming that it had
32:18strong regulatory implication that could
32:20replace some of the other models and so
32:23I kind of cut both ways now it's kind a
32:27little history history to it all but I
32:29want to say that that over the course of
32:31time now as I mentioned before with now
32:34with new technologies develop really
32:36good mechanistic insights and we found
32:38that the harmonic dose response uh is
32:40also independent of mechanism and then
32:42you might find that odd that you can
32:44induce this by a plethora of different
32:46mechanisms and it doesn't make any
32:48difference what the mechanism is you
32:49still have the same quantitative
32:51features of that dose response very very
32:53interesting situation it's consistent
32:56with my plasticity hypothesis actually
33:00uh so now I have several hundred I have
33:02close to a thousand examples today um
33:05that are pretty good so um now the
33:09next slide here shows you kind of a an
33:12example of a hormetic dose response with
33:15with sodium arenite and it's looking at
33:17human the human embryo lung fiber blast
33:20cells that were published by a group um
33:24in this country and they they did a um
33:27showed a low dose stimulation and a high
33:29dose inhibition then they took some
33:32receptor cell signaling pathway
33:34Inhibitors and they could actually block
33:37this increase by blocking the pathway so
33:40it told us that these Pathways were
33:42instrumental to explaining the
33:45stimulation we also found that those U
33:49um Pathways which mediated this
33:54particular
33:55stimulation they basically had no impact
33:59at high dose but there was a different
34:02mechanism that could block that
34:04inhibition at high do so it showed that
34:06in this particular case we could begin
34:09to identify two mechanisms that could
34:11begin to explain the the stimulation and
34:14the inhibition it's really getting to
34:16the point where that editor really
34:19wanted to see this now and I have as I
34:22said probably close to a thousand
34:25examples of those kinds of things sure a
34:27few more later on but the hormetic
34:29responses themselves deal with
34:31integrated responses across multiple
34:33biological levels of uh organization you
34:36see hormesis for cell proliferation for
34:39facundity tissue repair learning and
34:41other behavioral endpoints diseases
34:44resistance DNA damage tumor incidents
34:47aging and Longevity anything that's
34:49important to you you'll find hormesis
34:53relating to that endpoint essentially
34:55give you some examples here here these
34:57are just chosen um to show you the
35:00diversity really of hormetic dose
35:02responses this is the effects of ethanol
35:04acute ethanol on social behavior in
35:06adolescent rats at day 30 you can see
35:09not unexpectedly that high doses really
35:11just silences their social behavior but
35:14at low doses it actually activates them
35:17considerably but they're in this 30 to
35:20to 60% range it's a very reproducible
35:23assay by the way this is a a fruit fly
35:26study with methanol very toxic at high
35:28doses as you can see but at low doses
35:31this toxic agent actually extends the
35:34the longevity of male and female um
35:37animals um fruit flies this over here is
35:40arsenate at high doses it inhibits the
35:44stimulation of the
35:45lymphocytes um in this assay you would
35:48might might expect this should just be
35:50random bounce at the bottom but it flips
35:52over these little dots at the top
35:54indicate statistical significance here
35:57we have the most toxic element that EPA
36:00is concerned with really P pm10 I'm sure
36:03that they I mean any dose just kills you
36:05we as we heard what Lisa Jackson said
36:09but uh but basically methyl Mercury is
36:12really considered to be I think their
36:14most feared pollutant it's a it's a
36:17potent
36:19neurotoxin um how and it and this is a
36:21neurotoxic assay actually and at high
36:24doses it it actually destroys these uh
36:27neur this these neuronal cells but look
36:29at this at low doses it actually
36:31enhances the vi viability of those cells
36:35it's very very interesting
36:38phenomenon uh this over here is a more
36:41of a biomedical one and and and actually
36:44I was doing a review of a lot of work in
36:47the Neuroscience area and this is
36:49studies in this in the seizure area and
36:52seizures are studied by inducing
36:55seizures in Animals by different
36:56different different uh ways and and this
36:59is with biochemical called PTZ induces
37:02seizures and in this particular study
37:04they then treated the animals with
37:05morphine and once you treated them with
37:07morphine in this Zone it took more PTZ
37:11to induce the seizures this identified
37:13morphine as a potential anti-seizure
37:16agent I looked at this and I says
37:18hormesis it follows a biphasic dose
37:21response it conforms to the to the area
37:24of you know to the to the magnitude
37:27we're talking about very large number of
37:30doses then I went into the seizure
37:32preclinical literature I found about 80
37:34different chemicals tested preclinically
37:36for seizures with animal models and they
37:39all showed an inverted u-shaped dose
37:42response I said this field is just
37:46dominated by hormesis and the seizure
37:49experts don't even know it then I went
37:52into the anxiolytic drug area the the
37:56the uh deal drugs dealing with stress
37:58and so forth and anxiety and and you can
38:01study this in Animals by take rodents
38:04they like to H they they don't like to
38:05go in open areas you put them in an open
38:08area with a lot of light and and they
38:10will not spend their time there because
38:12it's they're at risk now if you can get
38:14drugs to make them spend time in the
38:16open Zone it's it's helping them it's
38:19interpreted to overcome their anxiety
38:22it's like getting me to drive into New
38:24York City um and you can here with this
38:27drug
38:28DHEA at low doses it increases the time
38:32that they spend in the lighted Zone but
38:35at high doses it actually makes it worse
38:37so low dose stimulation high dose
38:39inhibition the anxiolytic drug
38:42literature just like the anti-seizure
38:44drug the preclinical literature is
38:46loaded it's it's totally dominated by a
38:50hormetic dose response and the
38:52pharmacologists for the drug companies
38:54don't actually even appreciate that at
38:56all this over here is the
38:59Resveratrol uh component of red wine
39:02it's considered perhaps one of the
39:04factors why a glass of wine today is is
39:07good for you with cardiovascular health
39:09and you can see a biphasic dose response
39:12here looking at myoc cardiio site and
39:14infar damage and so forth then you can
39:17see at low doses you get a decreased
39:18risk but at high dose actually the risk
39:20can go up now I started the presentation
39:24talking about preconditioning when you
39:26stressing animal and here over here I'll
39:29kind of give you a little preface to
39:31this back in 1986 investigators at Duke
39:34were studying um myocardial infarctions
39:38and ways you perhaps could modulate
39:40these and they they had they wanted to
39:43look at what would happen if you
39:44pre-stress the
39:46animal um with very slight but I say
39:50slight to modest uh hypoxic stress a day
39:53or two before you in induce the
39:55myocardial infarction and what they
39:57found when they did this they found that
40:00uh the animals that were slightly that
40:02were Moder moderately lightly stressed
40:05with hypoxic stress the day or two
40:07before they got the major myocardial
40:09infarction they had about 80% less
40:12damage than those that didn't have the
40:13pre-stress it was kind of the equivalent
40:15of giving an angina having angina pain a
40:17couple of days before the heart attack
40:20and these investigators were shocked
40:22really with the magnitude of their
40:24Discovery they replicated work others
40:27replicated their work uh they then
40:29extended this to um look at other organs
40:32to the brain to the liver to the kidney
40:34to skin um and preconditioning became U
40:38massively significant finding because
40:41there was this upregulation of adaptive
40:44mechanisms uh as a result of being
40:46exposed to low-level stress that would
40:47then protect against subsequent stress
40:50then others as you know investigators do
40:52they decided to induce the heart attack
40:54and give this low level of stress after
40:56the heart heart attack which I figured
40:57could never possibly work and they got
40:59protection the same degree of protection
41:01and and and and and this is actually
41:04revolutionizing the field today in terms
41:08of trying to find ways of um uh really
41:13slowing down various types of diseases
41:15protecting you against all kinds of
41:16potential trauma this over here of
41:19course it now has a very strong
41:21experimental basis here you're giving a
41:23low dose of carbon you're giving um a
41:26essentially a low dose of of um hydrogen
41:29peroxide and then you're giving it a a
41:31somewhat um substantial dose more
41:33massive dose later and at low doses you
41:37can see you these low doses prior low
41:39doses protect against the initial um the
41:43subsequent challenging dose but at
41:45higher doses the protection goes away so
41:48there's an optimal level and you can see
41:50that this preconditioning dose conforms
41:52very nicely to a hormetic dose response
41:56over here this is another example of the
41:59same except this is looking at
42:00myocardial damage in a sprad dolly rat
42:03uh and giving the nitrite 15 minutes
42:06prior to the cardiac damage causes a
42:09nice j-shaped dose response this little
42:12blob over here uh describes uh various
42:16types of research that was done to
42:18identify uh Pathways that mediate this
42:21protection showing a mechanism here the
42:24point of it is is that this lowd do this
42:26hormetic activity is really explaining
42:29the this preconditioning
42:31phenomenon now on the cancer side of
42:34things environmental side this is a
42:37study that's showing gamma rays and Lung
42:40adomas and it's a big study with each
42:43each little blob over here Triangle
42:46Square having about 500 to 750 animals
42:49it's big study and you can see that that
42:53you know this this uh gamma razor
42:56supposed to cause cancer in a linear
42:59fashion but actually they don't there's
43:02a lowd do effect that is decreasing the
43:07the risk that by about I don't know 30
43:10to 40% higher doses it goes up as
43:12expected it's it's very inconsistent
43:15with the linear dose response
43:17relationship this is a study out of
43:19Japan looking at uh effects on this DD
43:22Mouse strain which is predisposed to
43:24developing uh um diabetes Now the the
43:29group got this 65 uh um migr per hour
43:35it's equivalent to about 65 times higher
43:37than background and they got this
43:39throughout their whole
43:40life and you can see here that the ones
43:44in red are the ones that had the uh
43:47radiation and the unexposed group would
43:50be the control and they they really
43:52outlived them by about 25 to 30% now in
43:57the next slide it doesn't show it up
43:59particularly well here but but I think
44:02you can see it here this is the control
44:04group at 90 weeks it it really looked
44:07like my dad my dad lived to be 95 and at
44:1095 he was what you call
44:13welln um and when I look at this slide
44:17reminds me of how my my dad looked at 95
44:19he was he was thin his hair was falling
44:23out he he he he his mind was still good
44:28actually but but he was really well worn
44:31put it that way the same age this animal
44:34is the this it's the fur is full it's
44:39it's it's shiny it's plumped it looks
44:42healthy I said give me that and that's
44:45the lowd dose radiation group I said if
44:48that was coming from a drug from Coster
44:50Rica they'd be they'd be trying to sell
44:51it but it's lowd dose radiation so it
44:54actually is bad for you so it's a very
44:58interesting phenomenon I've seen this in
45:00a series of papers this is not the only
45:02paper a series of papers uh by really
45:06good investigators and really good
45:09journals and even if people see what I
45:13what I don't understand is why these
45:16these inconsistencies with L&T don't
45:19make people who believe in lnt Wonder
45:22are they right uh if these data are
45:25reproducible which they actually are
45:28what does that mean to your theory to
45:30the universality of your theory it has
45:33to mean it has to be a problem actually
45:37it has to be a problem this over here is
45:39looking at radiation gamma rays on
45:41lifespan in crickets and at high doses
45:44it wipes them out but at low doses you
45:45get that same degree of stimulation
45:48we're looking at the effects of uh
45:51x-rays uh I think we have x-rays gamma
45:54rays on on um mut ations in the fruit
45:57fly genome this is the same model that
46:00Herman Muller used who got the Nobel
46:02Prize for showing that x-rays could caus
46:04cancer mly looked at the high do group
46:07high do is way out here someplace if M
46:10had just lowered the dose they might
46:12have given him two Nobel
46:15prizes uh over here um uh an
46:18investigator um Dr redpath from
46:21University of California at Irvine I
46:24think he shows the same type of dose
46:26response looking at neoplastic
46:29transformation frequency uh with a human
46:32nontumor fiberblast cells um a nice
46:35j-shaped dose response these are kind of
46:37Representative of different aspects
46:39through the cycle cancer kind of a cycle
46:42over here DDT is banned because it
46:44causes cancer in the Fisher male Fisher
46:47344 rat and and it does it actually
46:50causes cancer at high doses Japanese
46:53investigators have used a predictor of
46:55uh liver cancer cancer the liver fosi
46:57and at high doses they they show that at
46:59high doses you get these transformation
47:01changes the Japanese however decided not
47:03to look at just two or three high doses
47:05they decided to look at a lot of Doses
47:07and what they found was something weird
47:09happened at low doses they actually got
47:11a decrease in the liver cancer cells and
47:15and they also then looked at this in
47:17tremendous mechanistic detail to try to
47:20explain what is going on at high
47:22mechanistically and low it's it really
47:25is opens up a whole other way of looking
47:28at this um over here you may have heard
47:31of the mega moue study 24,000 animals
47:34try to figure out what the nature of the
47:36dose response was the FDA took this
47:38chemical to AAL Amino Florine they
47:41tested it U um as I say in great detail
47:45and they found yes indeed it was a
47:47bladder carcinogen nice dose response
47:49relationship but they looked at low
47:51Doses and they had six major rooms with
47:53thousands of animals in these rooms
47:56each room showed the same j-shaped dose
47:59response the US Society of Toxicology
48:02put a great board together of 14 people
48:05and they claimed that this dose response
48:07j-shaped was real was hormetic and was
48:12in contrast to the
48:14lnt now the hormetic dose response is
48:18has a lot of applications affects drug
48:20development for anxiolytic anti-ia
48:22memory drugs osteoporosis wound healing
48:25and really many more it's inherent
48:27within biological
48:30systems um you have this preconditioning
48:33and post conditioning also explains the
48:36hormetic base hormetic dose response
48:39explains their phenomenon as well with a
48:42mechanistic uh
48:44underpinning so essentially what happens
48:47now when you have multiple memory drugs
48:50if one let's say there's an Alzheimer's
48:52patient and you can get a memory boosted
48:54up you know know and actually I have a
48:56friend of mine a retired UMass Professor
48:59who was just diagnosed with with
49:01Alzheimer's you know he's being treated
49:03with particular drug he's getting some
49:04little benefit out of it at the present
49:06time his wife is really going you know
49:08kind of crazy trying to cope with her
49:11situation and and so what happens if
49:14they could give well increased his set
49:17point up to certain level maybe they
49:19could give him another drug on top of
49:21that could you what happens if you layer
49:23on three or four or five drugs that it
49:25might be effective and it's a good
49:28question and the data that I have seen
49:30when people have actually tried to do
49:31that in animal studies the way you have
49:35grids of this drug with that drug and
49:37multiple drugs and how you can try to
49:39tease it out and actually what you find
49:42is that in fact um you can't get beyond
49:46that 30 to 60% grade you just can't do
49:49it you can get synergies if you lower
49:51the dose lower enough and get synergies
49:53under that 30 to 60% Zone but in these
49:56studies you can't do it and I've seen
49:58that in a dozen or so to other studies
50:00and so to me it's telling that you're
50:03pushing against this cap this has huge
50:06implications for the pharmaceutical
50:08industry and others because when you are
50:11trying to have drugs that deal with
50:13seizures or analytics or memory or other
50:15things osteoporosis and the like all
50:18acting bi A hormetic drugs you are
50:20constrained
50:22by the gain in the system
50:26and you're not going to go I don't think
50:28Beyond this 30 to 60% a lot of people
50:31are trying in the world of metabolic
50:32engineering they lay on 500 genes they
50:36do this they do that you try to tweak
50:38the systems very hard to break through
50:42redundancies they are trying to the
50:45metabolic
50:46redundancies um so so what is hormesis
50:50actually indicating hormesis in is
50:53really it's a lowd dose stimulation and
50:54it's different from um from high does
50:57toxicity the lowd dose stimulation in my
51:00opinion I believe it's measuring
51:02biological performance it's not really
51:05measuring toxicity it determines how
51:07much the system can respond it's the
51:10first quantitive estimate of biological
51:13plasticity um the hortic haresis
51:17stimulatory response is constrained by
51:19the limits of
51:20plasticity now try to put this all
51:23together hormesis is a general concept
51:27and it's it's a central biological
51:30concept it affects all disciplines that
51:33utilize the dose response and really
51:35everything in biology is going to be
51:37using a dose response concentration
51:39response represents a general adaptive
51:42strategy through which biological
51:44performance uh is enhanced and
51:47mediated uh it provides both the
51:49theoretical basis and the molecular
51:51foundations to create biological Shields
51:55to protect against chemical radiological
51:57and microbial threats and I I love to
52:00ride a bike I ride many thousands of
52:03miles a year and um thanksgiv Sunday
52:07after Thanksgiving in 20 in in 2010 I
52:10took off on a 50 m bike ride I was
52:12coming back home through the UMass
52:14campus I live about a half mile away I
52:16looked at my watch and it was 6 it was
52:182ast 6 and I said oh great the Patriots
52:20are playing I'll watch the second half
52:21of the game be great and the next thing
52:23I knew I fell down and I I was lucky in
52:27a sense it was right next to the um to
52:29the uh Amherst fire department but it
52:32wasn't so lucky and that I had broken my
52:34pelvis in two places not a good day and
52:37so they came out and they dragged me to
52:40the hospital and and um and a couple
52:44days later I saw this big black and blue
52:45down my right leg and I said what's that
52:46they said oh you were just bleeding like
52:48crazy and you're lucky that you weren't
52:50out in the farm country someplace cuz
52:51you just could have bled out and died
52:52there lucky you you fell down next to
52:54the fire station
52:56and so then about 3 months later 4
52:58months later I'm searching the internet
53:00and I come up with see this study from
53:01this guy from Toronto who's looking at
53:04at shock and they're removing blood from
53:06these animals and then they are
53:07preconditioning them with a with a
53:09remote me method which is taking a blood
53:12pressure cuff pre-treating them on their
53:13back leg and and then they are giving
53:17them the the shock treatment and they're
53:20finding that the the preconditioned
53:22animals have about 70 to 80% less damage
53:24than those that didn't get it and I'm
53:26thinking wow maybe I should treat myself
53:29you know day before every single long
53:31bike ride um but the point is is that
53:33shock loss of blood and so forth is
53:35really significant especially for
53:37soldiers wounds and other kinds of
53:39things could be very significant also
53:42this preconditioning remote
53:44preconditioning which people can use uh
53:46with a blood pressure cuff with various
53:48methods and so forth it could be used I
53:52this will protect the brain against
53:54subsequent uh damage and and other kinds
53:57of tissues preconditioning is is used in
53:59a lot of ways to enhance U the
54:01functioning of stem cells and the life
54:03very big very significant but the issue
54:06is improves functioning creates
54:07biological Shields could really help
54:10with the protecting from harmful aspects
54:12with stressful surgeries lots of
54:14different things um so the this has
54:18implications for numerous and diverse
54:20medical interventions as well as
54:22affecting health and performance of
54:24milit Personnel athletes and the general
54:27public um fail you to consider hormesis
54:30and it's been totally failed I mean
54:32hormesis has just
54:34been it's I'm calling it The New Kid in
54:37the block but it was
54:38marginalized
54:40ridiculed um anything you want to call
54:43it throughout the 20th century and the
54:45failure to to consider hormesis within a
54:48hazard assessment and risk assessment is
54:50really a serious failing of modern risk
54:53assessment uh risk assessment needs to
54:56consider the entire dose response
54:58Continuum actually needs to consider
55:00basic biology understanding not be not
55:04be victimized by using only high doses
55:07and a few high doses and thinking that
55:10that the biologies the same at low doses
55:12it actually is not uh and there's too
55:16much data now to suggest otherwise
55:20hormesis can play a role significant
55:22role in drug discovery drug development
55:26and evaluation and in my opinion
55:28hormesis should become incorporated into
55:30educational programs dealing with the
55:33dose response thank you very
55:35[Applause]
55:43much great job uh Ed uh I think
55:47everybody here of course is familiar
55:50with the uh climate change uh debate and
55:53uh there's an incredible similarity
55:56between the hormesis problem and climate
55:59change the science is totally ignored um
56:02but I want to ask you 40 years ago uh
56:06Walter hiy wrote a 1100 page uh book on
56:11hormesis that seemed to have been
56:14ignored uh where was hormesis you know
56:18back then and this predates uh your work
56:21in it well hormesis um I think mesis got
56:26its its its start its real modern start
56:31put it this way with the work of two
56:33real two people one on the radiation
56:35side one on the chemical side on the
56:37radiation side he spoke in here he died
56:39a few years ago uh Dr lucky uh he he
56:43made the move back in 1980 published a
56:46book ionizing radiation and uh and and
56:49hormesis and um and lucky lucky was
56:53actually more insightful than than any
56:54anybody because in 1975 I found in in
56:58the preface of a book that he published
57:00before EPA um began their regulatory
57:03practices really um lucky said the
57:07hormetic dose response is significant
57:10it's a real component of the dose
57:11response and Regulatory Agencies would
57:13be very wise to consider this as they go
57:15forth on their activity I mean he was
57:19actually preent he he was ahead of us
57:21all um and um uh and at the same time at
57:26the very same time do uh Anthony
57:28stebbing from the um U Marine biological
57:32research station in in Plymouth uh UK
57:35was making similar discoveries um
57:38looking at Metals in the marine
57:40environment and came up with very
57:42comparable things they never really
57:44communicated with each other but they
57:46were very independent and very
57:47significant and a third person uh Dr uh
57:51Elmer zabadi from University of um
57:54Liverpool did the same thing
57:56pharmacologically in the late 7s and so
57:59those three for me um they they had
58:02Persona Beyond one paper and and book
58:05and so forth and for me they they uh
58:08what we what I have done is basically um
58:11they they brought it from uh they
58:14separated hormesis from the historical
58:17antipathies with and relationships to
58:19Homeopathy to really Central core
58:21science and and I viewed those as my my
58:25role models and uh but things have then
58:30moved on from there but those to me but
58:32that was Circa
58:341975 to 83 and then what happened to
58:38really make it big was the was the inv
58:41vitro revolution of the 8S it allowed us
58:44to go in vitro and allowed us to test
58:46lots of concentrations at the same time
58:49which you couldn't really do with whole
58:50animal studies and now about 80% of the
58:52papers are in vitro so the the the inv
58:54vitro Revolution dovetailed with that
58:57and my own stuff I think to push it
59:00ahead hi uh I'm Howard Hyde and I have a
59:04doctorate in nothing um my father was a
59:07re a nuclear scientist my brother's a
59:10physics Professor I remember reading a a
59:13story a few years ago about a city in
59:16Asia someplace where it had been
59:18discovered that a some cluster of
59:20buildings had above legal levels of
59:23radon or some other radioactive material
59:26in the building materials and this this
59:28caused a great uh shock and they they
59:31took measures to uh you know Mi mitigate
59:34this but in a subsequent follow-up study
59:37of the rates of cancer in in the area
59:40they found that the cancer rates were
59:42actually lower clustered around these
59:44buildings that had the radon in them
59:46than uh in the larger area I think that
59:50uh somewhat fits the the theory that
59:52you're talking about it does fit and and
59:53I actually invited the investigators
59:55from
59:58um directed that study to one of our
1:00:00conferences have U their papers have
1:00:03been published they're out there in the
1:00:04literature and uh uh it's a significant
1:00:08um you know unique opportunity to study
1:00:12these types of these types of effects
1:00:15but yes it does exist it's out there
1:00:17searchable and should be read that
1:00:20particular paper was published in our
1:00:22Japan's Journal of AAP yes there's
1:00:25apartment buildings in Formosa that uh
1:00:29were concrete buildings Cobalt 60 had I
1:00:32don't say contaminated I say enhanced
1:00:35the rebar and you're right about your
1:00:37statements there uh thank you so much Dr
1:00:40Cales you showed initially the
1:00:44linear do uh the the the
1:00:47linear line and then the threshold and
1:00:51straight line I know the these are used
1:00:53extensively in the regulatory sphere are
1:00:56there any real life examples in biology
1:01:00where the linear response is the true
1:01:03response every single curve you've shown
1:01:06has been curved one way or the
1:01:09other it's a really basic question is
1:01:13um where is where did the L&T come from
1:01:17actually that's going to be the topic of
1:01:18my next presentation today and so if
1:01:21it's okay with you I will I will answer
1:01:23that in the next
1:01:25presentation because I will spend quite
1:01:27a bit of time on it next question Ed
1:01:30great talk I really appreciate it uh one
1:01:32question I had for you you said hormesis
1:01:34applies what was it 40% of toxic stuff
1:01:38exhibits hormesis actually what I what I
1:01:40specifically said was when we went in
1:01:42with extremely rigorous our priority
1:01:44entry and evaluative criteria our study
1:01:47showed that 40% satisfied those criteria
1:01:50if we had loosen them up just a little
1:01:52bit U we could have
1:01:55easily bumped that over to 65 to 70%
1:01:58okay um and and then there are other
1:02:01reasons why you know you you have
1:02:03statistical reasons that just don't show
1:02:05things I think that hormesis is is far
1:02:07more common than the 40% but it but I
1:02:11had to be so
1:02:13darn tough on the study so I could make
1:02:16sure that I handled all the criticisms
1:02:19possible that that the criteria that we
1:02:22used were actually unreasonable
1:02:24severe and and understated what the
1:02:27actual occurrence was in that particular
1:02:29study so my followup is the two big
1:02:32bugaboos that are out there in terms of
1:02:34toxic stuff lead and asbestos is there
1:02:38anything you have in the data or
1:02:39anything you've read that that may also
1:02:41apply to those two biggies it's
1:02:43interesting I I have looked at both of
1:02:45those as a matter of fact I have
1:02:47actually a substantial amount of
1:02:48literature on LED uh to show hormetic
1:02:52dose responses in multiple multiple
1:02:55biological models um I've actually
1:02:58actually in the in the original work
1:02:59that was published by Dr needlman that
1:03:02really turned the field on its head with
1:03:04respect to lead back in the late 1970s
1:03:07the original papers actually have
1:03:09hormetic DOS responses in them that
1:03:12apparently at least in my opinion they
1:03:13look pretty strong as hormetic and were
1:03:16uh and were not uh you know dwelt upon
1:03:21but but I have lots of other aspects
1:03:23with lead showing hormetic dose
1:03:25responses at at low doses as to the
1:03:28asbestos one that's more problematic it
1:03:31hasn't been studied within that fashion
1:03:33but I do have a series of uh of cell
1:03:37culture studies a multiple series of
1:03:40studies with cell culture that do show
1:03:42hormetic effects with some asbestos
1:03:45fibers that actually is U is an
1:03:48interesting thing to follow up
1:03:50on hey oh I'm sorry um in Orthopedics we
1:03:55all have colleagues that have developed
1:03:56lymphat totic disease you know and we're
1:03:59always exposed to radiation and I have
1:04:01to say they tend to be the guys that
1:04:02refuse to wear lead in the O but for
1:04:04those of us who actually do wear lead I
1:04:06mean I'm I've always wondered what is
1:04:08the I mean what is the dose response
1:04:10curve where is the The Beneficial
1:04:12radiation dose you know we think that
1:04:14that's due to and there have been number
1:04:15of studies it's due to Total cumulative
1:04:18lifetime whole body radiation or
1:04:20radiation dosage what do we know what
1:04:22the optimal radiation dosage for humans
1:04:26is uh to be like the mouse well well
1:04:28it's a great question I I'd have to say
1:04:30that that that's a great question um and
1:04:33I can there are number of ways to try to
1:04:35address it um but I'd have to say that
1:04:39that the answer might not be U really
1:04:41satisfying because the optimal dose is
1:04:44is really tied into the end point that
1:04:46you're looking for for example if you're
1:04:48looking for a cancer end point it would
1:04:51it would I believe there will be a
1:04:52j-shaped response for a cancer point but
1:04:54it may depend upon the tumor that you're
1:04:56looking for now if you're looking for
1:04:59radiation to enhance an immune response
1:05:01which it does at low doses it would also
1:05:04depends on the particular immune
1:05:06response however I would say that that
1:05:09in general the optimal response is above
1:05:12background um so so what we're we are
1:05:16living in today is a probably um
1:05:19suboptimal radiation ionizing radiation
1:05:22exposure to optimize um the activation
1:05:27of um um I'm going to say certain types
1:05:29of uh immune responses that could be
1:05:32useful and other endpoints so it's it's
1:05:35it's kind of a squishy answer because I
1:05:37I really have to sit down with you and
1:05:39and try to figure out which end points
1:05:42are important to you and which ones are
1:05:43important to me and which ones are
1:05:44important to others well I guess I was
1:05:45interested in all cause mortality but I
1:05:47mean you know I mean Mo mostly I mean we
1:05:49just don't want to die in our 50s of you
1:05:52know lymphatic put cancer but we we're
1:05:54all above Baseline so the issue is how
1:05:56far above Baseline we should be and what
1:05:58we need to because because it it does
1:06:00impact how much pounds of lead we wear
1:06:02and how much we really it's it's there's
1:06:04a cost it's just like EPA there's a cost
1:06:07of doing business and it's standing for
1:06:0812 hours and 35 pounds a lead versus 50
1:06:10pounds of lead you know as as you can
1:06:13see in the studies that I gave for the
1:06:14model The Strain that I provide you with
1:06:16there and I have many others along these
1:06:18lines that those an animals are getting
1:06:2165 times greater than background for
1:06:23their entire life and they had uh
1:06:27beneficial components for them how it
1:06:30plays out
1:06:31epidemiologically is uh that's another
1:06:34question

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