The Society annually presents an award to an outstanding
individual in recognition of their contributions and achievements in the resolution of
public environmental concerns. There are no specific criteria, no age limitations,
however, international scientific developments in toxicology are of special interest.
Michael G. Bird, Ph.D., FRSC
December 13, 2011
After retiring from ExxonMobil at the end of
August of this year, Dr. Bird became an Affiliate at the R. Samuel
McLaughlin Centre for Population Health Risk Assessment at the University of
Ottawa, contributing to the IARC project on mechanism of carcinogenic action
and tumor site concordance.
Presented by Dr. Michael Bird
‘Well done is better than well said’
I open with this quote from the great
experimenter, Benjamin Franklin, as it captures my personal belief of the
value of data over controversy. That does not mean that I want to
underestimate the value of discussion and expression of alternate views, but
I’m only too keenly aware of the label that I and many of my colleagues bear
as ‘industry scientists’ that tags our discussions as advocacy, and this has
led me to discover the value of hypothesis-generated studies and of
interdisciplinary working.
Today, as you graciously honor me with
the Society’s International Achievement Award, I would like to describe to
you two principles which I feel are important in achieving key data for
science-based regulation, and to do so by illustrating this from my
experiences as an experimental toxicologist over the last 40 years. These
are -‘hypothesis generation’ and ‘collaborative interdisciplinary working’.
I’m going to describe these together with the three ‘p s’ - positivity,
perseverance and patience that have helped me throughout…...
At age 16, I read in the back pages of
Scientific American - in the section ‘Amateur Scientist’ - articles on “how
to build you own X-ray machine”, or, ” a simple magnetic-resonance
spectrophotometer” and one that caught my attention in particular, “how, for
the price of a set of golf clubs, to build your own atom smasher”.
Well, thanks to outreach at the bus
stop, a fellow passenger provided me with the necessary mercury diffusion
pump (complete with a charge of mercury), a letter I wrote to the Mullard
valve company achieved a back-up vacuum pump, and so it began. However the
dramatic corona discharges achieved with the apparatus, which I assembled at
school, caused the Principal to hand me and my apparatus over to the UK
Radiological Protection Authority who helpfully radiated the target of my
study – flat worms (euplanaria dorotocephala).
I was able to study the egg production
of my worms and found that 2000 + rads of B- radiation, caused sterility but
(surprisingly) not lethality –which would be the case for a human. The
sterility was only temporary and its duration was dose-related. The
radiation did not result in changes in subsequent offspring as I observed
multi-generations over the next 40 years, confining my flat worms to the
garden tanks of my parent’s Victorian greenhouse. My story illustrates the
value of outreach, an inkling of my own stubborn perseverance and perhaps
the triggering of my interest in species differences!
Although I did not know it at the
time, my graduate education at Nottingham University in the UK, where I
jointly studied Chemistry and Zoology gave me an invaluable chemistry-base
for a subsequent interest in mechanistic toxicology. At that time, a
chemistry degree was more in demand than one in zoology, and so it was in
that capacity that I was hired by BP. Initially I worked on synthetic
lubricants for SST’s such as Concord, but because of my biology background I
was elected to take premarket formulations to the site medical officer for a
health review. Then, the Technical Director unimpressed with my experimental
efforts to incorporate biological antioxidants (porphyrins) into the
lubricants found me a role in the medical department and the Company
supported me to attend the very first MSc. Course in Toxicology in the UK.
My activities as BP toxicologist,
ranged from assessing the potential immunological effects from ingesting
protein in the form of artificial chicken made from yeast grown on oil, to
being involved in one of the first joint industry studies, but which in
those days really was designed to detect tumors and did little to understand
human relevance.
Over the years I have been involved in a broad range of studies, many were
initiated for reasons of responsible product stewardship, still others to
address specific regulatory concerns. In particular I have been fortunate to
study aromatics – such as benzene, naphthalene, and lower olefins such as
isoamylene, butadiene and isoprene. It has given me an appreciation of how a
small change in the substitution position of a methyl group can make the
difference between the presence, or absence of genotoxic activity, as in the
case of isoamylene isomers. It can also remove the potential for lymphoma
induction in mice in the case of isoprene versus butadiene, while retaining
the spectrum of other tumor types. It showed me the value of comparative
toxicology and what can be learnt from looking at toxic potential both
within and across structural series.
Thanks to collaborative molecular
modeling studies carried out at Surrey University, we can understand that
some of these differences can be explained by how these substrates fit to
the initial metabolizing cytochrome enzyme. We now also understand that the
cytochrome too can have subtle structural differences between mouse, rat and
man which can contribute to species differences in response.
To tackle the health concerns that
often arise from rodent cancer bioassays, there needs to be an initial
mechanistic working hypothesis, a careful consideration of possible
outcomes, and then experimental designs to accommodate these outcomes. In
this case, proactive peer review (including involvement of a
biostatistician) is much preferable to retrofit!
The next step is then to develop a
plan that supports a series of structured research steps comprised of
studies conducted by knowledgeable experts funded over a decent period of
time, say 5 years. Such an undertaking requires regular collaborative
meetings of the investigative teams both in terms of sharing samples, data
and peer review. A cohesive overall mechanistic picture is likely to emerge
from a strategy of engaging different teams and approaches, starting from
different edges of the puzzle. Add a symposium in a nice topical (but not
tropical) venue and peer reviewed publications, and you have a process that
that has potential to produce better-based regulation and one that builds
industry credibility and responsible working with regulatory agencies……….
A case in point is that of
naphthalene. I believe that the Consortium of naphthalene interests which
was formed some 6 years ago was viewed initially with some justified
skepticism, but with a charter of research, NOT advocacy, and a five year
structured transparent program involving six independent institutes and
regular publication of data – some regulatory agencies agreed to await the
completion of the program of research before setting new air standards. I
believe that based on the present and pending research publications, that
these agencies will find that their decision was well-founded.
If I can claim any achievement to
support the great honor of this award to me today, it is that I have had the
opportunity to help lead some of these groups, and to have the privilege of
working internationally across industry, academic and regulatory boundaries
(and where personalities have been as interesting as the science if not even
on occasion more challenging).
The above shows benefits of
inter-company research, but intra- company research has a place too. It has
enabled the linking of dialkyl sulfates formed in the strong acid
isopropanol process to esophageal cancer – this was triggered by reports, in
the old process files, of a fruity odor in the process which suggested to me
the presence of an ester; likewise - alcohol intolerance post-work shift and
recorded in the files, triggered studies into effect modulation of process
agents and of monomer co-exposure in the styrene butadiene rubber process.
These investigations benefited from interdisciplinary working with
epidemiology, industrial hygiene, and process engineering colleagues – an
invaluable combination and contribution of industry health scientists.
I suppose I have always enjoyed having
each foot in a different camp. It started in Nottingham, as mentioned, with
being in both the Chemistry and Biological Science departments, my PhD was
through Surrey University with the late Professor Dennis Parke but with a US
working base at Rutgers with Prof. Goldstein and Dr Witz. My industry career
is split 50/50 between Europe and the US. Hence I have a good appreciation
of the benefit of working with others in their own settings and also of the
differing approaches and communication challenges – I owe each of these
mentors a debt that I hope this recognition from you somehow repays.
Ten years ago my family and I lived in
France when I had the opportunity for a sabbatical year with the
International Agency for Research on Cancer (IARC) in Lyon, France in
association with my adjunct position at the University of Vermont. The
original intent was to help identify data needs that if filled proactively
could improve subsequent IARC Monograph evaluation of carcinogenic risks to
humans. This was not accomplished, not because of imbibing Rhone wine, but
we did achieve an interdisciplinary workshop (and Scientific series
publication) on the relationship of various biomarkers in the cancer
processes. The time at IARC helped me fully appreciate the IARC process and
the value of working within and between diverse scientific organizations –
it also had a great influence on my family, and two of my four children have
happily established their adult lives in Europe, one in Sweden and one in
England. It was an extraordinary experience for us all and I hope that this
Society might consider encouraging such internships and temporary placements
as a way of furthering its mission.
But data on its own is not enough. It
is also necessary to integrate such interdisciplinary data and also to
provide a rational mode of action for its use. Fortunately there are now new
approaches that have received increasing attention and validation. The
‘Weight of Evidence’ evaluation allows the best candidate mode of action for
the effect in the animal species to be selected from alternatives. This, in
turn, feeds into to the ‘Human Relevance Framework’ -developed over several
years by ILSI and WHO. The Framework provides a transparent and ordered
process to assess the relevance of animal data for the human and indicates
the best endpoint for the risk assessment. It is to be hoped that these
approaches will be increasingly adopted by regulatory agencies, but industry
together with the science community as a whole, needs to develop case
studies and associated data to assist in this important next step…….
In this respect, it is essential to
learn more about the mechanisms involved – and about the respective dose
ranges applicable. This should be an all-important component of regulatory
–based risk assessment. Many of you are aware that IARC recently reviewed
all the IARC Class I carcinogens, i.e., the known human carcinogens. This
will be published as an IARC Monograph 100 volume series. But there are
companion volumes planned on mechanism and tumor site concordance in which
it is hoped to develop correlations and increased understanding from this
opportunity to look across all the known carcinogens. These will describe
the types of mechanism and the acquisition of characteristic hallmarks in
the development of different tumor types. This should really help us all
with the regulatory assessment of agents where data are less clear-cut.
I hope that this has been a useful
insight into some industry approaches to improving science-based regulations
and has made a case for collaborative generation of data and a broadening of
work cultural experiences of those involved. Above all though, there is the
need to be an active participant in the regulatory process and which can be
achieved through contributing data ‘well done’. I hope I have made some
contribution to that goal through the work on which my industry, my
companies, and my colleagues have all collaborated throughout my career.
Once again, allow me to thank each of you and the Society for this humbling
honor you have given me. I look forward to our work together in the future,
and to that end, I will mercifully close with another quote from Benjamin
Franklin, ‘Great talkers, little doers’. Lets not be these!
-
(2010)
Gio Batta Gori, Ph.D.
-
(2009) Michael Dourson,
Ph.D., DABT, ATS
-
(2008)
Mildred S. Christian, Ph.D., Fellow, ATS
-
(2007)
Bernard A.
Schwetz, D.V.M., Ph.D.
-
(2006) Elizabeth I. Anderson,
Ph.D.
-
(2005)
Jerome H. Heckman, Esq.
-
(2004) Lester M. Crawford,
M.D.
-
(2003) Curtis D. Klaassen,
Ph.D.
-
(2002) Donald
Hughes, Ph.D.
-
(2001)
Joseph F.
Borzelleca,
Ph.D
-
(1999) Dr. Alan Rulis,
Director, Office of Premarket Approval (OPA)
-
(1998) Dr. Roger O. McClellan, President, CIIT, Research
Triangle Park, NC
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(1997) Dr. Ian C. Munro, Principal, FRCPath
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(1996) Dr. John Higginson, Retired Professor of Medicine,
Georgetown University
-
(1995) Robert C. Barnard, Esq., Cleary, Gottlieb, Steen &
Hamilton
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(1994) Dr. Philip Abelson, Science Magazine, Washington, DC
-
(1993) Dr. C. Jelleff Carr, Managing Editor of RTP, Columbia, MD
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(1991) Dr. John P. Frawley, Health & Environment
International, Ltd., Wilmington, DE
-
(1990) Dr. John Doull, University of Kansas Medical Center, Kansas
City, KS
-
(1989) Dr. Frederick Coulston, Coulston Foundation, Alamogordo, NM
-
(1988) Dr. Robert A. Neal, Retiring President of CIIT, Research
Triangle Park, NC
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(1987) Dr. Gaston A. Vettorazzi, Geneva, Switzerland and Dr. Frank
C. Lu, Miami, FL, WHO