DISCLAIMER

     The following is a staff memorandum or other working
document prepared for the members of the Advisory Committee on
Human Radiation Experiments. It should not be construed as
representing the final conclusions of fact or interpretation of
the issues. All staff memoranda are subject to revision based on
further information and analysis. For conclusions and
recommendations of the Advisory Committee, readers are advised to
consult the Final Report to be published in 1995.

                                                           
               þþþDRAFT þ FOR DISCUSSION PURPOSESþþþ

MEMORANDUM

TO:       Members of the Advisory Committee on Human Radiation 
	  Experiments

FROM:     Advisory Committee Staff

DATE:     October 18, 1994

RE:       Plutonium Injections Case Study:  Ethical Analysis



     The memorandum on the historical background of the plutonium 
injections should be read in conjunction with this one.

I.   Harm-Benefit

     At the time that the injections were given it was recognized that 
much remained to be learned about the biodistribution of the 
transuranic elements.  Wide variations had been observed among species 
and among individuals, both in animals and in man.  

     In 1944, J. Robert Oppenheimer concluded: 

          Interpretation of Dr. Hamilton's data on rats in terms of 
          humans indicates that 50-100 micrograms of plutonium 
          [3.3-6.6 uCi Pu-239] in the skeletal system is the lethal 
          dose.  Calculations of the dangerous dose of plutonium in 
          lung tissue leads to answers between 0.5-5.0 micrograms 
          [.033-.33 uCi of Pu-239] depending on the assumptions which 
          have been made. [Oppenheimer to Hempelman, August 16, 1944]                                                                                                    

     However, Robley Evans had concluded by 1944 that data 
extrapolated from rats to humans was unreliable because rats could 
tolerate higher rates of radium than humans. (R. Evans, Amer J 
Roentgen and Rad Ther LII, October 1944)  Evans subsequently focussed 
on retrospective studies of radium dial painters.

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     At the time, the primary motivation for the plutonium injections 
was the need for accurate excretion data to determine body burdens in 
atomic industry workers and accident victims.  The problem was
highlighted by an accidental explosion of 10 milligrams [660 uCi Pu]
in the face of Don Mastick at Los Alamos in 1944. The questions raised
were, in Oppenheimer's words: 

          1) How much plutonium was absorbed by the gastro-intestinal 
          tract in this case, 2) what fraction of a serious dose does 
          the absorbed plutonium represent and 3) is it safe for 
          Mastick to go back to work in Building D at his old job.  
          [Oppenheimer to Hempelman, August 16, 1944]

     In the 18 plutonium injection cases, injected doses of Pu-239 
ranged from 0.095 to 5.8 uCi (.0013 - 0.15 uCi/kg).  Thus, the high 
end of the dosages received (5.8 uCi  in the subject Chi-II) would 
have been within what Oppenheimer interpreted as the range for a 
"lethal dose."  It is unclear what Oppenheimer meant by a "lethal 
dose."  For example, this term could have been used to refer to the 
risk of death many years in the future or to more immediate risks.

     The following table provides important information about the 
three Cal subjects:


No.  	Sex  	Birth     Disease      uCi       Material     

Cal-1	M    10/11/1886	  Gastric      5.2       Pu-238**
                    	  carcinoma*   0.12      Pu-239

Cal-2	M     6/26/41	  Osteogenic   0.17	 Pu-239
                          sarcoma

Cal-3	M    1/26/11   	  Chrondomyxo  0.095     Pu-238
                    	  sarcoma l. leg***
-----------------------
*misdiagnosed peptic ulcer
**there is some doubt about the exact dose Cal-1 received because 
  Pu-238 and Pu-239 could not be separated at the time.
***amputated 4 days after injection


Thus, if Pu-238 was for relevant purposes the equivalent of Pu-239
[This point is being further researched.], Cal-1 received a dose 
that was within the range of what is termed a "lethal dose" in 
Oppenheimer's letter of August 16, 1944.

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     Plutonium was in those days being considered as a potentially 
effective treatment for some types of cancer.  Like strontium and 
radium, both of which had been studied, plutonium is a bone-seeker.  

     Nevertheless, there is no basis for inferring a therapeutic 
intent in Cal -1-3.  In the case of  Cal-1, who was mistakenly thought 
to have stomach cancer, there has never been reason to believe that 
plutonium, strontium or radium could lodge in stomach or tumor tissue.  
Therefore Cal-1 appears to have been a metabolic fate experiment 
undertaken for the Manhattan Project in light of laboratory worker 
exposures.

     Cal-2 and Cal-3 had bone cancers, but in both cases the dosages 
were too low for therapeutic purposes.  Moreover, Cal-3's leg was 
amputated a few days after the injection; if there was therapeutic 
intent in this case, it is hard to square it with the fact of the 
amputation.  

     Thus, although it is plausible that the injections of Cal-2 and 
Cal-3 were motivated in part by the desire to eventually develop a 
treatment for bone cancer, it is extremely unlikely that there was any 
basis at the time for concluding that there was any prospect that 
Cal-2 and Cal-3 might themselves benefit from the injections.

     Another problem is the basis for the specific dosages that were 
given.   It is possible that the dosages were determined by the needs 
of analytical techniques available in the laboratory at the time.  
Some support for this hypothesis is found in Oppenheimer's observation 
that, since Pu is excreted at a low rate, "As yet no satisfactory 
method of assaying excreta has been devised. . . ." [August 16, 1944 
Oppenheimer to Hempelman].  In general, then, the primary (if not 
sole) aim of the series of plutonium injections might well have been 
to determine whether the excretion of the material could be measured 
with existing instruments, to justify developing this technique as a 
tool for industrial health.

     Besides medical efficacy, another form of  benefit to research 
subjects is their sense of service to the nation or to the community.   
Although intangible, it is nonetheless quite important for some 
people.  In the case at hand, it has been argued that those who worked 
with plutonium accrued substantial benefit from these plutonium 
experiments, since their body content of plutonium could henceforth be 
estimated within reasonable confidence limits.  Had this possibility 
been made known to Cal-1 and Cal-3 and to the parents of Cal-2, they 
might have enjoyed the psychological benefit of knowing that they had 
performed an important altruistic act.  We have no evidence that bears 
directly on whether or not the potential importance of these 
injections to science and worker safety, as well as to the national 
defense, was ever shared with these subjects and parents (see below).  
What is known about the information provided is discussed in Sections 
III and IV.

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II.  Subject Selection

     The execution of this aspect of the study is suspect:  in order 
to maximize the possibility of autopsy and minimize the possibility of 
long-term harm, patient selection was based on limited life 
expectancies (less than ten years).  Both Cal-1 and Cal-3  exceeded 
this life expectancy by decades. Subject selection thus appears to
have been mishandled.  It is unethical to intentionally select as 
subjects individuals who cannot, within a reasonable range of medical 
certainty, be said to meet the criteria indicated by the study design.
It is possible, however, that these misdiagnoses were a function either
of  incompetence or "honest mistakes."

     Besides this problem, the deliberate selection of patients 
thought in some sense to be "dying" by no means eliminates ethical 
obligations on the part of the scientific investigator.  Like any 
other patients, those with terminal illnesses have a right to decide 
whether they shall be experimental subjects or not.  The rationale 
that persons who are facing death have "nothing to lose" has 
historically been the basis for grave abuses of the self-determination 
of the dying.  Current medical ethics explicitly rejects this notion 
in favor of the principle that patients should make an affirmative 
decision whether to participate in medical research.

III. Information Disclosure

      According to Hamilton, the subjects were told that they would 
receive an injection of a new substance, that it was too early to say 
what it might do, and that other substances like it had reduced cancer 
growth in other patients.  The latter seems to have been a reference 
to strontium, which had been used for palliation in patients with 
solid tumors, but was subsequently abandoned.  It is not clear whether 
plutonium or radioactivity were mentioned.  Technically "plutonium" 
remained a classified term at the time of the injection of Cal-1; the 
term was no longer classified when Cal-2 and Cal-3 were injected.  

     Cal-1 -   There is no evidence about what, if anything, Cal-1 was 
told.  (Other than the reference by Hamilton, who was the investigator 
responsible for the plutonium injections at UCSF.)

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     Cal-2 - A medical student's note states that the parents were 
eager to begin the "plutonium treatment."  If this was the physicians' 
formulation then the parents appear to have been misled.  On the other 
hand, this might have been the parents' formulation, in which case the 
word plutonium was known to them.  Finally, this could have been the 
intern's shorthand for whatever "treatment" the parents had been told 
might be available, and not a direct quotation of the parents.  In any 
case, other than the medical student's note, there is no documentary 
evidence about what the parents might have been told.

     Cal-3 - There is no information about the content of the 
information disclosed.

     By current standards the subjects would have to be clearly and 
carefully informed about the nature of the material to be injected.  
Cal-1 would need to understand that he would receive a dose within the 
"lethal" range (whatever that was meant to represent), without any 
expectation of medical benefit.  Cal-2's parents and Cal-3 also would 
need to know that the risk of harm associated with the proposed dosage 
is low but not zero, while no medical benefit can be expected.  They 
also could be informed about the potential benefits to others and to 
society that might flow from their participation.


IV.  Consent

     Cal -1 -   According to the 1974 AEC Inspector General's report, 
although there are references in Cal-1's medical chart to the 
injection, there is no note in the chart about information disclosure 
or the soliciting or obtaining of consent.  Again, the only relevant 
available information is Hamilton's statement.  There is no evidence 
of consent.

     Cal-2 - There is no evidence that the parents gave specific 
consent to the plutonium injection, but the parents obviously agreed 
to have their child flown to the United States for some purpose.  If 
the phrase "plutonium treatment" is one that was given to the parents 
by a physician, then their consent would not have been valid anyway as 
it would have been based on a misrepresentation of the nature of the 
injection.  If the phrase is one of their own devising, then they may 
have given consent in a desperate, albeit misguided, effort to save 
their child's life.  Although it is plausible that the investigators 
did not intend to mislead the parents about the prospect of benefit 
for their child, the parents' consent would still have been invalid it 
was based on the false belief that their child could benefit from the 
injection.

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     Cal-3 - This subject fell under the AEC's new consent standard, 
which required documentation of patient consent by two physicians but 
not the subject's written consent.  There is no information concerning 
the exact content of the consent encounter that was documented by the 
physicians.  In particular, it is unclear how or whether the 
combination of plutonium injection and amputation was explained to 
him.  Elmerine Whitfield, daughter of Cal-3, is reported to have 
stated, "If they told my father that he was injected with plutonium, 
that would be like telling him he was injected with ice cream.  He 
would not know the difference."["The Plutonium Experiment," by Eileen
Welsome, Albuquerque Tribune, Special Reprint, at page 6.]  We hope to
hear from her at the October meeting.

     From the perspective of the ethical validity of consent, the 
central issue is whether Cal-3 had an adequate understanding of the 
purpose and potential harms and benefits of the injection.

     The only claim that can be made with reasonable certainty 
regarding the extent to which these three experiments complied with 
today's consent standards is that it appears that the contemporary 
requirement to obtain written informed consent was not satisfied.  
Moreover, if what Dr. Hamilton reported to Dr. Warren (in 1947) about 
what was explained to patients who received plutonium injections at 
UCSF (including Cal-1 and -3 and the parents of Cal-2) is both an 
accurate account of what they were told and also represents all that 
they were told, then valid consent likely was not obtained.[
  As noted in the accompanying memo, Warren recalled Hamilton as 
saying "he had explained to the patients that they would receive an 
injection of a new substance that was too new to say what it might do 
but that it had some properties like those of other substances that 
had been used to help control growth processes in patients. . . ."]

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V.   Prior Review

     The AEC put a prior review mechanism in place by 1948, in the 
form of isotope allocation  committees.  There was no such structure 
in the Medical Section of the Manhattan Project. [July, 1946 minutes
of the initial meeting of the Manhattan District's Interim Advisory 
Committee on Isotope Distribution Policy show a plan to administer 
isotope distribution through committees at the licensed institutions.  
See Briefing Book #5, Tab G, Attachment 9, at Page 11.] Rather, the 
experimental design and the procurement and conveyance of the 
radioisotopes all took place on an ad hoc basis among individual 
colleagues.  This unsystematic procedure is today wholly unacceptable 
in research with human subjects, and perhaps accounts in part for some 
of the methodological lacunae of the plutonium injection experiment.

VI.  Conclusion

     If in fact there was no valid consent then, ethically, the 
strongest case that can be made in favor of these three plutonium 
injection cases is that they were in the national interest (due to the 
danger to laboratory workers engaged in work critical to the nation), 
that some medical benefit might accrue to future patients if plutonium 
could be safely targeted to tumors (in the cases of Cal-2 and Cal-3), 
that animal models had reached their limit, and that the subjects were 
thought to be dying and therefore not likely to suffer harm.

     Considerations like the national interest and the advancement of 
scientific knowledge must today be balanced against the moral rights 
of subjects.  Today, human beings may not be used in experiments 
without their knowledge or consent.  Indeed, experience suggests that 
benefits to the nation and the community can be achieved without 
compromising individual rights, for many people are willing to 
participate in medical research even though there is no chance they 
will directly benefit.  The long-term result of failing to respect 
moral rights to information and consent tends, in fact,  to undermine 
citizens' support for science and confidence in its legitimate 
objectives.

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