Greg Wilkinson

Ah, you were joking of course. [Yes, I was joking--a--actually you have 8 minutes?]

Could I have the first slide, please? [clears throat] What I would like to do is to ah, review ah, a sample of the ah, human studies [clears throat] that have dealt with ah, effects due to alpha radiation exposures.

[clears throat] I've broken down these into several large categories and of course in the time that ah--that we have, we'll only be able to ah, review a brief smattering of results ah, for these various categories. Ah, perhaps, ah, the--the category of--of exposure that affects the largest population ah, in general, is ah, radon, ah, which was mentioned by Dr. Robbie earli--earlier. It was a goodly portion of the--of the, ah--the populace ah, exposed to naturally occurring radon.

Um, the research that has been conducted in this area [clears throat] has focused primarily on minors, ah, with ah--from which we, ah, know today ah, that minors exhibit an excess risk of ah--of lung cancers. Studies of the general populace, however, have not been quite so definitive and in fact there--right now, there's a slew of studies, primarily case control studies that are looking into residential exposures to see whether exposures at the levels that the general populace ah, experience also result in, um, elevated risks for lung cancer.

Now, plutonium workers--[clears throat] exposures to plutonium--that's an area that I've ah, ah, worked in in the past, ah, particularly with regard to plutonium workers, ah, and ah, I'd like to just present briefly some results ah, regarding ah, some of those studies. The studies of the general populace, ah, ah, are really very ah, contentious and ah, I think at this point we know very little about effects ah, in the ah, general populace, at least ah, to the extent we can measure them.

Ah, the radium dial painters--the--the--these were mentioned by ah, Dr. Robbie, earlier and I--if I have time I just very briefly want to ah, ah, show some ah, ah, results from some of the early ah--early studies.

Radium 224 also was mentioned by Dr. Robbie. [clears throat] Radium 224 ah, was used ah, in the treatment of [anklosing spondilitics?] ah, [clears throat] primarily in Germany, ah, Portugal, ah, and Japan. Ah, recently, ah, well, I think what I'm going to do is--is pass over the ah, the studies of radium ah, 224. And then the [thoropress?] patients comprise another ah, group of ah, folks that are of particular interest, ah, [thoropress?] was used as a contrast medium um, [clears throat] Gerhard [van Kech?] ah, in ah, in Germany has published widely on--on the effects of ah--of [thoropress?] with--which has resulted in large, ah, excess risks for um, liver cancers.

[clears throat] More recently, a study has come out of Denver using the even--out of Denmark using the Danish tumor registry that has provided some quite interesting ah, results.

Ah, to begin with radon--just to mention some of the characteristics of radon. It's an odorless, ah, colorless gas. It's a decay product of radium 226 and uranium 238. It's present in soils and rocks. Ah, it's released from water. It has a half life of ah, ah, 3.8 days--just under four days. And it decays into radon progeny ra--ah, formerly called radon daughters, which are of ah, ah--of primary concern--plutonium 218, ah, plutonium 214, that emit alpha particles and this--it's thought to impact the [epithelial?] cells in the ah, in the respiratory tract.

What I'd like to do is present some ah, briefly some results from two studies of uranium miners. [clears throat] The reason for focusing on uranium miners is their exposures were ah, characterized ah, probably to about the best extent that they can be ch--ah, characterized, ah, at this point in time. Ah, this is the--these are the results from a study of French miners ah, reported ah, by ah, [...?...] colleagues in 1993. It's based on a cohort of just under 1800 miners who are employed from '46 to '72 for greater that two years.

Ah, the mean, ah, exposure was 14 ah, just under 15 working level months, ah the ah, the cumulative exposure was about 70 ah, working level months with the age, ah--the average age at ah, first exposure being just under thirty, ah, thirty years.

Um, in these studies the reference population ah, was the ah, general population ah, of France. And in this first slide, um, [clears throat] you can see what we would expect to ah, to see--an increase ah--an increased ah, standardized mortality ratio. It's the same calculation that Hal Morgenstern used, ah, at least in a portion of his, ah, study, of over a--a--just over two, for a cancer of the lung. Somewhat surprisingly is this ah, ah, elevated SMR for laryngeal cancer of 2.4, [clears throat] with all--all cancers ah, just being ah, very slightly ah, ah, elevated.

[clears throat] Um, looking at the--at the dose response, ah, for lung cancers, you can see that the ah--the SMR, ah, increases from just under two, ah, up to about five ah, with ah, mean cumulative working level a month. [clears throat] And this is a--ah, ah, significant ah, trend indicated a dose response, ah,--a trend. The confidence limits um, are all above one except for this one, ah, ah, level, ah, as--as the ah, exposure increases, we see the confidence limits getting wider, indicating fewer and fewer cases at these ah, higher exposed ah, ah, levels. Now this is for--that was for lung cancer.

When we looked at laryngeal cancer ah, we don't see the same kind of effect. [clears throat] Um, we see the SMR bouncing around, without an overall ah, increase, although it's ah somewhat higher at this ah, exposure level, but no cases were seen at the ah--at the highest, ah, working level month ah, exposure category. [clears throat] With the dose response trend not being ah, significant. Ah, ah, so, what this--this indicates is that ah, laryngeal cancer is probably not due to ah, ah, exposure um, to ah, ah, uranium, or if it is, it's confounded by other exposures, ah, perhaps, ah, smoking, ah, perhaps ah, alcohol intake or--or other factors.

[clears throat] The second study I wanted--want to ah, ah, just briefly mention the results of is a study reported by ah, Roscoe--Bob Roscoe and his colleagues, ah, at [Nyelzh?]. [clears throat] Um, this is a study of ah, of white uranium miners, ah, compared to white males in New Mexico, Arizona, Utah, and Color--and Colorado, ah, for the period 1960 to 19 ah, 90. [clears throat] In this study, um, Roscoe reports, ah, SMRs of ah, just under three for all cancers for this group of miners. Ah, under just under six for ah, lung cancers and then there's this ah, ah, ah, slight elevat--[...?...] elevation of ah, just over two, ah, for this catchall category of benign and unspecified, ah, tumors. The confidence intervals in ah, the case of all cancers--the lung cancers are above--ah, considerably above one and being fairly tight, ah, indicating ah, fairly good numbers ah, in ah, in those cohorts.

Um, the--the--this particular study was based on the larger population. If you recall, the French study was about--based on about 1600 deaths, I think I mentioned that. Um, here--I mean, s--a population of 1600, um here the ah, the ah--we have a ah, a population of about 3300, ah, just over 3300 ah, white miners in these ah, ah, States. Um, [clears throat] and it was a total of ah--of ah, 1595 deaths. Um, some other um, causes of death, ah, also were elevated among this group including ah, tuberculosis, ah, the general category of respiratory ah, diseases pneumokonioses, very high ah, increase of pneumokonioses ah, other chronic obstructive disease and emphysene--emphysema. Now the degree to which these, ah, ah, causes of death are related to ionizing radiation is in doubt, probably what these are s--ah, these findings reflect are exposures to ah, dusts, ah, other kinds of contaminants--these were all underground miners and perhaps, ah, a s--ah certain lifestyle ah, habits such as ah, smoking.

[clears throat] Um, in an attempt to ah, ah, get an idea of ah, the relationship between the level of exposure ah, and risk, [coughs] um, they categorized exposure into various working level month ah, categories and then conducted, ah, two types of analysis. Um, the--these are the results from the ah, the SMR analysis indicating tha--that I previously showed in a previous slide--indicating an increase ah, with ah, working level month. And then they also ah, conducted ah, a--an internal comparison which, again is similar to what Hal Morgenstern ah, ah, ah, mentioned earlier, where you compare um, higher level risks and higher level exposure categories with that at the lowest level, ah, internal to the population that you're studying.

One o--one of the problems, and Hal mentioned this, was the healthy worker effect ah, when comparisons were made with the ah, the external popula--with the general population or a population that's external to the ah, ah, experimental population that you're interested in. [clears throat] In the case of working populations this causes the bias called the "healthy worker effect," which helps to underestimate any effects that ah, might be seen, but also, ah, some epidemiologists have argued that the use of that kind of ah, population is really compri--really comprises an inappropriate ah, comparison.

[clears throat] In--in conducting the internal ah, ah, comparisons where we're comparing risks in the higher level ah, ah, exposure categories with the lower level, we see that risks--that the risks increase--just as they did, similarly with regard to the ah--the SMR analysis. Um, the risk estimates are somewhat lower, ah, they increase, though, with the, ah, cumulative working level month, ah, and the confidence intervals are all ah, above one, um, ah, for each of these exposure ah, categories.

[clears throat] Um, th--here this--this breaks down the ah, findings. What I've done is ah, ah, ah, adapted from the data reported by Roscoe, ah, and just--just looking at the ah, standardized [integrations?] with the internal comparisons because it's a stronger ah, kind of analysis ah, for lung cancer this is repeating what was shown in the previous slide. Ah, all cancers except lung and ah, here what happens--remember we saw slightly elevated risk ah, earlier? Here what we see is that ah, it ah, falls--ah, falls away, so that we don't see any evidence, ah, for all cancers except lung, with lung excluded, of any relationship between exposure ah, to radon and ah, ah--and the increasing risk for all cancer. Ah, no evidence of such an association.

Ah, benign, unspecified tumors, which was also elevated--again, we see no overall increase, ah, in the risk associated with ah, working level month. Ah, the--one of the reasons I found benign and unspecified tumors interesting is because in and early study I was involved in of Rocky Flats, ah, excess of benign and unspecified ah, ah, tumors ah, ah, was one of the first things we saw and when we looked into it further, we found that ah, this category was comprised, ah, almost entirely--in fact, I think, exclusively of brain tumors--various kinds of brain tumors. [clears throat] Um, I--I--I did not ah, see what kind of breakdown--ah, I don't know what kind of breakdown, ah, this catchall category for this ah, ah, population, ah, is comprised of.

Um, [clears throat] skipping over now to ah, a study ah, that ah, was recently reported by Luben, [coughs] which involved a pooled analysis of ah, of ah, eleven cohorts of underground miners, ah, most of which were uranium miners, but ah, also included a large, ah, several cohorts of ah, underground miners that were not uranium miners. [clears throat] Um, I've only reported here, ah--the results are reported in a rather thick document um, [clears throat] and comprised a pooled analysis--an interesting ah, ah, ah, ah, i--ah, analysis ah--a very interesting approach. [clears throat] Um, this is just the ah--the model--the risk model for ah, all of the data combined across those eleven worker cohorts where the excess relative risk--ah, this is an excess relative risk model ah, increase about a half a percent for working level month across ah, all of these, ah, these average working level month, ah, categories.

[clears throat] One of the issues ah, that's particularly relevant to, ah, ah, uranium miners is ah, the issue about lung cancer in smokers and non-smokers. Charles [Land?] ah--the--this is taken from a paper by Land and--and s--and his colleagues, ah, that was published ah, fairly recently where they compared ah, the histology of ah--of ah, lung cancers in atomic bomb survivors, ah, and in a ah, sample of uranium miners for which they had just the logical data from the Colorado plateau [clears throat] and ah, this--this ah--there are several ah, types of models that they report or--or, ah, ah, groupings of ah--of, ah, r--of ah, findings. Ah, what I wanted to show you here is ah, this ah, shows the relationship between cell type ah, and smoking behavior [clears throat] ah, controlling for radiation ah, exposure, ah, and also controlling for population and several other factors. [clears throat] and what they found is--and this is similar to what we would expect--is they found ah, elevated ah, odds ratios, ah, estimated odds ratios for [scoima?] cell, ah, ah, tumors, and of course, [scoima?] cell c--cancers are--that's the most common histology for smoking related lung cancers, ah, ah, that we know of. Ah, small cell and [abocarcinomas?] were somewhat lower. Ah, we see the same kind of ah, relationship with [cumulative pack?] years ah, which is an attempt to get at ah, ah, ah, a dose response ah, ah, kind of associations. And what we see here is that with [cumulative pack?] years we see the--the increase in risk ah, for both atom bomb survivors and--and ah, uranium miners of just over two.

[clears throat] Ah, taking the same ah, ah, approach, here what they've done is that they've looked at the relationship between histology in atom bomb survivors, ah, independent of uranium miners, controlling for smoking and some of the other ah, ah, ah, factors and confounders that they were able to control for, and what you see here is ah, ah, a very ah, large increase in the risk of ah, of s--of small cell tumors--lung tumors--among atom bomb survivors [clears throat] almost tenfold ah, ah, ah, risk ah, and a--and a much smaller [...?...] a slight elevation of just under 40% for the [scoima?] cell tumors. Ah, for the uranium miners we see a similar kind of a finding with the small cell tumors being elevated ah, [clears throat] associated with ah--with ah, working level month, ah, and controlling for smoking where scoima cell are much loader--ah, lower.

Ah, ah, Land argues that the difference ah, ah, in the degree of the elevation between ah, uranium miners and between A-bomb survivors has to do with the type of radiation exposure that they ah--that they received.

[clears throat] Um, I just briefly want to mention, ah, ah, the results from a study that ah, ah, I was involved in down in Galveston. Ah, this was a study of ah--of ah, of ah, residents in ura--in a uranium mining area ah, I had mentioned earlier that one of the, ah, questions concerns the extent to which the general populace is affected by ah, exposures to ah, ah, naturally occurring radon [clears throat]. Um, we identified an area in Texas where uranium mining ah, had been conducted ah, and which con--ah, c--ah, c--ah, contains some areas of unreclaimed ah, uranium tailings.

[clears throat] Ah, one of the difficulties in doing these kinds of studies, however, and studies of the general populace is you have difficulties in--in looking at exposure and you also--even in worker studies you have difficulties in the size of the population--takes large populations to be able to come up with results that are ah, even approach [physical?] precision. And so, um, a--at Galveston we had a very large group of environmental toxicologists ah, who were i--interested in ah, chromosome ah, studies and other kinds of ah, of ah, bio-marker studies [clears throat] and ah, I linked up with ah, one of the individuals who wanted to have some ah--[William Oud?] who wanted to have some epidemiologic ah, input and what we did is we identified a population that resided in a uranium mining area and a--a population ah, that was close, but did not reside in the same area, and ah, obtained blood samples, ah, and ah, ah, conducted the standard, ah, William [Oud?] conducted the standard ah, chromosome, ah, aberration study and in addition he did ah, ah, what he calls ah, ah, a study of ah, DNA repair deficiency where what he did is he takes and irradiates the--the ah, samples with a hundred [centigrey?] ah, one dose of ah, of ah, gamma radiation and then takes another sample of the same cells and ah, irradiates to ah, breaks the--protracts the radiation into 50 and 50 ah, ah, [centigrey?].

[clears throat] What these results show is that we really didn't see much of anything in the standard chromosome aberration study, ah, when we got into the--when we got into the ah, the DN--the--the study of ah, where ah, the cells were irradiated with gamma radiation--we s--we found this kind of ah, of an increase, ah, w--in th--in the percent of aberrant cells, ah, for both of these ah, cases where ah, the--the samples were irradiated.

[clears throat] Now, the problem is there--there are several problems with this kind of--this kind o--of study. First of all one of the problems is we don't really know what the exposure to these groups were. Ah, the--the in--ah, radon, ah, [track etch?] ah, dosimeters were place in the homes of these individuals and there was no difference in radon levels, ah, indicating that ah, whatever is causing ah, this kind of discrepancy between ah, study residents and those in the reference population ah, is probably not due to radon exposure, then we don't really know what it's due to ah, it may be due to some kind of ah, ah, ah, other kind of exposure in the area or maybe, ah, ah, to some population difference, um, whatever, ah, at this point it's ah, it's quite unclear.

I want to ah, move on to ah, just briefly mention ah, some--some results from [cough] studies of plutonium workers. The--these findings are taken from ah, the long term study of Manhattan Project workers that was originally ah, started ah, s--ah, soon after the second world war by [Wright Langham?] and ah, Louis Hempelmann [clears throat] and it--its consists of ah, t--group of twenty six ah, Manhattan Project workers who were ah--who at the time had ah, what were kn--the highest known plutonium exposures. These folks have been brought in periodically, ah, every five to ten years for ah, ah, in depth ah, clinical follow-up, ah, and one of the main purposes, in fact the main purpose ah, was not only to see if there are any clinical kinds of abnormalities that occurred among these individuals but primarily was to measure the amount of plutonium that was excreted in urine. Um, at some point, however, the--the individuals there started looking at SMRs, trying to see well, what was the--the ah, rate of death ah, ah--how it compare and this small group of ah, Manhattan Project workers with ah, with the general populace [clears throat]. And ah, as of ah, the last follow-up--this was just reported in nine--in ah, 1997, we see about 13 deaths occurred out of this ah, cohort of 26, including one bone cancer [clears throat] which gives an humongous, ah, ah, SMR, ah, we also see ah, one case of prostate cancer ah, ah, that occurred which gives us a slightly [elevated?] SMR.

Now the problem is the--there's--there's a major problem with this kind of approach and the first is that as an epidemiology-ist--epidemiologist it causes me to shudder to--to think about looking at a cohort of 26 people and following them up over time and then f--then comparing them with the U.S. population. The--the second ah, thing that bothers me with this is that, ah, even if you do find something such as is the case with bone cancer--one bone ca--all it takes is one bone cancer and where you expect only ah, ah, .01, and you--you get this very ah, elevated ah, standardized mortality ratio--the problem is nobody believes it or very few people believe it, ah, because you only have one--one case. Ah, this--th--this is an interesting finding. Ah, I don't think that it should be disregarded, but on the other hand it's very difficult to explain and what we would like to have is not 26 workers but at least 2600 or better 26 thousand.

Let me just ah, ah, finish with ah, ah, ah, [clears throat]--let's see, this--this ah, shows, ah--this is the same--OK this is ah, ah--[Volz?] carried this ah, study a little bit further and looked at--ah, ah, selected a sample of about 8 hundred and--and twenty some ah, control subjects and--and ah, compared the rate and this group of Manhattan Project workers with the rate of control subjects and ended up with ah, ah, that kind of finding.

And finally, I just wanted to ah, ah, mention the ah, plutonium depositions in these cancer cases in this small study [clears throat] um, the--the ah, ah, deposition in the bone cancer case, ah, based on Jim Lawrence's program, his estimate was 580 ah, [beckerels?] ah, [clears throat] whereas in--when--this person was brought to autopsy and ah, 252 [beckerels?] were ah, ah, were identified in the case of the autopsy study. Now, this--this exposure is--is m--is quite low. Ah, it's not what you would expect to see ah, [clears throat] ah, any relationship between ah, a bone cancer and this kind of ah, of exposure level. So, it's very difficult to--to ah, to explain ah, [clears throat] and I guess what I would like to say in closing--I guess I'll close here--is that at some point, the--the radiation biology and the epidemiology have to come together to try and explain some of ah--some of these findings. Ah, they don't ah, exist ah, ah, ah, in opposition to each other, ah, we need to ah, at some point, ah, come to closure so that we understand ah, what some of these results are telling us. Thank you very much.