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ROYAL COMMISSION ON THE USE A N D EFFECTS OF CHEMICAL AGENTS ON AUSTRALIAN PERSONNEL IN VIETNAM
Commissioner: The Hon. Mr Justice P. Evatt, DSC , LLB
Final Report—July 1985
Volume 3: Birth Anomalies
Presented 22 August 1985 Ordered to be printed 19 September 1985
Parliamentary Paper No. 290/1985
ROYAL COMMISSION ON THE USE AND EFFECTS OF CHEMICAL AGENTS ON AUSTRALIAN PERSONNEL IN VIETNAM
Commissioner: The Hon. Mr Justice Phillip Evatt DSC. LLB.
A Judge of the Federal Court of Australia
FINAL REPORT
July 1985
VOLUME 3
Australian Government Publishing Service Canberra 1985
© Commonwealth of Australia 1985
ISBN 0 644 04339 3 Set of Volumes ISBN 0 644 04342 3 Report Volume Three
Printed by Canberra Publishing and Printing Co., Fyshwick, A.C.T.
ROYAL COMMISSION ON THE USE AND EFFECTS OF CHEMICAL AGENTS ON AUSTRALIAN PERSONNEL IN VIETNAM
Commissioner: The Hon. Mr Justice Phillip Evatt DSC
G.P.O. Box 4842 Sydney, N.S.W. 2001 Telephone: (02) 239 6222
Your Excellency,
Secretary: Mr B.D. Meade
31 July 1985
In accordance with Letters Patent issued to me on 13 May 1983, 27 June 1984, 3 August 1984 and 23 April 1985, I have the honour to present to you the Final Report of my inquiry.
I believe that the Report complies with those Letters Patent and that my task is therefore completed.
Yours sincerely
JUSTICE PHILLIP EVATT Royal Commissioner
His Excellency the Right Honourable Sir Ninian Stephen, A.K., G.C.M.G., G.C.V.O., K.B.E. Governor-General and Commander-in-chief Government House CANBERRA A.C.T. 2600
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TABLE OF CONTENTS VOLUME 3
CHAPTER VII
HEALTH EFFECTS - REPRODUCTIVE OUTCOMES AND BIRTH ANOMALIES
1. THE ALLEGATIONS 1
2. THE COMMISSION'S APPROACH 5
3. AUSTRALIAN BIRTH DEFECTS STUDY 12
3.1 Study Design 17
3.2 International Opinion of Australian Study 24 3.3 Criticisms of AVHS Birth Defects Study 28
3.4 Consistency 37
4. RANCH HAND II 39
4.1 Study Design 43
4.2 WAA's Final Submission on Ranch Hand II 51
5. CDC BIRTH DEFECTS STUDY. ATLANTA. GEORGIA USA 54 5.1 Methods 55
5.2 Spina Bifida 62
5.3 Coloboma 63
5.4 Cleft Lip 64
5.5 Congenital Neoplasms 65
6. NEW ZEALAND APPLICATORS STUDIES 6.1 Smith et al (1981) 66
6.2 Smith et al (1982) 67
7. THE VIETNAMESE STUDIES 7.1 General 68
7.2 Descriptive Studies (a) Tung et al 1980 72
(b) Ministry of Health/US Military Assistance Command Vietnam and US Department of Defense 73
(c) Huong and Phuong (1983) 75
(d) Tuyen et al 77
(e) Trung et al 78
(f) Phuong & Huong (1983) 79
(g) Trung & Chien (1983) 80
(h) Can et al (1983) 81
(j) Lang. Van and Tung (1983) 83
7.3 Analytical Studies (a) Can et al (1983) 84
(b) Huong & Puong (1983) 86
7.4 Conclusion 87
8. OTHER DESCRIPTIVE STUDIES 87
(a) Field and Kerr 1979 88
(b) Thomas (1980).Thomas and Czeizel (1982) 88 (c) Nelson et al (1979) 90
(d) Hanify et al (1981) 90
(e) Townsend et al 91
(f) Balajaran and McDowell 93
(g) The Seveso Accident 94
(h) Alsea 2 95
(j) Conclusion 96
9. SPECIFICITY 97
v
10. DOSE-RESPONSE RELATIONSHIP 98
11. BIOLOGICAL PLAUSIBILITY 98
12. TIMING OF EXPOSURE 101
13. MUTAGENICITY 105
13.1 Summary of Dr Pearn's Background Report to the Senate (1982) re Birth Anomalies and Chemicals 106
13.2 Genetic Toxicology - Mutagenicity -Dr Brusick 117
14. POSSIBLE MUTAGENICITY OF RELEVANT CHEMICAL AGENTS 122 2.4-D 123
2,4,5-T 125
TCDD 126
Diquat 128
Paraquat 128
Picloram 128
Dalapon 129
Diuron 129
Monuron 129
Bromacil 130
Cacodylic Acid 130
Creosote/Distillate 131
Borate/Chlorate 131
DDT 131
Malathion 132
Dieldrin 132
Ch.lordane 133
Lindane 133
Diazinon 133
Pyrethrins 134
Diethyl-m-Toluamide (DEBT) 134
Dimethyl-Phthalate (DMP) Insect Repellent 134 Di-n~Butyl Phthalete (DBP) (Tick and Mite Repellent 135
Dapsone, Chloroquine, Primaquine & Paludrin 135 Solvents 136
Conclusion 136
15. SYNERGISM 136
16. THE REPRODUCTIVE OUTCOMES CONSEQUENT UPON MALE GERMINAL MUTATION 142
17. ANAESTHETIC GASES 146
18. THE FINAL OPINION OF EXPERT WITNESSES 152
19. CONCLUSIONS 155
20. FINAL CONCLUSIONS 164
21. PUBLICITY 165
21. ADDENDUM WAA's Tasmanian Study 166
ENDNOTES 188
Vi
TABLE OF CONTENTS - REPORT
VOLUME 1 - INTRODUCTION and EXPOSURE
Prologue
I Introduction II Standard of Proof III Ascertainment of Claims IV Exposure
VOLUME 2 - TOXICOLOGY and GENERAL HEALTH
V Toxicology and Safe Doses VI Health Effects General
VOLUME 3 - BIRTH ANOMALIES
VII Health Effects. Reproductive Outcomes and Birth Anomalies
VOLUME 4 - CANCER
VIII Health Effects, Cancer
VOLUME 5 - MENTAL WELL-BEING
IX Health Effects. Mental
VOLUME 6 - MORTALITY CLASS ACTION W A A and SECTION 47
X Mortality XI Class Action XII Status of W A A XIII Interim Report and S. 47
VOLUME 7 - BENEFITS and TREATMENT
XIV Benefits and Treatment
VOLUME 8 - CONCLUSIONS. RECOMMENDATIONS and EPILOGUE
XV Conclusions and Recommendations Epilogue
VOLUME 9 - EXHIBIT LISTS AND BIBLIOGRAPHY
vii
CHAPTER VII
HEALTH EFFECTS - REPRODUCTIVE OUTCOMES AND BIRTH ANOMALIES
"Felix qui potuit rerum cognoscere causes"
Virgil, Georgies ii. 490
(trans) "Happy is one who knows the causes of things
CHAPTER VII
HEALTH EFFECTS - REPRODUCTIVE OUTCOMES
AND BIRTH ANOMALIES
No aspect of this Inquiry has been approached with more
concern than this. One only has to use the words 'Vietnam
conflict1, 1 multi-national chemical company1 and 1 birth
defect1 in a sentence to realise that here indeed is a
volatile emotional mix.
1. THE ALLEGATIONS
Prior to the commencement of this Inquiry the allegation
both in Australia and in the United States was that
exposure of service personnel to Agent Orange in Vietnam
had led to congenital anomalies or birth defects in their
children conceived after their return to their home
countries.
That this was the allegation is reflected in the Terms of
Reference.1
Paragraph j of the Letters Patent reads:
VII-1
j. Evidence relating to the extent to which exposure to the chemical agents used has resulted in congenital anomalies among the children of Australian personnel;
The Commission has decided against a narrow approach to
this paragraph of the Terms of Reference. Stillbirths and
miscarriages could. if causally connected, be described as
"effects on Australian personnel of exposure to the
chemical agents" and also of course as "effects on the
.... health and well-being of their spouses". referred to
in paragraph (i) of the Letters Patent.
Accordingly, this section of the Report will deal with
untoward reproductive outcomes of all kinds including
infertility, miscarriage, stillbirths as well as
congenital anomalies.
The initial submission of W A A included the following:
The submission is that a large number of
veterans' children have suffered from congenital disabilities. The consistency of reports of similar disabilities and the number of veterans complaining of those disabilities is
significant.2
In relation to wives of veterans, the submission included
the following:
VI1-2
The most common complaint is (sic) stillbirths, miscarriages, urinary tract infection and cervical cancer.3
At pp 65-66 is to be found the following.
It is submitted that there is an abnormal rate of congenital defects. Whilst some such as talipes, hair lip, cleft palate are not rare in the
general population, it would appear that the incident (sic) is much higher than the normal population expectation. More rare forms of disability such as absence of limbs or digits, absence of bones in limbs, bone abnormalities and
the like are appearing. Other disabilities which are common are kidney abnormalities, asthma, children are small or underweight, hyperactivity, deafness, eye problems, enlarged head, enlarged
liver, internal haemorrhaging, spina bifida, slow learning capacity, epilepsy, heart problems and skin rashes.
It would appear that further research is needed to establish how the veterans' exposure to chemicals is passed on to the wives and children.
Deformities in children, stillbirths and miscarriages may be explained by chromosonal (sic) alterations * in the veterans and passed on in the spermatozoa" (sic).
The other area which needs investigation is the possibility that the seminal fluid has been altered in some way to become caracinogenic (sic) or has some other characteristic which causes urinary tract infection and/or birth deformities.
4
In its final submission W A A has not attempted to
summarise its position nor to put into orderly form the
conclusions which in its submission ought to be drawn from
the evidence.
VI1-3
However, in the first: paragraphs
final submission does focus on
question. It reads:
on Birth Defects the
what is a critical
The first question which must be asked is whether it is biologically feasable (sic). to have paternally mediated birth defects. It is
submitted that clearly the answer to this
question is in the affirmative.
In support of this claim the submission appears to rely
upon:
(a) Joffe;
(b) An assertion of a positive male-mediated effect from
anaesthetic gas exposure;
(c) An allegation of an increase in spontaneous abortions
following the Seveso incident;
(d) The Vietnamese studies;
(e) The C.D.C. Study;**
** A number of the comments made in the submissions of W A A indicate misunderstanding of the nature of case-control studies and the meaning of statistical significance
VI1-4
The Commission will deal with what it takes to be the
underlying bases for the submission as well as its bald
assertions.
(f) Criticisms of the Australian Birth Defects Study.8
2. THE COMMISSION 1S APPROACH
Finding WAA's approach inadequate. the Commission dealt
with the problem from basic epidemiological principles.
The allegation which is made, namely, that there is an
increase in the incidence of certain outcomes amongst
those with a certain exposure, is of a type validly tested
only by epidemiological science. In truth, the exposure
alleged is Vietnam service, although chemical use in
Vietnam is postulated as the reason for the untoward
outcomes.
Epidemiology is that science which is concerned with the
patterns of disease or outcomes occurring in human
populations and with the factors that influence those
patterns.
VI1-5
The science involves basically three forms of activity,
counting, comparing and interpreting.
Counting involves ascertaining the frequency of occurrence
of the condition in the particular population or group.
The frequency must be expressed as a rate where the cases
(or numerator) are related to the population (or
denominator) and both numerator and denominator must be
carefully defined.
Next, a comparison is made of the frequency of occurrence
of the condition of interest under two or more different
circumstances, (e.g. the birth defect rates amongst the
offspring of men with chemical exposure compared with
those of men with no chemical exposure).
The next step is interpretation. This involves first the
identification of circumstances under which the frequency
of the condition cited as an outcome is different.
Then one must determine whether the differences observed
are likely to have come about by chance. This is done by
statistical testing, a mathematical operation.
VI1-6
Next, in circumstances where differences are unlikely to
have occurred by chance, all the possible plausible,
biological explanations of the observed relationship
between the circumstances and the condition should be
considered and a judgment should then be made as to the
most likely explanation for the association which has been
found.
It has been said that epidemiological data alone cannot
establish that a certain factor really causes an outcome.
This is because what is being measured is association not
causation. (Laboratory investigations of causation are
difficult when the subjects are men and putative
poisons.) Nonetheless, an inference of causation is
logically reliable if the following are present:
(a) A strong association between the risk factor and the
outcome (called a high relative risk);
(b) Consistency - that is. if the association is found in
many different data sets. sometimes called
replicability;
(c) Specificity - that is to say, whether the association
between the risk factor and the outcome has some
VI1-7
significant teature which distinguishes it from
associations shown by other risk factors and other
outcomes;
(d) A dose-response relationship - that is to say, if
increasing exposure to the risk factor is associated
with increasing occurrence of the outcome;
(e) An association between the risk factor and the outcome
is biologically plausible;
(f) Changes in the prevalence of the risk factor results
in the predicted change in prevalence of the
condition.9
On the other hand if:
(a) there is no association or a very weak one between the
risk factor and the disease;
(b) the association is not found in different data sets;
(c) exposure to the risk factor does not produce the
particular condition of interest with regularity;
VI1-8
(d) there is no dose-response relationship;
(e) the association is biologically implausible;
(f) changes in the prevalence of the risk factor do not
produce change in the prevalence of the condition;
it is probable that there is no causal connection between
the risk factor and the outcome.
The Commission will adhere to these principles so as to
ascertain whether or not a connection between chemical
exposure in Vietnam and untoward reproductive outcomes has
been established in the epidemiological sense. This may
permit inferences as to causation to be drawn.
At the outset it must be said that no evidence of adverse
reproductive outcomes associated with either Vietnam
service or chemical exposure of any kind was in fact
produced by W A A in the course of the Commission. ** This
is perhaps surprising despite the high cost of good
quality epidemiological studies.
** Apart from the Tasmanian study and the Kerr and Field Report thereon, see Addendum.
VI1-9
In view of the substantial amount of Government money-
provided to W A A for preparation and presentation of its
case, the comment must be made that no expert was called
by Counsel representing W A A to make any analysis in
support of the allegation that, "the consistency of
reports of similar disabilities and the number of veterans
complaining of these disabilities is significant".10
Nor was any lay person called to speak to any numbers.
It is important to remember that the standard texts stress
that only a small percentage of the total burden of human
developmental defects can be attributed to drugs or
chemicals.11 Indeed, environmental causes including
radiation, infection, maternal metabolic imbalance and
drugs and chemicals have been responsibly estimated as
causing only between 8 and 11% of birth defects. The
12
following table gives more detail.
VII-10
Causes of Developmental Defects in Man- Estimates Based on Surveys and Case Reports in the Medical Literature
Known genetic transmission 20%)
Chromosomal aberration Environmental causes
3-5%)
Ionizing radiations 1%)
Therapeutic Nuclear )
Infections 2-3%)
Rubella virus Varicella virus(?) )
Herpes virus hominis Syphilis )
Maternal metabolic imbalance 1-2%)
Endemic cretinism Phenylketonuria )
Diabetes Virilizing tumors )
Drugs and environmental chemicals 4-5%)
Androgenic hormone Anticonvulsants )
Folic antagonists Oral hypoglycemics(?) )
Thalidomide Few neurotropic- )
anorectics(?) )
Oral anticoagulants Organic mercury )
Maternal alcoholism )
Combinations and interactions ?)
Unknown 65-70%
Again, in every 100 live births there will be between 2
and 7 children with a congenital defect requiring
treatment sooner or later. The size of the percentage
depends on the method of counting and to some degree on
the standard of living. But the underlying load of
defects has been found to be present in all countries and
at all times when reliable measurements have been taken.
- 11%
VII-11
3. AUSTRALIAN BIRTH DEFECTS STUDY13
The Commission is fortunate in that it had available to it
an extensive study measuring the incidence of birth
defects amongst the offspring of Australia's Vietnam
veterans. This was conducted by the Australian Veteran's
Health Study Group, (AVHS), a special section of CIH, in
1982 - 1983.
Since this study constitutes the only direct evidence
concerning reproductive outcomes amongst Australian
Vietnam veterans, it is dealt with in some detail at this
stage.
This is both epidemiclogically and forensically
appropriate - epidemiclogically, because "counting" and
"assessing the relative risk" ought to be the first steps:
forensically. because of the "best evidence" rule.
14 As has been previously described. there was prior to 1980 much public concern, particularly amongst Vietnam
veterans, that the frequency of congenital anomalies in
their children was disproportionately high. The alleged
higher frequency was attributed by some to exposure to
Agent Orange although herbicides of other kinds and
VI1-12
insecticides as well as some other aspects of Vietnam
service have been blamed.
In 1980 the Commonwealth Institute of Health (CIH), an
academic institution within the University of Sydney (and
constituting that University's School of Public Health),
agreed with the Australian Government to conduct a series
of scientific investigations into the health of Vietnam
veterans and their families and for that purpose set up a
special and separate unit, AVHS.
Part of this series was a case-control study of congenital
anomalies and Vietnam service. Planning for the study
began in May 1981. A protocol or plan for the study was
prepared and referred by the then Minister for Veterans'
Affairs to a Scientific Advisory Committee (SAC) which had
been established to advise him on the scientific merit of
such studies. The study was originally designed by Dr
Robert Maclennan who was Associate Professor of
Epidemiology within CIH.
The SAC consisted of Australian public health and
epidemiological experts. They are all of such eminence
that in the ordinary course one would not bother to
reproduce curriculum vitae. However, as things were said
VI1-13
of some by advisers to W A A in the course of conferences
designed to reach agreement on the structure of the
15 proposed Morbidity Study to be conducted by the same scientific group, the Commission is of the view that its
opinion of the impartiality, integrity and high
qualification of two at least should be stressed. They
are:
1. Dr Bruce Armstrong
Since 1979, Dr Armstrong has been the Director of the
National Health and Medical Research Council Unit in
Epidemiology and Preventive Medicine within the
University of Western Australia. He graduated in
medicine from that University in 1969 and then trained
as a specialist in internal medicine at the Royal
Perth Hospital, becoming a Member of the Royal
Australian College of Physicians in 1972. He became a
Fellow of the College in 1975. He trained in
epidemiology between 1972 and 1975 and obtained a
Doctorate in that discipline in 1975. Subsequently he
was Senior Lecturer in Medicine at the University of
Western Australia. thereafter. Director of Health,
Research and Planning in the Department of Health,
Western Australia, which position he held until 1979.
VI1-14
2 . Dr Tony McMichael
Dr McMichael is presently Principal Research Scientist
at the CSIRO Division of Human Nutrition, Adelaide.
He is a most highly regarded epidemiologist,
particularly known for his work on the "Healthy
Worker" effect.
The SAC, following a meeting oil 11 August 1981, reported
to the then Minister for Veterans' Affairs that the
proposed study, "could produce scientifically valid data
on the association between Vietnam service and the
fathering of malformed children".16
The study was under the ultimate direction of Emeritus
Professor, R.J. Walsh, the Director of Scientific Studies.
The investigation was commenced by Dr Robert Maclennan and
continued by Dr John Donovan, a Senior Adviser in
Epidemiology within the Commonwealth Department of
Health. Dr Donovan was assisted by Dr Michael A. Adena, a
statistician; Mr Glen Rose, a Senior Research Officer and
M/s Diana Battistutta also a statistician.
Again, in view of some inappropriate comments by the
advisers to WAA, the Curriculum Vitae of Dr Donovan and
Dr Adena are set out.
VI1-15
Dr John Donovan
MB BS 1965
PhD 1970
FFCM 1984 (MFCM 1973)
FRACMA 1980
1965 Junior Resident; Medical Officer, Royal Prince Alfred Hospital. Camperdown. NSW.
1966-1969 Postgraduate Medical Research Scholar, Dept of Mathematical Statistics, University of Sydney.
1969-1971 C.J. Martin Travelling Fellow of National Health and Medical Research Council of Australia. in Dept of Medical Statistics and Epidemiology, London School of Hygiene and Tropical Medicine.
1971-1974 Jointly, Lecturer in Epidemiology, Dept of Medical Statistics and Epidemiology. London School of Hygiene and Tropical Medicine, and Medical Statistician, Office of Population Censuses and Surveys.
From 1974 Australian Dept of Health. Canberra. May 1974 to July 1975 - Specialist (Epidemiology); twice during this time acted as Assistant Director-General. July 1975 - Promoted to Medical Services Adviser Class 1; following that acted as Director of State Division, and several times as First Assistant Director-General. June 1978 - promoted to Medical Services Adviser, Class 2; since then acted several times as First Assistant Director-General, and as Deputy Chairman, Capital Territory Health Commission.
VI1-16
Michael Adena
1971-1974 BSc University of Melbourne.
1975-1978 PhD. Australian National University.
1971-1972 Research Associate with Dr D.A. Holton, Dept of Mathematics. University of Melbourne.
1973-1974 Programmer/analyst with UC Compunet Ltd.
1974 Research Associate with Miss B Laby, Dept of
Statistics. University of Melbourne.
1978-1980 Research Officer, Dept of Population Biology, Australian National University.
1980-1982 Post-doctoral Fellow. Dept of Population Biology, Australian National University.
1982- 1983 Statistician, Australian Veterans Health Studies.
1983-Managing Director. INTSTAT Australia Pty Ltd. Fellow of the Royal Statistical Society.
3.1 Study Design
The basic design of the study was that of a case-control
study with one individually matched control for each
case. In case-control studies groups of individuals are
selected who do (cases) and do not (controls) have the
"disease state" under study. In this study the "disease
VI1-17
state" was strictly being the father of a child with a
defined congenital anomaly or anomalies; however, the
terms "case" and "control" are used loosely to refer to
the children. The children of the cases will be referred
to as "malformed" and those of the controls as "healthy",
using that word in the sense of not malformed.
The two groups were then compared with respect to the
exposure characteristic alleged to have caused the disease
state, namely. Vietnam service of the father.
In case-control studies, controls are matched to cases.
In this study healthy infants born in the same hospitals,
to mothers of similar ages to the mothers of children with
anomalies, and born as closely as possible in time to the
births of children with anomalies were selected as
potential controls. Where the "payment category" of the
mother of the malformed child was readily available, the
mother of the healthy child had to be in the same payment
category, e.g. Private (expensive), Intermediate, or
Public (free).
The investigation involved examination of hospital and
cytogenetic laboratory records of Infants born with
anomalies in New South Wales, Victoria and the Australian
VI1-18
Capital Territory between the years 1966 and 1979
inclusive. In all, 34 hospitals and 4 cytogenetic
laboratories were involved and co-operated fully with the
investigating team. To emphasise, whenever the birth of
an infant with an anomaly was detected. it was matched to
a healthy control infant born in the same hospital to a
mother of similar age and as close as possible in time to
the birth of the child with the anomaly.
The fathers of both cases and controls were identified in
8517 instances and those identified were compared with the
list of every man who served in the Australian Army
between 1962 and 1972, which was the period of Australian
involvement in Vietnam. Fathers identified as having
served in the Army during this period were then classified
according to whether or not they had served in Vietnam.
The sample was. as a matter of statistics, large enough to
enable the study to meet its stated aims.
An important thing to notice is that the original pool was
a pool of birth defects selected by their occurrence and
without reference to any question of service or
non-service, whether in Vietnam or otherwise. In short,
without bias.
VI1-19
In other words, there were to be 8,500 pairs or sets of
infants. Of these, one was a malformed infant and the
other a healthy infant matched in an appropriate way by
maternal status to the malformed infant. Thereafter, the
question was asked, "Is a malformed infant (case) more
likely to have been exposed in the sense of having a
Vietnam veteran for a father than an infant in the healthy
group? (control)."
It is emphasised that this study exceeded the statistical
power usually sought in epidemiological studies and had a
90.5% chance of detecting as statistically significant a
true 1.5-fold risk of anomalies in the children of Vietnam
veterans had there been such an increase. (R/R = 1.5)
One hundred and twenty-seven of the fathers of children
with anomalies were Vietnam veterans whilst 123 veterans
were amongst the fathers of healthy children. This study
provides no basis for the suggestion that Army service in
Vietnam relates to the risk of fathering a child with an
anomaly. It is of such quality and size as to be strong
evidence that no such association exists.
VII-20
The study of course did not stop there. It needed
confirmation by statistical analyses. These used methods
which have been described by all who have examined them as
the most appropriate and up to date. Amongst the
statistical analyses was one which confirmed that the
matching of malformed with healthy infants was generally
adequate but which suggested that an adjustment for the
age of the mother might be necessary in a more detailed
analysis. Observe that risk was least for mothers aged
25, which accords with known community norms.
Other factors on which information was available and which
might bear upon the risk were then examined. Factors
which were found to be of relevance were that the risk of
malformation is higher in male children than in female, in
multiple rather than in single births. The country of
birth of the father also affected the risk.
Factors examined which proved to be irrelevant (i. e.,
statistically insignificant) included the age of the
father, the socio-economic group of the father. the birth
place of the mother and perhaps most significantly urban
or rural residence of the parents. Significantly, because
it is generally agreed that rural residence increases the
VI1-21
likelihood of exposure to the constituents of Agent
Orange, namely 2,4-D and 2.4,5-T.
These examinations provided internal statistical
validation of the study and its methods.
The study also produced other most useful information.
First, the risk of fathering a malformed child is
independent of service' in the Army whether as a National
Serviceman or as a member of the Australian Regular Army.
It is also independent of service in Vietnam either as a
National Serviceman or as a member of the Australian
Regular Army.
Furthermore, the risk for both groups was found to be
independent of length of service in Vietnam. If exposure
to chemicals in Vietnam was associated with birth defects
one would have expected to find an increase in risk by
increase in length of service. In fact the study found
the contrary, there was a tendency towards lower risk
amongst veterans with longer Vietnam service.
Furthermore. the risk for both National Servicemen and
members of the Australian Regular Army is independent of
the time between homecoming and conception of a child, and
VI1-22
also of the time between year of departure for Vietnam and
conception. That is to say, the time between service in
Vietnam and the time of conception of the child was
irrelevant, as was the year or years of service.
The significance of these matters is apparent. One of the
mechanisms postulated by W A A for the production of birth
defects in the children of Vietnam veterans conceived
after the father had returned was a theory of contaminated
sperm or semen.
No healthy young soldier's mature sperm or semen would 17
remain in his system for more than 90 days. If
chemicals were to blame, then, on this postulate, birth
defects would cluster in babies born around 9-12 months
after the fathers' return from Vietnam. They did not.
Again, if Agent Orange were to blame one would expect
clusters in the offspring of those who served during
periods when the chemical agents were used and a falling
off after cessation of possible exposure. Neither
phenomenon appeared.
Dr Armstrong assisted in the supervision of the
investigation and critically reviewed the final report and
its relationship to the data. Dr Mathews, as consultant
VI1-23
Uo AVHS, was also Involved. Dr Armstrong and Dr Mathews
later became consultants to the Commission. During a
period in excess of 12 months the Commission has developed
the highest possible regard for their capacity, their
integrity and their total lack of bias.
Dr John Donovan who headed the team which prepared the
final report was examined and cross-examined before the
Commission. His conscientiousness in performance of the
study and his capacity, integrity and total lack of bias
in reporting have been clearly demonstrated.
3.2 International Opinion of Australian Study
The Commission's untutored views of the study are
confirmed by independent experts of the highest
international repute. Amongst those experts were a number
interviewed personally by the Commission but not called to
give evidence at formal hearings. These included Dr George
Lathrop and Dr William Wolfe, Epidemiologists of high
qualification and the principal investigators in the Ranch
Hand studies. The principal investigator in the Centre for
Disease Control's (CDC) Birth Defect Study, Dr Dave
Eriksson, also discussed the Australian Study with the
Commission.
VI1-24
All three approved the study and indeed expressed
admiration for its design, size and execution.
Professor Bo Holmstedt was called as a witness before the
Commission. He is a physician but his special interest and
qualif ication is in toxicology. It is fair to say that
there is probably no more highly respected toxicologist in
the world. Prior to retirement he was Professor of
Toxicology at the Karolinska Institute, Stockholm,
Sweden. He remains the President of the International
Union of Toxicology.
His comments on the Australian Study are:- "I think it is
an extremely well conducted study and it takes care of the
confounding factors in the way you would expect of a
modern toxicological ‘ epidemiological study and I am very
impressed with the way they went about this".18
Dr David Brusick, an eminent scientist and internationally
renowned expert on genetic toxicology although anxious to
disavow any expertise as an epidemiologist said:
(The study) appears to have been careful in searching for any possible effects that might have arisen. It seems to be consistent with the conclusions that I have generated on the basis of
VII-25
the discussion in that it would be unlikely in my opinion for an agent, which I consider to be non-mu tagenic, to have been expected to produce any elevated inheritable genetic effects which would have then resulted in an increase in
congenital malformations in the offspring of women.19
Doctor Fiona Stanley, a medical doctor and presently
Deputy Director and Senior Research Fellow in the National
Health and Medical Research Council's Research Unit in
Epidemiology and Preventive Medicine at the University of
Western Australia, is a most eminent expert on birth
defects both in Australia and abroad. She became a
consultant to the Royal Commission with particular
reference to the Vietnamese studies.
Of the Australian study she said:
. . . the value of this study is that it was large and was extremely well done. It could not really have been better done. ... It is set up with a
large enough number to answer the question that it wanted to ask ... (the cases) in fact were
matched well and (the researchers) found a relative risk which was not significantly different from zero which means that the study basically found a negative association. Now that
really means that you can say with confidence that a Vietnam veteran is not more likely than anyone else to father a child with a structural malformation noted at birth. (emphasis
added).20
The Professor of Public Health (Epidemiology) in the
Columbia University School of Public Health, New York
State. Dr Zena Athene Stein, gave evidence before the
VII -2 6
Commission. She has for many years specialised in the
epidemiology of reproduction and birth outcomes with
particular emphasis on developmental disorders.
She gave general evidence about the likelihood of birth
anomalies consequential upon chemical exposure but also
considered the AVHS study. Of this, she said:
In some senses many epidemiologists would like the Donovan study best.. They would like it
best, first of all it is very big and that is
important. It is bigger ... than the CDC study. But what they like particularly is the design which takes the birth defects from the hospital and links them with the fact of Vietnam service and the circumstances of service. and there is no
intermediary group of people who would have - would be able to contaminate the two sets of findings."21 ....
It is difficult to find a flaw in that study
insofar as it set out to look at birth defects that could be discovered at birth on the one hand as an end point .and then the fact of service in Vietnam on the other. One feels that on these
two issues the result is a very strong
result....
It is a very big study and a major study and I do not think anyone has really found a serious flaw in it.22
There are many other comments to be found in the
transcript approving of the study. Those selected are
well qualified and representative.
VI1-27
3.3 Criticisms of the AVHS Birth Defects Study
The first and most valid criticism is that the study
focused upon birth defects generally, rather than upon
defects of notorious genetic origin. As structural
defects are the predominant anomalies apparent within the
first week of birth in any population, it came as no
surprise that this position was demonstrated in the data
collected by the investigators.
Amongst the hypothesis suggested by W A A for the
production of male-mediated birth defects is only one
hypothesis which has even the remotest plausibility,
namely, that the male gonads were in some way affected by
chemicals so as to continuously produce defective mature
sperm cells causing consequential birth anomalies. This
mutagenic hypothesis would lead one, with hindsight, to be
looking for chromosomal and other genetic abnormalities
and a study which focused on such abnormalities might have
been logically more appropriate.
This criticism was one of the two caveats that were
suggested by Drs Armstrong and Stanley in their review of 23
the study in the Medical Journal of Australia.
However, it should be noted that when the study was being
VI1-28
designed there was no emphasis on genetic/chromosomal
abnormalities. Those complaining were complaining "across
the board". Indeed, up until the final written submission 24
made on behalf of W A A in late January 1985, no such
emphasis appears.
Accordingly, it would have been politically pointless for
a study to be designed around a limited class of
abnormalities when what was being complained about was a
general increase in birth anomalies, including structural
ones, amongst the children of veterans.
The second criticism is that the study was only of defects
discoverable in the first week of life. The argument goes
that many defects are discovered after the first week of
life and that the study is therefore flawed by. in effect,
missing the many defects which manifest themselves after
the first week of life. But there must be some end
point. Some birth defects or congenital anomalies are
discovered in the teens of the child, in early adulthood
and indeed in middle age.
The criticism has very limited validity. But to suggest
that by reason of it the study is flawed reveals some
misunderstanding of the concepts. If the case was that
VI1-29
the children of Vietnam veterans were vulnerable only to
those defects discovered after the first week there might
be some validity in the criticism.
2 5
Dr Armstrong and Dr Stanley have pointed out that this
limitation on the scope of the study means that most
congenital heart defects, some chromosomal anomalies,
metabolic disorders, renal anomalies and some major gut
defects are not taken into account. However, they go on
to point out that:
Whether or not their exclusion limits the value of the study depends on the prior credibility of the proposition that paternal exposures suffered in Vietnam would have produced only defects of
this type, (emphasis added)26
No mechanism has been suggested by which such a narrow
range of effect might be postulated. Moreover, as will be
discussed later, the results of the Australian Study are 27
very similar to those found in the CDC Study, which
was not so limited, but which took into account defects
discovered during the first year of life.
But the study chose as its subject that which was readily
ascertainable, namely, defects discovered in the first
week of life. This was a valid decision on epidemiological
grounds. Not the least of those grounds was that the data
VI1-30
were recorded by people unconnected with the study before
any furore about Agent Orange and birth defects.
The particular case-control design which required no
interview and which used extant data records meant that no
bias is introduced by the selection of the subject matter
of the study. Accordingly, on a true understanding of
epidemiology, this study remains valid.
Thirdly, it is said that the numbers are too small to
detect small increases in relative risk. This is a valid
criticism in the sense that it is true that the study will
not detect increases in relative risk smaller than that
which it says it will detect.
However, the study exceeds the statistical power usually
sought in epidemiological studies. Of course any study is
improved by the increase in its statistical power which
flows from the increase in the numbers.
Dr Schneiderman1s suggestion that the numbers were too
small was adopted by W A A . 28 That the truth of this
criticism does not bear upon the validity of the study is
however emphasised by the evidence of Dr Schneiderman.
The transcript when he was being cross-examined by Mr
VII-31
O'Keefe in respect of some mathematics he had worked out
concerning the study and which workings were
2 9
exhibited , reads:
.... If for example I was looking at a birth defect which constituted perhaps 5% of all birth defects I would have to divide that 17,997 and 14,538 by decimal 05 in other words multiply it by 20.
MR O'KEEFE: So you would multiply 17.997 X 20? --- Yes.
Can you tell me what that is? --- Approximately 360,000.
And if you wanted it at about 90% you would multiply it by about 290,000? --- Yes.
And you would be looking at 290,000 births. ---Births.
I gather from your comments that if you had done the study you would have done it differently would you? --- I would probably have done it very much as the people who did it did
it. What I would have done was perhaps - I think that I would have attempted to do a substantially larger study than they have done.
What, using 360,000 and 290,000 births as a test structure? --- Possibly if I could do such a thing."30
It flows from what Dr Schne.iderman said that his imaginary
study would have involved an examination of more children
with birth defects than would have been born in
Australia. The postulation of such a study is
mathematically and theoretically correct. In practical
terms it is impossible.
VI1-32
Perhaps it should be observed that Dr Schneiderman is not
an epidemiologist.
Dr Armstrong and Dr Stanley also point to the study's lack
of power to detect an increase in any single defect or
category of defects.31
This difficulty was acknowledged by the authors at p 35 of
the study. However, the study did separately consider
those diagnostic groups of malformations in which the
prevalence of the condition was sufficient to detect odds
ratios of more than 1.5 and found that in each such
diagnostic group there was no statistically significant
difference in the risk of fathering a malformed child by
32
veteran or non-veteran fathers.
3 3 It has also been suggested by Reznik et al that as the exposure studied was service in Vietnam and not exposure
to any particular herbicide, the concluding statements
made by the investigators in an article published in the
34
Medical Journal of Australia of 31 March 1984 was
unjustified. The conclusion referred to was in the
following terms:
VI1-33
The potential hazard which we studied was service in Vietnam. In the public mind this has become associated with exposure to chemicals,
particularly to herbicides and their
contaminants. The failure to identify any risk of fathering malformed offspring associated with Vietnam service means that these postulated causes do not need to be considered.35
In response to Reznik et al's criticism of that
conclusion, the investigators pointed out36 that the
study was commissioned in response to allegations of
increased anomaly rates in children of Vietnam veterans as
a whole and that accordingly the design was appropriate to
that situation, no groups of veterans with high exposure
to chemicals having then been identified and the
possibility of their existence being no more than
speculation.
The evidence as to exposure given before the Commission
has done nothing to elevate that possibility: on the
contrary, exposure, except in a handful of veterans,
remains a speculation which is now shown on the balance of 37
probabilities to be without real foundation.
Accordingly, this criticism fails, and the investigators'
conclusion is valid.
VI1-34
As well, at the time of the study, the investigators
believed that the construction of a reliable herbicide or
other chemical exposure index was not feasible but more
up-to-date research by AVHS has led to the view that such
an index may be possible. In the result, however, it is,
in a sense, fortunate that no attempt at an exposure index
was made at the earlier stage.
In the time between the commencement of the Birth Defect
Study and the commencement of this Commission the veterans
had changed their ground from Agent Orange exposure to a
blanket allegation of chemical exposure. One of the
benefits of the Birth Defect Study is that it negates
service in Vietnam as an exposure which increased birth
defects apparent in the first week of life. It
accordingly answers the allegation about other chemical
exposures.
It is normally a valid criticism of an epidemiological
study that it does not address dose-response
relationship. The present study did consider dose
relationship, in the sense of length of service in
Vietnam. In an ideal world it would also have addressed
the herbicide exposure question, as the CDC Study did.
VI1-35
This failure does not undermine the force of the study for
the Commission's purposes.
The study is also subjected to a criticism which, frankly,
is not understood. WAA's final written submission38
says. "The AVHS study is limited to the statement that the
study for all practical purposes does not support an
association between Vietnam service and birth defects."
It continues. "Alternatively it does not show that there
is no association between Vietnam service and birth
defects."
These statements are contrasted with what the study itself
says at p 29 of the summary, "There is no evidence that
army service in Vietnam has increased the risk of the
birth of a child with an anomaly."
If WAA's submission means that there could be an
association between Vietnam service and birth defects of a
size smaller than that which the study design is able to
detect with high confidence, that is simply a truism.
But the study was sufficiently powerful to detect that
fathers born in Australia. The United Kingdom, New Zealand
or Eire were more likely to father a malformed child than
VI1-36
fathers born in Greece. Italy. Yugoslavia or Lebanon. The
odds ratio for this effect was 1.13 with a 95% confidence
interval of 1.05 to 1.23.
If the evidence before the Commission in respect of birth
defects had been only the AVHS Birth Defects Study and had
the criticism of that study been only that which was led
before the Commission. then the Commission would have
determined, on the balance of probabilities, that Vietnam
service by the father did not increase the risk of the
veteran fathering a malformed child.
But the Commission is fortunate to be able to test such a
determination by the consideration of other evidence,
namely, the biological implausibility, consistency of the
evidence with thosa of other studies and other
epidemiological and logical factors. These matters are
now considered.
3.4 Consistency
The next step in the process is to consider whether the
non-association found in an examination of the actual
group which the Commission is charged to study is
consistent with other data.
VI1-37
There are a number of studies directed to the presence in
Vietnam of various male populations and the subsequent
reproductive history of those populations. A consideration
of the mechanisms postulated for increased birth defects
amongst the children of Australian Vietnam veterans will
show that epidemiological studies of human reproductive
outcomes based upon the exposure of the female or of both
partners are of limited value in the present context.
This Inquiry is concerned with an alleged association
between male-only exposure in Vietnam and untoward
reproductive outcomes. The Commission will deal with
female experimental data in a limited way but in this
section will consider those studies which are of direct
relevance.
Those studies include:
39
(a) Ranch Hand II (1984);
40
(b) The CDC (Atlanta) Birth Defects Study (1984);
(c) Tung et al (1980) - The Problem of Mutagenic Effects 41
on the First Generation Exposed to Herbicides;
VI1-38
(d) Other Vietnamese Studies.
The three studies first mentioned are those most directly
relevant to this Inquiry.
There are also two other studies of the reproductive
effects of male exposure to phenoxy herbicides in a
context other than Vietnam:
(a) J.C. Townsend et al (1982) Survey of Reproductive
Events of Wives of Employees Exposed to Chlorinated
Dioxins.42
(b) A.H. Smith et al (1981) Congenital Defects and 43
Miscarriages Amongst New Zealand 2,4,5-T Sprayers.
4. RANCH HAND II
In the search for consistency or otherwise. the first
target is the birth defect aspects of Ranch Hand II.
Senior Counsel Assisting and the Senior Consultant, Dr
John Mathews, were present at the release of the Ranch
Hand Base Line Morbidity Study in Washington, DC USA on
February 24, 1984. They advise that the pressures upon
the investigators were apparent. Those pressures were
both internal and external.
VI1-39
Internal pressures resulted from a need to give value to
self-reported data without over-emphasis and a need to
report in a way which precluded suggestions of cover-up.
There seemed also to be some tension created by differing
epidemiological/medical judgments and statistical ones.
External pressures included: the extraordinary interest
(even harassment) of the American media; pressure to meet
a reporting date imposed by Congress; lack of time for
follow-up in areas where technically statistically
significant results might be misleading.
Whilst in the US, the Commission interviewed not only the
principal investigators but also the staff employed in the
study and found their professionalism, objectivity and
dedication outstanding.
At the heart of the Ranch Hand study was the dose-response
principle. If the Ranch Hand population was more exposed
to herbicides and dioxin than others, then it should
manifest stronger and/or earlier indications of adverse
health if such consequences are connected with that
exposure.
VI1-40
It has been widely accepted that the average Ranch Hander
was substantially exposed to the herbicides and dioxin.
Exposure calculations estimate that an average Ranch
Hander received, as a minimum, 1000 times more exposure to
Agent Orange than would an average sized naked man,
standing in an open field directly beneath a spraying 44 aircraft.
For some reason this degree of Ranch Hand personnel
exposure vis-a-vis ground personnel has been consistently
undervalued. Various adversary groups and the media have
sought to reverse it. It was seriously challenged in
WAA's submission to the Commission. The basis for the
undervaluing. the reversal and the challenge remain a
mystery. Certainly, no evidence before the Commission
contradicts rational inference or the dose calculations
mentioned above.
The Commission finds that the Ranch Hand population was
the most herbicide exposed military cohort to serve in
Vietnam. The exposure data in respect of Australian
personnel is at best equivocal.
The undeniable exposure of a totally ascertained
population, matched to an equally clear cut non-exposed
VI1-41
cohort, provided for the Ranch Hand II study as ideal an
epidemiological setting as is possible from this war time
environment.
In view of the controversy however, reference to the
evidence of the two Ranch Hand officers who were called
before the Commission is appropriate.
The Commission finds each of these men to be a witness of
truth and reliable in his recollection. They were
straightforward military men and in a sense just what one
would expect to find amongst a group who volunteered for
one of the most dangerous jobs to be done in South
Vietnam.
Mr R.J. Dudenhoeffer in his statement said:
The flight engineer was often drenched in the herbicide. It was the duty of members of the air crew to check the herbicide level in the tank before commencing a mission. I was often
drenched by herbicide under pressure escaping when the filling cap was removed for this
purpose. Nobody worried about being drenched in this way. Getting wet with the herbicide was regarded as an inconvenience and not as a health hazard. We would continue with the mission and put up with the inconvenience of being wet.45
VI1-42
Colonel Hubbs in his statement said:
Agent Orange was in puddles on the ground in the vicinity of where the aircraft were being
filled. I walked through this area as did the others. Some Agent Orange was always on the floor of the aircraft. It was guite common for our boots to be wet with Agent Orange. Unless a
tank or hose had been shot out and you were
really saturated in herbicide, it was not normal to shower until the end of the day, even though you smelled of Agent Orange, had been walking in it and it was all over your boots. The spray
from the lead aircraft was at times sucked
through the open windows and funnelled back through the aircraft.46
Each of these men was cross-examined but no undermining of
their evidence about exposure was achieved.
The Commission's considered view is that no Australian
achieved an exposure to Agent Orange equivalent to direct
spraying in an open field whilst naked. It follows that
an average Ranch Hander received at least 1000 times more
exposure to this chemical agent than an average Australian.
4.1 Study Design
Ranch Hand II used a matched cohort design in a concurrent
prospective setting, incorporating mortality, morbidity
and follow-up studies. A detailed population
ascertainment process identified 1269 Ranch Hand personnel
who served in Vietnam, during the period 1962-1971. A
VI1-43
comparison group was formed by identifying all individuals
assiqned to selected Air Force organisational units with a
mission of flying cargo to, from and in the Republic of
Vietnam during the same period.
By a computerised "nearest neighbour" selection process,
up to 10 comparison individuals were matched to each Ranch
Hander by job category, race and age to the closest month
of birth. An average of 8.2 comparison individuals for
each Ranch Hander was determined by record review to be
fully suitable for study.
Each living Ranch Hander and the first living member of
this comparison set were selected to participate in the
Morbidity Study which consisted of an in-home interview
and a comprehensive physical examination.
Data concerning fertility and reproductive events were
collected during the questionnaire and the physical
examination.
It must be borne in mind that the analyses were based on
non-verified and therefore subjective questionnaire
reporting. In addition, the data on children is data on
parent-reported defects, not defects per se.
VI1-44
Fertility and reproductive information was limited to
reproductive events that occurred whilst the participant
was married or living with a partner, unless reported in
the questionnaire as "other pregnancies." Such
information was reconciled as far as possible with data
collected from all available spouses and partners.
Response rates were excellent. Amongst Ranch Handers
1,174 (97%) participated in the questionnaire and 1,145
(87%) participated in the physical examination. The
response rates amongst controls were somewhat less.
Despite some initial difficulties the control group was
adequate for the study's purposes, particularly in view of
the large number of comparisons which were available.
47
The following findings are relevant for present
purposes: The Commission's conclusions or remarks in
relation to certain findings are set out.
1. On a total fertility index the Ranch Hand group scored
higher than the control group;
VI1-4 5
2. On a married fertility index 60% of Ranch Hand couples
had the number of children they desired as compared
with 58.6% of the original controls and 58.2% of the
added controls.
The Commission concludes that the Ranch Hand group did
not suffer any relative loss of fertility, the only
probable outcome in the unlikely event of a chemically
induced mutagenic effect on gonads.
3. No significant difference was found in the sperm
counts of Ranch Handers and non Ranch Handers. Nor
was there any difference in the sperm morphology of
the two groups. This provides no evidence for any
effect of chemicals on spermatogenesis in the Ranch â , 48
Hand group.
4. The Ranch Hand group and controls were compared in
relation to miscarriage and stillbirth. Such
comparison was made both pre- and post-South East
Asian service. In relation to miscarriage although
there was some excess in the miscarriage rate
post-South East Asia for the Ranch Hand group it was
nearly equivalent to a similar excess existing between
the two groups pre-South East Asia. In the overall 4 9
analyses there was no significant difference.
VI1-46
Similarly there was no significant difference in
stillbirth rates and the rates against both parameters
were found to be comparable to observed rates in the
general United States population. The increase in
both Ranch Handers and comparisons post South East
Asia is appropriately attributed to increasing
* n 50 maternal age.
Once again there was no evidence for any chemically
induced effects on the rates of stillbirths and
miscarriages.
The finding of a slight statistical increase in
miscarriage rate amongst the sub group of officers is
an anomaly. The same effect was not found either
amongst enlisted flying crew or enlisted ground 51 crew.
5. A smaller percentage of Ranch Hand personnel reported
children with birth defects than did the comparisons.
When the relative situations were compared, pre-South 52
East Asia and post-South East Asia there was no
statistically significant difference between the two
groups in relation to birth defects.
VI1-47
6. A statistically significant difference between the two
groups was found in relation to neo-natal death. This
statistical significance flows not from any increase
in the rate of neo-natal deaths amongst the children
of Ranch Hand personnel, which remained constant at
1.5%, but by a diminution in the reported incidence of
neo-natal deaths amongst the comparisons. This
diminution was from 1.2% to .4% which was, in the view
of the investigators, a mere artefact arising out of
under-reporting on the part of the comparison group.
Professor John Mathews advises that a .4% neo-natal
death rate is well below the rate which might have
been expected from any general population. The other
three figures, 1.5, 1.5 and 1.2 are more approximate 53 to those one would expect.
The Commission is of the view that the relative risk
based on this artefact should be ignored.
7. When the broad category of birth defects was analysed,
after adjustments for maternal co-variables (smoking,
drinking and age) a statistically significant excess
was found for the Ranch Hand group in relation to post
South-East Asia live births.
VI1-4 8
However. when the results were further analysed after
omitting skin anomalies included in ICD Category 757
(these anomalies are of minor medical consequence, and
include what are usually called birthmarks, not birth
defects), no significant group differences remained.
Suggestive group differences however, could not be 54 excluded.
There appeared to be a small clustering of birth
anomalies in the skin of children of the Ranch
Handers. This suggests that those who were exposed
were, naturally, more alert in their examination of
their offspring and consequently found such birth
defects.
To date the analyses have relied in large measure on
unverified spouse reports. Amongst exposed people,
higher differential recording of conception and birth
outcomes is tu be expected and the study could not
measure its effect.
The omitting of the skin anomalies is an appropriate
epidemiological device. The suggestive association
that remains is readily explained by differential
reporting, and does not in the Commission's view
contradict the Australian Birth Defect Study.
VI1-4 9
8. The investigators themselves warn about the absence of
verification and the effect of differential
reporting.
9. It is instructive to compare the cluster of ICD 757
defects (that is, skin anomalies) with corresponding
findings in the Australian Birth Defect Study, where
only one out of 32 cases with defects in this
classification was the child of a veteran. Thus, no
corresponding cluster is to be found in the Australian
Study which suggests that the Ranch Hand investigators
fear of over-reporting in relation to post-South East
Asia children may be justified. Note that the
Australian Study was not based on self reports.
10. Dr Stein (whose high qualifications are referred to
above) emphasises the objective parameters of
fertility, sperm count and sperm morphology which
argue strongly against the operation of what seems to
be the only plausible theoretical mechanism for the
production of adverse reproductive effects, namely,
mutagenic damage to the male germ cells.This makes a 5 5
skin or neo-natal death connection unlikely.
VI1-50
11. W A A called Dr Schneiderman to comment upon the Ranch
Hand II findings. He did not seek to place any stress
upon the artefactual increase in relative risk of
neo-natal death nor upon the suggestive excessive
birth defects in ICD 757 classification. Dr
Schneiderman sought rather to rely upon what he called
a trend of differences said to be evident in a number 5 6 of end-points.
4.2. WAA's Final Submission on Ranch Hand II
This matter is taken up by W A A in its final submission,
as follows:-
In looking at the data in Ranch Hand II in
respect of unfavourable birth outcomes it is seen that 10 items of data have been collected,
namely, childless marriages, abnormal sperm, miscarriages, stillbirths, non live births, learning disability, physical handicaps, infant
deaths, birth defects and neo-natal deaths. There is a statistically significant increase in neo-natal deaths in the children of Ranch Hand
personnel. What is more important is that out of 10 listed items there is an increase in 9
instances.57
The submission continues that the likelihood of this
happening by chance is less than 1%. Dr Schneiderman,
whose proposition this was, was cross-examined.58 The
following points were made by the cross-examiner:-
VII-51
1. The doctor took a list of twelve items and drew his
conclusion from only 10 of them. There is of course a
difference between 9 out of 10 and 9 out of 12. This
makes the 1% theory incorrect.
2. The list analysed by the doctor included both
stillbirths and non-live births. The doctor was
unable to draw a distinction between these 2
categories.
3. The doctor conceded that what he had counted as an
increase in respect of neo-natal deaths was not an
increase but a difference. He conceded that this
difference reflected a decrease in the comparison
group which was a result of either a protective
effect, improved neo-natal care or, most likely,
under-reporting.
4. The doctor conceded that the physical handicap
classification was one where there was not an increase
or worsening but rather an improvement on the part of
the Ranch Hand group.
5. The doctor conceded that the live birth incidence
figure revealed no difference in real terms.
VI1-52
6. He further agreed that the miscarriage rate difference
was not significant. Indeed his own phrase was, "I
wrote it down for myself, the ratios have not changed
over time, one."
7. He conceded that the report showed that Ranch Handers
were more fertile.
8. He conceded that the report showed Ranch Handers
scoring higher on the test of having the desired
number of children.
9. He agreed that Ranch Handers were shown to be more
likely to marry post South-East Asia.
10. He agreed that sperm abnormalities were higher amongst
controls than amongst Ranch Handers.
Having regard to these matters, the Commission does not
regard the "trend of increases" argument as having any
weight.
The Commission accepts Dr Schneiderman as a witness of
truth. His speciality is as he readily conceded that of a
VI1-53
mathematician. He is not an epidemiologist, a geneticist
or an expert in reproductive outcomes. His conclusions
insofar as they are mathematical, have not been
disregarded.
5. CPC BIRTH DEFECTS STUDY. ATLANTA. GEORGIA USA59
The next study which requires consideration in the process
of assessing the consistency of data is the US Study of
Eriksson et al, called "Vietnam Veterans Risks for
Fathering Babies with Birth Defects" known as the CDC
Study.
The impetus for the study was the concern expressed by US
Vietnam veterans at the possibility of increased risks for
fathering babies with birth defects.
The concern was that the increased risk might stem from
exposure to herbicides, particularly Agent Orange. The
study was however designed to determine if Vietnam
veterans (in general) had been at increased risk. This
approach was taken because at the time when the study was
designed the investigators took the view that it might not
be possible to obtain any measure of exposure to
herbicides other than by questioning individual Vietnam
VI1-54
veterans. which, of course could lead to the criticism
that the cases would be likely to suffer recall bias.
This is because of the well-known phenomenon that those
who have the "outcome" are inclined to "remember" the
exposure in circumstances where there has been a great
deal of publicity connecting the one with the other.
Accordingly the basic design focused on that which could
be easily checked, namely, service in Vietnam.
5.1. Methods
Atlanta, Georgia, has a Congenital Defects Register
conducted by the Metropolitan Atlanta Congenital Defects
Program (MACDP). This program attempts to ascertain all
babies with defects diagnosed during the first year of
life born to mothers resident in the area.
The study chose births during the years 1968 through 1980
and registration in the register as "tickets of entry" to
the study. In all. about 13,000 babies qualified.
From the register of babies, only those who had defects
coded by ICD code-8 rubrics were chosen as cases. Such
classification usually signifies a serious or major birth
defect.
VI1-55
This selection process resulted in an initial choice of
7,529 babies as cases. The final number eligible for the
study was 7,133. This reduction occurred for various
reasons including the exclusion of babies thought to have
been given up for adoption, the random choice of one baby
from families with more than one registered baby, and the
selection of babies for a pilot study.
The control group was selected from amongst 323,421 live
born babies born in the Atlanta area during 1968 through
1980. These were selected with the aid of the State of
Georgia Vital Records Unit and matched to the babies in
the case group with respect to-
(a) Race;
(b) Year of Birth;
(c) Hospital of Birth;
Some of the babies thus chosen were babies from the case
group and these were deleted from the control group
although retained in the case group. The study was thus a
classical case-control epidemiological study and was
conducted with great care.
VI1-56
The Commission had the opportunity of two days detailed
discussion with Dr Eriksson. Dr Mulinare and their
associates. One could not fail to be impressed with their
professionalism. The study was a powerful one by any
epidemiological standard, having sufficient power to
detect an odds ratio of 1.2 for all types of birth defects
with 70% probability and power to detect odds ratios of
1.5 or greater on a 2 tailed test with confidence of
almost 100%.
The study used computer-assisted telephone interviewing
techniques. Great care was taken to preclude interviewer
bias and to this end tracing staff were not aware of the
case or control status of the families.
When the parents were contacted (and both mother and
father were interviewed where possible) they were asked to
participate in a study designed to help learn about the
causes of birth defects; no mention was made either of
Agent Orange or of service in Vietnam.
Each parent was interviewed twice. The first interviewer
for each parent asked about the parents' reproductive
history. Because such history would include a description
of the health of the index baby, the first interviewer
VI1-57
could usually not avoid knowing whether the baby belonged
to the case or control group. Accordingly, in order that
interview bias might be avoided, a second interviewer for
each parent asked questions about a wide variety of
exposures (that is to say, Vietnam service and Agent
Orange questions were interspersed with occupation,
chronic disease, drugs etc so as to remove bias flowing
from a small number of questions).
Answers about Vietnam service were verified as far as
possible from Army records and two measures of Agent
Orange exposure were designed. One was a "self-report"
exposure index where the veteran himself gave an
assessment of his likely exposure. As well, the Agent
Orange Task Force, Army, in Washington, under the
direction of Richard Christian provided indexes of
"exposure opportunity" from contemporaneous military
records including the HERBS tapes.60
The Commission's primary concern about the CDC study has
been the low response rates. Overall, only 69.9% of
eligible mothers and 56.3 of eligible fathers completed
interviews. Participation rates for parents of the white
race were substantially higher than those for parents of
other races. Statistical techniques showed that this
VI1-58
participation difference was of little concern insofar as
it might affect the inferences to be drawn regarding the
risks of Vietnam service.
Of course the difficulty with low response rates is that
those in the non-responding group may have fared worse or
differently from those in the responding group.
It is the practice in the United States to conduct
epidemiological research through outside contractors. In
the case of the CDC study contractors were employed to
trace and find the parents of the babies. It seems that
the contract provided for a flat fee per parent traced;
accordingly the profit was to be made in the tracing of
those most easily found. There was. the Commission feels.
a lesson to be learnt for those contracting for
epidemiological research in the future. It would be
advisable to allow for increases in fees payable as the
number traced increases so as to ensure enthusiasm in the
contractor for participation rates in the highly desirable
90 percentiles.
Having regard to the careful statistical analysis
performed, to the selection of the index babies from a
register without possibility of bias and to the careful
VI1-59
selection and matching of controls, the Commission is
satisfied that, notwithstanding the low response rates,
the study is an extremely valuable one for its primary
purpose.
In general terms the study indicates that there is no
evidence that Vietnam veterans have any increased risk of
fathering babies with the measured defects. The relative
risk was found to be .97 which is suggestive of reduction
of risk but not significantly different from 1.00 with a
confidence level of 95%. This study is consistent with
and supportive of the negative findings in the Australian
Birth Defect Study. Each study reinforces the other.
Dr Zena Stein, whose qualifications have already been
discussed was a persuasive witness. She said, discussing
the Australian Study and the CDC Study together:
Quantitatively, one could rule out even a
moderately raised risk (say 1.5) with a high degree of certainty (say 80%) in either study. Taken together one would want to make an even stronger negative statement. In general, the two studies taken together support each other in the consistency with which 1 no effect1 is shown.61
VI1-60
One observes that the Ranch Hand Study was of a group
known to have been exposed, and heavily exposed, to Agent
Orange. The CDC study incorporated an index of exposure,
albeit of questionable validity. Neither Ranch Hand nor
CDC was limited to birth defects discovered in the first
week of life. Accordingly neither study is subject to the
two postulated limitations of the Australian study. All
three studies reach the same negative conclusion.
W A A 1 s submission relied upon three elevated risks in
sub-categories of birth defects found amongst the 96
selected for examination, from the ICD code.
The study tested 96 hypotheses. The significant level
chosen for deciding whether to accept or reject these
hypotheses was .05. That means that if there was in fact
no true difference in risk between the populations from
which the case and control group parents were drawn, a
false positive result would be expected to occur by chance
alone about 5 times in 100 (i. e. , 4 or 5 times in 96
cases).
Observe the following. Statistical reality is always in
the mind of the Casino owner, but usually forgotten by the
Casino client. If 7 heads in a row never came up the
VI1-61
Casino would always be empty. Because they sometimes do
the Casino is full. Because the overwhelming tendency is
towards 50%-heads, 50%-tails. in the long run the Casino
owner must win.
On the other hand, W A A makes no submission based upon the
following finding. Vietnam veterans were found to have a
significantly lower risk for fathering babies with complex
cardio-vascular defects.
Again, veterans (excluding Vietnam veterans) were found to
be at a lower risk for total sex organ defects.
5.2 Spina Bifida
Next, an association of spina bifida with a high score on
the Agent Orange exposure opportunity index was noted.
The authors note that the anencephaly scores suggest a
lower risk for this defect amongst men who had the higher
index scores. These two defects are aetiologically
related and indeed were described by experts in evidence
as the same defect presenting differently.
All of this suggests that the finding for spina bifida is
a chance phenomenon. This view is enhanced by comparison
VI1-62
with the Australian Birth Defect Study. Table 6.7 of that
study, where anencephaly and spina bifida were grouped
together, shows that it was more likely that the father of
a control was a Vietnam veteran than the father of the
case. The Commission is satisfied that no real
association exists.
5.3 Coloboma
The CDC study also indicates statistically significant
increases in the risks for exposed fathers in respect of
the defect. coloboma.
This is a very rare disease and there appear to have been
only 16 cases in the study. The authors point out that a
four-fold increase of* risk would still produce only about
.3 cases per 1,000 live births.
When one makes a comparison with the Australian study, one
finds not a single case of coloboma amongst the children
of Vietnam veterans. This too, the Commissioh finds is an
unreal association.
VI1-63
5.4 Cleft Lip
The study found a significant increase in the defect cleft
lip without cleft palate in association with the Agent
Orange exposure opportunity indices.
It should be noted that amongst non-Vietnam veterans an
odds ratio in respect of this defect of 1.4 was found;
this was statistically significant. The odds ratio for
Vietnam veterans is only 1.1, and statistically associated
only with the exposure opportunity index.
Second, there is actually a finding of decreased risk both
in non-Vietnam veterans and Vietnam veterans in the
aetiologically related defect of cleft palate.
Third, in the Australian Study, the item cleft lip and/or
palate, was analysed in Table 6.7. There were 10
occurrences in which a veteran was father of the case and
11 where a veteran was father of the control, suggesting
an absence of any association in relation to these
defects. As well Dr Schneiderman conceded62 that no
conclusion as to an association could be drawn from the
material contained in the CDC study. Professor Mathews in
his evidence was also of this view.63
VI1-64
The Commission concludes that this is a chance finding.
5.5 Congenital Neoplasms
Another "elevated" risk found in the CDC Study was that of
having babies with congenital neoplasms. This risk was
1.8 with 95% confidence limits of .99 to 3.29. The point
estimates of the risks found here are rather low - of such
a level that they could conceivably be the result of some
unknown bias or confounding factor, or they could be
chance results. The Commission inclines towards chance.
Certainly, on the balance of probabilities, this is a
chance finding. When one has regard to the conclusions
the Commission has drawn, later discussed, of the
feasibility of the mechanisms involved in production of
male-mediated birth defects the Commission has no
hesitation in finding that there is no real association.
When one is dealing with a study in detail and analysing
small apparent increases in risks so as to decide whether
or not they are real, a reader may be distracted from the
overall conclusions. Vietnam veterans were shown to have
no increased risk of fathering babies with defects. Even
those Vietnam veterans who had upon their own estimation
greater opportunities for Agent Orange exposure were not
VI1-65
at greater risk for fathering babies with defects. These
conclusions are consistent with the Ranch Hand Study and
the Australian Birth Defect Study and therefore have great
scientific weight.
These three studies taken collectively, powerfully negate
the proposition that service in Vietnam and exposure to
the chemical agents used there increased the incidence of
birth defects.
6. NEW ZEALAND APPLICATORS STUDIES
64
6.1 Smith et al (1981)
This well-done New Zealand study compared the rates of
congenital malformations and spontaneous abortions
(ascertained by interview) in the families of agricultural
sprayers, with rates in families of agricultural workers
who did not use sprays.
No differences were observed between the two groups, nor
were confounding factors likely to have masked an effect.
The rates were similar to those expected from population
data which is corroborative.
VII-6 6
6.2 Smith et al (1982) 65
These investigators examined pregnancy outcomes of wives
of professional agricultural sprayers in New Zealand who
had sprayed 2,4.5-T during the same calendar year as, or
during the calendar year before that outcome. The
pregnancy outcomes were compared with those of a control
group of agricultural contractors who did not spray
2.4,5-T.
Relative risk of 1.19 for congenital defects and of .89
for miscarriages were found. In each case the difference
was not statistically significant. The authors concluded
that the results should not raise concern for pregnancy
outcomes among wives of professional 2,4,5-T sprayers.
It may be noted that at least in some cases, the exposure
studied was not wholly paternal because wives may have
been exposed themselves by assisting their husbands in the
spraying activities, handling the chemicals or at least
by washing clothes wet with spray. The negative study is
made more convincing by this circumstance. This study,
carefully done, is quite consistent with the general
epidemiological picture, and supports the conclusions of
Ranch Hand II, CDC and the Australian studies.
VI1-67
7. THE VIETNAMESE STUDIES
7.1 General
The next group of studies to be considered in an
assessment of the consistency of data are the Vietnamese
studies.
The Commission had the advantage of journeying to Vietnam
and had an opportunity therefore to assess not only the
reports of the studies but also the facilities available
for the performance of the scientific work. As well, the
Commission was able to observe and sense the political and
emotional climate in which the work was done.
The Commission was accompanied on its journey to Vietnam
by its Senior Scientific Adviser, Professor John Mathews,
and also by Dr Fiona Stanley, an expert in the
epidemiology of birth outcomes. The qualifications and
standing of both have been discussed elsewhere in this
Report.
The Vietnamese Government made available to the Commission
all scientists with whom it wished to have contact, except
Professor Can who unfortunately was not available. The
VI1-68
party met with all those who had worked with Professor Can
in the preparation of his studies and although failure to
meet him was a disappointment, in view of the quality of
his work, nothing was lost.
All scientists spoke freely and frankly to those
Assisting, to the scientific advisers and indeed to the
Commissioner. Expert Vietnamese translators were made
available to the party and, additionally, by resorting to
French, the common language between the two groups,
communication was further facilitated.
Dr Fiona Stanley took a leading role in the detailed
questioning of the Vietnamese experts. She took this role
not only because the field was in a sense most
particularly hers or because her command of French was the
best of the Australian group, but most of all because her
flair for friendliness combined with direct and probing
questioning produced excellent results.
The Commission has nothing but admiration and respect for
the individual Vietnamese scientists. They were helpful,
frank, hospitable and intelligent. However, specialised
training in epidemiological techniques of the kind
necessary for the drawing of valid conclusions was
evidently lacking.
VI1-69
A number of other comments are necessary. There is in
Vietnam a strong Governmental commitment to the view that
the use of herbicides in Vietnam amounted to chemical
warfare as a matter of International Law. This view has
prevailed in that country since the early years of the
conflict and the passage of time apparently has done
nothing to diminish it.
Governmental commitment to that view includes a commitment
to the view that herbicides caused serious health problems
amongst the Vietnamese people. That strongly held belief
is carried through into effective propagation of the
idea. In particular. the Vietnamese Government is
committed to the notion that the use of herbicides caused
birth defects. This is displayed not only by commentary
in the state-owned newspapers, in radio programs and in
pamphlets distributed to all willing to read them, but
also by exhibitions such as the Museum of Atrocities. The
Exhibition of War Crimes is devoted to the
herbicides/birth defects connection.
The propagation of this viewpoint is expressed in highly
emotive terms and the exhibitions are regularly visited
by, inter alia, organised groups of school children.
VI1-70
A further example is that there is an official path along
which visiting journalists, scientists, politicians and,
indeed. Royal Commissioners are taken. All those who write
of a visit to Vietnam tell the story of the chromosomal
defects, the deformed babies in bottles, the conjoint
twins, the mothers of the molar pregnancies threatened
with cancer and the Exhibitions mentioned above.
It must also be said that it was apparent that the
scientific people themselves reflect, at a personal level,
the Government commitment. Two scientists actually said.
"I know this study does not prove it but I still believe
it is happening."
An examination of the work done by Vietnam scientists
displays conditions under which they worked were far from
ideal and in many cases totally inadequate. The
researchers did their work whilst carrying a full clinical
load. The research was done after hours with little staff
and no facilities. In addition, the public record keeping
has substantial gaps and at many levels is totally
unsatisfactory. Such records as are kept are on fine rice
paper in large storage boxes with only a primitive system
of indexing.
VI1-71
In Vietnam (as elsewhere) the bearing of a defective child
is a matter for shame. Early records obviously seriously
understate birth defect incidence. Stories of infanticide
abound and the Commission was told of concealment of
defective births in earlier times.
The Vietnamese studies are considered in two groups,
descriptive and analytical.
7.2 Descriptive Studies
(a) Tung et al 198066
These authors report a rather confusing set of studies on
North Vietnamese War veterans who went to fight in the
South and who were stated to be extensively exposed to
herbicides. In a population of 10,000 civilians, 700 were
veteran families and it was claimed that of 30 children
with malformations born in 1975-78, 15 were to veterans
and 15 were to civilians.
No denominators, (that is. numbers of births) were given.
VI1-72
In another province of 4,500 people. there were 30
veterans. Amongst 233 births between 1976 and 1978, the 9
children with malformations noted were all veterans'
children!
These studies are poorly reported and cannot be judged due
to insufficient detail. It is obvious that observer bias
could be operating when veteran status is known as cases
are being ascertained. Exposed veterans in the Vietnamese
atmosphere are much more likely to bring forward malformed
children than either unexposed veterans or civilians who
have normal children.
The figures themselves are inherently unlikely. The study
is unhelpful.
(b) Ministry of Health/US Military Assistance Command.
Vietnam and US Department of Defense
In 1970, five years after spraying with defoliants had
commenced in Vietnam, and after the first reports of
possible teratogenicity of 2,4,5-T in rats,67 a study
was undertaken by the above bodies. This study collected
data on congenital malformation, stillbirths and
hydatidiform moles in the Republic of Vietnam before and
after the widespread use of defoliant chemicals.
VI1-73
Twenty-two public hospitals were in the study and provided
499,119 birth events, including 16,166 stillbirths, 2,866
hydatidiform moles and 2,355 congenital malformations.
The hospitals were located in both metropolitan Saigon and
in rural areas. Standard criteria were set for each
abnormal outcome but accuracy depended on the quality of
records kept which varied from hospital to hospital and
even within hospitals. Some hospitals had no records at
all for some periods.
The number of live births in these hospitals increased
steadily and markedly from 1960-69, particularly in
hospitals outside Saigon. Qualitative changes in the
maternal population (which could result in selection bias)
were not recorded, and thus any changing characteristics
of the sample are not known.
The overall stillbirth, hydatidiform mole and congenital
malformation rates fell during 1960-69. The rates are
roughly what would be expected (stillbirth rate 33.7 per
thousand and mole rate 6 per thousand) except for the
malformation rate which at 4.9 per thousand was very low.
VI1-74
The study concluded that meaningful correlation of
abnormal birth events to herbicide use was precluded
because the data were inadequate. However, if spraying
was causally associated with defects, a rise in rate would
have been expected because of the increased proportion of
rural births in the later years. No such rise was
demonstrated. The study is, if anything, negative.
(c) Huong and Phuonq (1983168
This study reports a rise in spontaneous abortions,
hydatidiform moles and congenital malformations from the
major obstetric hospital in South Vietnam between
1952-1981.
Discussions with the authors of the study revealed that
there had been a change in the pattern of obstetric
practice between the early part of the period studied and
more recent times. As the decentralisation of obstetric
services occurred, establishment of midwifery clinics at a
local level developed and the major obstetric hospital
became increasingly a clearing house for the more
difficult cases.
Nonetheless, the claim made by the authors is that the
increases reflect real changes in the rates and that the
rise followed the war and the increases in spraying.
VI1-75
However the following should be noted:
(a) No data are presented which permit investigation of
the rises or the reasons for them.
(b) The reported rises in adverse pregnancy outcomes
occurred after the U.S. animal experiments
demonstrating the teratogenic effect of 2,4,5-T were
published in 1970.
(c) There are no reported rises in any Vietnamese study
before this date although spraying had been occurring
since 1964-65.
(d) The rates of spontaneous abortions. stillbirths and
congenital malformations in the 1960-65 period
reported in this study were lower than rates being
observed now in the most developed countries in the
world.
(e) The rates are lower than those mentioned in the US
Ministry of Defense Survey (1970) reviewed above.
VI1-76
The Commission concludes that marked under-ascertainment
early, followed by better ascertainment together with the
selective referral of high-risk women account for the
stated rise in frequency.
(d) Tuven et al69
This is one of a group of studies investigating somatic
mutational effects. It examined chromosomal anomalies.
The authors suggest that structural chromosomal anomalies
were more frequent amongst South Vietnamese civilians and
their offspring than amongst North Vietnamese and
unexposed South Vietnamese. Note that:
(a) No evidence of exposure was provided.
(b) More samples were observed from exposed people than
from those not exposed and it is possible that this
reflects repeated (biased) sampling from exposed
individuals showing abnormalities.
(c) It was not clear that cells from exposed and unexposed
subjects were examined "blind".
(d) Samples were not examined on the same day.
Technique is very important in such studies. The study is
so flawed as to be totally inconclusive. Additionally,
VI1-77
the significance of such abnormalities as sister chromatid
exchanges has yet to be determined and may amount to 70 nothing. The Commission finds this study unhelpful.
(e) Truna et al
71
These two studies were carried out in 1983. The first
compared the peripheral blood lymphocyte chromosomes in 15
"exposed" adults and children with 5 controls (adults) and
found a larger number of sister chromatid exchanges in the
former than the latter.
72
The second was a study in areas documented as heavily
sprayed. Structural chromosomal anomalies were assessed
in 56 adults (men and women) and 10 controls and
significant differences were found in numerical and
structural chromosomal defects.
The methodology of these studies is unreliable. Both
studies selected exposed persons who were related to those
with defects or who had defects themselves. The controls
appear to have been chosen because they were genetically
healthy as well as unexposed I Thus chromosomal
abnormalities were much more likely to have been observed
in the "exposed" than in the "unexposed". The Commission
finds these studies unhelpful.
VI1-78
This study compared two areas of South Vietnam, one
sprayed and the other not. Whilst no details of how this
was documented were given, 100% of couples interviewed in
the former and only 8% interviewed in the latter reported
exposure. A health interview survey was conducted in
these areas in 1982 to ascertain the long term
reproductive effects of exposure. 1,249 exposed and 1,244
unexposed families were interviewed. Markedly higher
rates of congenital malformations, (no criteria or
definitions given), fetal deaths, spontaneous abortions,
molar pregnancies and new-born deaths were noted in the
exposed than the unexposed groups.
This study which is methodologically vague has a number of
obvious defects. The high percentages are per hundred
women interviewed and not per hundred pregnancies and thus
do not take parity into account. The outcomes are based
on recall and interpretation is therefore difficult. Most
importantly, the rates amongst the non-exposed group are
lower than expected. They are just too good to be true.
Material rebutting probable observer and selection bias is
not shown. The Commission cannot rely on this study one
way or the other.
(f) Phuonq & Huong (1983)73
VI1-79
These researchers collected data on spontaneous abortions
and birth defects in the families who lived in sprayed
areas in South Vietnam during the war and who have
remained there since. There may well have been selection
bias operating in those remaining in sprayed areas.
Data were collected in 1982 by informal interview, with
the potential for bias from knowledge of exposure by the
interviewer.
Before spraying, the spontaneous abortion rates were 5.2,
4.3 and 7.2 in three areas. After spraying, these rose,
it was said, to 12.2, 11.6 and 16% respectively.
The non-sprayed area remained unchanged at around 7.5%.
The malformation rate rose from .14% before spraying to
1.78% after. The recorded defects ranged from
hydrocephalus to speech deficiency and thus the criteria
for congenital malformations were very broad. This study
has serious design flaws and the "control" rates are
implausibly low. It does not provide evidence of an
association. The Commission finds it unhelpful.
(g) Trunq. Chien et al (1983)74
VI1-80
This descriptive study deals with three North Vietnamese
districts where no spray was used. Two groups were
identified:
(a) Neither parent exposed;
(b) Father exposed whilst in South Vietnam during conflict.
No actual documentation of exposure is given. Data
collection was by interview in 1982 â (that is, by
retrospective recall of pregnancy outcomes) and validated
by checking abnormal outcomes against medical records
available in the area. Any abnormal children still alive
were examined and photographed.
There were 40,064 pregnancies in the 3 areas of which
11,023 were by fathers who had been in South Vietnam. The
rates for abortions, molar pregnancies, fetal deaths and
congenital malformations were calculated. They
demonstrated relative risks around unity (i.e. no
increased risk) for abortions, molar pregnancies and fetal
deaths in (b) groups compared to (a).
(h) Can et al (1983)75
VI1-81
Increased relative risks of 1.2 to 2.2 for congenital
malformations were reported. Poor recall of outcomes
(particularly abortions and molar pregnancies) occur in
retrospective studies and this makes interpretation
difficult.
The malformation rates are much lower than one would have
expected and may be biased as a result of recall. Such
bias would include possible bias towards greater recall
amongst those exposed (and therefore worried) and poorer
recall amongst those unexposed.
Stillbirth rates seem the most consistent and these showed
no differences between the (a) and the (b) groups.
Other differences between groups (a) and (b) which may
have helped with interpretation, were not sought. For
example, social class and demographic variables are known
to be associated with both poor pregnancy outcomes and
with war service in the South. This study, which is of a
higher epidemiological standard, is essentially negative.
VI1-82
This rather poor series of studies showed a higher rate of
congenital malformation amongst veterans' children in
Vietnam compared with civilian (2.6% compared with .46%).
However, data collection was poor and these rates were low
compared with those expected.
Baseline data on certain pregnancy outcomes are reported
by Nguyen Ho Dang (1983) in Tay Ninh Province which was
sprayed from 1961-1970. Data from 1979-81 show neo-natal
death rates, of 20 per thousand. abortion rates at 25%,
premature delivery rates of over 20%, moles at 2% and low
malformation rates (1%). No control data are available.
Whilst these levels seem high they are perhaps not
unexpected in modern and poor rural Vietnam.
In general terms, descriptive studies are of less
assistance than analytical ones. The Commission has had
available to it highly qualified advice concerning these
descriptive studies. Overall they do not provide any
clear or consistent relationship between birth defects and
chemical exposure. Having regard to the advice given and
the methodological problems of these studies the
Commission is of the view these results are not
(j) Lang. Van and Tung (1983)76
VI1-8 3
susceptible of meaningful interpretation. With the
exception of Can et al (1983) (h) supra, they must be put
aside.
7.3 Analytical Studies
(a) Can et al (1983)77
From the three North Vietnamese areas of his earlier
survey Professor Can collected 61 cases of birth defects
with well-defined criteria and had the cases re-examined
by two observers. Controls (N = 183) were matched by
maternal age. parity, residential area with a live child
born within 2 years of the case. The level of exposure
was then ascertained by questionnaire amongst cases and
controls. Recall bias (more recall by cases than
controls) was not checked. The relative risk between
exposed and unexposed was calculated and found to be well
over one (3.6). The study included confidence limit
calculations, with good analytic technique.
A major worry about this study is that cases were stated
by the
v 78
researchers to have been selected by the
village midwives with knowledge of sprayed status. In
other words, selection bias might well have operated. In
VI1-84
addition, the types of defects chosen (cleft oalate, limb
defects. megacolon, congenital cataract, deafness and
blindness) include those associated with social and
demographic risk factors perhaps related to Army service
in South Vietnam and not chemical exposure.
The Commission observes that this is the only analytical
Vietnamese study which meets even the most basic
epidemiological standards.
The criterion for exposure was that the husband "had been
in South Vietnam on business during the war time". There
is also a somewhat oblique reference to using "the lots
drawing" method to choose the districts and the cases for
investigation.
Dr Stanley closely questioned the colleagues of Dr Can
during the Commission's Vietnam visit and she gave the
following evidence:
.... whilst on paper this study looks good, one has this suspicion that in fact they were chosen with exposure status known. The controls were non-cases, again we do not know how exactly they were chosen. We hoped that they were not chosen
on non-exposure status. There again, we were not able to ascertain that clearly.79
VI1-85
The Commission's own recollection of this encounter was
that the questioning was vigorous and that the point of it
was well understood. Interpretation from Vietnamese into
English at this particular meeting became difficult
although the same interpreter was used as at other
meetings and when direct communication between the
Commission's party and the investigators in French began,
the interpreter displayed his restlessness and interrupted
in Vietnamese, effectively preventing continuance in
French.
In view of the probability of selection bias, the
Commission cannot be strongly persuaded by this study
although it can be regarded as a solid scientific attempt.
(b) Huong & Phuona (1983)80
These investigators conducted a case control study in 1982
which was poor by epidemiological standards. Cases were
molar pregnancies (N = 100) and congenital malformations
(N = 15). It is odd tha t so few malformations were
included as they are much more common than molar
pregnancies. The method of case selection was not
detailed. Controls (N = 284) were chosen from the same
hospital (mother with genital infection). Maternal (not
VI1-86
paternal) exposure to herbicides was obtained by
questionnaire along with certain cultural and other
potentially confounding factors.
Exposure levels were 56% for moles, 33% for defects and
10% for controls. There were also differences in smoking
and alcohol (a trend, but not significant, to higher
exposure in cases than controls) and malnutrition (higher
in control parents than cases).
Methodological difficulties in case and control selection,
collection of exposure data and the lack of control for
confounding makes interpretation of this study impossible.
7.4 Conclusion
Overall there is nothing in the Vietnamese data that would
be regarded as sufficient to disturb the consistency of
the results obtained in the Ranch Hand, CDC and the
Australian studies.
8. OTHER DESCRIPTIVE STUDIES
The following studies are of inconsistent quality. The
Commission includes them with appropriate comment for the
sake of completeness.
VI1-87
(a) Field and Kerr (1979) 81
These investigators described a statistical correlation
between two poorly ascertained pieces of data namely,
neural tube defects in New South Wales (known to be rising
because of better ascertainment over time, particularly in
view of recent X-ray diagnostic techniques), and the
quantity of 2.4,5-T supplied for the whole of Australia
during a given period.
Thus the exposure was a very indirect measure. For
example, very few of the mothers in metropolitan Sydney
giving birth to the malformed babies would have been
exposed at all, but, if exposed, such exposure could have
resulted from only an extremely small percentage of the
Australia-wide 2,4,5-T supply.
In addition, the graph shown in the paper appears both to
the Commission and to other more expert observers to show
the line of correlation being more convincing than was
appropriate.
(b) Thomas (1980).82 Thomas and Czeizel (1982)83
These investigators presented a similar ecological
descriptive study on data from Hungary. Hungary has an
VI1-88
excellent congenital malformations register which has been
producing good population data for many years. Thus there
was no problem of changes in ascertainment over time.
Over 1969-75 national 2,4.5-T usage in Hungary rose from
46 to over 1,200 tonnes, mainly in rural areas. There was
no rise in rates of congenital malformations and in fact
the rate for neural tube defects fell during 1970-1976.
The authors noted that exposure in Hungary was more likely
than in New South Wales (or in the UK) as more Hungarians
live in rural areas than in metropolitan areas by
comparison with Australians who predominantly live in
major cities on the sea board (less than 30% live in rural
areas).
The authors also refer to a study of female agricultural
workers in Hungary who showed no increase in congenital
malformation rates amongst their offspring. (Thomas
1980). Rates of malformation, stillbirths and spontaneous
abortions were actually higher in metropolitan (ostensibly
lower exposure) than in rural areas.
Thus a better conducted ecological study contradicted the
conclusions of Field and Kerr.
VI1-89
(c) Nelson et al (1979)84
These investigators conducted an ecological study of cleft
lip and palate (CLP) incidence in relation to 2,4,5-T
usage in Arkansas between 1949 and 1976.
Rural areas of Arkansas were divided into high, medium or
low exposure based on types of crops and cultivation
(which indicated the amount of 2,4,5-T used). CLP cases
were obtained from only two sources with probable
resultant under-ascertainment. No association between CLP
incidence and 2,4,5-T exposure (as defined) was observed,
although a rising rate of CLP was noted with time and
attributed by the investigators to better case
ascertainment.
(d) Hanifv et al (1981)85
This was a New Zealand ecological study. The rate of
malformations noted at birth was compared with
quantitative estimates of 2,4,5-T exposure in the same
areas. No spraying occurred in 1959-60 but was common in
1972-1976. Positive associations of some congenital
malformations with spraying in 1972-1976 were noted. the
relative risks of some being more than one (congenital
heart defects, talipes and hyperspadias) .
VI1-90
After further analysis of the data allowing for season and
other potential confounding factors. only talipes remained
statistically significantly associated with 2.4,5-T
spraying. The study was well done. It is nonetheless
only a descriptive study and the finding is probably due
to chance.
(e) Townsend et al86
This was an "in-house" study of Dow Chemical Company
employees. The Company as a manufacturer of 2,4.5-T,
known at times to be contaminated with dioxin, has an
interest in demonstrating a "no association" result.
The investigators identified employees exposed to dioxin
as a result of being assigned for at least one month to
specified jobs in the chlorophenol processes between
January 1939 and December 1975. A one for one control
group of employees not so exposed was also identified.
After some 930 employees were identified as exposed
attempts were made to trace the wives of both cases and
controls. The shortfall in numbers of wives resulted from
difficulties in the original location of cases and
VI1-91
controls, the limiting of the survey to those living
locally and, in particular, from wives declining to
participate.
As always, one must be concerned with such a low response
rate. Those who failed to respond may have had more
abnormal pregnancies than those who came for interview.
Reproductive outcomes were determined by interviewer
administered questionnaire.
No statistically significant associations were found
between exposure and pregnancy outcome. Techniques
included stratification by pertinent sets of up to nine
co-variables. Nor was there evidence of adverse outcomes
correlating with duration of exposure.
It is worth noting that the malformation rates observed
were slightly higher than expected on a population basis.
This could be related to over-reporting since husbands in
both groups were employed in chemical factoriesâ
putatively a risk factor.
The study does not support a connection between TCDD
exposure and adverse reproductive outcomes.
VI1-92
(f) Balaiaran and McDowell87
These investigators reported upon congenital malformation
rates by occupational group in the United Kingdom. They
chose groups in whom occupational exposure to pesticides
such as 2,4,5-T would be expected to be high and compared
their rates with those for all occupational groups. No
actual documentation of exposure was attempted (for
example, by questionnaire or assessment of actual duties
performed by individuals).
An excess of spina bifida and cleft lip and palate was
found amongst the offspring of agricultural workers,
gardeners and groundsmen compared with other occupations.
The authors felt that this required further investigation.
It must be emphasised that many other factors could be
different in these groups of people and no allowances were
made for important confounding variables such as alcohol,
tobacco. social status, etc. The authors concede the
inconclusiveness of their observational study.
Two other descriptive studies - the Yusho bran oil and the
Korean rice oil investigations (Reggiani et al 1983)
contribute nothing to the reproductive debate.
VI1-93
(g) The Seveso Accident
In 1976 there was an accidental release of a cloud of TCDD
from a factory in Seveso, near Milan. Data have been
collected from three defined zones in the Seveso district
of varying exposure and exposure levels have been
carefully documented.88
Data on spontaneous abortions and congenital malformations
were not available for the exposed areas before the
accident. The data collected afterwards must be
interpreted in the light of significantly increased
awareness and diligent ascertainment by the authorities.
A large number of unrecorded, unreported induced abortions
were allegedly performed on Seveso women in other parts of
Europe, particularly in London. No numbers can be
ascertained but the anecdotal evidence of these inductions
is widespread.
The latest reports are from Dr Bruzzi of the Istituto
Superiore di Sanita, Some. These do demonstrate some
differences in malformation rates between the highest and
the lowest exposed zones. Few are statistically
significant and all are well within normal European
VI1-94
limits. The relative risks are small. 1.2 in the highest
zone, and easily explicable by increased ascertainment
amongst the exposed.
The Commission had the advantage of detailed examination
and cross-examination of Dr Bruzzi. in Rome. Afterwards,
informal discussion between the Commissioner and Counsel
and Dr Bruzzi occurred. Dr Bruzzi stated that he feels
that there is "Something in it".
However, the Commission feels that these inconclusive
studies do not demonstrate increased risk after a major
parental exposure of both males and females. It finds
comfort in that conclusion by its coincidence with the
view of the head of the Research Institute, Dr Pocchiari,
a most astute epidemiologist, who stated that there is
"Nothing in it".89
(h) Alsea II
This descriptive study has been criticised at an
international level. It compared three areas of Oregon,
one with supposedly high levels of exposure and two
control areas, one rural and one urban. The area with
high levels of exposure was later found to be an area of
very low population density.
VI1-95
Data in respect of spontaneous abortions was collected.
Higher levels were found in the high exposure area
compared with the two control areas.
The major deficiencies of this study include:
(a) differing methods of data collection in the three
areas,
(b) no control for confounding factors such as maternal
age and social condition.
(c) ignorance of the marked seasonal changes in
population,
(d) poor exposure data,
(e) the abortion rates were much lower than expected.
No causal connection can be inferred from this study.
(j) Conclusion
The Commission concludes that many of the different sets
of data analysed above demonstrate no association between
exposure of the father to chemical agents and untoward
birth outcomes: the consistency is most persuasive.
VI1-96
9. SPECIFICITY
The next question to be discussed in whether association
between a risk factor and a particular outcome is
specific. It follows from the lack of association above
demonstrated that no specific outcome is found in
association with the risk factor. This would always be
significant but it is more significant than usual in the
particular case.
One of the postulated mechanisms. of which more later. for
the paternally mediated effect is the suggestion that,
following exposure of the male to chemicals, some chemical
or contaminant constituent is absorbed by the male into
his system. This finds its way into the seminal fluid and
then at the time of fertilisation, or during the pregnancy
as a result of later intercourse, the fertilised ovum or
the embryo is exposed to the chemical carried by the
seminal fluid with toxic results. Without dealing for the
moment with all the arguments against such a mechanism, if
it were operating one would certainly expect a specific
and characteristic response, such as occurred in the
thalidomide tragedy.
It follows that the lack of any specific outcome negates
the postulation of WAA.
VI1-97
10. DOSE-RESPONSE RELATIONSHIP
None of the studies indicate any association between
unfavourable birth outcomes and dose. In particular, the
Australian Study shows no association between birth
outcome and (a) numbers of tours to Vietnam, (b) length of
time in Vietnam, and (c) the time since the soldier
departed for or returned from Vietnam. The lack of any
dose response relationship is highly significant.
11. BIOLOGICAL PLAUSIBILITY
The next step in the process of assessment is a
consideration of the biological plausibility of the
outcome being associated with the exposure.
As has been observed in the Exposure Chapter of this
Report, Chapter IV, no evidence exists of Australian
personnel having been exposed to Agent Orange or to other
chemicals to an extent likely to give rise to any
long-term toxic effects.
A mere possibility (as opposed to actuality) of exposure
to Agent Orange spray has been demonstrated in the same
VI1-98
chapter. This was shown as a possibility only in relation
to a very limited number of Australian personnel.
So far as the evidence discloses, only one female amongst
the Australian personnel became pregnant whilst in
Vietnam. Her daughter is well and attending school in
Victoria. Few women performed Special Overseas Service as
part of the Australian contingent.
Accordingly, the postulate must be that exposure of the
male to chemicals in Vietnam caused untoward pregnancy
outcomes amongst their offspring. Those offspring must of
necessity have been conceived after exposure ceased and
within women themselves unexposed. That this is the claim
is made clear by the final submission on behalf of
90
WAA.
That submission,
mechanisms. At p
appears:
somewhat
112 of the
cryptically, postulates
submission the following
The first question which must be asked is whether it is biologically feasable (sic) to have
paternally mediated birth defects.
It is submitted that clearly the answer is in the affirmative. Several witnesses have spoken of the possibilities and types of birth defects, they are:
VI1-99
1. Mutation; 2. Germ cell damage; 3. Teratogenic effects by the release of
chemicals in the seminal fluid.
Dr Stanley expresses the hypotheses somewhat differently.
She says:
The most likely hypotheses being tested by those who suggest that Agent Orange in the father is the cause of congenital malformations in his offspring are:
(a) a mutation in his germ cells has been
transmitted and is evident as a defect in organ development ⢠(b) a mutation in his germ cells has been
transmitted as a marked increase in genetic susceptibility to some environmental teratogen;
(c) a less likely hypothesis is that the
chemical remained in the sperm/seminal fluid until conception (months/years after exposure) and then the developing embryo was exposed during sexual intercourse (after conception)-that is a teratogenic effect.91
Whilst maternal exposures and the possible teratogenic
effects of drugs, viruses and radiation have received much
attention, paternal exposures and possible mutagenic 92
effects have been relatively neglected. Agent Orange
has become an exception to this but attention has mostly
been caught by unscientific and sensational media articles
rather than by reports of epidemiological studies.
VII-100
12. TIMING OF EXPOSURE
The next factor that must be considered is the timing of
exposure before conception. The development of mature
sperm in the human male takes approximately 74 days. Only
mature sperm can impregnate the ? female ovum. About
mid-way in the development of the mature sperm is a step
called meiosis.
This is a maturation process of the gametes, consisting of
chromosome conjunction and two cell divisions in the
course of which the diploid chromosome number becomes
reduced to the haploid. This process is important in that
it weeds out damaged sperm cells in which there are broken
chromosomes or other types of structural damage. Such
cells with damaged criromosomes cannot "make it over the
bridge." Thus. it is seen that the whole process of
spermatogenesis in the male is one of protecting the
species by ensuring that mature sperm is as good as
possible.
The result of all this is that if there is exposure even
to a most powerful mutagen causing mutagenic damage to the
DNA of the sperm, either all of the damaged sperm would be
eliminated at the meiotic stage or it would simply pass
VII-101
through the system and be disposed of by replacement with
normal sperm after a maximum of 90 days. The 90 days
assumes a slowing down of the process as a result of toxic
response. The time span for the normal maturation process
is about 74 days.
Since the case for the veterans is that there is an
increase in birth defects amongst children of veterans
generally and not only amongst those children who were
conceived within 90 days of their father's return from
Vietnam, one must postulate a mutagen of sufficient power
to damage spermatogonial cells. One notes that the
Australian Birth Defects Study found no association
between the date of conception of the cases and the
proximity of that date with the date when the father
returned from Vietnam.
In animal models only two mutagens have been found to be
of sufficient, power to damage spermatogonial cells. One
is tri-ethylene melamine, the other is mitomycin C. These
are compounds which are used in cancer therapy and are
amongst the most powerful alkylating agents. Another
known mutagen is radiation. Even exposure to high doses
of radiation following the explosion of the atomic bombs
at Hiroshima and Nagasaki has not been proven to increase
VI1-102
mutation frequency. As a mutagen, radiation was powerful
enough to be responsible for increases in malignancies but
did not increase birth defects.
In his evidence Dr John Poliak postulated a mechanism
which involved the binding of 2,4-D and/or 2,4,5-T to DNA
so as to cause mutation in the spermatogonial cells. His
only warrant for this theory was research by
93
Bamberger . indicating a potential for these herbicides
to bind to DNA in plant cells. Dr Brusick suggests that
DNA binding in plant cells seems to be irreversible
covalent binding, whereas in animal cells it has been 94 found to be reversible: it follows that the
extrapolation made by Dr Poliak is quite unreliable.
The result of these considerations is that one must seek
for a powerful mutagen, a mutagen of a type never before
found to have operated in human populations: one must
seek it by an examination, not of human populations, but
of necessity by an examination of laboratory experiments
in animals and in cell cultures.
If this issue was not of such concern to veterans and
their families. one might not embark upon such analysis.
VI1-103
W A A pointed to no particular chemical nor, indeed, to any
particular data as supporting the biological proposition
other than the very late presentation of the W A A
collected Tasmanian data dealt with as an addendum to this
chapter of the Report.
Accordingly, it has been necessary for those assisting the
Commission to collect, collate and investigate all data in
relation to every chemical listed by W A A and/or known to
have been used in Vietnam. This was necessary to assess
whether or not there was any basis for a conclusion that
there was exposure to such a powerful mutagen.
From the evidence. it is clear that human beings and
indeed all mammals have evolved a system which is
extremely protective of the species from mutagenic agents.
Dr Fiona Stanley, consultant to the Commission, confirms
that a powerful mutagen would be necessary to damage 9 5 germinal cells.
The Commission will turn then to those studies which have
examined the question of chemical exposure of the male and
the mutagenic effect on male cells. It will also deal
with the theory of a male mediated teratogenic mechanism
VI1-104
operating by way of the seminal fluid or perhaps by the
sperm itself.
13. MUTAGENICITY
Mutagenesis is the process by which an agent (e . g .,
chemical, viral. physical etc.) causes a genetic change in
a cell. There are two kinds - somatic mutations and
germinal mutations.
Somatic mutations are changes to the genetic material in
somatic cells and may occur to those cells within either
the formed embryo (teratogenically) or within an
individual after birth. In the latter case, such mutation
may cause problems in the individual, e.g. neoplasia, but
the problem is not transmissible to that individual's
future offspring. Similarly, the problems suffered by an
affected embryo are not transmissible to any future
propagation of that embryo. In both cases, because the
germinal cells are not involved, the problems are not
transmissible to the next generation.
Germinal mutations are changes to the genetic material in
germinal cells which result in permanent transmissible
change in the genetic material. They occur in either
VI1-105
maternal or paternal germ cell lines (ova or sperm) and
will be transmitted to the embryo (maybe lethally) if the
fertilised ovum acquires a chromosome carrying a mutation
from a germ cell of either the father or the mother.
Accordingly, where male chemical exposure and its possible
effect on his subsequent offspring is to be examined (as
is the case here) then germinal mutations are those that
are most likely to be relevant.
At the outset, it should noted and clearly understood that
no chemical human mutagen has been definitely
identified.96
13.1 Summary of Dr Pearn's Background Report to the
Senate (1982) re Birth Anomalies and Chemicals
The Commission is grateful to Dr John Pearn, Head of the
Department of Child Health at the Royal Childrens'
Hospital. Brisbane. who acted as a consultant to the
Commission from time to time. His "Congenital Defects and 97
Exposure to Militarily Used Herbicides" was presented
to the Senate Standing Committee on Science, and the
Environment in April 1982 and has been a valuable source
document to this Commission. The following summary has
been prepared from this source material.
VII-106
1. 2,4-D and 2,4,5-T are relatively non-toxic in acute
dosage. The LD5Q for Rodentia is in the range of
480-940 mg,'kg.
2. The dioxin 2.3.7.8-TCDD is extremely toxic to mammals
both in acute dosage, and in lesser doses administered
chronically. There are considerable species
differences in susceptibility to its toxic effects.
The LD50 for guinea pigs is approximately 1
microgram/kg, and the LD5Q for primates is
approximately 70 micrograms/kg. TCDD binds to
specific cell receptors and modifies the synthesis of
a range of critical enzymes within cells.
3. The acute toxic effects of TCDD include chloracne,
hyperkeratosis, hepatocellular mecrosis and immune
depression. Effects are dose-related. The long-term
clinical effects of significant exposure to herbicides
remain unresolved. TCDD is stored preferentially in
fat with a mammalian half-life (in that tissue) of
several months. The risk of angiosarcomas may be
relatively increased following chronic exposure, but
absolute risks remain low. Cohort studies of factory
workers from trichlorophenol and herbicide plants have
VI1-107
not demonstrated any greater mortality from neoplasms.
or from circulatory or other diseases. The
carcinogenicity of 2,4-D and 2,4,5-T is low.
4. Teratogenic chemicals act via the transplacental
route, act for only a critical period during
embryogenesis, are dose-dependent, depend on genetic
factors relating to both the mother and fetus (and
hence, also relate to the genotype of the father) and
may or may not produce specific dysmorphogenetic
syndromes.
5. 2,4-D and 2.4.5-T are teratogenic in mice if
administered either by the oral or subcutaneous route
to the pregnant mother, at critical stages of
pregnancy.
6. The "no-effect teratogenic dose" for 2,4,5-T is 20
mg/kg.
7. There is a positive dose-response curve for 2,4,5-T
with respect to the induction of cleft palate in
susceptible mouse strains. It is probable that there
is also a dose-response curve for the qualitative
severity of soft tissue lesions which involve the
VI1-108
kidney as well. The anatomical defects produced
(cleft palates and renal lesions) have not been
described in detail.
8. In the case of 2,4,5-T, the genotype of the mother,
the father, and the offspring are all important in the
question of susceptibility to the effects of the
teratogen, when it is administered to the mother.
9. No worker has reported being able to produce
teratogenic effects in rodentia other than mice, or in
other vertebrate species including primates, using
2,4,5-T and 2,4-D.
10. The dioxin TCDD is a potent teratogen in Rodentia.
Mice, rats and hamsters have all been shown to be
susceptible. TCDD produces defects with the smallest
effective dose of any known chemical teratogen in
mammals. The 50 per cent teratogenic dose in strains
of susceptible mice is 6.5 micrograms/kg given orally,
continuously over nine days of pregnancy.
11. Experimental results to date have not demonstrated
that TCDD is teratogenic in primates.
VI1-109
12. TCDD is excreted in mammalian milk, and has been shown
to be capable of abnormal enzyme induction in neonatal
Rodentia following prior administration to the
pregnant mother.
13. TCDD is toxic to embryos and fetuses exposed to it via
the transplacental route, in both rodents and in
primates, as evidenced by small fetal weight and
reduced litter size.
14. There are no experimental reports of fetotoxicity in
cases where maternal dosage with 2,4,5-T or TCDD was
insufficient to cause clinical signs of poisoning in
the mother.
15. A major review of all possible associations between
herbicide exposure and teratogenic effects in man has
been undertaken. There are to date no examples where
there is acceptable evidence that herbicides may have
caused congenital abnormalities, by a direct effect on
the pregnant mother.
16. There are a number of proven teratogens in rodents
which do not affect man. By contrast, all the proven
human chemical teratogens produce lesions in
VII-110
experimental animals (these include 4-pteroylglutamic
acid, high-dose progesterone, anti-metabolites used as
anti-cancer drugs, tetracycline, thalidomide and
alcohol).
17. There is no evidence to indicate that the baseline
rate of congenital malformations is increased in women
exposed to TCDD (the Seveso accident), or to
herbicides used in agriculture or forestry. In all
cases where individual questions linking possible
maternal herbicide exposure and congenital
malformations have been studied, no cause-and-effect
suspicions have remained.
18. There is no satisfactory evidence of any clustering of
congenital malforma tions in time and space, with a
link to real or suspected maternal herbicide
exposure. Epidemiological studies in the United
Kingdom, Hungary, Italy, the United States. New
Zealand. and in Australia (the Yarram study) have all
failed to demonstrate any clustering of congenital
malformations.
VII-111
19. There is no evidence (in the world's literature) of
any new or unusual dysmorphogenetic syndrome
clustering in time and place, which could be related
to herbicide exposure.
20. In Australia in the last eight years, two reports have
highlighted demographic patterns of neural tube
defects (in New South Wales) and of cleft lip defects
(in Western Australia) which show variations from
previously established secular trends. In each case
there has been no direct cause-and-effect association
between such defects and herbicide exposure.
21. Questions of miscarriage and stillbirth rates relating
to herbicide exposure remain unresolved; there is
however, no positive evidence from any of the
international studies, or from the Australian
experience, to indicate a significant degree of
suspicion in this area.
22. There are no reports in the world's literature of
teratogenic effects in the children of groups of women
who have been exposed to high levels of herbicides and
where there has been an exposure-free period before
the subsequent conception of children.
VI1-112
23. A full analysis of all experimental and clinical data
concerning the effects of possible teratogens acting
through the male, is contained in Exhibit 877. In
particular, the question of toxic changes acting prior
to the subsequent conception of offspring is
addressed. There is unequivocal evidence that toxic
exposure of the male may result in temporarily-reduced
fertility.
24. Toxic agents such as lead, carbaryl and vinyl chloride
are known to reduce fertility in humans acutely
exposed, to such agents. Teratospermia is a feature of
such toxicity in the human male. Toxic
paternally-mediated effects on fetal outcome have now
been positively detected in at least six vertebrate
species. The poor reproductive performance of such
males maybe reflected in an increased rate of
miscarriages noted both among wives of such workers
(in the case of humans). or the dams of experimental
sires who conceive during the period when the sire is
poisoned. An increased rate of congenital
malformations is not a part of this syndrome either in
human, clinical or epidemiological studies, nor has it
been reported in any experimental studies involving
animals.
VI1-113
25. Reproductive outcome may be compromised by at least
three mechanisms if the male is exposed to acute or
chronic toxic agents - a direct effect on higher
physiological function, a direct effect on the sperm
itself, or changes in the seminal fluid modifying
sperm motility or function. It is known on
theoretical and empirical grounds that abnormal sperms
are selected against, in the competition to fertilise
a mammalian ovum.
26. Male Rodentia acutely poisoned with TCDD may produced
litters of reduced size and with small offspring. In
no case has TCDD administered to a male experimental
animal resulted in a raised congenital malformation
rate in offspring, even when the male shows clinical
features of acute dioxin poisoning.
27. An analysis of all available experimental data
indicates that if a poisoned male animal is allowed to
recover, and is tested subsequently following a
significant toxin- free interval. the effects of
initial reduced fertility can no longer be
demonstrated.
VI1-114
28. Exposure of male experimental animals to either acute
or chronic toxic doses of 2,4-D or 2,4,5-T does not
increase the rate of congenital malformations among
offspring. Male animals exposed in utero to
herbicides do not themselves show significant changes
in reproductive performance. Male mice experimentally
poisoned with replicated high-dioxin Agent Orange
cocktail are known to manifest acute toxic signs
clinically, but there is no increase in teratospermia,
or a reduction in reproductive capacity, or an
increase in the rate of congenital malformations.
29. Primates fed a long-term high-dioxin diet manifest
reduced spermatogenesis and altered testicular
histology, but no reports of congenital deformities in
offspring have yet appeared.
30. A full review of appropriate literature has
demonstrated that there is no evidence to link
herbicide exposure in human males with an increased
abnormality rate in their children, either (a) during
periods of acute or chronic exposure which have
resulted in clinical signs, or (b) after an
exposure-free interval prior to the conception of a
chiId.
VI1-115
31. The interpretation of suspected clustering of
congenital abnormalities depends on an assessment of
the baseline or background rate. A review of the
rates for several countries is presented, and an
anlysis of disease-specific rates for individual
malformations is presented. Major congenital
malformations occur with a frequency of 2 to 3 per
cent, and minor malformation with a further rate of 5
to 8 per cent for the general population. Social
class, parental age, race, season of conception, and
drug-taking modify the rate of congenital
malformations and other unfavourable outcomes of
pregnancy, in sub-groups within society. These
influences are reviewed in the context of questions
concerning possible herbicide-malformations links.
32. In the absence of any specific teratogenic agent. a
group of 40,000 young males would be expected to
produce 1,000 children with major malformations, and a
further 2,400 with minor cosmetically-obvious but
functionally insignificant malformations, at a
conservative estimate. In addition, even in the
absence of any defined teratogenic influence, 800 of
their children would manifest significant intellectual
handicap.
VI1-116
33. A personal series of 17 Veterans and their wives have
presented for genetic advice following concern about
exposure to Agent Orange. These have presented as
part of the more general case load of 800 families
seen in the Genetic Cline at the Department of Child
Health in Brisbane. In three of these cases there
were major congenital malformations present. Six of
the presenting families came for advice only; in the
remaining 11 families there were no features which
would specifically distinguish these from the pattern
of families who attend genetic clinics generally.98
13.2 Genetic Toxicology - Mutagenicity - Dr Brusick
That it is with the genetic activity of the various
chemicals that this Commission must be concerned is made
abundantly clear by the evidence of Dr David Brusick. He
is a most eminent genetic toxicologist, and the author of
one of the standard texts, "The Principles of Genetic
Toxicology".99 He is a member of the American
Association for the Advancement of Science, the American
Society for Microbiology, the Environmental Mutagen
Society, the Genetic Society of America and the Society of
Toxicology.
VI1-117
He conducts a program on mutagenicity testing in his
capacity as a Director of the Biological Safety Evaluation
Division of Litton Bionetics, Inc.
Before becoming Vice-President of that organisation he had
extensive teaching experience including professorial
status in both Virginia and Washington.
Dr Brusick began his evidence by describing the origins of
congenital malformations. The overall average of
congenital malformations, he said, is of the order of 2.5
per hundred live births. Of these approximately 10% are
non-genetically related, and result from what are usually
teratogenic agencies which would include viral infection,
dietary deficiencies, hormonal imbalances consequent upon
drugs, chemical exposure and the like. These are not
inheritable, and result from female exposure only.
Accordingly for the Commission's purposes they may be put
to one side. The rest are genetically related. These are
of three types:
1. Somatic cell mutagen. Such mutations occur in utero,
result from female "exposure" only, are not
inheritable and are of environmental origin. For
present purposes these too may be put aside.
VI1-118
2. Single gene and chromosome traits, maintained in the
population. This group includes about 10% of
congenital malformations. A single gene trait means
that the inheritance pattern. or the congenital
malformation, is the result of an aberration or damage
to a single gene. Once that gene is damaged the
malformation can be expressed. There are
approximately 50,000 individual genes in the human
genome, i.e. within the DNA of one cell there are
located 50,000 genes. The genome represents the total.
These single gene malformations account for about 10%
of the total and can be traced back through a family
tree. The particular trait will appear, not in every
generation, but from time to time.
3. Mutiple gene traits. 80% of all congenital
malformations are maintained in the human population
through multiple gene traits.
A good example of a multiple gene trait is height. Height
in an individual is the consequence of many genes working
together in concert. An average person may have an equal
number of tall genes and short genes and therefore be of
VI1-119
average height. Two average height individuals could
conceivably give all of their short genes to their progeny
resulting in an extremely short child or alternatively
they could give all of their tall genes to one child and
have a very tall child.
The same is true for congenital malformations. All human
beings carry genes which contribute to the formation of
normal bone structure, normal organ structure and so on.
Malformations caused by multiple gene traits are of course
extremely difficult to study because there is no way to
determine how many of each kind of gene will be given to a
particular offspring. It is totally random. One cannot
do a family tree and look for cleft palate in families
where only one individual may, within recordable history,
show it.
It follows therefore that if one is dealing with male-only
exposure there is only one source of congenital
malformation left open, that is, a source which would
affect the DNA because in the fertilisation process only
one male cell is involved and the exposure must affect it.
Thus if a chemical is going to cause a congenital
malformation by male-only exposure it must be genetically
VI1-120
active; that means it must be able to produce a single
gene mutation, a chromosomal mutation, or a mutation in
one or more of the various genes which would contribute to
a multiple gene trait.
A single gene mutation may be either dominant or
recessive. A developing embryo gets chromosomal material
from both the mother and the father. If the mutation
occurs in only one of the parents then the mutation must
be dominant if it is to appear in his or her child. That
is to say, a dominant mutation will be expressed when it
is transmitted irrespective of what the other parent
contributes. So single gene mutations of the dominant
type will appear in the very first generation, and this
then must be the type with which this Commission is
concerned.
Recessive gene mutations are those which are not
necessarily expressed even though transmitted to the
offspring. If a recessive mutation occurs in the male and
is transmitted then, unless the mother is also carrying
the very same mutation and transmits it. the mutation will
only be transmitted in a single dose and will not be
expressed. The chances of the same mutation occurring in
the female are small, and for practical purposes, amongst
V I 1-121
the Vietnam Veteran cohort of 45,000, a recessive gene
mutation is unlikely to be a cause of a birth defect.
Thus for practical purposes it is only relevant to look
for a chemical which is not only genetically active but
one which is an extremely powerful mutagen.
14. POSSIBLE MUTAGENICITY OF RELEVANT CHEMICAL AGENTS
As the Commission is dealing with a purely theoretical
model it seems appropriate to examine the mutagenic
potential of all of the chemicals as disclosed by the
standard tests.
Methods of testing for mutagenicity are of various types
and complexity. The animal teratogenicity or reproduction
studies show that there are no teratogenic effects arising
from male only exposure. They also provide a foundation
for believing that there are no mutagenic effects
operating by male only exposure. Such studies were not
designed to look for mutagenic activity in either the
short term or the long term but the results tend to show
no such activity.
VI1-122
Nonetheless, since the animal studies are not capable of
completely closing the door on the mutagenic effect
argument, the Commission has considered the mutagenicity
studies. These extensive examinations are not reported in
detail herein. They do however permit the following
reliable conclusions to be drawn as to the particular
chemicals used in Vietnam.
2,4-D
The Commission concludes that 2,4-D may be a very weak
mutagen. Such mutagenicity as it might have is without
significance in the context of exposure in Vietnam.
The most substantial bases for the conclusion are as
follows:-
(i) Dr Frank Dost reviewed the data in detail and said:
2,4-D has been extensively evaluated for mutagenic potential, using a wide range of test systems. ... The lack of positive
response in most tests and the very high dosage requirements in the positive assays indicate that 2,4-D may be a very weak
mutagen, but it is without significance as an environmental mutagenic hazard.100
VI1-123
Dr Ian Munro, a toxicologist of high repute101 also gave
evidence and, although in slightly more complicated terms,
agrees.
The International Agency for Research into Cancer said:
2,4-D in the range of 50-500 micrograms per millilitre had a dose dependent inhibitory effect on cell growth of L929 cells in monolayer
cultures. With 350 to 500 micrograms per
millilitre complete inhibition of growth occurred after 24 hours incubation. On removal of 2,4-D a rapid resumption of cell multiplication took place.102
J.P. Silar in "The Genetic Toxicology of Phenoxy Acids
Other Than 2.4,5-T" pointed out that except in yeast 103
testing there was no strong mutagenic activity.
Dr Brusick summed the matter up as follows:
Studies in Drosophila, tissue culture cells and yeast have es tablished a very limited potential of phenoxy herbicides to induce mutation and chromosome aberrations. Yet when evidence for expression of these phenomena in vivo (either rodent or human) is sought the results are
essentially negative. Animal studies with 2,4-D. 2,4,5-T and TCDD have not shown evidence of somatic cell chromosome damage and more
importantly no evidence of genetic damage in the male germ cells (negative dominant lethal test) .... Thus in my opinion there is no evidence
supporting a concern that phenoxy herbicides pose a substantial genetic risk to the germ cells of exposed humans.^·04
VI1-124
2.4.5-T
In the United Kingdom the Government's Advisory Committee
on Pesticides has reviewed the safety for use in the
United Kingdom of the herbicide 2,4,5-T on three separate
occasions, in March 1979,105 December 1980106 and
December 1982. 107
The most extensive review was conducted in 1980. The
later review makes no qualification. The Committee
concluded:
It is known that physical radiation is the most powerful mutagen in the laboratory. However, in some human populations exposed to high doses of physical radiation from atomic bombs, no
significant effects have been observed in progeny. (Grosch and Hopwood 1979). Thus even if Dioxin and 2,4,5-T were, at most, weak mutagens it is exceedingly unlikely they could give rise
to any observable increase in the incidence of congenital malformations.
As appears above. Dr Brusick and Dr Dost agree with this
conclusion. Dr Tuchmann-Duplessis also agrees. The
Commission concludes that 2,4,5-T is at worst a very weak
mutagen.
VI1-125
TCDD
The eminent toxicologist. Dr Ernest McConnell, reviewed
the toxicity of the dioxins in 1980 and said:
In summary, it appears that the mutagenic
potential of these chemicals is equivocal, at most, they would be considered weak
mutagens.108
The United Kingdom's major review, referred to above,
said.
It is impossible to come to any firm conclusion, except that, like 2,4,5-T, TCDD cannot be
considered as a powerful mutagen.109
In 1981 The Canadian National Research Council said, "The
available data on mutagenicity of TCDD indicate that this
compound is not mutagenic". The Committee also referred
to certain chromosomal abberrations and then said, "The
data on these effects are equivocal, but the majority of
the more carefully conducted studies have produced
negative results."110
This conclusion is one with which Dr Brusick agrees.111
Dr Alistair Hay, who gave evidence for W A A said:
VII-126
The only evidence of chromosomal damage in humans arising from exposure to TCDD is from Vietnam. Vietnamese scientists claim that there is higher incidence of chromosome breaks and gaps in
individuals exposed to the herbicide Agent Orange when it was used as a defoliant in Vietnam.
However, the level of chromosomal damage reported as abnormal by Tung et al is considered normal in the West.... No chromosome abnormalities have been reported in workers engaged in the
manufacture of 2.4.5-T at Dow Chemicals in the United States or men exposed to TCDD as a result of industrial accidents in West Germany and Britain.112
The IARC in its cancer review of TCDD said, "Extensive
studies on workers and on adults, children and fetuses
exposed to TCDD in the Seveso incident have not revealed 113
any increase in chromosomal aberration frequencies."
The conclusion to which the Commission has come is that
the constituents of Agent Orange are at worst weakly
mutagenic and most unlikely to cause the kind of germinal
damage required to produce increases in unfortunate
reproductive outcomes amongst the offspring of those who
served in Vietnam.
These compounds are those which have taken up most of the
time of the Commission and indeed are those which gave
rise to the controversy. Nonetheless, many other
chemicals were used in Vietnam and the Commission's
conclusions about their mutagenicity are set out below.
VII-127
Diquat
The Commission. having reviewed all the material, is
114
content to adopt the evidence of Dr Munro in respect
of this compound and concludes that diquat is neither
carcinogenic nor mutagenic.
Paraquat
The Commission concludes that paraquat has no significant
mutagenic, carcinogenic or teratogenic effect in 115 mammals. The mutagenic potential of both diquat and
paraquat has been explored in vivo and in vitro. They
failed to demonstrate mutagenicity in the murine dominant
lethal test.116 The International Program on Chemical
Safety concluded, "Paraquat has been found to have minimal
to no genotoxic activity when evaluated in a variety of in
117
vitro and in vivo test systems."
Picloram
The Commission concludes that picloram is not mutagenic,
adopting the opinion of Dr Ian Munro118. The Commission
reviewed the literature extensively, particularly that
VI1-128
referred
W A A . 119
to by Dow Chemical (Australia) Limited and
Dalapon
The Commission concludes that dalapon is not mutagenic.
It has reviewed the literature and notes negative results
120
in all four bio-assays by Anderson et al and in three 121 by Carere et al.
Diuron
Diuron was found to be negative for mutagenicity in four
assay tests. In the Commission's opinion it is not
mutagenic in man or animal. The literature was
extensively reviewed and the Commission reaches its
122
conclusion notwithstanding Seiler's work.
Monuron
Monuron also gave negative results in all four assay
systems. The Commission finds that monuron is at most a
very weak mutagen. adopting Dr Brusick's opinion 123
notwithstanding some conflicting data.
VI1-129
Bromacil
Bromacil gave negative results in four assays and the
Commission finds that it is not mutagenic, as did the N.H.
& M.R.C. and the Pesticides & Agricultural Chemicals 124 (Standing) Committee.
Cacodvlic Acid
This compound presents a somewhat more difficult problem.
There is both negative and positive data in respect of its
mutagenicity and one must say that looking carefully at
the evidence and acknowledging some negative studies the
compound must be regarded as a candidate mutagen.
Certainly the negative testing suggests that if it is a
mutagen it is not a particularly powerful one.
Nonetheless the Commission finds that cacodylic acid is a
candidate mutagen Dr Munro points out that the compound
induces birth defects in laboratory animals only when
administered to the mothers at toxic or near toxic (i.e.
125
very high) doses. Thus even if mutagenic it is not
the kind of powerful mutagen that must be postulated.126
VI1-130
Creosote/Distillate
Dr Munro concludes that creosote is not mutagenic for 127
animal cells or for animals. Creosote/distillate is
however a mixture of polycyclic hydrocarbons and must be a
candidate mutagen at least in theory, as the
salmonella/microsome assay suggests. Again however it is 128
not the powerful mutagen that must be postulated.
Borate/Chlorate
No material has been discovered which suggests that
borate/chlorate is relevantly mutagenic and the Commission
finds accordingly.
DDT
This insecticide has been tested extensively for
mutagenicity and although there is some conflicting data
the Commission concludes that it is not mutagenic. The
Commission has reviewed the conflicting data in detail and
has no hesitation in adopting the conclusion of Dr
D . .129 Brusick.
VI1-131
Malathion
Malathion data is substantially negative for mutagenicity
but there are some positive results. Notwithstanding
reports of chromosomal damage at very high exposure levels
which have been unreliably reported, the Commission has no
hesitation in finding that malathion has no relevant
mutagenic activity at the exposure levels likely to have
been experienced in Vietnam. Van Bao et al is
difficult to evaluate. The US Department of Health notes 131
several negative studies in conflict with this work.
132
The Commission adopts the conclusions of Dr Brusick 133 and Dr Ian Munro. See also I ARC 1982 June 30th Vol 30
and Malathion Research, June 1984 American Cyanamid.
Dieldrin
There are mixed test outcomes in some systems but the
Commission concludes that dieldrin has no relevant
mutagenic activity. This coincides with the views of WHO
134
Expert Groups on Pesticide Residues and IARC.
VI1-132
Chlordane
Notwithstanding the work of Ahmed et al, the negative Ames
test and a review of the whole of the material leads the
Commission to the conclusion that chlordane is not
relevantly a mutagen. It poses no risk for heritable 135
genetic activity. The view is shared by I ARC and
IPCS.136 The Commission adopts Dr Brusick1s
. 137
opinion.
Lindane
The Commission concludes that this compound
mutagenic, adopting Dr Brusick1s opinion.138 , 140
and WHO agree.
Diazinon
Notwithstanding one positive in vitro test on human 141 lymphocytesj. the Commission comfortably concludes
that diazinon is not mutagenic in the relevant sense and
that there is no evidence of any mutagenic effects in
animals or man. Dr Brusick agrees142 as does the
14 3
Australian Department of Health.
is not
139
IARC
VI1-133
Pvrethrins
The conclusion to be drawn from the whole of the extensive
testing conducted on these compounds is that they are not 144
mutagenic, as Dr Brusick deposed. The Department of 145 Health agrees.
Diethyl-m-Toluamide (DEET)
The material in relation to this insect repellent is
sparse. No evidence has been led by anybody suggesting
that it is mutagenic and the Commission's own
investigations reveal only the work of Swentzel et al
which was negative.146 The Commission concludes that it
is not mutagenic.
Dimethyl-Phthalate (DMP) Insect repellent
These compounds are used widely as insect repellents and
also as perfume diluents. In some tests they were found
to be weakly mutagenic and in others to be non-mutagenic.
No contention that it is mutagenic or powerfully mutagenic
has been made on behalf of W A A and the Commission
concludes that it is either non mutagenic or so weakly
mutagenic as to be irrelevant in the present context.
VI1-134
There is some conflicting data but it is only of weak 147 responses.
Di-n-Butyl Phthalete (DBP) (Tick and Mite Repellent)
The Commission reaches the same conclusion as that reached
in respect of DMP, that is to say it is either not
mutagenic or it is so weakly mutagenic as to be non
mutagenic for present purposes. Dr Brusick is of the view
that it is not mutagenic.148
Dapsone. Chloroquine. Primaquine and Paludrin
No material has been put before the Commission which
suggests that any of these drugs are mutagenic. They have
been widely used over many years in malaria control.
Dapsone has been studied and found to be non mutagenic in
the normal test systems. The Commission finds no reason
for concluding other than that these four widely used and
internationally accepted drugs are anything other than non 149
mutagenic. IARC found Dapsone to be non-mutagenic.
VI1-135
Solvents
The International Program on Chemical Safety recently
reviewed the toxicity of selected petroleum products.
Benzene, diesel fuel and jet fuel were found to produce
positive cell transformations. DMSO, Dimethyl Sulphoxide,
has been said to be a solvent which induces quicker
absorption, but nothing has been said to suggest that it
is mutagenic. The solvents are accepted by the Commission
as potentially capable of causing cell transformations but
unlikely to be genetic mutagens.
Conclusion
From the above it must be concluded that none of the
chemicals relied upon by W A A fall into the category of
"powerful mutagen". This makes the hypotheses relied upon
biologically most implausible.
15. SYNERGISM
A further suggestion which seemed to be made by W A A is
that, although none of the chemical compounds used in
Vietnam is itself mutagenic, a mutagenic effect was
possible as a result of some synergistic or additive
VI1-136
effect between many different chemicals used in different
ways in Vietnam. The matter was specifically put by
WAA's Counsel to Dr Frank Dost as follows:
MR MCINNES— But if a person is exposed to other chemicals. has been subjected to them before a toxic chemical is applied, you may expect to see an increased effect of the last
applied chemical?--- It is not likely at the levels of exposure that we are talking about in this kind of situation.150
Later in his evidence Dr Dost was asked by Senior Counsel
Assisting about the issue of synergism. Among other
things, he said:
To begin with the prospect that any group of these kinds of chemicals, pesticides of any kind, virtually, will interact within the environment to form new compounds is virtually nil. These
are substances that are from the point of view of the chemist, reasonably stable. They have to be or they could not be used as a product because by the time they were used they would be something other than that which they were when they were produced.151
And later:
There is no magic in chemistry and the rules, the basic rules that govern reactions in the
environment or for that matter in the body, would really militate against the formation of strange and wonderful compounds with enormous power. It just does not happen.152
Dr Munro in respect to the question of synergism said:
VI1-137
Of course the whole question of the level of exposure needs to be considered, when one thinks about the probabilities of interaction. My feeling would be that given the nature of
conditions we are talking about here, the
probability of interactions would probably be quite remote.
And further:
But I think in general the totality of exposure to these chemicals would not lead me to the
conclusion that this matter (the suggestion of synergistic effects) warrants study in any way.
The Commission itself then asked:
And the remoteness of the probability leads you to the conclusion that study of the
suggestion of synergism is not
warranted?--- No.
Yes. well if I could put this to you. Is there a real possibility that it may happen?--- No.
Dr Munro was further asked on this question:
Under conditions of daily use of malathion for vector control and the use of 2,4-D and
2,4,5-T contaminated at 2 parts per million with TCDD as a herbicide?-- 1 would not expect any synergistic effects at those levels".15^
Dr Phillipe Shubik in his written statement to
Commission said:
the
VI1-138
I have been asked to speculate on the matter of possible synergism between the various
herbicides, pesticides, drugs and possible environmental factors on any potential cancer producing (mutagens) effects that may have occurred. I can only respond that I have no
knowledge of any studies that would suggest that any of the agents involved have ever been
evaluated in any combination to examine this possibility. Neither am I familiar with any studies that would suggest theoretically that
such a possibility exists.154
Dr Bernard Stewart in his written statement to
Commission said:
There is no adequate experimental data to provide a basis for predicting the possible carcinogenic or mutagenic consequences to experimental animals of exposure to low doses of the suspect chemicals
in combination. Predicting such consequences for humans on the basis of experimental data must be regarded as speculation. If speculation upon the worst possible, but nonetheless credible,
scenario is made, then it would be predicted that some increase in environmentally determined promotional influence might be experienced by the exposed population. Nonetheless such a
prediction must be qualified. To be biologically effective, exposure to the promoters normally involves a long period (that is a significant
proportion of the individual's life time). Despite promotional activity being possible it is most likely that it would be impossible to
demonstrate such an effect amongst those who served in Vietnam. Either there will, in fact there would have been no effect or the effect would have been so minor as to be undetectable by
current investigative procedures. (emphasis added)155
the
V I 1-139
WAA's case on synergism is a bald statement of the
generality that chemicals can work in a potentiating or
accumulative way. The evidence satisfies the Commission
that as far as the chemicals being discussed are concerned
there is no synergistic or potentiating effect which would
translate the chemicals from non-mutagens or marginal
mutagens to the kind of potent mutagens required for the
dramatic effect relied upon by those contending for the
unfavourable outcome thesis.
returning then to the main argument.
The Commission assumes for the purposes of argument that
it is theoretically possible that exposure of a male to a
chemical substance can cause a mutation of the male
germinal cells.
Not only has it not been demonstrated that either TCDD or
the primary herbicide components of Agent Orange nor
indeed any of the other chemicals upon which W A A broadly
bases its claim can effect a mutagenic change in human
germ cells, but as well no human chemical mutagen has yet
been definitely identified. This is deposed to by Dr
Fiona Stanley.156
VI1-140
Further, in the studies specifically directed to the
question of whether exposure of veterans in Vietnam gave
rise to any excess of chromosome breaks or sister
chromatid exchanges, no differences were found between a
group of self selected Australian veterans and a group of 157 non veterans.
Similarly, in the pilot study by Newell et ai158 no
differences were found in the comparison between 50
Vietnam veterans and 50 matched controls in:
(i) the % of cells with chromosome breaks;
(ii) the number of breaks per cell;
(iii) the number or appearance of sperm;
(iv) the % of fluorescent bodies of sperm.
This study although carefully done and 159
investigators was subject to limitations
by its authors. It is nonetheless a useful
to the debate.
On the basis of the Commission's assumption postulated
above, what kind of reproductive outcomes would one expect?
by "blind"
referred to
contribution
VI1-141
16. THE REPRODUCTIVE OUTCOMES TO BE EXPECTED UPON MALE
GERMINAL MUTATION.
The view was consistently expressed by expert witnesses
giving evidence before the Commission that the most likely
reproductive outcomes of a male exposure giving rise to a
germinal mutation are infertility, miscarriage or
spontaneous abortion and peri-natal death. Putting it at
its highest, structural congenital malformations are an
unlikely outcome, as Dr Stanley deposed.160
Dr Jacobs, Professor of Anatomy and Reproductive Biology,
University of Hawaii, an eminent cytogeneticist, expressed
the following view in her evidence:
Well if any of the pesticides that we used in Vietnam caused an increase in the level of
chromosome abnormalities these could be either of number or of structure. This increase could be present in the somatic cells of the exposed
individual, that is the non-germ cells, and/or the germ cells. If it were to be present in the germ cells it could result in an increase in the number of chromosomally abnormal conceptuses. Now the majority of these chromosomally abnormal
conceptuses would miscarry so one would find an excess of miscarriages due to this particular situation of having chromosome abnormality and a minority would probably present as congenitally abnormal live births.16^ ·
Dr Stanley, in her oral evidence, said:
VI1-142
Most of the literature suggests that the expected reproductive abnormalities are more likely to be infertility - I use the words spontaneous
abortion, you probably know it better as
miscarriage - spontaneous abortions in animals anyway. peri-natal death; actual structural congenital malformations are not reported very often and the general literature says that if you're going to look for the effects of germinal mutations you really need to look at infertility, miscarriage as your major outcomes, and
chromosomal anomalies. Now that is not to say that point mutations could not result in birth defects. We do not know what causes birth
defects, but from the literature it is less likely, put it that way, but we really do not know about the cause of birth defects ... A
germinal mutation causes either infertility because the sperms are just so abnormal that they cannot fertilise the egg, or that they are normal
and can fertilise the egg but the egg is so
abnormal that it will be miscarried early. ... These germinal mutations that end up in
chromosomal anomalies - I mean the vast majority of those are aborted well before 12 weeks. Very few of those get through to live birth, the
chromosomal anomalies. The only really major one that does is Downs' Syndrome which is Trisomy 21.162
Even in animals, there is an absence of evidence of
congenital malformations consequent upon the
administration of drugs or chemicals to the male parent.
In Dr Joffe's review paper, "Influence of Drug Exposure of
the Father on Peri-natal Outcome"163 the author sets out
in Table 1 a summary of adverse effects of drugs and
chemicals administered to male mammals prior to mating, on
their progeny. In only two of the studies cited are
malformations noted as an outcome, those studies being two
of the studies of Lutwak-Mann, reported in 1964 and 1967
VII-143
respectively. A further study by the same author was
reported in 1965.
None of these three studies in fact justifies the
conclusion that malformations in the offspring of male
animals to which a chemical substance was administered
prior to conception were produced as a consequence of that
administration.
In the first of her three studies (1964) Dr Lutwak-Mann
reported experiments involving the mating of 6
thalidomide-treated male rabbits with 40 untreated does.
From the matings, 291 offspring were born.166 Two of
those offspring had gross malformations. The
malformations were not the same, one being spina bifida,
and the other involving the absence of a tail. Both
malformed pups were sired by the same male. Dr
Lutwak-Mann reports that "the incidence in our colony of
gross congenital malformations arising spontaneously is
low (1%)".167 The incidence in the experiments was even
lower and accordingly there is no basis for any suggestion
that the experimental drug was causing the malformations
observed. The study certainly does not provide evidence
that by a process of mutagenesis or otherwise male
exposure to a chemical can produce malformations in
offspring sired by that male.
164
VI1-144
In her 1965 study168, 31 experimental matings were
reported without any "gross malformation" although the
author did find it necessary to report that in a litter of
12 resulting from a mating of one of the males done since
the termination of the experiments, one pup was born with
paralysed hind legs.
In her 1967 study Dr Lutwak-Mann reported 6 malformations
from 103 experimental matings without disclosing the
number of offspring born. The author had. in her first
study, regarded a litter of 5 or less as a reproductive
shortcoming, and upon this basis, it is reasonable to
infer that the rate of malformation in the third study was
not greater than the normal rate of 1%.
Professor Tuchmann-Duplessis in his oral evidence noted
that despite the very large number of male persons who
over many years have received chemotherapy treatment for
cancer by the administration of chemicals with known
mutagenic qualities, he knew of no cases of male mediated
birth defects arising out of such treatment:
Here again, the situation is the following - people who are treated, the sperm count is going down we get sterility and it is coming back. To my knowledge there has never been any
modification of the embryonic development.169
VI1-145
17. ANAESTHETIC GASES
The one area in which there has been a suggestion of
congenital malformations in man associated with chemical
exposure of the father is in relation to anaesthetic
gases. but there is substantial inconsistency among the
results of the various studies and the suggestion has to
be regarded as doubtful at best. Dr Stanley said of these
studies.
These data on anaesthetic gases are just so inconsistent around the world that you really get quite worried about it. I mean, in terms of the anomalies, mainly because of the small numbers and so on. If you pooled them altogether it
might be that you would get absolutely no
effect.170
The evidence is, the Commission feels, doubtful and
unconvincing even in relation to spontaneous abortion.
The relevant studies may be summarised as follows:
171
(a) Akrog and Anor. (1970) conducted a study in
Denmark directed to the effects of both male and
female exposure which included only 137 pregnancies of
wives of exposed male anaesthetists. A very
significant increase in miscarriages was found in this
group but a difference between the frequency of
VI1-146
congenital malformations in children conceived before
and during the employment periods could not be
demonstrated, although the authors noted that this was
possibly because of the small numbers involved.
(b) The American Society of Anaesthesiologists published
in 1974 the report of an ad hoc committee (Cohen et 172 al) on the effect of trace anaesthetics on the
health of operating room personnel based on
questionnaires completed by a total of nearly 50,000
exposed operating room personnel. That study found
"little evidence that male exposure results in
abortion in the spouse but found a statistically
significant difference in congenital abnormality rates
in children born to the wives of male physicians".
Other corresponding groups comprising nurses and
physicians also showed differences but they were not
statistically significant. The Committee did not
advance this as evidence of any causal connection but
rather as an unexpected finding which deserved further
investigation.
173
(c) Knill-Jones et al (1975) reported a study of
7,949 male doctors in the United Kingdom which found
that "paternal exposure did not appear to influence
VI1-147
the overall abortion rate or the frequency of major
congenital abnormality and involuntary infertility".
The authors did find some increase in the frequency of
minor abnormalities but attributed that difference to
biased recall due to awareness of the suggestion of
possible occupational health hazards associated with
work in operating theatres.
174
(d) The same Cohen et al. (1975) conducted a mail
survey of 4,797 general dental practitioners and 2,642
oral surgeons exposed to various extents (20.2% in the
first group and 74.8% in the second group) to
anaesthetic gases. That study found a highly
significant increase in miscarriages in the wives of
exposed subjects and a slight and insignificant
increase in congenital abnormalities. Although the
results of the study appear to have been carefully
analysed to allow for age and other factors, the
possibility of recall bias cannot be excluded among
the study group having regard to previous publicity in
relation to male and female exposure within a
relatively small professional group, and having regard
to the form of questionnaire used which bore the
heading "Effects of Waste Anaesthetics on Health" and
was quite patently directed to the association under
consideration.
VI1-148
Accordingly, of the four studies, two found
statistically significant associations between male
exposure and miscarriage, while two found none, one found
a statistically significant increase in malformations in
one group but not in others, while the other three found
no increase or a statistically insignificant increase,
which in one study was expressly attributed to recall bias.
Dr. Stanley quotes Rogers and Danks (1983)176 for the
proposition that it is now established that advanced
paternal age has effects on new autosomal dominant
mutations such as achondroplasia, Marfan's syndrome, and
fibrodysplasia ossificans progressiva and that males can
contribute the extra chromosome in cases of Trisomy 21
(Down's syndrome). She pointed out that each of these is
an extremely rare condition, Down's syndrome occurring in
one per thousand of births and the others constituting far
less than 1% of all congenital malformations which in turn 177
constitute less than 4% of all live births.
Accordingly, while there is demonstration of the
possibility of male contribution to congenital structural
malformation there appears to be no evidence of such
malformation due to male exposure to a chemical except
perhaps in the somewhat doubtful case of male exposure to
anaesthetic gases.
175
VI1-149
There are thus substantial reasons why it would be
surprising to find an excess of congenital malformations
among the children of Vietnam veterans, arising as a
consequence of the exposure of those veterans to Agent
Orange or the other chemical agents:
(i) As to Agent Orange there is an absence of evidence
that any or any more than a small number of
Australian veterans were exposed;
(ii) The only plausible mechanism for such an outcome
depends upon a mutagenic effect of the relevant
chemicals. but there is no convincing evidence that
any one of the chemical agents is mutagenic in
humans; and
(iii) There is no example (except perhaps the rather weak
suggestion in relation to anaesthetic gases),
either in animals or man, of male exposures to a
chemical giving rise to birth defects in the
children of the exposed male.
As far as Agent Orange is concerned, the second and third
of those reasons are reinforced by such conclusions as may
be drawn from an experimental study using mice, which
VI1-150
study was expressly designed to test the hypothesis that
male exposure to Agent Orange could give rise to birth
defects and other adverse reproductive consequences.
That was the study of J.C. Lamb et al.178 The authors
administered 2,4-D. 2,4,5-T and TCDD in proportions
corresponding to those present in Agent Orange as used in
Vietnam to four groups of mice which were then mated with
untreated females. No changes were reported in any
reproductive parameters for the treated groups when
compared with a control group given a diet supplemented
only with the corn oil used as a vehicle for the
experimental chemicals. Parameters measured were mating
frequency, average fertility, percent implantation and
resorption, fetal malformations, germ cell toxicity, sperm
concentration, sperm motility, sperm abnormalities,
survival of offspring and neo-natal development.
Despite the absence of any reproductive effects, toxicity
of the liver and thymus and decreased body weights were
observed in the treated males, those effects being
dose-related, and reversible after treatment had ceased.
In other words, in at least one species, actual exposure
of males to Agent Orange to an extent sufficient to give
rise to measurable toxic effects in the males treated, not
VI1-151
only failed to lead to the production of any congenital
malformations in their offspring, but did not produce any
adverse reproductive effects at all over the wide range of
reproductive parameters considered. The significance of
this negative study is perhaps enhanced by the fact that
cleft palate, decrease in fetal weight and fetal mortality
have been produced as teratogenic effects in the same
species when Agent Orange was administered to pregnant 179 females.
18. THE FINAL OPINION OF EXPERT WITNESSES
It is of assistance to have regard to the final
conclusions expressed by various expert witnesses who gave
evidence before the Commission, as to the existence of any
relationship between service in Vietnam and exposure to
Agent Orange, and the subsequent occurrence of adverse
reproductive outcomes. The following views were expressed
by various witnesses in their evidence:
Dr Stanley
Doctor, we have talked about the balance of probabilities. On the balance of
probabilities in your opinion is an
Australian Vietnam veteran more likely than any other member of this community to father a birth defected baby?--- No.
VI1-152
Should a Vietnam veteran or his spouse have any more anxiety than any other member of the community about reproduction?--- May I add a rider to that?
Yes?--- The only reason that they have is they have not got the data and they have not been able to interpret it properly because the media have been so emotive about it. I feel very strongly about that. The media have been so emotive about it, so a lot of them are anxious, extremely stressed about
their reproductive outcomes but based on data which is very flimsy indeed.
Doctor. if. a Vietnam veteran came to you and he had had a child with a birth defect and he asked you, was it likely to be connected with chemical exposure in Vietnam, what would your answer to him be?--- 1 think that
I would say that the cause of birth defects are unknown, that it - is unlikely - very unlikely that the chemical exposure in Vietnam of himself had anything to do with
the birth defect in that child.1®0
Dr Stein
... On the balance of probabilities, in your opinion, is an Australian Vietnam veteran more at risk of fathering a child with a
birth defect than any other member of the community?--- 1 would think not.
Has a Vietnam veteran, an Australian, any more reason to fear child-bearing or has his spouse any more reason to fear child-bearing than any other person?--- 1 would think not.1®1
Dr Jacobs
From a cytogeneticist's point of view, on the balance of probabilities, is a Vietnam veteran in your view more likely than any other member of the community to father a
birth defected child?--- 1 do not think he is any more likely to.
VI1-153
And has a Vietnam veteran or his spouse any more reason to be apprehensive about
reproduction, than anybody else?--- None at all.182
Dr Mathews
... On the balance of probabilities, in your opinion, is a Vietnam veteran, an Australian Vietnam veteran, more likely to father a birth defected child than any other
person?--- I think I would have to say no.
And on the same standard in your opinion is there any reason for a Vietnam veteran or his
partner to be more apprehensive about having children than any other member of the
community?--- It is easy to answer no to that question because any risk that might be there must be exceedingly small.183
Dr Brusick
Have you an opinion about that study (the Australian Birth Defects Study),
Doctor?--- 1 have read the study during the past few days and I obviously would state that I am not an epidemiologist and would not want to comment on the actual design of the study. I have looked at it and it
appears to have been careful in searching for any possible effects that might have arisen. It seems to be consistent with the conclusions that I generated on the basis of the discussion in that it would be unlikely in my opinion for an agent, which I consider to be non-mutagenic, to have been expected to produce any elevation (of) inheritable genetic effects which would have then
resulted in an increase in congenital
malformations in the offspring of women....
Are you saying. Doctor, that although you are not an epidemiologist the study got the answer you would have expected it to get?--- It did.184
VI1-154
19. CONCLUSIONS
The Commission concludes:
1. In considering whether the children of Australian
personnel serving in Vietnam have suffered adverse
reproductive outcomes as a result of chemical exposure
in Vietnam, a teratogenic mechanism for such effects
may be dismissed.
2. The only plausible theoretical mechanism is one
involving mutagenic effect of the male germ cells.
3. Such a mutagenic effect would require a most potent
mutagen and a significant degree of exposure, beyond
that of the mutagenic effect of radiation at Hiroshima
or Nagasaki.
4. The evidence is that none of the chemical agents to
which Australian personnel were exposed in Vietnam is
such a potent mutagen. Any exposure to those agents
was not of sufficient degree to be significant.
5. Even if one of the chemical agents could be said to be
a powerful mutagen the more likely reproductive
VI1-155
outcomes would be infertility or miscarriage. There
is no evidence that infertility levels or miscarriage
levels are in any way higher than normal amongst the
wives of Vietnam veterans.
6. The three major epidemiological studies relating to
service in Vietnam confirm the above expectations.
They are negative as to any overall association
between service in Vietnam and adverse reproductive
outcomes including infertility, miscarriage and
congenital malformations.
7. Earlier in this Chapter the Commission set out the
circumstances under which an inference of causation
might logically be made from studies of
epidemiological data.
The Commission finds that there is no association
between the risk factor, namely exposure to chemicals
in Vietnam and any untoward reproductive outcomes.
8. There is no consistency between the purportedly
positive studies.
9. No specific outcome has been identified.
VI1-156
10. No dose response relationship can be ascertained.
11. The mechanisms suggested are biologically implausible.
All that is left is the fanciful theory of male mediated
teratogenesis. The suggestion seems to be that following
the exposure of the male to chemicalsâ one or more of the
chemicals is absorbed into the system and years later
finds its way by means of the sperm or seminal fluid into
the mother's vagina and thence to the embryo or fetus
transplacenta as a result of absorption into the mother's
blood stream. This happens, so the theory goes, either at
the time of insemination or after fertilisation during
subsequent intercourse. These postulated effects were
considered by a number of expert witnesses and each of
them rejected it out of hand.
Dr. Poliak was called by W A A to give evidence. In
discussing the studies of Lutwak-Mann in relation to
supposed male-mediated effects of thalidomide in the
offspring of exposed male rabbits he said:
In this study it was also found that appreciable amounts of thalidomide were present in the ejaculate, but there is no indication if any of the malformations and other deleterious effects were induced by the thalidomide carried by the
spermatozoa. The fact that all the malformations
VI1-157
were non-specific, instead of the highly specific effects caused by thalidomide, suggests that another mechanism was involved.185
Indeed. Dr Lutwak-Mann herself, at a symposium in 1965,
disclaimed any suggestion that this mechanism had operated
in studies carried out by her:
It was never suggested that in the type of
experiment described by me, thalidomide was actually transferred to the female reproductive tract and that the amount present in ejaculates could affect pregnancy.186
Dr. Fiona Stanley dealt with the theory as follows:
Virtually no seminal fluid, only the sperm swim up here (where the fetus is implanted). No
seminal fluid will get up there so it is not an effect directly on the developing fetus. What would have to happen is that the chemical would have to be absorbed into the blood stream from
the vagina or cervix. It would have to go into the bloodstream, circulate around the mother into the placenta, cross the placenta, get into the fetus as a teratogenic effect and that really is a very unlikely hypothesis ... It is biologically very implausible.18' 7
Dr. Brusick expressed the following view about the theory
insofar as it relied on transport of a chemical by sperm:
It is almost impossible to devise a mechanism by which exposed males could transmit teratogenic effects to unexposed females via sperm.188
That would be an extremely rare possibility simply because fertilisation occurs in the
VI1-158
fallopian tubes quite high up away from the site of insemination. Insemination occurs in the vagina of the female, the sperm then begin to swim and travel up into the fallopian tubes.
There is a very few number of sperm which reach the egg for fertilisation and the amount of semen material would have been quite diluted before the sperm reaches the egg. I think that would be an
extremely unlikely possibility.189
Dr. Stein in her oral evidence said of the theory:
Well it has been suggested that the actual
seminal fluid might be affected, but as Dr. Brusick and many other people have shown, the seminal fluid is protected quite strongly from many of the circulating substances and so we do not quite know how things get into the seminal
fluid and what kinds of chemicals get in and if they do get in we do not know how long they would have an effect either, so it is not a very viable theory and also not been demonstrated ... I have postulated this to biologists and they usually answer me that it is a far-fetched idea.190
Professor Tuchmann-Duplessis expressed a similar view.
especially in relation to the suggestion that contaminated
seminal fluid might accompany the sperm at the time of 1 q Î fertilisation.
In the evidence taken in Zurich Professor Larsson rejected
the possibility of harm being caused by TCDD in seminal
fluid coating the sperm at the time of fertilisation,
having regard to the minute quantity which could
conceivably accompany the sperm. Professor Larsson's
VI1-159
evidence, based on calculations and the same principle of
dilution to which Dr. Brusick referred. was given upon the
hypothetical assumption that TCDD could find its way into
the seminal fluid of a male exposed in Vietnam.
There is no evidence of any TCDD having been found in the
seminal fluid of a human male exposed to Agent Orange or
some similar chemical.
Dr. Brusick in his oral evidence explained how unlikely it
was that a chemical such as TCDD should enter the testes
in a human:
Well, the blood testes barrier has been studied extensively in biochemistry and metabolism in humans as well as other animals. If you expose an animal or administer a chemical of any type to any animal you can follow the distribution of this throughout the body. In most cases you will find that where the circulatory system travels you will get a steady set-up in various organs
nearby the circulatory system. The exception to this - or one of the good exceptions - is in the testes whereby you will find gradients of
exposure, such that you will find high
concentration in the blood near the testes, but you will find very low concentrations if any in the testes itself and the reason for this is again believed to be an evolutionary protective device that is called ' the blood testes barrier1 and primarily it limits all except very small molecules from being transported from the circulatory system in the testes - small
molecules, low molecular weight, get transported back and forth. Ethanol for example is a good one which is not affected by the blood testes
VI1-160
barrier. ... I would think the TCDD would be one which probably would be prevented from entering the testes.19^
Having regard to the mass of evidence against the theory,
and the absence of any evidence to support it, the claim
of a male-mediated teratogenic mechanism is rejected. Such
a claim, in the Commission's view, is not only fanciful
but is one having no reasonable hypothesis to support it.
Accordingly, a tribunal could readily be satisfied beyond
reasonable doubt that there are insufficient grounds for
accepting such a claim.
Royal Commissions are not bound by precedent. Indeed they
need have no regard thereto. But the reasons for judgment
in two major decisions of Courts dealing with the same
subject matter have been read with interest. This
Commission is of the view that both are persuasive.
The first is that of the Supreme Court of Nova Scotia
(Trial Division) in Palmer et al v. Nova Scotia Forest
Industry 60 N.S.R. (2d) 271.
Broadly speaking, a group of environmentalists brought
action in Sydney, Nova Scotia before Mr. Justice Nunn for
an injunction restraining the use of phenoxy herbicides by
VI1-161
the defendant. The trial Judge came to the conclusion that
no injunction was warranted. In giving his reasons for
judgment he made the following findings:
591 I am satisfied that the overwhelming
currently accepted view of responsible scientists is that there is little evidence that, for humans either 2,4-D or 2,4,5-T is mutagenic or
carcinogenic and that TCDD is not an effective carcinogen, and further, that there are no-effect levels and safe levels for humans and wildlife for each of these substances.
593 Having reached this point it is appropriate to add that the evidence of risk assessments clearly indicates that any risk here in Nova Scotia, if, indeed, there is a risk at all, is
infinitesimally small and many, many times less than one in a million which level, apparently, is regarded as a safe and acceptable risk by most of the world's regulatory agencies. Putting this in
perspective, as indicated by Dr Wilson in his evidence, the risk of cancer to a smoker is 1 in 800 and for a non-smoker continuously in the same room with smokers it is 1 in 100,000, while the risk to a person drinking two litres of water per day from a stream immediately after being sprayed
(which will not happen with buffer zones) is 1 in 100,000 million or which itself is regarded as a "de minimus" risk.
594 To my mind, after hearing all the evidence and reading all the exhibits, there is no doubt that the weight of current responsible scientific opinion does not support the allegations of the plaintiffs. I feel it is my responsibility, in view of the nature of this matter, to add that, while I do not doubt the zeal of many of the
plaintiffs' scientific witnesses or their ability. some seemed at many times to be
protagonists defending a position, thereby losing some of their objectivity. There was a
noticeable selection of studies which supported their view and a refusal to accept any criticism of them or contrary studies. Where the study was
VI1-162
by anyone remotely connected with industry there was a tendency to leap to the "fox in the chicken coop" philosophy, thereby ruling out the value of
the study as biased. In my view a true
scientific approach does not permit such
self-serving selectivity, nor does it so readily decry a study on the basis of bias.
596 It would be a Herculean task to go through the evidence of each witness indicating which particular facts were accepted or rejected. However, it is not necessary, for reasons already
stated. I will say though, as a general point, that I accept the evidence of the defendant's witnesses as representing the generally accepted view of responsible scientists, and also as
indicative of the risks involved. Each of them categorically states that neither 2,4-D or 2,4.S-T, nor the concentration of TCDD presently
in 2,4,5-T, nor the mixture of 2,4-D and 2,4,5-T in the concentrations to be sprayed on Nova Scotia forests pose any health hazard
whatsoever. I am unable to accept that the
plaintiffs have proved any strong probability or a sufficient degree of probability of risk to health to warrant the granting of the remedy sought, a quia timet injunction.
The second decision was that of Chief Judge Weinstein
dealing with (inter alia) independent claims by veterans'
wives and children on a class action basis. His Honour
(although leaving open future claims on behalf of the
infant children on the basis that science may one day find
some connection to support a claim) dealt with the claims
that children were born with birth defects as a result of
their father's exposure to chemicals in Vietnam as follows:
Plaintiffs have produced no evidence of any probative value to contradict the Government's overwhelming showing of no present proof of causation.
VI1-163
20. FINAL CONCLUSIONS
The Commission finds that any untoward reproductive
outcomes amongst the offspring of Vietnam veterans did not
result from exposure of the father in Vietnam to any
chemical agent.
The claim that such outcomes are so associated is fanciful.
No reasonable hypothesis linking such outcomes with
chemical exposure in Vietnam can be postulated.
The hypotheses postulated by W A A have been overwhelmingly
dispelled.
The hypothesis of Dr Stanley that living with an unhappy
husband, particularly a heavy drinking one. might lead a
pregnant wife to expose herself to potential teratogens is 1 9 4 not fanciful.
Nor is the proposition that a disturbed family system
caused by a distraught father. may cause illness,
behavioural problems, learning difficulties and asthma in
the children of the family. There may well be an excess
of these problems among the offspring of disturbed Vietnam
veterans.
VI1-164
It is for this reason, amongst others, that the Commission
recommends that the services of the W C S continue to be
available to all members of a Vietnam veteran's immediate
family.
21. PUBLICITY
In view of the concern and apprehension of veterans and
their wives. the conclusions which the Commission has
reached in this area must be given the widest possible
publicity and the Commission so recommends.
VI1-165
22. ADDENDUM
WAA's Tasmanian Study
The Commission concluded its hearings on birth anomalies
on 5 September 1984. As early as December 1983 those
assisting the Commission were informed of a W A A proposal
to conduct an investigation into the reproductive outcomes
of Vietnam veterans who were residents of Tasmania.
During the year or more that followed, regular inquiries
were made of Senior Counsel for W A A as to the progress of
this study. These regular inquiries which were informal
and courteous became somewhat more insistent at the end of
the birth defects hearing in September 1984. At an open
hearing on 12 December 1984 Mr O'Keefe raised the question
of the appropriate report.
Mr Mclnnes said.
Your Honour, my latest information now is that whether it is Professor Kerr or Dr Field, (he or she) will not have that completed until
February.195
The Commission expressed its concern about the delay. Mr
Mclnnes responded:
VI1-166
It is what comes before Your Honour that counts and that is why we have been pressing for this to be completed.
By February 1985 insistence had become nagging. Contact
with Mr Phillip Thompson (which had replaced contact with
his legal advisers by this time) led eventually to a
direct contact between Senior Counsel Assisting and
Professor Kerr. This occurred in early April 1985.
Professor Kerr told Counsel that all the data had been
gathered, that it was in computer form but that he was
reluctant to produce any report before the data was
thoroughly analysed. Indeed he expressly said:
In view of what Dr Donovan has said about us. we must be sure of our analysis and its
correctness.196
Professor Kerr emphasised in that conversation that he was
personally extremely busy but that he hoped to be able
with Dr Field's assistance, to get the analysis to the
Commission by the end of the week of 18 April.
In the Sunday Telegraph of 21 April 1985, over the by-line
of John Dikkenberg. the following appeared:
VI1-167
VIET VET KIDS IN DEATH BLOW
There are more deaths among children of
Australian Vietnam veterans than among high-risk Aboriginal children. according to a report expected to be released shortly.
The report shows a sample group of veterans in unpolluted Tasmania had a higher mortality rate among their children than a comparable group of Aboriginals cut off from health services.
according to lawyers Orange inquiry. connected with the Agent
The Aboriginal child mortality rate was last publicly estimated at live births. about 30 deaths per 1000
The report, which is expected to stoke the
smouldering Agent Orange issue, has been compiled by geneticists Professor Charles Kerr of the Commonwealth Institute of Health and Dr Barbara Field of Sydney's Westmead Hospital.
Professor Kerr, formerly Professor of
Preventative Medicine at Sydney University headed the Ranger uranium inquiry and more recent Kerr Committee, which reported on British nuclear tests at Maralinga.
The two geneticists combined with Drs Peter Hall and Ben Selinger of the Australian National University in 1981 to compile a controversial preliminary report on the suspected links between Agent Orange and birth defects.
Agent Orange is the name given to a toxic
defoliant used in the Vietnam war. Its active ingredient is the chemical 2,4,5-T, which contains the dioxin molecule, one of the most potent poisons ever made.
According to the lawyers, the new report is based purely on a sample group of Vietnam veterans living in Tasmania, where the unpolluted
environment was most unlikely to introduce further complicating outside elements to the research.
VI1-168
It is believed more than 1000 veterans were used in the study and the outcome was worse than
anyone had feared.
The 1981 Kerr and Field report uncovered evidence which invalidated the $20M official Federal Government study into the effects of Agent Orange on the health of Vietnam veterans.
The study was referred to again in the National Times on
May 17 but in uninflamatory terms.
On 25 May 1985. the Australian published an article over
the by-line of Laurie Quinn which repeated the passage in
Mr Dikkenberg1s article concerning high-risk Aboriginal
children.
The Editor of the Sunday Telegraph has informed the
Commission that its article was written after consultation
between Mr Dikkenberg and Mr Alun Hill formerly Junior
Counsel for WAA. Mr Hill concedes that he spoke with Mr
Dikkenberg but denies that he gave him the information
about the report contained in the article.
There is conflict between Dikkenberg and Hill. In this
regard. the Commission is not able to say whose imaginings
the statements in the Sunday Telegraph are. But it is of
serious concern that false information received widespread
publicity.
VI1-169
A preliminary confidential report prepared by Professor
Kerr and Dr Field was delivered to the Commission under
cover of a letter dated 30 April 1985.
Having read the report the Commission set in train
inquiries as to the method by which the data had been
gathered. It became apparent that Professor Kerr and Dr
Field were really not able to help the Commission as to
the manner in which the data had been gathered.
Accordingly, the Commission's staff issued 3 summonses for
the production of the documents constituting the source
data for the confidential preliminary report.
Those summonses sought from WAA, Dr Field and Professor
Kerr the following documents 1 2 3 4
(1) The questionnaires;
(2) Any records of methods of tracing and selection of
veterans;
(3) Any computer programs, disk records or print-outs
connected with the study;
(4) All clinical notes and records connected with the
study, including death certificates;
VI1-170
(5) All records from which incidence rates in the general
population were drawn;
(6) All correspondence connected with the study;
(7) All work sheets and calculations used in connection
with the study.
The relevant documents were produced by those who had them
on Monday, 27 May 1985.
The evidence of Professor Kerr and Dr Field confirmed the
Commission's belief that they were unable to assist as to
the manner in which the data was gathered.
It became clear that the investigation had been under the
control of one, Ms Andrea Shaw. Ms Shaw is an
Undergraduate in Arts and Science of the University of
Melbourne, a Graduand in Science, who had acted as
"para-scientist" advising Senior Counsel for W A A from
time to time and had also acted as assistant to Mr John
Evans. WAA's "scientific adviser".
Ms Shaw was unavailable to give evidence. It was said
that she was in hospital on the Friday prior to the
hearings of 27 and 28 May 1985. There seems also to have
been some failure of good relations between her and W A A
in about August 1984.
VII-171
As became clear, Ms Shaw had travelled to Tasmania and
arranged for the data to be gathered and established a
method for its gathering.
In a statement given to Counsel Assisting Mrs Murtagh gave
the following account of the manner of collection of the
, - 197 data.
ROSE MURTAGH OF 47 JUNEE ROAD, MAYDENA. TASMANIA STATES:
My husband, Kerry, was the President of the Tasmanian Branch of the Vietnam Veterans
Association of Australia.
During second half of 1983 Mr Phil Thompson told me that he had access to a nominal roll of
veterans who had been to Vietnam and who had enlisted in Tasmania.
I decided, at that stage not for the purpose of any study, to get names from the nominal roll and to check it against telephone books and electoral rolls so as to get together a list of Vietnam veterans in Tasmania. We were unable to get a
photocopy of the nominal roll and there was some delay but eventually Terry Loftus read the names, the service numbers and the units of Vietnam veterans who had enlisted in Tasmania to me over the phone.
There were between 1300 and 1400 names
transferred onto a list and my husband and I worked first with phone books matching names and initials and thus obtained a list of potential Vietnam veterans which I then checked against the
electoral rolls from the area where the phone book indicated the potential veterans last lived.
VI1-172
This list came to be called "Rose's list" and I added to it by carefully checking the actual electoral rolls (5) so as to pick out Vietnam veterans or potential Vietnam veterans who were not on the phone.
In January of 1984 I spoke to Thompson and he said to me that Andrea Shaw was interested in my list.
Later Andrea Shaw rang me and asked me to draw up a list of Vietnam veterans who were not members of the WAA.
I prepared such a list and as far as I can recall there were about 680 non members on the list. This list was created by highlighting out those who were members of the Association.
Andrew Shaw then asked me to get together
competent reliable people who could be trusted to conscientiously question people from a
questionnaire prepared by her. I gathered together six women I knew, some of whom were Vietnam veterans' wives but all of whom were competent and reliable.
Andrea then said that she wanted a random 200 selected from both members and non members. She applied some form of logarithmic selection process to the listed members and non members and
selected 200 names. I supplied the list of members and non members to Andrea and letters were sent out to all shown on it from Sydney
(i.e. from WAA's office and on its letterhead) which invited Vietnam veterans to co-operate in the study and suggested that they give an
appropriate time and telephone number where the questionnaire could be applied.
Andrea came to Tasmania and spent an afternoon training the people who were to ask the questions emphasising that the questions should be asked in the same way to both the veterans and to the
controls. We questioned a few people under her supervision and we always worked in two's so if a problem arose we could get advice and help.
The ones who responded (to the letter), about 316, we rang first. When we ran out of those who
VI1-173
had responded we also rang those who had not responded doing the best we could to contact everybody.
We found some non veterans on the list.
We would speak preferably to the veteran but we would also speak to a wife of a veteran if she wished to have contact with us or if the veteran was unavailable.
Sometimes the husbands and wives would consult with each other or the husband would suggest that we ask an obstetric or other guestion of the wife.
The guestioner nominated the next door neighbour to be a control. If the veteran did not want the next door neighbour to be a control he or his
wife was asked to nominate someone who did not go to Vietnam but who lived in the same area as the veteran and had children born since Vietnam time.
The same interviewer did both the case and the control. It was obvious that the interviewer knew veteran and/or non veteran status at the time of interview but we were careful to ask the questions in the same way. The questions
themselves of course told the interviewee what it was we were questioning about.
Amongst the 200 there were obviously people we were not able to contact. When a person who had been thrown up by the random selection process was unable to be contacted I provided the
substitute by the following method. I selected by a process of finding the nearest regimental number combined with the same year of service and as close as possible a match for age.
The evidence discloses that after the questioning process
had proceeded, the questionnaires were placed in files and
numbered. Those completed were forwarded to Sydney in
July 1984 and made available to Dr Barbara Field at WAA's
then headquarters at Newtown.
VI1-174
Dr Field went through these in detail and wrote to the
treating doctors on a paediatrician to paediatrician basis
to verify the major defects and serious medical conditions.
The verifications came in over a period of time.
Dr Field worked on 386 completed questionnaires and also
had a list of single veterans, non-parent veterans and
veterans who had children only pre-Vietnam. There were
also about 20 questionnaires in a different form. This
list and questionnaires totalled 100 veterans.
She then prepared the results in tabular form and she and
Professor Kerr wrote the preliminary report together. with
Professor Kerr physically writing the first versions.
THE REPORT AND ITS CONCLUSIONS
In addition to general conclusions the report drew two
particular conclusions.
These were:
VI1-175
(1) The incidence of malformations of particular tissues
within this study of 885 children shows significant
increases by comparison to rates observed in the
general populations. There follows a table:
VETERANS GENERAL POPULATION
Open neural tube defects (3 cases) 3.4/1000 2/1000
Chromosome abnormality (4 cases) 4.5/1000 1.6/1000
Hydrocephalus (3 cases) 3.4/1000 1.6/1000
Congenital Heart Disease (10 cases) 11.7/1000 6-8/1000
(2) Under the Table the following appears:
In terms of coincidental occurrence in a
relatively small randomly selected population there appeared to be a concentration of rare syndromes diagnosed as cerebromandibular syndrome, Werdnig-Hoffmann disease and a degenerative central nervous system disease. These were recorded in addition to other some uncommon diseases viz. x-ichthyosis, diabetes -
(onset aged 2), and, in particular 7 neoplasms of childhood.
The report drew the following general conclusions:
(1) This study has identified a high peri-natal and infant
mortality rate among the children of Vietnam veterans
VI1-176
in Tasmania: the majority of lethal incidence
occurring in the years immediately following return to
civilian life.
(2) By comparison to the general population there were
significantly increased rates for major malformations
of the central nervous system, skeletal and
cardiovascular systems and certain childhood
malignancies.
(3) Accordingly the only plausible interpretation of the
observations in this study is that the increase in
offspring detriment is in some way related to events
that took place in Vietnam.
Each of the above five conclusions has been demonstrated
from the source documents and by cross-examination to be
totally unfounded.
Giving all the weight that can be given to the claimed
pressures of time, the presentation by trained people of a
report which disregards the most fundamental tenets of
science establishes in the Commission's view bias and
irresponsibility of a high order. The material could have
been presented without conclusions.
VI1-177
To present the material with numerical errors in favour of
the conclusions. with omission of necessary denominators,
with failure to compare like with like and with
misclassification of neoplasm is unforgiveable. If the
matter were not of such importance the Commission would
simply reproduce the answers that Professor Kerr gave
disavowing the conclusions in the preliminary report. The
circumstances however demand more.
Of the conclusions drawn, perhaps the most frightening
from a veteran parent point of view is the suggestion that
there were significantly increased rates of childhood
malignancies. The basis for this assertion was that there
were 7 neoplasms of childhood found amongst the offspring
of the alleged 500 veteran families examined.
Neoplasms
Dr Field was asked in her evidence to nominate the 7 cases
of childhood neoplasm.198 She nominated the case
numbered on her sheet 59, a hydatidiform mole; case no. 60
a brain stem glioma; case no. 61 a lipoblastoma; case no.
62 an astrocytoma; case no. 63 a vascular hamartoma; case
no. 38 an arterio-venous malformation of brain; case no.
VI1-178
39 a porencephalic cyst; case no. 36 a giant hairy naevus
at base of spine and case no. 5 a teratoma of the brain.
The doctor conceded that the hydatidiform mole was
inappropriately placed amongst major malformations and
diseases in surviving children since the mole certainly
did not survive.
Similarly the teratoma of the brain was a case of
stillbirth and not a case of malformation or disease in a
surviving child.
Dr Field had available medical reports from the treating
doctors in respect of each of the rest.
(a) Case No. 60. the brain stem glioma (File No. 379).
This boy was admitted to hospital on 7 November 1977
with a history of gradual onset of diplopia and mild
ataxia. He suffered no change whilst in hospital, all
his investigations were found to be normal and he was
discharged on 6 December 1977 for review in
outpatients. A diagnosis of "?? brain stem glioma"
was made.
VI1-179
An examination of the parental questionnaire shows
that the boy was investigated for a year. The
interview took place in June 1984 and he was then
still alive. A reading of the questionnaire indicates
that the problem simply went away.
(b) Case No. 61. a lipoblastoma (File No. 257). The
treating doctor removed a smooth round disc shaped
lump from the child's back. He was able to completely
excise the mass and histological examination revealed
that this was a benign lipoblastoma. Nothing in the
report suggests malignant neoplasm. Dr Field suggests
that this lipoblastoma recurred in 1984. She conceded 199
that there was no evidence of neoplasm. The
treating doctor's report indicates that he reviewed
the child on 4 June 1984 at his own request and that
he found no evidence of recurrence.
The parents' questionnaire dated 13 April 1984 refers
to a "benign foetal lypoma (sic) attached to spine."
(c) Case No. 62 is an alleged astrocytoma (File No. 156).
Pathology reports from the Royal Children's Hospital
refer to a biopsy and a micro examination of the
biopsy. The report of 26 September 1983 reads. "The
features suggest a low grade astrocytoma."
VI1-180
This report was reviewed on 6 October 1983 , by two
pathologists. They together wrote an amended report:
Further sections have been prepared from the last pieces of tissues. These show that the tissue previously thought to be astrocytoma is in fact stromal tissue from choroid plexus showing focal calcification and haemorrhage.
Therefore there is no evidence of astrocytoma in any of this material. Diagnosis: brain "no pathological diagnosis" (choroid plexus).
Dr Field equivocated but finally conceded the later . . . 200
diagnosis.
(d) Case No. 63. a vascular hamartoma (File No. 246). In
1980 this boy had a lump under his right arm diagnosed
by the histo-pathologist as a vascular hamartoma.
There was no suggestion of neoplasm. Dr Field
vv.· 201 conceded this.
(e) Case No. 39. a porencephalic cyst (File No. 201).
This little girl had epilepsy. On a "cat" scan a
large right porencephalic cyst in communication with
her ventricle was discovered. The visiting
neuro-surgeon. Dr Duffy wrote:
VI1-181
There is nothing to suggest a tumour.
Almost certainly the appearances on cat scan now have been the situation for the whole of her life and I do not feel that any further investigation or change of management was needed.
There was nothing to suggest neoplasm, as Dr Field
, , 202
conceded.
(f) Case No . 38 an arterio venous malformation of the
brain. (File No. 189) . This little girl had a mass
removed from her left frontal lobe in March 1983.
Pathological examination of the tissue showed that it
was a blood clot with some organisation: it probably
resulted from a vascular malformation or a
pseudo-aneurysm. The treating neurosurgeon
specifically found, "there was no evidence of a
neoplastic process".
(g) Case No. 36. a giant hairy naevus (File No. 83). This
naevus was removed over a period in three operations
between 1976 and 1979. The pathology reports a
compound hairy naevus. There was nothing to indicate
neoplasm. Dr Field also included this giant hairy
naevus as a neural tube defect. She concedes that
there was no neoplasm in this case.
VI1-182
The result of this analysis is that far from there being
seven there is one genuine childhood neoplasm in a
surviving child amongst the group. One could expect
amongst a cohort of this size as many as four to six
neoplasms; accordingly the true rate of neoplasms amongst
this cohort was lower than expected. The conclusion that
the rates were significantly increased is quite untenable.
Selection Bias Potential
It must be said that the selection process is fraught with
potential for bias. From an original list of 1,390
veterans less than 500 were subjected to questionnaires.
The recovery rates are low. The selectors were Vietnam
Veteran Association officials or their wives. The
selectees were likely to have been influenced by the
controversy. The questionnaire itself is unsatisfactory
from an epidemiological stand-point.
Thus reliable conclusions from the data were unlikely.
Mortality Rates
Conclusion 4 was, "This study has identified a high
peri-natal and infant mortality rate amongst the children
VI1-183
of Vietnam veterans in Tasmania; the majority of lethal
incidents occurring in the years immediately following
return to civilian life."
The majority of the births also occurred in the years
immediately following return to civilian life and one
would expect the majority of lethal incidents to so
occur. Omission of the denominator is a classical
epidemiological error.
The study did not identify high peri-natal and infant
mortality rates when like was compared with like. The
study indentified 13 neo-natal deaths. (that is death
after a live birth up to age 28 days) and 9 stillbirths.
Amongst the stillbirths are included File No. 164, a
miscarriage in the 22nd week, which in 1971 would not have
been included in the Tasmanian or National statistics as a
stillbirth. Also included is File No. 117, a miscarriage
at 18 weeks which would at no relevant time have been
regarded as a stillbirth. The "true" stillbirth number
disclosed by the study is 7.
This produces a peri-natal death rate of 24.9 per thousand
which compares favourably with the West Australian rate
VI1-184
for 1968-70, of 27 per thousand and also with the
Tasmanian rates for the relevant period (1972, 20.2 per
thousand; 1973, 24.4 per thousand; 1974, 21 per thousand;
1975, 23.5 per thousand).
As to infant mortality, the rates thrown up by the study
are statistically indistinguishable from the Tasmanian
rates for the relevant period. The rate shown by the
study was 18.1 per thousand compared with Tasmanian rates
for 1972 of 16.2 per thousand; 1973, 18.7 per thousand;
1974 of 16.6 per thousand.
Dr Field and Professor Kerr both conceded that there was
nothing significant in 3 cases of open neural tube defect
from a population of 885 births by comparison with general
population figures for Tasmania. The general population
figure for Tasmania is 2.34 per thousand.
In each of the other categories the Professor and the
Doctor made similar concessions.
As far as the totality is concerned Professor Kerr
conceded that the study showed no difference between the
rates of those studied and the Australian and the
Tasmanian statistics.
VI1-185
Dr Field, in a quite extraordinary display, sought to
withdraw the report. She was questioned by
Commission. The following exchange occurred.
What do you mean, if it is necessary? I would only accept that if you said that, that is what you really feel after listening to some of the evidence given by Professor Kerr this afternoon and realizing, after the questions
that have been asked, that perhaps the study was done too quickly, the report was done too quickly, and it is not really worth the paper that it is written on. You see, it is very difficult if that is so, because I have been sitting here now for something like two years, and those who are assisting me and I, myself, have read literally hundreds and hundreds of reports done by people
throughout the world on relevant matters, and at the heel of the hunt this study has got a great deal of publicity in the press of this country. You see there are parents
in this country who are very, very
distressed about having children with abnormalities, or anomalies as you people call them. Now, they are not told that that is normal in this human race, that there are a percentage of children born each and every day throughout this world with defects. The general public are not told; the press will not say that. They grab hold of this study of yours and it has got wide publicity over Australia now, alleging that in Tasmania the
children of Vietnam veterans are giving birth - the fathers are begetting children with defects which are in excess of the
norm?-- 1 hope your Honour is - - -And it has been demonstrated to me - I have not heard all the evidence yet on it - that up to this stage it has been demonstrated that
that is not so?-- 1 agree, your Honour.203
the
VI1-186
The study has many deficiencies not the least of which is
its potential for selection bias. Its conclusions are
patently ill-founded. It provides no support for the
proposition that Vietnam veterans are fathering children
with birth anomalies or bringing about other untoward
pregnancy outcomes by reason of service in Vietnam as a
result of exposure to chemical agents or otherwise.
Indeed the rates discovered by the study suggest normal
birth outcomes amongst such veterans. It would however be
as unwise for anyone to draw negative conclusions from the
study as it was for Professor Kerr and Dr Field to draw
positive ones.
Nothing in this flawed and deceptive study leads the
Commission to change any of its final conclusions set out
above.
VI1-187
ENDNOTES
1. See Ch 1 pp 1-4.
2. Exhibit 1040 p 62.
3. Ibid p 65.
4. Exhibit 1879.
5. Exhibit 1879 at p 122.
6. Exhibit 1427.
7. Exhibit 1391.
8. Exhibit 1248.
9. See Ch II Standard of Proof.
10. Exhibit 1040 p 62.
11. Bradford Hill. 1977, Adopted by Dr Stanley,
Exhibit 1422, pp 17-20.
12. "Handbook of Teratology" Wilson and Fraser (1977) Plenum Press p 310.
13. Donovan et al Exhibit 1248.
14. See Ch 1 Introduction.
15. See Ch VI "The Proposed Morbidity Study" at pp 5 et seq.
16. Ex 1248 1 p 1.
17. E.g. Dr Brusick, Transcript p 3900 et seq.
18. Transcript p 2006.
19. Transcript p 3931.
20. Transcript p 4353.
21. Transcript p 4501.
22. Transcript pp 4502-3.
VI1-188
23 .
24 .
25 .
26 .
27.
28 .
29 .
30.
31.
32.
33 .
34 .
35.
36.
37.
38.
39.
40.
41.
42.
43 .
44 .
45 .
46.
Exhibit 1879.
Exhibit 1398.
Ibid p 388.
Exhibit 1398.
Transcript p 5434.
Exhibit 1673.
Transcript at p 5434.
Exhibit 1398.
See Table 6.7 Exhibit 1248.
part of Exhibit 1398 pp 194-5.
"Vietnam Service and the Risk of Congenital Anomalies" - part of Exhibit 1398 p 397.
Exhibit 1398 p 397.
Letter, Medical Journal of Australia on 4 Augustâ 1984, p 195 part of Exhibit 1398.
See Ch IV "Exposure".
Exhibit 1879 supra p 122.
Exhibit 1394.
Exhibit 1391.
Exhibit 1284P.
Exhibit 1431.
Exhibit 1233.
Exhibit 1394, p 1-2.
Exhibit 1121 Paragraph 7.
Exhibit 1122 p 16.
Exhibit 1398 pp 388-9.
VI1-189
47. Exhibit 1394 table Xl-1.
48 .
49.
50.
51.
52.
53 .
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
6 8 .
69 .
Exhibit 1394 Figure Xl-2.
Exhibit 1394. table Xl-5 p Xl-12.
Ibid.
Exhibit 1394 Xl-8.
Exhibit 1394 Table Xl-12.
Exhibit 1394 Table Xl-12.
Exhibit 1394 p XI-29.
Transcript p 4495. '
Transcript p 5493 et seq.
Exhibit 1879 at p 124.
Transcript p 5493-5508.
Exhibit 1391=
As to which see Ch IV "Exposure".
Transcript p 4520 - Exhibit 1434 p 9.
Transcript p 5462.
Transcript pp 4073-9.
Exhibit 1540.
Exhibit 1233.
Exhibit 1284P.
Bionetics Research Laboratories, Inc. 1968. Evaluation of Carcinogenic. Teratogenic and Mutagenic Activities of Selected Pesticides and Industrial Chemicals, see also endnote 32 in Ch 1.
Exhibit 1284H.
Exhibit 1284C.
VI1-190
70.
71.
72.
73 .
74.
75.
76.
77.
78.
79 .
80.
81.
82.
83 .
84.
85.
86 .
87.
8 8.
89 .
90.
91.
See Bloom "Guidelines for Studies of Human
Populations Exposed to Mutagenic and Reproductive Hazards" March of Dimes Birth Defects Foundation 1981. Hook. E.B.. 1983. Exhibit 1905 at p 393.
Exhibit 1284N.
Exhibit 1284B.
Exhibit 1284J.
Exhibit 1284K.
Exhibit 1284L.
Exhibit 1284F.
Exhibit 1284M.
Personal communication to the Commission. March 1984.
Transcript at p 4352.
Exhibit 1284H.
Exhibit 67.
Exhibit 608.
Letter to Nature 295 (5847) p 276.
Exhibit 424.
Exhibit 1244A.
Exhibit 1431.
Letter to Lancet (1983) i (833 ):1112-3.
Bisanti et al cited in Exhibit 1257 . see also
Exhibit 1265.
Informal Discussions between Dr Pocchiari and the Commissioner. Counsel Assisting and Counsel for W A A and Monsanto in Rome in October 1984.
Exhibit 1879.
Exhibit 1422 p 9.
VI1-191
92. Exhibit 1428.
93 .
94 .
95.
96.
97.
98 .
99.
100.
101.
102 .
103.
104.
105.
106.
107.
108.
109 .
110.
111 .
112.
113 .
Exhibit 1295.
Transcript p 3919.
Transcript p 4334.
See Huffier P.A. & Aase J.M. (1982) J. Occup. Med. 24(4):305-314.
Exhibit 877.
Exhibit 877, I - XIII.
Plenum Press (1980) New York.
Exhibit 1268, pp 31-33.
The Canadian Government's Senior Adviser on herbicides and environmental hazards.
(IARC), Monograph Volume 15 (1977) at pp 125-126.
pp 218-221.
Exhibit 1377 p 17.
Exhibit 706.
Exhibit 777.
Exhibit 1363.
See Halogenated Byphenyls . . . And Related Products, edited R.D. Kimbrough. Topics in Environmental Health 1980, Amsterdam.
Exhibit 777 (1980) at p 49.
Polychlorinated Dibenzo-p-Dioxins, Criteria for their effects on Man and his Environment, NRCC No 18574 p 125.
Transcript p 3919.
Exhibit 1283 p 46.
Exhibit 1351 at p 240.
VI1-192
114 .
115.
116 .
117 .
118 .
119 .
120.
121.
122 .
123 .
124.
125 .
126 .
127.
128.
129 .
130.
131.
132.
133 .
134.
Exhibit 1288.
Exhibit 828 p 11.
Exhibit 1895.
Exhibit 1245, p 14.
Exhibit 894. Exhibit 1288. Exhibit 934.
Exhibit 894, Vol 1 Ch. 9. p 15.
Exhibit 894. Vol 1 Ch. 9 p 16.
Exhibit 894. p 15 & 16. Exhibit 1288. p 12.
Transcript p 3929. Exhibit 1379. Exhibit 1288. Exhibit 894.
Exhibit 894, Vol 1, Ch 9 p 15-16. NH&MRC meeting 11 November 1982 and Pesticide and Agricultural Chemical Committee. February 1983.
Transcript p 2376.
Exhibit 1379, Exhibit 1379A. Exhibit 894. Vol 3. Ch. 7. p 1-4.
Transcript p 3929.
Exhibit 1379, see also Bos et al (1983) Mutation Research 119 21-25. and Wood Preservatives. Technical Bulletin 1981, No 1658.
Transcript p 3 9 28. [cf WHO, Exhibit 1898 , Exhibit 1379, IARC Exhibit 1351].
Exhibit 704.
Exhibit 672, p 71-73.
Transcript p 3928.
Transcript p 2379/80.
Exhibit 1351, p 112.113 and Monograph. 1977 Geneva 6-15 December, WHO/FAO Panel of Experts on Pesticide Residues and Environment.
Exhibit 1245, p 15.
VI1-193
135. Exhibit 1351.
136. Exhibit 1666.
137. Transcript p 3926.
138. Transcript p 3931.
139. Exhibit 1351.
140. WHO, the Monographs Geneva, 1974, p 307.
141. WHO Data Sheets on Pesticides No. 45.
142. Transcript pp 3927-8.
143. Exhibit 1288.
144. Transcript p 3929.
145. Exhibit 1288.
146. US Army Hygiene Agency Report ISS
51-0034-78.
USA EHA
147. Kozumbo et al, Env. Health Persp. Vol 45.
103-109; Zeiger et al, Env. Health Persp . Vol 45, 99-101; Seed et al Env. Health Persp. 111-114. Vol 45.
148 . Transcript pp 392-930.
149. Exhibit 861. p 68 and Exhibit 1351, p 105 â¢
150. Transcript at p 2765.
Îβί. Transcript p 2792.
152. Transcript p 2793.
153. Transcript pp 2431-32.
154. Exhibit 1354 p 17.
155. Exhibit 1349 p 16.
156. P 11 of her written statement Exhibit 1422 citing and relying upon Buff let & Aase (1982) Genetic Risks and Environmental Surveillance. J Med. 24(4):305-314.
. Occup.
VI1-194
157.
158.
159.
160.
161.
162.
163 .
164.
165.
166.
167.
168.
169.
170.
171.
172 .
173 .
174 .
175.
176 .
177.
178 .
179 .
180.
Exhibit 1966.
Ibid (cf p 344).
Exhibit 1422 p 12; see also Figure 1 prepared by Dr Brusick and appearing after p. 1 of Exhibit 1377.
Transcript p 4563.
Transcript pp 4331-2.
Exhibit 1427.
Exhibits 1252 and 1252A.
Exhibit 1483.
Table. Exhibit 1252 p. 1091.
Exhibit 1252 p 1091.
Exhibit 1483.
Transcript at p 4792.
Transcript p 4401.
Nord. Med. 83:498-500.
Anaesthesiology 41 No 4 321-340.
Lancet: p 807-809. 25 Oct 1975.
1975. JADA Vol 90, June 1291-1296.
Which together form Exhibit 1967.
Exhibit 1571.
Transcript p 4333.
Exhibit 1383.
Exhibit 36.
Transcript p. 4356.
Exhibit 833.
VI1-195
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
194.
195.
196.
197.
198 .
199 .
200.
201.
202.
203 .
Transcript p. 4512.
Transcript p 4573.
Transcript p. 4085.
Transcript pp 3931-2.
Exhibit 1312 p 33.
Exhibit 1483 p 155.
Transcript pp. 4328-9.
Exhibit 1379 p. 3.
Transcript pp. 3911-2.
Transcript at p 4510-11.
Transcript p 4790.
Transcript pp 3935-6.
Ford v. United States. CV-79-747.
Transcript p 4357.
Transcript p 6452.
cf Dr Donovan's evidence Transcript p 4176 et seq.
Exhibit 1968. This Exhibit was circulated to the parties and no party sought leave to
cross-examine Mrs Murtagh.
Transcript pp 6837-6838.
Transcript p 6839.
Transcript p 6839.
Transcript p 6839.
Transcript p 6839.
Transcript at p 6834.
VI1-196