

ATTACHMENT 1



REPORT OF THE UCSF AD HOC FACT FINDING
COMMITTEE ON WORLD WAR II 
HUMAN RADIATION EXPERIMENTS
FEBRUARY 1995

UNIVERSITY OF CALIFORNIA 
SAN FRANCISCO
I.   INTRODUCTION

Between April 1945 and July 1947 approximately 18 1
{1. The actual number may have been 20 or 21 subjects.
A teenager injected with americium (so-called CAL-4 or CAL-A) 
is sometimes lumped with the plutonium recipients (Appendix 2).  
Additionally, six subjects drank a solution of water,]
hydrochloric acid, and plutonium at the University of Chicago 
(Appendix 3).} patients at three university hospitals in the U.S.
were injected with plutonium.  It is alleged that the patients 
were part of a secret research project sponsored by the Manhattan 
Engineer District (MED), the government agency responsible for the
production of atomic weapons.  The purpose of the MED-
sponsored project was to determine the excretion rate of
plutonium in human beings so that the government could set
safety standards for workers who would handle this
radioactive element in atomic bomb development and
production.

In November 1993 Eileen Welsome, an investigative journalist
for the Albuquerque Tribune, wrote a three-part report on
the plutonium experiment that came to the attention of
Department of Energy Secretary Hazel O'Leary.  The report
and Secretary O'Leary's call for openness about the U.S.
Government's role in secret war research and human
experimentation have resulted in a great deal of media
attention focused on similar government activities during
the Second World War and Cold War eras.

Although the plutonium experiment was reported in a textbook
published in 1951 (Appendix 1), was the subject of
Congressional hearings in the 1980s and was reported in the
press in both the 1970s and the 1980s, it is Welsome's
report that has generated widespread public concern about
the role of government in secret medical research. 
Allegations about unethical, coercive, and manipulative
conduct by government researchers abound in the media
reports (Appendix 4).  Three allegations especially relevant
for UCSF2 {2. UCSF, as it is known today, did not exist until 
1957.  Before then, all University of California programs in
San Francisco, including the University Hospital ("UC Hospital"), 
reported through the Berkeley campus.   With the appointment of
the first Chancellor and its formal designation as the University 
of California, San Francisco, in 1957, UCSF became one of the 
coequal campuses of the University.  Nevertheless, for purposes
of brevity, references throughout this report will be to UCSF.}
are:1) that patients at UCSF Hospital received "lethal" doses of 
plutonium from UCSF researchers, 2) that patients were not 
informed about the experiments, did not consent to participate, 
and, indeed, were unaware of their participation in this experiment, 
and 3) that the plutonium experiment was comparable to research 
performed in Nazi death camps during the same era.

				1

On January 7, 1994, Chancellor Martin appointed an Ad Hoc
Fact-Finding Committee (Appendix 5).  The Chancellor charged
the Committee with two tasks: 1) examine the scientific
nature of the experiments that were conducted, and 2)
examine the ethical nature of these experiments.  The
Committee members believe that UCSF participation in the
MED-sponsored plutonium project was the most important to
investigate because its highly secret nature typified
experiments that have raised public concern.  

The Committee retrieved and reviewed hundreds of documents,
many of which were previously classified.  The documents
included patient histories, laboratory notebooks, government
documents, memos and notes from the principal investigators
and numerous other documents from that era.  We have used
contemporaneous documents to try to understand the
intentions and the actual conduct of the scientists
involved.  The Committee tried to determine, as far as
possible, what the experiments were and if they were
justifiable, both in the context of science in the 1940s and
in the present day.

Recreating ideas, motivations, discussions and actions from
nearly 50 years ago is a daunting task.  Many of the
surviving scientific documents consist only of raw data,
with little explanation of the investigator's intentions. 
Other documents give scant illustration of how the
experiments fit into the ethical milieu of the time.

We do know that UCSF scientists injected three patients with
plutonium in that era.  It is generally assumed that the
three UCSF patients were participants in the MED-sponsored
plutonium project.  Sufficient documentation exists to
determine with certainty that one patient (CAL-1) was an
experimental subject in the MED-sponsored project.  The two
other patients (CAL-2 and CAL-3) may not have been in the
MED-sponsored project.  Regardless of the experiment in
which a particular individual may have been involved, the
Committee has examined the following questions about the
science and ethics of the experiments:

_    Was there adequate scientific rationale?

_    What are the biological effects of plutonium?

_    How were subjects chosen?

_    What was the quality of the subjects' medical care?

_    Were the patients harmed?

What were patients told, and did they agree to participate?


				2
_    
_    Were there third-party review and approval?

_    What was the balance of benefits and risks to human
     subjects?

_    Overall, was experimentation with radioactive
     substances appropriate and justifiable, both
     in the context of 1940's research on humans,
     and from the viewpoint of contemporary
     standards?

We offer this interim report regarding our findings to date. 
The Committee members unanimously agree that we have
reviewed sufficient information to offer this report. 
However, it is important to stress that a very large amount
of unexamined information exists.  Therefore, information
may become available that would mandate an alteration of our
current summary and conclusions.  The experiments conducted
by the UCSF researchers raise many concerns.  We summarize
our findings and concerns below.

II.  The Inception of the MED-Sponsored Experiments

Plutonium was first produced in 1941 in the cyclotron of the
University of California at Berkeley.  During World War II,
plutonium was recognized as a potential explosive component
of atomic weapons.  To exploit this potential, the MED began
large-scale production of plutonium in 1943.  As a result,
some workers associated with the MED had occupational
exposures to plutonium as a result of inhalation, ingestion,
and absorption.  Medical scientists associated with MED had
no means of determining the precise amount of plutonium
internalized3 {3.   Plutonium that has been inhaled or swallowed      
accidentally, or purposefully injected will be referred     
to as internalized plutonium.} by a worker nor did they understand 
the biological consequences of human exposure.  Concern for the
health of MED workers was expressed in March 1945 in a
letter from Dr. J. Robert Oppenheimer, Scientific Director
of the MED, who requested that the medical scientists expand
efforts to investigate the hazards of human plutonium
exposure (Appendix 6).

Joseph Hamilton, M.D., Kenneth Scott, Ph.D., and Robert
Stone, M.D.,4 {4.   Stone was on leave of absence at the time of 
the MED-sponsored plutonium project, but was closely associated
with the MED and the project.  Other UCSF physician-researchers 
were also involved in the UCSF experiments, but did not appear to 
be "principal" investigators. The most notable of these were 
Drs. Earl Miller, acting Chair of Radiology, and B.V.A. Low-Beer.}
from the Crocker Laboratory in the Department of Physics of the 
University of California at Berkeley, held appointments in the UC 
Radiology Department and thus they had access to UCSF Hospital 
patients for their research. They became involved in a multi-

				3
institutional research effort to determine the excretion
rate of plutonium after the intentional injection of animals
and humans (Appendix 7).  The work was undertaken to
determine permissible exposure levels for radiation workers. 
Important steps in this undertaking include correlating the
amount of exposure with the amount of radioactivity excreted
by human beings and studying the distribution of radioactive
material in the human body after exposure.

The first injection of plutonium into a California subject
(CAL-1) occurred on May 24, 1945, 2 months before the first
testing of an atomic weapon on July 17, 1945 (Trinity Test),
and less than 3 months before the use of atomic weapons on
Hiroshima and Nagasaki.  Even though WWII ended in 1945, the
full-scale production of atomic weapons continued under a
shroud of secrecy because of the threat of hostilities with
the Soviet Union that ushered in the beginning of the Cold
War.

Well into the 1940s, medical research on human subjects
generally was conducted by researcher/clinicians who
enrolled their own patients into their experimental studies. 
Investigators established the doctor/patient relationship
before asking patients to be part of research endeavors. 
The Second World War changed the nature of clinical
investigation: in war-related research, the study subjects
were not necessarily the patients of the investigators
(Appendix 8).  In the MED-sponsored plutonium project, like
much war-time experimentation, study subjects did not have a
relationship with the investigators and did not know them. 
The researBhers were not the primary care physicians of the
research subjects.

III. Scientific Rationale of the MED-Sponsored Experiments

A.   Research Objectives:  A prospectively stated protocol
for the MED-sponsored plutonium project has not been
discovered.  However, we infer from publications and other
MED/AEC documentation that there were at least two
objectives.  One was to "to determine the excretion rate of
plutonium in man to provide the information necessary for
setting safety criteria for the several thousand MED workers
handling plutonium" (Appendices 7 and 9).  The second was to
determine how plutonium was deposited in human and animal
tissue (Appendix 10, page 10).


				 4

B.   Detection of Plutonium:  Plutonium is a 5.1 MeV alpha
particle emitter.  Alpha particles have a very short range
and thus are far more difficult to detect than beta or gamma
particles.  The ability to detect plutonium in biological or
environmental samples is complicated by the fact that the
signal that identifies the presence of plutonium, the alpha
particle, is absorbed by the sample being analyzed. 
Therefore, mass must be reduced by dissolving, evaporating,
or ashing the sample.  If the sample was bone, analysis
required a further chemical extraction to remove the
plutonium from the ash.  If the sample was a liquid,
evaporation followed by plating out the residue was
sufficient.  These techniques not only removed the
interfering mass but also concentrated the plutonium
(Appendix 11).  Once processed, the sample could be counted
in an ionization chamber.

To determine if workers had been internally contaminated by
plutonium, the MED could collect their excreta and analyze
for plutonium.  Even though the samples could be processed
as indicated above, there was insufficient information
available to enable extrapolation from plutonium in excreta
to an actual amount internalized and deposited in the body
(known as the "body burden").  That relationship could only
be established by injecting a known amount of plutonium into
experimental subjects, then monitoring its excretion rate
and determining the extent to which it was deposited in
target organs.  In that way, urine and stool plutonium could
be related to a given level of intake.  In February 1944,
Hamilton received 11 mg of plutonium and he and
investigators at other sites began animal experiments. 
Results from those experiments indicated significant
variation among animal species regarding excretion rate and
tissue deposition (Appendix 12, pages 19-26).  This
variation made extrapolation from animals to humans
impossible.  While animal studies were continued,
intravenous injection of plutonium into human subjects
began.  Because animal studies established that plutonium
was a "bone-seeker," the deposition of plutonium into human
bone was studied.  Although sufficient amounts of excreta
could be obtained from any human subject, sufficient bone
samples could only be obtained from amputations or certain
thoracic or thoraco-abdominal surgical procedures requiring
rib resections.

IV.  Biological Effects of Plutonium

A.   Background:  Typically, a sheet of paper or the outer
layer of human skin easily stops alpha particles.  A 5 MeV
alpha particle such as that emitted by plutonium has a


				5
range in water of 44 micrometers.  Biological fluids or
tissue reduces the range of an alpha particle even further. 
Because skin alone is an effective barrier to alpha particle
irradiation, the risk from external exposure to small
quantities of plutonium is insignificant.  Likewise, a
subject injected with small amounts of plutonium poses no
radiation risk to other individuals or family members that
contact the subject.  Furthermore, the risk of contamination
of their surroundings is insignificant.

B.   Toxicity:  When considering exposure standards for non-
radioactive compounds, such as chloride or mercuric
chloride, scientists measure only the chemical toxicity of
the compound.  One such chemical toxicity measure is the
dose of the compound that is lethal to 50% of test animals
(called the LD50).  The LD50 is typically expressed as an
amount of test compound per kilogram of body weight.  For
example, when administered orally to rats, sodium chloride
has an LD50=3000 mg/kg and mercuric chloride has an
LD50=1000  ug/kg.  Even though extraplation of animal data
to humans is problematic, an LD50 value determined in
animals is useful because a) a lethal dose must not be
determined in humans and b)it suggests a toxic concentration
that must be avoided.  Researchers, both then and now, will
typically use a concentration at least 10-times lower than
the LD50 to set safe levels for administration to humans.

Radioactive compounds can have both a chemical and a
radiological toxicity.  Therefore, while radioactive
compounds can have an LD50 that has the same meaning as that
of non-radioactive compounds, they also have radiological
toxicity and this is usually of greater concern than the
chemical toxicity.  In addition, there are two types of
radiological toxicity to consider, acute or short-term and
chronic or long-term radiological toxicity.  At high
concentrations, the radioactivity of these compounds can
contribute to acute toxicity by mechanisms distinct from
those induced by the chemical properties of the compound. 
Investigators also measure acute radiological toxicity as an
LD50 but express this measure in units of radioactivity
(curies, Ci) per kilogram body weight.5{5.   Acute toxicity 
from radiation exposure includes suppression of the bone 
marrow, inflammation of   tissues, hair loss, and ulceration 
of the intestinal  tract, biological changes that are relatively 
easy for physicians to detect.} 

	A more difficult toxicity to  consider is the long-term 
effect of a radioactive compound.

				6


One expresses standards addressing long-term effects as
total quantity of radioactivity to which one has been
externally or internally exposed.  However, due to the low
penetration of radiation from plutonium, there is no
external radiation component of exposure and only internally
deposited material is of concern.  The quantity of
internally deposited plutonium capable of producing chronic
toxicity is much lower than the LD50 values for acute
chemical or radiological toxicities.  Thus, an amount that
is not acutely toxic may exceed standards addressing long-
term toxicity.  The standards addressing long-term effects
are limits of exposure and the values should not be
interpreted as the point at which long-term effects will
definitely be manifest.  Because long-term effects may not
become apparent for many years, standards for newly
discovered compounds are frequently derived by analogy to
other compounds for which data have been collected; in the
MED-sponsored plutonium experiment the researchers used
radium for this analogy.

C.   Acute Toxicity:  At the time of the MED-sponsored
plutonium project, animal studies suggested dosages of
plutonium that would lead to acute toxicity.  As with the
excretion data, toxicity varied among species.  The acute
lethal dose varied from 400 ug/kg (dogs) to 1000 ug/kg
(mice) (Appendix 12, page 20) and 1400 ug/kg (rats)
(Appendix 12, page 49, Table XXVII).  The most complete data
we found from that era appeared in a 1945 classified
conference report showing relative toxicity in rodents as a
function of radioactivity and mass (Appendix 12, page 49,
Table XXVII).  Our reading of this conference summary
indicates that Stone and Hamilton were participants and,
therefore, directly aware of the conference deliberations. 
Using those data, the amount of plutonium injected into CAL-
1 (the subject receiving the largest amount of
radioactivity) was less than 0.1% of the activity and
0.0012% of the mass required to achieve an LD50/40 in rats
(LD50/40 is the dose that was lethal to 50% of test animals
within 40 days) (Table 1).6{6.   Recalculating the activity 
and mass received by CAL-1  using the LD50 for dogs, the 
animal demonstrating the  greatest acute sensitivity to 
plutonium among the tested animal subjects, his dose was 0.35% 
of the activity and 0.004% of the mass that caused death in half
of the dogs.} Further, no UCSF research subject received more 
than 0.4% of the mass noted to produce a detectable acute effect.  
Therefore, based on the information available to investigators in 
1944-45, the amount of plutonium injected was unlikely to pose an
immediate risk to the health or physical well-being of 

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the subjects.  Indeed non of the patients suffered from
acute plutonium toxicity.

                          TABLE 1
                  Acute Plutonium Toxicity
       (based on rodent data available in 1944-1945)
                              
                                   %LD50/40       % of
                                   as a func-     minimum
                                   tion of        detect-
                                                  able
                                                  effect*
Patient  Weight   Isotope   uCi   ug    radio-      mass         mass
          (kg)                         activity  (1400 ug/kg) (50 ug/kg)
                                       (90 uCi/
                                         kg)

Cal-l    58.0    238/239  3.546  0.932. 0.0679%   0.0011%     0.0320%

Cal-2    15.5      239    0.169  2.683  0.0122%   0.0124%     0.3462%

Cal-3    73.3      238    0.095  0.006  0.0014%   0.0000058%  0.00016%

*This is not a standard measure of toxicity but was computed
by these researchers

D.   Long-Term Effects:  The long-term effects of plutonium
exposure were unknown in 1945.  The researchers did not do
long-term toxicity experiments in animals prior to
initiating the MED-sponsored plutonium project.  Although
long-term animal toxicity studies were eventually performed,
such studies take many years (Appendix 13, pages 682-83). 
Had long-term animal studies been conducted prior to the
injection of experimental human subjects with plutonium, the
results of the plutonium project would not have been
obtained soon enough to be of use in estimating the exposure
risk of plutonium workers.  In place of scientifically
documented evidence regarding long-term effects, estimates
on the long-term biological toxicity of plutonium were based
on analogy to radium.  The induction period of radium-
induced malignancy in humans, especially malignancy of the
bones, was reported as being 10-30 years after exposure
(Appendix 10, page 9).  The researchers made the assumption
that plutonium would act as radium did and would produce
similar effects (Appendix 14).  The researchers also
concluded that the amount of plutonium fixed in bone was the
greatest concern in chronic toxicity.7{7.   Chronic toxicity from 
radiation exposure includes development of solid tumors, leukemia, 
lymphoma,  chronic suppression of bone marrow function, and  
destruction of bone, abnormalities that are generally  
readily detectable by physicians.} 

For participation in the MED-sponsored plutonium project,
subjects were selected who

			      8
because of an existing disease had an estimated life
expectancy of less than 10 years (Appendix 15, page 755). 
The selection of such a patient population would minimize
the onset of possible but unknown long-term effects of
plutonium.  These experiments were not designed to study
whether or not long-term exposure to plutonium caused cancer
or other diseases in humans.  The patients who were injected
with plutonium and survived their disease for more than 10
years did not succumb to cancer or other conditions caused
by radiation exposure.  A 1991 review of all plutonium
exposures suggests that the probability of humans developing
cancer from plutonium internalization or exposure is not as
great as originally predicted based on animal models
(Appendix 13).

E.   Occupational Limits of Exposure:  The "maximum
permissible body burden" (MPBB) is the scientific term
applied to the permissible occupational limit for an
internally deposited radioisotope for an occupationally
exposed individual.  MPBB is a safety factor against
possible long-term effects.  The MPBB is an estimate of
safely tolerated exposure in the work place.  It is not the
level of exposure above which harmful effects will occur. 
Further, it is not equivalent to a "lethal dose."  Rather,
it is a safety measure for workers who might be continuously
exposed to a radioactive substance.  When the MPBB is
reached, that individual should no longer work with the
radioactive substance.  Nevertheless, an examination of how
these values were derived gives some insight into the
experimental design of the plutonium project.

At the time of the UCSF experiments, officially adopted
standards for MPBB did not exist.  Indeed, the researchers
designed the MED experiments, in part, to help establish
these values.  Yet, in that era there were several
recommended values that covered a range of 1-5 up of
plutonium fixed in bone.8{8.   Because a significant portion 
of injected plutonium is excreted (approximately 50%), the 
amount fixed in bone is less than the amount internalized.} It was 
not until 1950 that the National Bureau of Standards established a 
value of 0.5 ug (0.03 uCi) for plutonium (Appendix 10, page 9, and 
Appendix 15).  The Division of Biology and Medicine of the Atomic
Energy Commission officially adopted this value that same
year,9 {9.   In 1951 the International Committee on Radiological
Protection recommended a value of 0.04 uCi.  By the fall of 1953 
both the National Committee on Radiation Protection and 
Measurements and the International Committee on Radiological 
Protection were recommending the 0.04 uCi value, 3-5 years after 
the UCSF experiments.  It is important to note that the 
occupational limits were derived 

				9
from mass quantities (ug) thought to be fixed in bone, the
lowest limiting amount in that era being 1 ug (Appendix 1,
page 256).  Because mass is and was impractical to measure,
the MPBB limit was set at a given radioactivity equivalent,
a more practical physical property to measure.  The
radioactivity equivalent is derived from 239Pu (0.06
uCi/ug), the isotope used in weapons production, even though
238Pu (17.37 uCi/ug) is more radioactive.  In the 1940s, the
concern regarding the mass of plutonium deposited in bone
was derived from analogy to risks associated with radium
(Appendix 14).  The MED scientists believed that 1 ug of
radium deposited in bone was potentially carcinogenic over a
decade or more of exposure.  Their computed equivalence of
plutonium to 1 ug of radium was 50 ug.  They subsequently
applied a safety factor of approximately 10 and computed a
tolerance level of 3-5 ug of plutonium (Appendix 14).

The MED scientists had two issues to consider.  First, there
were safety limits to the mass of plutonium that could be
internalized by a human subject.  Second, their detection
equipment was inefficient.  Because the investigators in the
era of the UCSF experiments were concerned with the mass
efects, 238Pu was used in some experiments to reduce the
internalized plutonium mass while emitting sufficiently high
counts of radioactivity to circumvent the inefficiency of
their detectors.  When reporting on CAL-1, Hamilton wrote:

     A solution was injected which contained primarily
     94Pu238 in preference to 94Pu239 in order to avoid
     the mass effects of plutonium and at the same time
     to maintain counting accuracy (Appendix 16, page 
     0001843).

Even though using 238Pu reduced the mass of plutonium
injected into subjects, it significantly increased the
amount of radioactivity that would have been received by a
similar mass of 239Pu.  238Pu is 276 times more radioactive
than 239Pu.  Although this increase in radioactivity was not
harmful to either CAL-1 or CAL-3 because the total amount of
radioactivity was low (Table I), the use of 238Pu was one
reason why dose calculations reported in the press (see
below) erroneously resulted in high values, especially for
CAL-1.

Our interpretation of the literature at the time of these
experiments indicates that the MED scientists were concerned
more with the mass of plutonium deposited in the human body
as a potential risk factor for chronic toxicity than with
the amount of
				10


radioactivity (provided that the amount of radioactivity was
not acutely toxic).  The use of different isotopes of
plutonium confounds computations of potential radiation
toxicity that have been reported in the press.  The
radioactivity equivalent of 1 ug of 239Pu is 0.06 uCi.  To
use the 0.06 value for any computations other than mass
equivalence is incorrect, particularly with respect to
experiments carried out in the 1944-47 era.  Therefore, the
use of the 0.06 uCi value as a denominator and total
radioactivity received as a numerator (Table 2) is
misleading when employed to evaluate "radiation exposure" of
patients who received 238Pu and 239Pu, as was the case for
CAL-1 and CAL-3.

                          Table 2
                  Plutonium Injections at
        UCSF(CAL), Chicago(CHI), and Rochester (HP)

                         Radio-    Mass      Plutonium
Date      Subject        activity            Isotope
                           (uCi)   (ug)

05-14-45  CAL-1          3.546*    0.932**   238 + 239
04-26-46  CAL-2          0.169     2.683          239
07-18-47  CAL-3          0.095     0.006          238
04-26-45  CHI-1          0.40      6.5            239
12-27-45  CHI-2          5.79     91.9            239
12-27-45  CHI-3          5.95     94.4            239
10-16-45  HP-1           0.28      4.6            239
10-23-45  HP-2           0.31      5.1            239
11-27-45  HP-3           0.30      4.9            239
11-27-45  HP-4           0.30      4.9            239
11-30-45  HP-5           0.31      5.1            239
02-01-46  HP-6           0.33      5.3            239
02-08-46  HP-7           0.39      6.3            239
03-09-46  HP-8           0.40      6.5            239
04-03-46  HP-9           0.39      6.3            239
07-16-46  HP-10          0.37      6.1            239
02-20-46  HP-11          0.40      6.5            239
04-10-46  HP-12          0.29      4.7            239

*  3.500 uCi (98.7%) from 238Pu and 0.046 uCi (1.3%) from
239Pu

**  0.202 ug (21.7%) from 238Pu and 0.730 ug (78.3%) from
239Pu

			    11
V.   Dosimetry

A.   Background:  Alpha particles emitted by plutonium have
the characteristic short path of other alpha particles.  The
path of plutonium alpha particles in tissue is likely to be
less than the diameter of some cells.  However, the energy
deposition along the path is relatively intense.  The target
cells (at the end of the path) will more likely be killed
than mutated.  Because the path is short and the energy
deposition is great, the biological effects of alpha
particles are very localized.  This is not to suggest that
exposure to plutonium is without risk.  In sufficient
amounts, plutonium is toxic and may be carcinogenic or
lethal.  Present practice for assessing risk is by
calculating the dose to a specific organ or group of organs. 
These methods did not exist during the 1940s.

B.   Relevance of Dosimetry Calculations for Plutonium: 
Some press accounts reported dose calculations in the
plutonium experiments based on assumptions adopted by the
Medical Internal Radiation Dose (MIRD) Committee of the
Society of Nuclear Medicine.  Using the MIRD calculation
method, the Committee has reproduced the reported dose
calculations (Appendix 17).  While the committee went
through the exercise of reproducing these calculations, it
is important to state that the MIRD method is not applicable
to dose computation for alpha particle emitters; it is
designed to calculate doses only for beta particles and
gamma radiation.

The MIRD method provides a convenient uniformity and
simplicity to the calculation of absorbed dose.  The method
includes a number of assumptions such as the "uniform
isotropic model."  This particular model assumes that all
anatomical regions are uniform and homogeneous and that the
activity is uniformly distributed within these regions.  The
method accommodates a range of different radioactive
emissions used in clinical nuclear medicine.  However, alpha
emissions reside at the extreme end of this range and this
model does not accurately predict the dose resulting from
alpha emissions because of the short distance that the
average alpha particle travels in tissue.  The probability
of a beta particle depositing its energy within numerous
cells is great.  In contrast, the short track of an alpha
particle will result in its energy being deposited only in
its micro environment.  That micro environment is not always
cellular but may consist of calcified bone, connective
tissue, or fluid filled spaces.  There would be little
consequence if these structures were in the path of an alpha
particle.  Thus, depending on where an alpha emitting
particle is deposited, relatively high organ doses can be 

			12

tolerated with few radiological effects.  Conversely,
devastating effects could occur if the alpha particle were
located where it could mutate cells by depositing its energy
into a cell nucleus.  Dosimetry calculations based on the
MIRD assumptions will not distinguish between these
eventualities.

The inappropriateness of the MIRD method of dose calculation
for alpha emissions is illustrated when considering the
dosimetry of plutonium to the red marrow.  Plutonium
deposits on the trabecular endosteal surfaces of the red
marrow.  Trabecula are spaced at distances of 100 to 900
micrometers from each other with the hemopoietic cords of
the red marrow lying within the trabecular cavities. 
Therefore, the plutonium activity is not homogeneously
dispersed throughout the red marrow, but at the periphery,
and the distances the alpha particles must travel to deposit
their energy uniformly within the hemopoietic cells are
prohibitive.  In this situation, the MIRD calculation method
would result in an unrealistic estimate of dose and it is
inappropriate to draw conclusions about the biological
consequences of internalized alpha particle emitters based
on these calculations.

C.   Variation in Amount of Plutonium Injected:  We did not
discover information in published literature or MED/AEC
documents to explain the differences in the amount of
plutonium injected into the patients purported to be
participants in the plutonium project (Table 2).  The
variation was particularly notable in the experiments
conducted at the University of Chicago (CHI) and UCSF (CAL). 
Only the University of Rochester patients (HP) received a
uniform amount of plutonium.  Reports of the experimental
results suggest that the Rochester phase of this project was
planned solely to establish the relationship between the
amount of internalized plutonium and excretion rate.  The
disparity in the amount injected into the UCSF patients is
confusing.  Plausible explanations would include poor
scientific design, a sound scientific design for a phase of
the experiment thus far unknown to the Committee, or that
the patients participated in an experiment other than that
sponsored by the MED.  Because bone samples were collected
from each CAL patient, a plausible explanation is that the
CAL patients were also involved in studies examining the
deposition of plutonium in bones.

				13

VI.  Choice of Subjects and Patient Care

A.   Overview:  Dr. Hamilton, the principal investigator,
was not the primary care physician responsible for the
diagnosis and treatment of the patients who were eventually
selected as subjects.  Further, he was not involved in the
day-to-day care of the research subjects nor did he try to
influence their medical or surgical treatments.  That he was
not the clinically responsible physician himself
differentiated him from most medical researchers of his era.

The experiments with radioactive materials were initiated in
war-time secrecy.  It is not clear to the Committee what, or
how much, the UCSF doctors who were responsible for patient
care knew about the MED-sponsored experiment.  We do know
that the word, plutonium, was classified, at least in the
earlier phases of the study, and thus not mentioned to
patients or most health professionals who cared for them.

A detailed analysis of the patient records of CAL-1, CAL-2,
and CAL-3 is attached (Appendices 18-20).  The patient
record of CAL-4 (CAL-A) was not available for review and we
believe was destroyed.  The summaries address the accuracy
of diagnosis and appropriateness of treatment for that era,
comparing contemporary treatment where possible.  There is
no evidence that the investigators were involved in
diagnosis or decisions regarding treatment.  No evidence was
uncovered to suggest that patient treatment was compromised
by their selection as experimental subjects.

The pre-operative diagnosis of cancer was wrong in CAL-1. 
The review of CAL-1's medical record notes that a consultant
had recommended gastroscopy prior to surgery.  The attending
surgeon duly noted the recommendation.  However, for reasons
not stated, a gastroscopy was not performed preoperatively
(for further details see Appendix 18).  Today, a
preoperative gastroscopy would have included a biopsy to
confirm the suspected diagnosis.  However, in 1945, biopsy
under direct visualization through a gastroscope to verify
diagnosis was not technically possible.  Even a blind biopsy
through a gastroscope would be difficult because of the
location of the patient's lesion (the gastric cardia). 
Further, had a biopsy been done, it would have been
negative.  Clinically, a negative biopsy has limited value
and does not supersede a clinical and radiographic diagnosis
of cancer.  A leading gastroenterology textbook (see
Appendix 18) of the era states, "In most cases of malignant
disease (of the stomach), the Roentgen

				14


method will establish the diagnosis with sufficient
certainty so that a decision can be made concerning the type
of therapy to be employed."  However, the investigators
could have elected only to accept subjects with
pathologically proven diseases to avoid potential errors. 
Though CAL-1 was misdiagnosed, his care was not compromised
by the plutonium experiment.  The operations and subsequent
care of the three CAL patients were not altered because of
the plutonium experiment.10 {10.  CAL-3's surgery was delayed 
3 days because his plutonium injection occurred on a Friday.  
The surgeon postponed the procedure until Monday.}  Other than 
the injection, the only difference from standard care was the 
collection of urine and fecal specimens.}

B.   Agency Guidelines:  As noted earlier, the experiment
was begun under the auspices of the Manhattan Engineer
District in 1945.  An act of Congress replaced NED with the
newly formed Atomic Energy Commission (AEC), a civilian
agency, on January 1, 1947.  The Atomic Energy Act of 1946,
also known as the McMahon Act, gave the U.S. Government,
through the AEC, an absolute monopoly of ownership and use
of fissionable material, including plutonium.  A few days
before the change from military to civilian authority, the
military called a halt to the human experiments with
plutonium.  Then in April 1947, the AEC declared that
"radioisotope treatment (with plutonium) will be
administered only when there is expectation that it may have
therapeutic effect."  Furthermore, there must be proof that
"each patient understood the nature and possible risk of the
treatment and consented to receive such treatment in the
presence of two witnesses."  (Appendix 21, pages 5,6 and the
last 2 pages.)  It is possible that some studies performed
at UCSF were not sponsored by the MED/AEC (Appendix 22), but
permission of the AEC was required to possess or use
plutonium.

The MED and AEC expressed concern with public perception of
the experiments.  In a memo dated April 17, 1947, from the
U.S. Army Corps of Engineers, Manhattan District, to the
newly formed Atomic Energy Commission, the following
statement appears:  "It is desired that no document be
released which refers to experiments with humans and might
have adverse effect on public opinion or result in legal
suits.  Documents covering such work should be classified
"secret."  Further work in this field has been prohibited by
the general manager."

CAL-3 was injected on July 18, 1947, after the AEC had been
formed.  As documented

				 15

in Appendix 20, physicians wrote in the medical record of
CAL-3 that they had explained the experimental nature of the
injection to the patient and obtained his agreement.  The
amount of plutonium injected into CAL-3 was too small to be
therapeutic for him.  Thus, the injection of CAL-3 may not
have met the AEC guidelines.  To complicate the Committee's
evaluation, we know that the AEC did recognize that
hospitals and other institutions could conduct research that
was not directed or funded by the AEC (Appendix 11).  Dr.
Scott stated in a letter of October 21, 1949, that some of
the UCSF studies were not sponsored by the AEC (Appendix 22,
page 2).

Data on CAL-2 and CAL-3 were not published in the scientific
literature until 1971 (Appendix 12, pages 104-5).  One
possible explanation disturbs the Committee: did Dr.
Hamilton knowingly inject CAL-3 after these experiments were
prohibited by the AEC, thereby inducing him to withhold
publication of the outcome of the experiments on CAL-3 and
possibly CAL-2?

C.   Hypotheses Regarding Goals of the Experiments

1.   Hypothesis #1:  All three UCSF patients participated in
the MED-sponsored project to determine human excretion rates
of plutonium.

A specific rationale for the selection of each patient has
not ben discovered.  The Committee has considered two
hypotheses.  The first, as stated above, assumes that all
three CAL patients were part of the MED-sponsored plutonium
project.  This was the conclusion made by the AEC when
follow-up studies were performed in the 1970s on individuals
with known, precise amounts of internalized plutonium
(Appendix 21).

Considering the hypothesis that all three CAL patients who
were injected with plutonium participated in the MED-
sponsored project, we speculate that the UCSF patients were
selected primarily because the treatment recommended by
their primary physicians for their diagnosed disease cancer
in all cases, would produce bone samples, the primary site
of plutonium deposition (Appendices 2 and 16).  CAL-1 was
diagnosed with stomach cancer and thus required surgery that
would remove a piece of rib.  CAL-2 and CAL-3 were diagnosed
with bone cancer and both were scheduled to have amputations
of a leg.  Those two patients were injected with plutonium
several days before biopsy (CAL-2) or surgery (CAL-3) and in
both cases the injections were indicated in their

			16

medical records and, in the case of CAL-3, specifically
identified as plutonium.  The details regarding the
plutonium injections and analysis were part of the
experimental record, and were not kept in the medical chart.

Although a protocol for patient selection is not available,
the Committee's interpretation of published papers and
available MED/AEC documents appear to indicate two general
inclusion criteria for experimental subjects (Appendices 10
and 15).  These include: 1) a diagnosed condition likely to
result in the patient's death within 10 years, and 2) age of
45 years or more.  These "criteria" were not strictly
applied by the medical centers participating in the MED-
sponsored plutonium project.  However, it is appropriate to
compare the three California plutonium recipients to these
criteria.  Although CAL-1 was misdiagnosed as having gastric
cancer, he met both inclusion criteria.  CAL-2 had a disease
likely to result in death in less than 10 years but he was a
child, thus not meeting the age criterion.  Independent of
parental approval, he was incapable of making an informed
decision to volunteer for an agreement.  If CAL-2 was a
participant in the MED-sponsored plutonium project without
informed parental consent, then his inclusion in the
experiment was unethical for two reasons.  First, the
injections could have been carried out on adults who were
capable of making an informed decision to participate. 
Second, subject selection was inappropriate because a
child's excretion parameters might differ from those of
adult plutonium workers.  Inclusion of a child would
therefore be unethical with or without parental consent. 
CAL-3 did not have a disease likely to result in his death
within 10 years and was only 36 years old.  

2.   Hypothesis #2:  Only CAL-1 was part of the MED-
sponsored project while CAL-2, CAL-3, and CAL-4 participated
in a University-sponsored medical research project aimed at
finding a new treatment for bone cancer.

There are several puzzling aspects to our above analysis. 
One of the most puzzling is that CAL-2 received a much
larger dose than CAL-2 or CAL-3.  Also, independent of any
ethical problems, CAL-2 was a child and the biological fate
of plutonium injected into a child could be quite different
from that of plutonium internalized by adult plutonium
workers.  Finally, the supervising agency first prohibited
further injections of plutonium and then revised that
decision, permitting further plutonium injections provided
that certain guidelines were followed.  The general public
presumption has been that all three CAL patients
participated in the MED-sponsored plutonium project. 
However, a 
				17

However, a plausible explanation for these seeming 
inconsistencies is that CAL-2 and CAL-3 were not part of the 
project.  An alternative hypothesis is that they were, instead, 
part of University-sponsored medical research aimed at 
discovering a new treatment for bone cancer.  The data on 
plutonium kinetics gathered on these patients also may have been
useful to the AEC, but the primary purpose of the
experiments was therapeutic research.

Although this interim report focuses on patients who
received plutonium, the Committee is also investigating the
"strontium experiments" and is aware of a child (so called
"CAL-A" or "CAL-4," Appendix 2) who received an
intramuscular injection of 241 Americium.  The circumstances
surrounding the injection of radionuclides into these
patients provide an important clue to understanding the
presumed inconsistencies in the plutonium experiments
conducted here at UCSF.

Because of the serious allegations surrounding the plutonium
experiment, the Committee has concentrated its investigative
efforts on the plutonium patients even though the strontium
experiment preceded the plutonium experiment by several
years.  To date, the Committee is aware of 12 UCSF cancer
patients who received injections of bone seeking
radionuclides as part of experiments during the pre-WWII and
WWII era (8 strontium, 3 plutonium, 1 americium).  Of these
12 cancer patients, 9 had primary bone cancer (the patient
list, below, is in chronological order).

     Strontium l         Chondrosarcoma           1941
     
     Strontium 2         Osteogenic Sarcoma       1941

     Strontium 3         Ewing's Sarcoma          1941

     Strontium 4         Osteogenic Sarcoma       1941

     Strontium 5         Osteogenic Sarcoma       1941

     Strontium 6         Myxofibroosteosarcoma    1941

     Plutonium 1(CAL-2)  Osteogenic Sarcoma       1946

     Americium           Osteogenic Sarcoma       1947

     Plutonium 2(CAL-3   Chondrosarcoma           1947

CAL-2 and CAL-3 were the only patients with primary bone
cancer who received plu-

			  18

tonium (Appendix 23, pages 100-105).  The incidence of
primary bone cancer, age adjusted to the 1970 U.S. standard
population, is 0.8 per 100,000.11 {11.  SEER Cancer Statistics 
Review 1973-1990 published by the National Cancer Institute of 
the National Institutes of Health.} In the group of UCSF
patients injected with bone-seeking radionuclides, 9 of the
12 (75%) had primary bone cancer.  It is highly unlikely
that this number of rare cancers occurred randomly in a
group this small.  The alternative explanation is patient
selection by design.

We expect a future report to examine more closely the
strontium experiment in which patients received this
radionuclide to achieve a therapeutic effect (Appendix 24). 
However, no therapeutic effect was seen in the primary bone
cancer patients reviewed to date who were injected with
strontium.  It is reasonable to assume that Hamilton and his
colleagues had pressed on with further attempts to treat
bone cancer as new, potentially useful radionuclides were
discovered at the Berkeley cyclotron (plutonium in 1941 and
americium in 1944).

It is important to understand the timing of the strontium
experiments.  These experiments began before the U.S. became
involved in World War II.  The MED and the AEC did not yet
exist.  Indeed, the AEC did not express an interest in these
patients until nearly 15 years later.  Therefore, the
strontium experiments proceeded without government oversight
or wartime secrecy.

The UCSF investigators knew that plutonium and americium,
like strontium, were "bone seekers," making them potential
candidates as bone cancer therapeutic agents.  The
laboratory data gathered following the plutonium injection
of CAL-2 parallel the laboratory data gathered on the
strontium patients to a far greater degree than they do to
those gathered on CAL-1 or other participants in the MED
project to determine human plutonium excretion (Appendix
25).  The injection of CAL-2 follows the strategy employed
by scientists in the therapeutic strontium experiment
(Appendix 26).  First, the strontium investigators injected
a small test dose before biopsy of the tumor.  Subsequently,
they compared the uptake of strontium in the bone tumor to
its uptake in adjacent normal tissues.  They obtained urine,
stool and blood samples to analyze for strontium excretion.

In the medical record of CAL-2 there is a written note
stating that the surgeons took a

				19

generous section of the bone tumor at the biopsy for
pathology as well as "for studies to determine the role of
uptake of radioactive material that had been injected prior
to surgery in comparison to normal tissues" (Appendix 19). 
This was the predominant tissue analyzed in CAL-2.  The
amputation specimen from CAL-3 was analyzed in a similar way
as the biopsy specimen from CAL-2 (Appendix 25).  A goal of
the MED-sponsored plutonium experiment was to determine the
deposition of plutonium in normal bones, not the deposition
of plutonium in an osteogenic sarcoma.

The hypothesis that CAL-2 and CAL-3 were part of a clinical
research program to discover a treatment for bone cancer
potentially explains many of the apparent inconsistencies
that arise from the hypothesis that all three subjects
participated in the MED-sponsored plutonium experiment. 
First, and as noted above, CAL-1, who unambiguously
participated in the MED-sponsored plutonium project,
received an amount of radioactivity that was much greater
than either CAL-2 or CAL-3 (Tables 1 and 2).  Indeed, CAL-2
and CAL-3 received the smallest amounts of radioactivity of
any subjects receiving intravenous or intramuscular
plutonium (Table 2).  If the amounts of plutonium injected
into CAL-2 and CAL-3 were test doses for a therapeutic
experiment, then the amount of radioisotope injected
appropriately would be smaller.

Secondly, CAL-1 met all the requirements that the Committee
has discovered for participants in the MED-sponsored
experiment where there was no therapeutic intent.  At the
time, he was thought to have a disease (gastric carcinoma)
that all available evidence indicated would cause his death
within 10 years and he was older than 45 years.  CAL-2 and
CAL-3 did not meet these criteria.  CAL-2 was a child and
CAL-3 was only 36 years old.  Further, CAL-3 did not have a
disease that was likely to result in death in 10 years if
adequately treated by the surgical methods available in
1947.  These are only inconsistencies if we accept the
hypothesis that CAL-2 and CAL-3 were participants in the
MED-sponsored plutonium project.  Alternatively, if we
reject that hypothesis and accept the hypothesis that they
were participants in bone cancer experiments, then their
ages and exact prognoses become irrelevant.  Further, the
occurrence of children (6 out of 12 patients) in Hamilton's
work can also be explained by the bone cancer therapy
hypothesis, because children are a significant proportion of
patients diagnosed with bone cancer.

Thirdly, reports by the MED investigating scientists written
in the several years follow-

			     20

ing the plutonium excretion experiment mention only CAL-1. 
CAL-2 and CAL-3 were not described in those reports but were
discovered in Hamilton's files during a 1971 review
(Appendix 23, pages 104-5).  In a report about human
plutonium exposure written by Russell and Nickson in 1951
and edited by Robert S. Stone (Appendix 1, pages 257 and
263), the authors specifically mention an individual studied
by Hamilton (CAL-1).  They never mention CAL-2 or CAL-3. 
Further, Russell and Nickson spoke directly with Hamilton
before writing this report.  The exclusion of CAL-2 and CAL-
3 by two individuals familiar with the data from the MED-
sponsored plutonium project (Hamilton and Stone) becomes
understandable if these two subjects were not part of that
MED research protocol.

Yet another peculiar feature explained by the hypothesis
that CAL-3 was not part of the MED-sponsored project is the
inordinate time delay between the injection of CAL-1 and
CAL-3, more than two years.  It is very likely that at any
given time there were ample patients in UC Hospital that
fulfilled the entrance criteria for the MED-sponsored
plutonium experiment.  This time gap in patient selection is
consistent with the hypothesis that Hamilton was awaiting
the admission of relatively rare primary bone cancer
patients.

The hypothesis that CAL-3 was not part of the MED-sponsored
study explains the most troublesome inconsistency in the
records reviewed by the Committee.  Hamilton's colleagues
injected CAL-3 after the supervising federal agency called a
halt to the plutonium excretion project.  The military
called the halt before oversight of such experiments changed
from military to civilian authority (AEC).  Then, shortly
thereafter, the AEC issued a memo that revised the
prohibition, allowing plutonium injections provided that
investigators met certain provisions, the major one being an
"expectation that it may have a therapeutic effect."  The
complete text of the memo is somewhat ambiguous (Appendix
21, pages 5-6).  There are two possible interpretations of
the AEC memo.  The first interpretation is that the memo
prohibits further injections of plutonium into human
subjects unless the injection is meant to be therapeutic for
that individual.  The second, broader interpretation is that
the memo permits further investigations of therapeutic
intent, what would today be called a phase I investigation
to determine potential therapeutic effect that may not be
beneficial to the individual receiving the test dose. 
Hamilton was the only investigator to employ plutonium
following the memo modifying the prohibition.  If, as with
the strontium patients, the injections

				21


given to CAL-2 and CAL-3 represented a small test dose in a
therapeutic experiment then all the requirements set out in
the AEC memo were met by Hamilton and coworkers during the
injection of CAL-3.

The Committee discovered no direct evidence that CAL-2, CAL-
3, or CAL-4 were participants in a clinical investigation to
discover a treatment for bone cancer.  Further, designation
of the UCSF patients as CAL-2 and CAL-3 and the inclusion of
CAL-3 in DOE-sponsored follow-up studies in the 1970s
implies that these subjects were part of the MED-sponsored
plutonium project.  It is, however, important to point out
that the child (CAL-4) with osteogenic sarcoma who was
injected with americium also received the "CAL" designation,
but was obviously not part of the "plutonium" project.12
{12.  Nor do we know when the designation "CAL" was applied
to subjects CAL-2, CAL-3, or CAL-4.}


CAL-2 appears to be unique among the subjects injected with
plutonium in that he received a mixture of 239Pu along with
the radioactive elements cerium and yttrium (Appendix 25). 
In a September 1945 report entitled "Technical Progress
Report on the Metabolic Properties of Plutonium and Allied
Metals" (Appendix 27), Hamilton states:

     Tracer, smoke, radioautographs and human studies
     will be continued for the next two months.  In
     addition, the next human subject that is available
     is to be given, along with the Pu 238, small
     quantities of radio-yttrium, radio-strontium, and
     radio-cerium.  This procedure has in mind two
     purposes.  First, the opportunity will be
     presented to compare in man the behavior of these
     three representative long-lived Fission Products
     with their metabolic properties in the rat,
     and second, a comparison can be made of the
     differences in their behavior from that of
     plutonium.

Because CAL-2 received cerium and yttrium, the above
statement suggests his participation in the MED-sponsored
project to determine plutonium excretion rather than a
therapeutic investigation.  However, the statement quoted
from Hamilton leaves several questions unanswered.  Why was
CAL-2 injected with 239Pu, not 238Pu?  Why was he not
injected with radio-strontium?  Why did seven months
transpire before CAL-2 was injected, well beyond Hamilton's
stated date for termination of the studies?

			    22

CAL-3 received his injection immediately before an
amputation that was likely to be curative.  Therefore, the
only potential therapeutic benefit to him would be in the
event of a recurrence.  However, the therapeutic intent may
have been directed at future patients as is commonly the
situation in early, so-called phase I, experimental
therapies.  Plutonium is an alpha emitter with an energetic
but short path length.  To effective in cancer therapy it
would have to concentrate in the tumor.  Once concentrated
in the tumor, alpha emitters are potent cytotoxic agents
(Appendix 28).  Hamilton's research demonstrated that
plutonium indeed preferentially localized in osteogenic
sarcoma relative to normal bone (Appendix 25).

The Committee has considered two hypotheses regarding the
scientific investigations carried out on the subjects
injected with plutonium.  Neither hypothesis explains all
conflicting pieces of evidence.  Because no direct
confirmation of therapeutic intent in the injections of CAL-
2 and CAL-3 has been discovered, and the September 1945
report to the MED from Hamilton suggests CAL-2's
participation in the MED-sponsored project, the alternative
hypothesis discussed above cannot be established to the
satisfaction of all Committee members. The Committee
suspects that the areas of conflict between the two
hypotheses probably arise from an attempt by Hamilton and
colleagues to piggyback two experimental designs.  Once
satisfied the MED contract restrictions while the other
satisfied their medical research interests.  These
investigators received research funding from the federal
government.  It is likely that they attempted to embark on
clinical research efforts (i.e., the discovery of a new
treatment for bone cancer) while completing the tasks and
adhering to the restrictions defined in their contracts.
Indeed, AEC memos issued in early 1947 discuss such
restrictions (Appendix 21, pages 4-5).  This scenario
explains why Hamilton stated a plan to inject a subject with
three radionuclides and then performed a detailed analysis
of these elements in cancerous tissue.  While the former
analysis would be useful to the MED, the latter analysis
would not be.

Finally, the Committee believes that regardless of the type
of experiment in which CAl-2, CA-3 were involved, consent
was necessary, although the nature of information given to
the patients to secure their participation would have
differed.


				23

D.   Consent of Research Subjects

1.   Common Practice during the 1940s:  Most medical
researchers of that period were also clinicians.  They
usually asked and obtained verbal agreement of their
patient-subjects to participate in studies.  Clinical
researchers of that era generally did not discuss or
disclose to their patients the purpose or specific nature of
the research, the procedures involved, or the risks.13 
{13.  Faden RR. Beauchamp TL. A History and Theory of   
Informed Consent.  New York Oxford University Press, 1986:152.}
While written consent was obtained in some experiments
during the 1940s, it was not standard practice.  Further,
the AEC specifically states, with regard to therapeutic
plutonium experiments, that "the Commission does not request
that written released be obtained"  (Appendix 21, page 6).

During this era, patients agreed to participate in research
because of trust in their physician, not because of formal
consent procedures or documents.  There were no
institutional review committees that considered the risks
and benefits of the research before commencement of the
study, as is required today.  An eminent clinical researcher
of that era recalled his own studies during the war years in
his life history:

          Some of the ethical problems abut this sort of
          investigation that trouble us now never dawned
          on us then.  There wasn't much clinical
          investigation as such in the early 1940s......
          We never asked permission of those patients to
          go through this procedure.  We certainly never
          explained it.  We never told them, this isn't
          going to help you one bit, but it may give us
          a better understanding.  No patient ever
          refused to participate.14 {14.  Kaufman SR  The 
	  Healer's Tale.  Madison: University of Wisconsin 
	  Press, 1993: 170.}

Even as late as 1963, many well-respected clinical
investigators did not disclose to research subjects
important information about the facts or risks of
experiments or obtain their specific consent.15 
{15.  Katz J. Capron AM, Glass ES.  Experimentation with     
Human Beings.  New York:  Russell Sage Foundation,     
1972:292-306.}

The Committee was concerned that only poor and vulnerable
persons were selected as subjects for this research.  During
the 1940's, it was common for physicians to ask charily
patients to participate in research projects.  Research
physicians assumed that


				24

patients would participate as an implicit exchange for
receiving free care.16 {16.  Kaufman SR. Op. cit: 220.}
However, it is unethical to require subjects to participate 
in research in order to obtain standard medical care.  While 
CAL-1, CAL-2, and CAL-3 were all unable to pay for the full 
costs of their treatment, so were many individuals of that 
period who required hospitalization and surgery.  Few 
individuals had health insurance then.

The small number of patients injected with plutonium at UCSF
makes it difficult to determine whether the proportion of
subjects who were members of ethnic minorities (1 out of 3)
differ from the proportion in all patients admitted to the
UCSF surgical ward in that era.  Further, if CAL-2 and CAL-3
were selected for University-sponsored therapeutic research
because they had primary bone cancer, their participation
was based more likely on the rarity of their disease process
than their race or financial status.

2.   Experimentation during World War II:  An increase in
biomedical research coincided with the Second World War.  As
well, the nature of human experimentation began to change. 
What had been occasional efforts by relatively few,
individual researchers became extensive projects involving
large teams of researchers, funded by the federal
government.  Human research lost its intimate character as
an enterprise conducted between physician and patient and
patient and was instead devoted to seeking solutions to war-
related problems.  There was a strong sense of urgency in
medical research during those years.

In many studies, subjects were not informed about the
details of the research.  At least one research project of
that era did meet the more rigorous standards of informed
consent that would be required today.  In a World War II
project in which soldiers were infected deliberately with
gonorrhea, careful attention was given to informing patients
and obtaining their consent.  Potential volunteers received
written information about the experiment and its risks and
provided signed consent.17 {17.  Rothman DJ.  Strangers at 
the Bedside.  New York: Basic Books, 1991: 43-50.}  Thus, 
while there was a range of actual consent procedures used 
during those years, the WWII gonorrhea study documents that 
investigators understood the concept of written informed 
consent and applied this concept correctly in at least one 
instance.


				25


The federal Office of Scientific Research and Development,
overseeing the Committee on Medical Research (CMR), was
established in 1941.  The CMR reviewed and recommended
hundreds of research proposals during the war.  In 1942,
there appeared a pressing need for research into gonorrhea. 
In response to a proposal for human experimentation, Dr.
Richards, chair of the CMR, wrote to Dr. Charles Carpenter
of the University of Rochester, who proposed the research:

          Human experimentation is not only desirable,
          but necessary in the study of many of the
          problems of war medicine which confront us.
          When any risks are involved, volunteers only
          should be utilized as subjects, and these only
          after the risks have been fully explained and
          after signed statements have been obtained
          which shall prove that the volunteer offered
          his services with full knowledge and that claims
          for damages will be waived.  An accurate record
          should be kept of the terms in which the risks
          involved were described (Appendix 29).

3.   The UCSF Subjects:  We do not know, and cannot know,
exactly what was told to the research subjects or what they
understood regarding the nature of the radioactive injection
or its risks.  The three UCSF subjects did not give signed
written consent to participate in the experiments.  The
Committee was able to identify witness-signed and patient-
signed consents for surgical and anesthetic procedures in
all the medical charts of all the subjects.  The Committee
has only three documents from which to draw conclusions
about verbal consent:

     1)   A note in the chart of CAL-3, dated July 18, 1947,
states:  "the experimental nature of the intramuscular
injection of the radioactive tracer sample was explained to
the patient, who agreed upon the procedure.  The patient was
fully oriented and in sane mind."  The note is accompanied
by the signatures of three physicians and a nurse but not
that of the patient (Appendix 18).  There is no explicit
mention of any risks being discussed with any of the
research subjects and no similar statement was found in the
charts of CAL-1 or CAL-2.  It is noteworthy that a memo from
the AEC dated March 7, 1947, required investigators to show
proof that each patient understood the nature and possible
risks of the procedure and to have two witnesses signed the
notation (Appendix 21).  The patient's signature was not a
requirement.  CAL-3 was the only UCSF patient to be injected
with plutonium following the March 7, 1947, memo from the
AEC.

     2)   The oral history of Kenneth Scott, Ph.D., as
recorded by Sally Hughes, a med-



				26

ical historian at UC Berkeley, in December 1979, in which
Dr. Scott claimed that he never told CAL-1 what was injected
into him and that the experiments were "incautious" and
"morally wrong (Appendix 30, pages 48-50).

     3)   Besides these documents a report entitled
"Disclosure to patients injected with plutonium" (Appendix
21, page 9) implies that CAL-1 and CAL-2 received verbal
information about the experiment.  That report was the
result of an AEC investigation authorized by the General
Manager on April 14, 1974.  The inquiry was directed to the
question of whether consent had been obtained.  The AEC
investigators interviewed the Director of the Crocker
Laboratory regarding the UCSF subjects and were told "that
the patients were informed that they were to receive a
radioactive substance having certain properties."

E.   Patient Benefits:  The injections of plutonium were not
expected to be, nor were they, therapeutic or of medical
benefit to the patients.  However, there is indirect
evidence to support that the injections of CAL-2, CAL-3, and
CAL-4 were part of an experiment intended to gather
scientific data on the deposition of bone-seeking
radionuclides within bone cancers.

F.   Were Patients Harmed:  When evaluating the
appropriateness of human experiments, the benefits to
research subjects are weighted against the potential risks. 
The MED-sponsored plutonium project offered no therapeutic
benefit to the individual subjects.  Hence a crucial
question is whether the risks to the subjects were
acceptable in the context of available knowledge about
plutonium.

It appears that the investigators took three precautions to
mitigate risks to the experimental subjects:  1) animal
experiments preceded human studies; 2) the dose administered
to humans was lower than extrapolations from animal studies
would suggest as a safe dose to avoid acute toxicity; and 3)
as precautions against long-term toxicity, small doses were
selected and subjects (for the MED-sponsored project) were
chosen who were believed to have a life expectancy of less
than ten years.

Theoretically, there is no threshold amount of radiation
below which zero risk is guaranteed.  However, the amount of
plutonium injected into the CAL patients was too small to
pose a significant risk of physical harm.  CAL-1 and CAL-3,
who both lived much longer than a decade after the
injections (CAL-1 more than 20 years and CAL-3


			27

more than 40 years), did not develop any medical
complications from the radioactive substance, such as cancer
or leukemia.  Nonetheless, the plutonium researchers can be
criticized for not taking into account the possibility that
their estimates of prognosis could be wrong and that some
subjects could live much longer than expected.  They
expected that these patients were likely to die within 10
years, but could not guarantee that each diagnosis or
prognosis on which they based that expectation was correct.

G.   Follow-up Studies:  UCSF was not involved in any of the
follow-up studies on the surviving patients conducted by the
U.S. Department of Energy.

VII.      Other Ethical Considerations

A.   Were Patients Wronged:  Even without medical
complications, subjects might have been wronged.  According
to ethical standards of the period, their integrity and
dignity were violated if they did not understand or agree to
the interventions performed on them.

As noted above, we do not know what any of the subjects was
told, what they understood and what opportunity each had to
ask questions.  If these patients were not told about the
experiment and were not given the opportunity to make a free
choice about whether to participate, the Committee believes
that they were wronged, even through they did not suffer any
medical complications from the plutonium injection.

B.   Ethical standards for Consent in Research During the
1940s:  The idea that patients should be informed about
experiments and agree to participate was accepted during the
era of the MED-sponsored plutonium project.  However,
published discussions of informed consent for medical
research were sporadic before 1946.  One scholar has
written, "There was in fact no broad interest in consent to
research prior to the Second World War,"18 {18.  Faden RR, 
Beauchamp TL.  A History and Theory of  Informed Consent.  
New York: Oxford University Press,  1986:152.} as mentioned
above.  The disclosure of Nazi atrocities carried out in the
name of "research" led to the codification of ethical
principles already in existence to guide research on human
subjects.  At the request of the U.S. Government, the
American Medical Association (AMA) appointed Andrew Ivy,
M.D., vice-president of the University of Illinois, to
represent the organization and to advise U.S. military officials

			    28


in Nuremberg on ethical guidelines for human research.

Dr. Ivy reported on war crimes and outlined basic ethical
standards for research that were echoed in the Nuremberg
Code.  The standards he described did not, however, arise
after the ward.  Dr. Ivy wrote:

          On my last trip to Germany I took affidavits
          and legal documents showing the conditions
          under which human beings were used as
          experimental subjects in the U.S.A. during the
          war.  These are the conditions:  (1) Consent of
          the subject must be obtained.  All subjects have
          been volunteers in the absence of coercion in any
          form.  Before volunteering, the subjects have been
          informed of the hazards, if any.
          (2) The experiment to be performed must be so     
          designed and based on the results of animal 
          experimentation and the knowledge of the natural  
          history of the disease ... and must not be random      
          and unnecessary in nature.  (3) The
          experiment must be conducted only by 
          scientifically qualified persons ... Such rules 
          are required to insure the human rights of the 
          individual, to avoid the debasement of a method 
          for doing good, and the loss of the faith of the 
          public in the profession.19{19.  Ivy AC.  "Nazi war 
	  crimes of a medical nature."   Federation Bulletin 
	  1947;33: 133-146.}


Dr. Ivy's work led to widespread discussion of the ethics of
human research in U.S. medical journals.  An editorial in
the Journal of the American Medical Association in November
1946 stressed that people have the right to decide whether
to participate in research. The editorial pointed out that
in U.S. research conducted during World War II, "The right
of the human being to determine for himself whether he would
participate was recognized."20 {20.  "The Brutalities of Nazi 
physicians." JAMA 1946; 132: 714-715.} This is consistent with 
the 1942 views of the Chair of the Committee on Human Research
of the federal Office of Scientific Research and Development, 
as stated previously.  However, historical studies indicate 
that many U.S. experiments conducted during World War II 
involved persons who were incapable of giving informed consent.  
One historian noted.


				29

          The research into dysentery, malaria, and
          influenza revealed a pervasive disregard
          of the rights of subjects -- a willingness
          to experiment on the mentally retarded,
          the mentally ill, prisoners, ward patients,
          soldiers, and medical students without
          concern for obtaining consent.21 {21.  Rothman DJ. 
	  Strangers at the Bedside. New York Basic   
	  Books, 1991:33.} 

The question of how much information patients need or must
have to make an informed decision about participation in
research is problematic both in contemporary research and in
evaluation of past experiments.  Nevertheless, the House of
Delegates of the American Medical Association (AMA) in 1946
adopted the following position, and reported it in JAMA.

          In order to conform to the ethics of the
          American Medical Association, three
          requirements must be satisfied:  1) the
          voluntary consent of the person on whom
          the experiment is to be performed; 2) the
          the danger of each experiment must be
          previously investigated by animal
          experimentation; and 3) the experiment must
          be performed under proper medical protection
          and management.22 {22.  Supplementary report of 
	  the Judicial Council.  JAMA  1946; 132: 1090.}

The writings of Dr. Ivy strongly influenced development of
the Nuremberg Code.  The Nuremberg tribunal declared in
August 1947,

          The voluntary consent of the human subject is
          absolutely essential.  More specifically, the
          subject must be told about the nature, dura-
          tion, and purpose of the experiment; the method
          and means by which it is to be conducted; all
          inconveniences and hazards reasonably to be
          expected; and the effects upon his health or
          person that may possibly come from his
          participation in the experiment.23 {23.  Katz J. 
	  Capron AM, Glass ES. Experimentation with Human
     	  Beings. New York Russell Sage Foundation, 1972:
     	  292-306.}


These standards are being refined and codified at the time
of the MED-sponsored plutonium project.  However, the impact
of these standards on actual research practices during this
era is questionable.  One historian has written.

				30

          The events described at Nuremberg were not
          perceived by researchers or commentators to
          be directly relevant to the American scene.24
	  {24.  Rothman DJ.  Strangers at the Bedside.  
	  New York Basic Books, 1991: 62.}

Although the concept of research subject consent was well
articulated at the time, several important issues that are
pertinent to the plutonium experiment were unclear.  What
information needs to be disclosed to research subjects, so
that their decision to volunteer is an informed one?  One
can begin to address this question by examining the
development of standards of disclosure in medical practice. 
Two standards of disclosure developed.25 {25.  Appelbaum P. 
Lidz C. Meisel A.  Informed Consent: Legal Theory and Clinical 
Practice.  New York Oxford  University Press, 1987: 41-49.}
In 1957, the term "informed consent" was first used in case 
law.26 {26.  Salgo v. Leland Standford Jr. Univ. Bd. of 
Trustees. 317 P.2d 170 (Cal. Ct. App. 1957).}  In the
late 1950s and 1960s, the courts enunciated a physician-
centered standard, requiring disclosure of what a reasonable
physician would disclose under similar circumstances.  In
practice, the standard required physicians to disclose what
is customarily disclosed.  Today, slightly more than one-
half of the states employ a reasonable physician standard
for disclosure.27 {27.  Furrow BR, Johnson SH, Jost TS. Schwartz 
RL.  Health Law:  Cases, Materials, Problems. St. Paul: West  
Publishing Co., 1991: 336.} By analogy, researchers who disclosed
what other researchers of that era would have disclosed
could arguably be considered to have fulfilled their ethical
obligations.  In the 1970s a patient-centered standard was
developed, requiring disclosure of what a reasonable patient
would find pertinent regarding the decision to accept a
medical intervention.  Generally, the patient-centered
standard requires more disclosure than the physician-
centered standard.  By analogy, a researcher would need to
disclose information that a reasonable patient would find
pertinent to the decision to participate in research.  Under
this more demanding standard, disclosure of what other
investigators customarily disclose could be judged
insufficient.

The Committee has no conclusive evidence whether or not the
UCSF researchers disclosed sufficient information to the
patients for them to make an informed decision about
participating in the plutonium experiments.  One
determination of whether disclosure was adequate presumes
that it was not unless the researcher proves that he or

			    31

she disclosed sufficient information.  An alternative
approach is to presume that disclosure was sufficient unless
these is specific evidence that it was inadequate.  The
present-day standard for informed consent in research is the
former, and it serves to enhance protection of research
subjects.  At the time of the plutonium experiments,
however, these issues were not discussed.  The Committee is
hesitant to apply current-day standards to another
historical period.

The Committee considered whether standards for consent
should have been loosened because of wartime concerns for
national security in the 1940s.  World War II and the Cold
War were considered justified struggles against
totalitarianism.  An historian has written,

          Wartime conditions brought a reliance on such
          procedures as the draft, forced military duty,
          and assignment to combat -- and these new
          facts of life inevitably affected the mind-set
          of researchers.  Every day thousands of men were
          forced to face death, whether or not they under-
          stood the campaign, the strategy, or the cause.
          Since these investigations were integral to the
          military effort, the rules of the battlefield
          seemed to apply to the laboratory.  Researchers
          were not more obliged to obtain the permission
          of their subjects than the Selective Service was
          to obtain the permission of civilians to become
          soldiers.28 {28.  Rothman DJ.  Strangers at the 
	  Bedside.  New York Basic  Books, 1991: 33.}

At the Nuremberg trials, Nazi physicians argued that war and
national security justify conduct that would otherwise be
considered reprehensible.  The Allied tribunal rejected this
reasoning.  The Committee believes that the conclusions of
the Allied tribunal ought to be applied to wartime research
conducted in the U.S. as well.

Overall, the Committee believes that practices of consent of
the era were inadequate by today's standards, and even by
standards existing at the time.  Although researchers of the
1040s usually did not discuss with patients the details of
the experiment or the risks involved, the Committee believes
that researchers should have discussed risks with potential
subjects.


				32

The plutonium experiments were consistent with accepted
medical research practices at the time. However, the
Committee has no documentary evidence about whether these
experiments satisfied the ethical standards of the period,
which required voluntary consent from informed subjects. 
The Committee found no evidence that the experiment was
designed with malevolent intentions.  The UCSF plutonium
injections were not carried out to determine whether human
being could tolerate high doses of plutonium or radiation
from plutonium.

VIII.     Conclusions

1.   Reasons were advanced by the government suggesting a   
need to study how the human body handles plutonium.

     a.   Large quantities of plutonium were being produced.
     b.   Plutonium was thought to be a dangerous substance.
     c.   Human workers were being exposed.
     d.   Animal experiments were not totally sufficient to
          predict human response.
     e.   Many Americans might be exposed to plutonium.

2.   Precautions were taken to mitigate possible and unknown
     risks to the experimental subjects.

     a.   Animal experiments preceded humans studies.
     b.   The investigators reasoned that the dose of
          plutonium administered would not produce          
          acute toxicity.
     c.   As precautions against long-term toxicity, small
          doses were used and subjects with a presumed life
          expectancy of ten years or less were chosen for
          the MED-sponsored project.

3.   The experiment produced results that helped establish
permissible exposure levels for plutonium workers, data on
plutonium in human tissues, and information enabling
selection of appropriate animal models for future
experiments.

4.   It was common, but not universal, practice during World
     War II to conduct medical research experiments on human
     being without signed consent.  The standards



				33

and practice discussed both within and outside the medical
profession called for explaining risks and obtaining consent
from volunteer subjects.  The urgency of war did not justify
a departure from prevailing moral and ethical standards.

5.   Practices of obtaining consent during the era did not
meet the standards of the time or today's standard (Appendix
31).

     a.   The ethical principles of the 1940s state that a
          research subject be told about "the nature,
          duration, and purpose of the experiment; the
          method and means by which it is to be conducted;
          all inconveniences and hazards reasonably to be
          expected; and the effects upon his/her health
          which may possibly come from participation in the
          experiment".29 {29.  Katz J. Capron AM, Glass Es.  
	  Experimentation with Human Beings.  New York Russell 
	  Sage Foundation, 1972:292-306.}

     b.   Signed consent was required by the federal
          government for some human research conducted
          during World War II.
     c.   However, written documentation of consent was, in
          practice, generally not obtained in that era.

6.   We do not know, and cannot know, exactly what was told
     to the research subjects or what they understood
     regarding the nature of the radioactive injection or
     its risks.

7.   It was unethical if the injections of any of the CAL
     patients were done without their knowledge, consent,
     and free participation.  Further, it was unethical if
     the injection of CAL-2 or CAL-4 (both minors) was done
     without the proper consent of their parent or guardian.

8.   The inclusion of CAL-2, a child in the MED-sponsored
     plutonium project, if such was the case, constitutes
     inappropriate subject selection and, therefore, would
     be unethical with or without parental approval.

9.   The MED-sponsored project to determine human plutonium
     excretion was halted before the injection of CAL-3. 
     The AEC subsequently set forth criteria under which
     future plutonium injections could be performed.  The
     criteria are ambiguous when read 50 years after they
     were written.


				34

     a.   One interpretation is that injections could be
          performed only when they would result in direct
          therapeutic benefit to the individual.  The
          injection of CAL-3 is judged by the Committee not
          to have been therapeutic for him.
     b.   Another interpretation is that injections
          performed to identify potential therapeutic
          benefits were permitted.  If CAL-3 was part of
          University-sponsored medical research on
          development of a treatment for bone cancer, his
          injection satisfied the criteria set forth in the
          agency directive.

10.  Substantial indirect evidence exists supporting the
     hypothesis that CAL-2, CAL-3, and CAL-4 were part of
     University-sponsored medical research directed at
     finding a new treatment for bone cancer, and were not
     participants in the MED-sponsored project to determine
     humane plutonium excretion.

11.  The evidence reviewed indicates that patients not were
     physically harmed by the experiment(s).

12.  Patient care was not compromised by participation in
     the experiment(s).

The MED sponsored plutonium experiments were scientifically
valid.  In many ways they resemble, in principle, product
testing by pharmaceutical companies.  They addressed
legitimate problems and produced useful information that was
published in scientific reports (Appendix 16), books
(Appendix 1), and journals (Appendix 32).

IX.  Addendum

Because of the complexity of several issues in this report
and the difficulty of a single report to reflect the views
of all, Committee members were invited to write a personal
statement if they wished.  These unedited statements are
appended (Appendix 33).


					34
The Committee




                        Roy A. Filly
                        Chairperson



Michael J. Banda                        Sharon Friend



Gretchen A.W. Gooding                   Karl Hittelman



John Huberty                            Reese T. Jones



Sharon Kaufman                          Bernard Lo



Robert Lull                             Seymour Packman



David C. Price                          Mack Roach



Carol S. Viele                          Judith C. Woodard



Elizabeth Zitrin




36
                         Appendices
                              
Number    Contents

  1       An Example of Early (1951) Unclassified Accounts  
               of the Plutonium Project
  2       Excerpts from Dr. Hamilton's Notes on CAL-4
  3       Excerpts from a 1994 Department of Energy press
          Release on Radiation Experiments not Described in
          the 1985 Markey Reports
  4       Compendium of Statements Made in the Press About
          Human Experimentation
  5       UCSF ad hoc Fact Finding Committee
  6       Letter from J.R. Oppenheimer to S.L. Warren, March
          23, 1945
  7       Letters from H.L. Hemplmann to J.R. Oppenheimer
  8       Ethical Standards and Practices for Human
          Experimentation at the Time of the UCSF
          Experiments (1945 - 1947)
  9       Official Project Description
  10      Report on the Intravenous Administration of
          Plutonium to Human (1950)
  11      Reports Describing the Methodology for Detection
          of Plutonium
  12      Report of Conference on Plutonium Dated May, 1945
  13      A 1991 Review of Exposures to Plutonium
  14      1944 Estimate of Tolerance Levels for Plutonium
  15      Occupational Limits of Exposure
  16      1946 Report to MED on the Experiment that Included
          Data on CAL-1
  17      Dosimetry & Biokinetics
  18      Summary of the medical record of CAL-1
  19      Summary of the medical record of CAL-2
  20      Summaries of the medical record of CAL-3
  21      Report containing excerpts of memos addressing
          oversight and approval of human experimentation
          supported y the Atomic Energy Commission
  22      1949 Letter from K.G. Scott, Ph.D. to the Atomic
          Energy Commission
  23      Excerpts from Plutonium in Man:  A Twenty-Five
          Year Review
  24      Articles on the Clinical Use of Radioactive
          Material
  25      Excerpts from Dr. Hamilton's records
  26      Excerpts from Dr. Friedell's Records on
          Therapeutic Use of Radioactive Strontium
  27      Metabolic Properties of Plutonium and Allied
          Materials.  A Technical Progress report
  28      Potential Use of Alpha Emitting Radionuclides in
          the Treatment of Cancer
  29      The Rights of Subjects in Human Experimentation: 
          An Overview
  30      1979 Oral History of Dr. Kenneth G. Scott, Ph.D.
  31      Oversight of Human Experimentation at UCSF
  32      Publications by Dr. Joseph G. Hamilton, M.D.
  33      Personal Statements from Committee Members