r.d. Lederberg

G ~18
For about 15 years, I have been thinking and writing about what I see as a very
dangerous and portentous collision between the different interests of innovation
and advance--particularly in the biomedical sphere--on the one hand, and the
rise in ecological-environment risk averting consciousness and the profession
of environmental hazardry that has been emerging on the other side. This was
_ fueled by many forces and one must say they included the somewhat thoughtless
and unstructured over-application of a wide variety of chemicals introduced
into our environment, far beyond the core of indubitable benefit and value

and without very serious regard to their subsequent health effects. You only
have to think about the polychlorinated aromatics, both as pesticides and PCB,
to have avery clear example of what I am talking about. I will expose my own
concerns, for example, about the quantities of lead that continue to be used

and where I think we do not have a cost effective balance between their obvious

advantages and fuel economy and their potential health dishazards.

The point is that for a very long time there has been little concerted concern
with, and no single institution devoted to, trying to rationalize the trade-offs
that are involved in the economic and health advantages of various introductions
and their corresponding disadvantages. And so we have been in a headlong
collision of these kinds of interests. I do view this as a major crisis in the
technological development of our economy. As the world tends to follow behind
us , I don't know what the final outcome will be particularly since there is now

a politically-articulated demand for verifying the safety for human populations
of essentially every new introduction of chemicals into our environment. While

the specific regulatory procedures of TOSCA may appear to be fairly mild--
after all, they are merely a reporting activity at this stage and the admini-
strator must use some discretion and is obliged to take account of the economic
tradeoffs in reaching his conclusions--I don't believe a word of it. I think the
same psychological and political forces that have fueled the zero-risk ideology,
which is of course essentially unachievable, will be very difficult to resist
when it comes to chemical introductions where one can always argue for sub-
stitutions of other products, for wide dissemination, for worker hazards and

so on and so forth .

My own political judgment, for what you think it is worth, is that industry
caved in and gave away a great deal, perhaps inevitably so, in the adoption

of that Act, far beyond the actual language of that particular legislation. Just
imagine any confrontation where there ends up being a retrospective determina-
tion that a compound had been allowed through the filter, that there then did
arise some human risk, and you could imagine a sort of Kefauver Amendments
coming in, fueled by a public crisis--in that case thalidomide, even though

it was essentially irrelevant to the actual issues of the legislation that then

followed through.

So I think we are in a fundamental crisis about some of the most important
elements of innovation in a technological society. We are operating without
guidance, really groping quite blindly with essentially random shots on the
particular issues that come to a fore at any particular point. One should be
alarmed at the inherent irrationality of the process. I don't see anything in the

present mechanism of exposure of compounds that suggests that that roster of
candidates is arrived at by any rational procedure of priorities that has sorted
out which agents are the ones that are most worthy of immediate attention and

which may be subject of deferred action and so forth.

Of course there are many reasons for this situation. It may be that the ones that,
_ as technical people we can do something about, are such a small part of the
whole story as to suggest trends that have a kind of inevitability as a religious
phenomenon rather than one that can be influenced by laboratory investigation.

I will come back to that a little later on. But, obviously, I think we are under
severe compulsion, both as a matter of public policy and also as a matter of

what it is that drives private enterprise to try to discover what can be done

to ameliorate the situation, to find some guideline that offers some reliability

to an industry like this in its further development.

I am well aware that, as long as regulations are applied with some reasonability
and predictability , a large company can do very well regardless of the level of
bureaucracy that it has to cope with. In fact, there are many respects in which

a company like Roche might want to encourage the bureaucrats, since the selected
impact of a tight regulatory system is much greater, as against market entry, for
your small, potentially innovative competitors than it would be for you. That is,
there would be a deadening of the overall process, but I am sure this company

would be one of the last actually to get hurt with respect to what it could deal

with with new innovation.

But I think the country will suffer , I think our people will suffer, I think the
world will suffer if that innovation comes to a grinding halt, as there are many

signs of it doing.
Now most of the content of what I have to talk about is probably less expertly
known by me than it is by some of you here. If you were to collect your own
sources of expertise and wisdom, I am sure that you would be able to add up

to far more than what I can offer. What I think I can present is a generally
sympathetic but basically detached perspective. I am not owned by you. I

. can argue with you. I can talk back to you. I can complain when I think you
do wrong. On the other hand, I am not a zealot trying to put corporations out
of business. I'm simply trying to find out what makes good and sensible public
policy. I think that there are not that many earnest but reasonable critics of

your own activity and operation that you ought to dispense with me lightly.

In a certain sense, the bottom line of the process that I am going to advocate to
you is to use not just me personally but but the whole network of my colleagues
at academic institutions for this purpose, and I hope in some way the Rockefeller
University in particular. We do have a group of very skilled, very specialized
investigators in the biomedical research area who are not making the kind of
contribution that they potentially could in areas of public policy determination,
wherein those skills might be most useful. So it's not for me and it's not for

my friends that I am speaking. I think there is a public interest that needs to

be addressed and that some better community between our respective sectors

might help. I will come back a little later with some specific proposals.

Now the tragedy, along with benefits of an action like TOSCA, is that these
dampeners on innovation are coming along at a time when the capability of

poisoning our environment is very, very great, usually with inadvertent by-
products of many other things. One really ought to think of the tobacco
industry and the automotive industry as perhaps the prime sources of envi-
ronmental hazards today in contrast to what you are likely to do from your
perspective. Here, at least, no compound gets out of these laboratories with-
out having been investigated for at least some of its biological effects. You will
have some interest in the mechanism of action of these agents. You will have
some rationale for the disposition within the human body, whereas most envi-
ronmental changes that are very comprehensive are more indirect than that and

no attention whatever is given to those concerns.

We are beginning to learn a little better. Thus, there is some thought when
coal is advocated as against nuclear power as the necessary alternative to the
oil that we are not going to get. We think a bit about the environmental side
effects of the utilization of coal. But it should take just a moment's thought
that whatever such effects are going to be, the use of coal on a large scale
again as an energy source is going to have an enormously greater effect on the
chemical pollution of our environment than anything this company could ever
do or the rest of any specialized chemical industry. Yet somehow those matters
are relegated to the bottom of the list. There is a list here of chemicals known
to be carcinogens in man and only a sort of side reference to soot, tars and
oils, which encompass a great deal. I think if one looks in quantitative terms,
introduction of these latter materials into our daily environments and our
indigenous consumption of them is far more pervasive, and in my own view
far more important, than saccharin or a large number of any specific addi-

tives that one can think of. I am not saying that you shouldn't worry about
saccharin from any of a variety of perspectives. There certainly is however,
a lack of balance, or no sense whatever , of priority in terms of addressing

important problems first in our present context.

The other side of that concern though--and the reason that I call it a tragedy

. since TOSCA was formulated because of the unprecedented capability of
industrial activity to modify the human environment--is that we are also facing
a time of equally important pervasive innovations for beneficial purposes. The
one that looms the largest in my mind are the oral contraceptives. They have
had a tremendously important, beneficial and in fact indispensable impact
throughout the world in dealing with the very important issue of population
control. And one has to face it, they have been a very important element in
the liberation of the majority group in this country. But I think it is fair to
say that if the present climate of regulation and concern prevailed 20 years
ago, it might never have been possible to introduce oral contraceptives into
routine practice. They might still have been available for high risk situations
where an individual life might have been at stake. But the ground rules have
shifted very, very sharply and I myself am totally persuaded, and I think the
current climate of work and research bears out Carl Djerassi's arguments
about the non-existence of birth control innovations after 1985 because the
cycle of introduction and regulation becomes longer than the steps needed in
order to catch up with it. That is to say, it takes longer to do a test that would
satisfy particular criterion than it does for some new hazard or new concern to
be discovered or invented that will invoke still some further regulatory pro-

cedure.
The situation is aggravated, as Dr. Djerassi points out, in cases where you are
dealing with a very large scale introduction of a compound that wouldn't be

used if it didn't have potent effects on human physiology but in essentially
healthy people at the time of introduction. There would be none of the argument
whatever about the steroid sex hormones with respect to life saving applications.
But even low levels of risk that are very difficult to predict and ascertain with
any assurance loom very, very large when the whole population of the world is
the target group that is involved with such introductions. Of course, it is for
comparable benefits that such materials are introduced. I think we are on the
threshold of discoveries which could have a similar impact in the prevention of
atherosclerosis and it would be very difficult to introduce them on any reasonable
scale because the benefits will take 20 years to discover, the risks will take 30
years to discover and the cycle of invention of new hazards will of course be

much quicker than that.

Now in some situations you may be able to glide in from some very high risk
medically-indicated situation into more general use. But you can well see how
the de novo introduction of such derivatives for which there have been some
very exciting developments recently would probably have been impossible

if they had to stand on their own feet admissio.

The fact is that even now I think there is a sleeper in the very large scale pro-
gram to encourage the prophylactic use of anti-hypertensive agents in people
that are essentially healthy. Now the 20 percent of the population that is at

that quintile of blood pressure has been defined to be at greater risk, although
why one defines that particular percentage isn't at all clear tome. There have
been aggressive efforts to try to promote the use of diuretics and other still
more potent approaches to blood pressure control. And I must say, in my own
view , no thought has been given to the possible side effects of very large scale
applications of these agents in such large populations with all the possibilities
of genetic idiosyncrasies , environmental interactions with other agents and so
forth. And it's been possible to even think of those because of ones already
established with drugs whose validity had been certified in a totally dif-

ferent framework than large scale prophylactic use. So I would be willing

to bet a dollar to a nickel that there will be a major scandal in that area, whether
it has any real substance or not, some few years from now. And we will wonder
why there hadn't been much more attention to concerns about side effects in

that arena.

To say that these substances are safe for such use when it is based entirely on
clinical studies for high risk individuals is open to the same criticisms as we've
seen over and over again in the past with other agents that have gone through
such transition. I am not saying that these are real hazards. I am predicting,
however, that there will be a backlash on this question and that it might be
well advised today to begin some studies in this direction, even though I don't
think such studies are going to get funded. We tried out of our department and
found that it was such a dull subject--to try to interest anyone on the effects

of diuretics on hyperuricemia, for example, with the possibility of picking

up some genetic polymorphism--that we weren't even able to get started in

getting such programs going.
You can all have your own pet theories on where chronic uses of new chemicals
may be most exciting. Just beyond the horizon are agents that would be quite
centrally involved in the fundamental process of aging. You can see how in
dealing with that issue we face the question of how to determine whether sub-
stances that are given over periods of 50 years are safe for their intended

application. We may be in an unsoluable dilemma.

At the same time, there are going to be other large scale interventions that,
because they don't fall into the environmental or additive framework , are not
going to be regulated but may be far more drastic in their implications for
human health on a chronic basis. I think of all the abstentions that people
argue about, for example, the most primitive method of birth control. I've

yet to see any carefully conducted clinical trials on a large scale to determine
whether or not abstention is or is not safe from a hygienic standpoint. I don't
think that is a non-issue. I don't think that trial will ever be done. You can
understand the difficulties in organizing that experiment. But if I approach
other areas of abstention in the dietary realm, for example, we already know
of some acute effects of strict vegetarianism regarding B-12, and who knows
whether that is going to be the whole story. There are many other areas of
changes in life style where things that may appear to be beneficial have just as
much risk of insidious hazard as do any of the chemicals that we are now talking
about. We ought to be at least thinking about how we would answer those
questions even if we know they are not going to be in the same bureaucratic

framework as the conscious use of new chemical introductions.
-10-

To get to a more substantial concern that I happen to have, I don't know how
many people share it, I am frankly quite worried about the long term impli-
cations of the high level of hygiene. The facts that we work very hard to
cleanup our environment from bacterial and parasitic insults and provide
vaccinations against every conceivable viral infection--these are all obviously
highly beneficial from a short term standpoint. However, I have no idea of
what that is doing to our immune systems, speaking fairly globally. We may be
setting the stage for potential explosive epidemics by having clean populations
which have not seen a variety of infectious agents for some period of time. We
may have very large naive herds for the reintroduction of poliomyelitis , more
virulent strains of influenza and perhaps the re-emergence of smallpox, although
I have no specific criticisms to make of Dave Henderson's wonderful campaign

and very careful controls and concerns as far as can be done in that area.

But I am just pointing out that there are several ways in which we are changing
the environmental context of the human organism on a very large scale and in
ways that have been virtually unexamined, in part because we don't have the
techniques and in part because we don't know that we should worry about
them. And I do think they belong in the same bag as our concerns such as

risk assessment of specific chemical introductions. The latter are easier to
study and they may help to overweigh what to do with respect to other changes

in the chronie human condition.

Now there are some policy implications of this perspective that I think are
only beginning to seep in. For example, people at WHO were deeply shocked

at the Depoprovera decision in this country essentially banning it for all but
-11-

high risk uses. This of course puts quite a serious wrinkle in efforts to have

a depo injectable, long-acting steroidal contraceptive that might be a very
useful technology for population control in other contexts, such as where taking
one pill a day might be simply unrealistic from the point of view of the particular
cultural and social framework. And while Don Kennedy and the FDA were very
careful to state that they did not wish to impose our standards of risk-benefit
assessment on other countries, and in fact requested legislation that expressly
permitted U. S. manufacturers to export drugs not permitted to be used here

to other countries, there is no question about the explicit impact of such
findings elsewhere. That was a rude shock and one has to sympathize

with the dedicated efforts over many years to set up a framework for the trials
of such agents on an international basis. I think, however, you also have to
fault the population control research executive of WHO in the same way that

one must now fault any drug company that would believe that risk problems

are a side issue to be dealt with when they arise or met in a defensive way

when some opposition arises to them.

I think it is perfectly plain that in the current climate it is essential that an
anticipation of risk assessment be @ central part of every chemical develop-
ment program from its very inception. And if you can't figure out how

you're in fact going to accomplish a useful demonstration of safety in the
context of a particular agent, then there is no point doing the rest of the
research which is necessary to bring it to validation. These kinds of chronic
public risks are no longer side issues. They are becoming the central question

that has to be answered before a new compound can be introduced into general
-~12-

practice. Unfortunately, you also have to anticipate by at least 10 or 15 years
both the scientific and public and regulatory climate of the context of a new
compound's use. That is very, very hard todo. Imagine yourself in the
position of distributing diethylstilbestrol in the early 40s. What could you
have done to anticipate the kind of reaction and the legal sanctions that may

_ indeed still be available on a very large scale?

It seems perfectly obvious to me that far more than the specific regulatory
restrictions that FDA imposes on an industry like this, the doctrine of implied
warranty and the very large target that a successful and thriving company will
be at sometime in the future if anything, however unanticipated , goes wrong

are major obstacles to having some spark in innovation and enterprise. Frankly,
I think any drug company, whenever it introduces anything, is taking risks

that I wouldn't dream of incorporating myself. I wonder how the institution

ever manages it because it is perfectly clear that, in our present technical
context, it is impossible to anticipate not even all but simply many of the

potential hazards that may arise with respect to any chemical.

At the same time, we have not gotten over the point that the beneficiaries of
such introductions, the people who profit and did not have the side effects
of a given drug, should share in the load, should share in the burden. I
am very much in favor of schemes for the compensation of victims of vac-
cination programs. There the distribution of public good is rather more

obvious since the person who submits himself to vaccination is benefiting

the community in the first instance at least as much as he is benefiting himself,
-13- *

as regards the spread of infection. But I think the person who benefits

from a new drug is benefiting the community as well by having provided

the incentives, the framework, the stimulus for development of those agents

as well as his own personal benefit. There is, however, obviously no place
in our present ideology for the explicit inclusion of insurance against hazard
to others in the pricing structure of a given agent. Perhaps that is some-

thing which ought to be thought about as an approach to that problem.

The one thing I have not seen FDA do is assume its own responsibility for
warranty , that it will pay the bill if a drug that it has approved in fact incurs
some later hazard. You better hope they don't, because if that doctrine were

ever to be established, obviously no drug would ever be approved.

Well, the specific substantive issues in this field today are very largely in the
area of carcinogenesis. I wonder a little bit why that is the case. Why is all
the action with respect to unanticipated risk in the field of cancer, since there
are so many other hazards that have a very long time delay? That's the obvious
first reason, that with cancer you are dealing with time bombs in terms of the
very long latent periods. I suppose above all, however, is that we have such a
profound mystification about its detailed etiology. It is also the disease most
feared by a large majority of the American people. I think most of us would
prefer to die of a heart attack than of a variety of cancers that we might
possibility be subjected to. Another reason is that a few links in the chain

of etiology have been established and it is possible to use an adjective car-
cinogenic and attach it to a chemical and perhaps stop thinking after that

point in terms of further implications of that attribution.
-14-

I don't think that that pride of place is going to last forever. My own candi-

date, if you are willing to pay a nickel for prophecy, is that the greatest problems
will be in the area of behavorial toxicology. Something that happens to all of

us is that our thinking apparatus goes awry at some stage in our lives. Some

of us become alcoholics, some of us will become psychotic, all of us will become
"neurotic and depressed and unable to work at some stage in our lives. And

some of the same things that I've said about cancer I am sure are going to

apply to the invocation of the history of chemical exposure as a basis for

such events. I have been saying this for about ten years and there have now
been two or three symposia that has been dedicated specifically to these problems.
They will be the most insidious because plainly there are essentially no animal
models whatever that could or could not corroborate the psychotogenic effects

of long-term exposure to whatever you name it. But there will be plenty of

actors very willing to look for culprits of this kind. You can be sure that they
will exist. I guess MSG is the first example I can think of where there was in

fact a major campaign directed against such effects of a given substance. The
talk about excessive doses of salt in baby foods would be very much of a kind.

So there already is some groundwork for that level of concern.

It is not at all clear to me what we are going to do about this in the absence of
animal models , except to say that we will not be bereft of these problems until
we have achieved a much more fundamental understanding of the diseases in
question. I think we will face these impossible dilemmas on carcinogenesis
until we know enough about cancer that we have a rational model for fitting
the role of environmental additives. And the same will eventually have to be

true on the behavorial side and probably be very much more difficult.
-45-

Now I would have spent more time and detail on the scientific basis for regu-
lation of chemical carcinogens except that three days ago there appeared a
remarkable review article in Science magazine by Thomas Small. Some of
you have already seen it and for those who have not, I have left a few copies
for your further pondering and perusal. This news report by a Science

. journalist is the broadest statement of the problem of extrapolation from
laboratory sources to human risk that I have seen so far. I am sorry that I
have to say that because, for a subject of such fundamental importance, I
would have expected risk assessment models would have been developed in
much greater analytical detail than has been the case up to this time. It has
taken the journalists to put it together, to get the controversial views of a
variety of participants in the process and to bring the level of dialogue to the
scale that it now is. The author says exactly what I would have, almost point
by point with some elaborations. SoI am going to confine myself to some critical

remarks on what Small states about this issue.

However, let me also say that the matter is too important to be left to scientific
specialists and they haven't dealt with it. The reason it has taken a journalist
is that it takes a very broad inter-disciplinary perspective to approach these
problems. Many of the questions are essentially unanswerable at the present
time. Respectable scientists don't go into important problems; they go into
answerable ones. And that's basically what we've got to do. But social policy
is still left hanging in mid air in those circumstances. We are becoming a race
of greater and greater specialization, knowing more and more about less and

less at a time when we have ever increasing needs for a broader point of view.
-16-

Not only are there very few individuals who can provide such a view, there
are almost no institutions that are devoted to doing so. And that's going to
be the final point of my remarks with an obvious appeal to try to create some

unit that can do a better job than we've had so far.

. The one point that I would take the sharpest issue with is his central stance
and that is that "the scientific basis for regulation of toxic substances probably
exists now" and there is merely the problem of the controversial character of
regulations that emanate from it. I believe we have to take a much more

critical view of that scientific base right now.

The general issues discussed here will be rather familiar to most of you. He
reviews the current guidelines of the National Cancer Institute for cancer testing
in animals, pointing out that each chemical should be tested in two strains of
animals and in both sexes. Chemicals should be administered by a route that
approximates human exposure. I guess he means that the route is that of
human exposure but at the maximum dose available at which the animal will
survive. The point that emerges from that is that if you want to design a
compound that will be most likely to get by the regulatory procedure, build
in enough acute toxicity so that you are only able to test it at doses that are

a small multiple of its human exposure. Then you will be unable to do the
animal experiments at levels enough higher to discover the dose at which that

compound does in fact become carcinogenic.

I am not suggesting that every compound will be found to be carcinogenic

in some system. I will be very much surprised, however, if one can't find
-17-

some condition, some circumstance and some dose in interaction with other
substances at which you could make a case for enhancement of carcinogenicity
for almost anything that you chose. So the limiting factors are the side issues
of how much you are able to pump in, whether that is acute toxicity or a mass
that can be introduced into the diet or whatever. Those of course are really

_ quite irrelevant to the thresholds involved for human application .

My main concern about such tests is their feebleness in the detection of chronic
hazard. It is very easy to see that compounds that might have very serious
effects on one percent of the exposed human population over a period of 15 to
20 years would pass muster very readily in animal experiences of this kind
and vice versa. I am not at all persuaded by the existing empirical evidence
based on past experience that this is either an efficient or credible way in
which to approach the problem of safety testing in the future. And of course
we are reaching the situation where the cost of trying to fight the hassle when
carcinogenicity indices are reached at fairly early stages of development of a
compound just aren't worth it. Most development programs are likely to be
stopped pretty early in the game, even if the FDA were to let you proceed with

further clinical testing , under those circumstances.

So we will never know, and one might say greatfully may never know in some
cases , what the potential toxicity is of a number of substances that have failed
to pass this particular hurdle. With all their inadequacies, these tests take
3 1/2 years or more and cost at least $250,000 per substance. One can also
say that they reveal absolutely nothing about mechanism, whether the results

are negative or positive, since they say are simply a tabulation of the number
-18-

of bumps that appear in the animal in different organs. They tell you nothing

about the etiology of the formation of tumors, nothing of the biochemistry , the

distribution of the drug, further transformations and so forth. As a research-
oriented scientist, I can't help but be appalled at the money that is going down
the drain in this kind of road-testing when, in the long run, a fraction of that

- sort of investment might be so much more productive in going after funda-

mental mechanisms of toxicity and of carcinogenesis.

I gather some 7,000 chemicals have been tested in this way. That comes out
conservatively to an investment of the order of $2 billion in this particular

kind of safety testing cumulatively. This is a lot of money compared to what
goes into basic investigations along these lines. What one gets out of these
kinds of assays as well as others is a label carcinogenic or non-carcinogenic,

as attached to a given chemical. I can't imagine anything more simplistic than
trying to give a one word answer to a highly multi-dimensional problem. I

just don't believe that that can begin to describe the multiplicity of ways in
which a compound can interact with the physiology of the organism in producing

a deleterious effect.

It is just beginning to be appreciated at this level, as the cancer research
people have known for a long time, that many substances operate in at least
a two-phase fashion. The well-known is known for 50 years and, therefore,
some of our modern molecular biologists don't know about it. Interactions

of croton oil with carcinogenic hydrocarbons , where croton oil by itself is
virtually without visible effect in production of skin cancers and where there

is an enormous potentiation of the action of some of the familiar carcinogens,
-19-

is just the beginning of that kind of analysis. As soon as you say that, you
realize you cannot put a simple, single label on a chemical and say it's car-

cinogenic or not.

I would have thought that much more pause than has been the case would have
- been given the fact that the plain of nutrition is an extremely important factor
in the determination of the levels of tumor genesis. That, to my mind, has
been one of the most important findings of cancer research of the last 50 years
and has been almost totally ignored. But pure calories could be defined as
being carcinogenic in experiments that follow that particular model in ways
that would be simply embarassing to these kinds of discussions. We have
substances that are very clearly carcinogenic to man, like asbestos, although
possibly through quite complex interactions with other environmental inputs,
they simply don't fit our chemical models at all. These agents, like plastic
films and other physical additives, when introduced in particular locales,
have an action that seems to be essentially independent of their chemical
structure. Put a little differently , the same chemical substances are totally
inactive in other chemical forms. Thus, you are not even talking about a
carcinogenic chemical; you are talking about a carcinogenic state of matter

in those circumstances. There plainly must be a very complex interweaving

of different etiological factors coming into the story.

Well, I am just reciting the obvious, perhaps in a slightly different context.
The whole conception of labeling substances as falling into one category versus

another is one that should be much more vehemently attacked. We need a far
-?0-

more sophisticated approach to the problem, in order to have good public
policy (not just to rescue your favorite drug or food additive) and to discover
those influences in our environment which involve very serious interactions.
As a most elementary example, the hazards of asbestos interact so strongly
with those of cigarette smoking that one would have thought that the most
immediate public health measure involved in that sphere would have been
education about the hazards of smoking in that context and some fairly severe
regulations about occupational exposure to tobacco where asbestos is present
in the environment. I think one could also have expected other important
side benefits from that equal to those of the immediate involvement. I am sure
we are going to discover equally important interactions in the future which will
be covered up if we talk about classifying the white hats and the bad hats in

the world in terms of individual compounds.

There are many other elements of the process of carcinogenesis that defeat
this simplistic characterization. There is an observed phenomenon called
"the malignant transformation" of cells often seen in cell culture which is
quite orthogonal to the abrupt DNA-mediated changes that alkalating agents
and so forth induce. We don't really know how to relate these two. I would
assume that malignant transformation is probably an epigenetic alteration.
But any number of hypotheses could be introduced. I simply point to the

need to complicate one's thinking in this particular area.

Well, there seems to be some admission about these points. There was an
argument that is discussed in this article about nitrulo-triasedic acid which

was proposed as a counter-measure to the pollution of the environment with
~21-

phosphates , which of course were serious sources of eutrophication of lakes.
Then came findings that large doses of NTA, completely predictably , would
cause some problems, followed by argument about the dose-effect relation-
ships in that particular area. Then the president of the new chemical industry
Institue of Technology , Dr. Leon Goldberg, maintained that the use of the

- maximum tolerated dose is completely inappropriate. Instead, he and others
argued, the complete spectrum of absorption, distribution, bio-transformation
and excretion of the chemicals should be considered before determining the
maximum dose for bio-assays. Dr. Rawl, who is the director of the National
Institutes for Environmental Health Sciences, says that he cannot disagree with
this viewpoint but notes that such studies would probably limit the number of

chemicals that could be assayed to about four per year.

The rest of the article goes on to how you are going to evade that issue and

do it "on the cheap." "On the cheap" means setting up some fairly arbitrary
standard, using one parameter of toxic hazard like the Ames test. This is a
perfectly legitimate and valid designator. Many of the compounds that produce
a strong positive on that test are very clearly agents that will alkalate DNA
and some of them are hazards that you and I would unquestionably avoid in
our daily lives if we could possibly do so without going into further compli-

cations.

However, I think the bottom line is that we are going to get "on the cheap" what
we pay for. If.we think we can substitute one simple test for a deep under-
standing of the mechanisms of interaction of a new chemical substance with

the physiology not only of a single organism but of the whole population of
organisms with its genetic variability and with its co-exposure to other
environmental agents, we are going to get what we deserve. And that is

roughly the present situation.

Obviously , we have to do better than look at four compounds a year. We do
_ have to find other answers to the question. But the rote examination of compounds
in a standardized pathology assay, on the one hand, or the simplified laboratory

test, on the other, is simply not going to accomplish the task.

Nor are they going to result in the capability of looking at the very serious
trade-off problems, which is really the second chapter of any book that one
would write here. There is always a trade-off. There is probably always
some possibility of a disbenefit even from the cleanest compound that one
could imagine. We have to find some framework in which that can be
measured against the costs and effects of alternatives in an economic sphere
which also intersects with our health sphere. We have a finite number of

dollars to put into other health preventive measures and so on and so forth.

There again the only institutions that we have today that do anything about it
are the regulators. And I have to say that the more I observe a bureaucracy ,
the more I believe in Parkison and that they have a life of their own. Perhaps
it is just as well that they do. I don't envy the bureaucrat's life in as much as
all of us share a certain exasperation in having to deal with it. But the
regulator today increasingly must be viewed as a self-interested adversary ,
not as a neutral judge. That is a point which has to be understood. He is

an adversary because he has to protect his neck. No one else is going to do
-23-

it for him when there is some nonfeasance on his part, and something gets
through that could arouse large public outery. Why complain, if bureaucrats
behave in that self-protective fashion when no one is going to watch out for

them when the ax does fall?

_ You have to recognize that as a fact of life. Every one of us is attached to
self-interest. I am attached to the promulgation of a neutral scientific
attitude and a successful career for my graduate students and myself in
doing public ‘good in a certain respect. The consumerist is self-interested
to the extent that he or she can arouse public excitement over a particular
issue; that person is also in business to do public good. Every one of us
here has some stance in those circumstances that we really ought to be very

honest about.

But this also suggests that the single elements in these adversary processes
are really not to be trusted for the whole story. I don't think we can trust
the regulatory bureaucracy for making the value judgments that are involved
in these tradeoffs because the life of the individual bureaucrat is too much
involved in the way that those decisions are reached. I don't have to give
all the reasons why industry can't be trusted, although in many respects it
is the most publicly-exposed party. The academic side has its own biases
that I have also indicated. Somehow, though, I think we have to put these

together.

The specific proposal that I would like to see some more thought about is

a consortium in which academic institutions can play a regulated role in
holding the bag in the study of these questions. Now they already do.

Most of the tests and assays and arguments and so forth about these dif-
ferent procedures have come from academic sources. But it's very hard to
pin a professor down to working on a problem that is of particular interest
in a particular locale. In a way, it's not his business to do so. If you are
_ talking about the central core of basic research and if you want the highest
level of creativity--which is the discovery of new problems--you really

don't want to tell that cadre of individuals what to do.

We then have a vacuum. We have a vacuum on a number of axes of applicable
science. Where the yield is immediately potentially profitable, industry will
do it. We know what drives private enterprise. But there is a large zone
where knowledge that is part of the commons, that is part of the common social
good, falls between the responsibility for problem discovery of the academic
laboratory and the proprietary interest of the industrial laboratory. I used

to think government was the place to do that and indeed it has to a large degree.
But, one, it is increasingly hard to get money to do anything new and different
these days, regardless of its merits. So we have a status quo problem against
us. Two, for all of the bureaucratic reasons that I indicated before, I think
industry in particular ought to have reason not to trust government to be the
only source of wisdom with respect to risk assessment of environmental

chemicals.

There is getting to be some cross-talk between the regulatory side and the

research funding side. As enthusiastic as I would be in principle about an
-95-

agency like FDA having a very strong scientific base, including a grants and
contract mechanism and so forth, I really wonder how that agency would be
able to live continuing to support outside activities that were in immediate
and direct conflict with its existing regulatory policies. Frankly , I don't
think it could. I just don't see the dynamics to make it possible. And I think

we do need some agency segregation.

Well, there may be many versions of what is needed here. The CIT is one

I have only recently heard about. It's the chemical industry's consortium
for the study of industrial toxicology at Research Triangle. It seems to me
that it is too close to industry to be completely credible. I don't see where
in its governance, its direction or problem choice, it has the neutral ground
which is required for an effective operation. This may be largely a problem
of public perception that hasn't emerged yet, although it's predictable that

it will.

There is also bound to be some reality to it, however. I found myself once at

a discourse on cost-benefit analysis involving a particular additive. Believing
myself to be a fairly calm, detached person sympathetic to both sides, I found
a consumer advocate inappropriately criticized during the discussion. I
wondered how come, how come I couldn't do the job myself of assimilating

his views. I thought I was as honest a person, as much involved in public
interest as that individual was. I wasn't as rash as he was. And that was

the point. We need people in the system who are protected in making

outrageous allegations , outrageous assumptions and hypotheses, but
-26-

rebuttable ones. If we don't have that element in the system, you can be
sure that it will also inevitably be co-opted to the fundamental interests of
law and order, in other words, to the prevailing mores of the group rather

than necessarily the long range public interest.

_ Very concretly, I think that there would be a place for a universities-industrial
consortium to manage laboratories oriented in the general direction of CIT

but at a more fundamental level. I think CIT is dedicated primarily to the
testing of particular compounds and in part to the development of new testing
methodologies. I think we need a further place for the development of
applicable science where the emphasis is a little on the other side, where

there are tasks that originate from industrial requirements which do require
new methodologies, new insights, and where very careful and critical
academic oversight is also important. Such an institute should embrace

the examination of fundamental issues of toxicological hazard from a very

new perspective , much more applied than the Roche Institute of Molecular
Biology (which I think is somewhat to the left of the Rockefeller University in
the purity of its academic objectives) and, of course, much more fundamentally
oriented than the research and development laboratories of this particular
corporation. I think that within that framework, we might also be able to

get a discourse which is almost totally lacking between the people who know
something about the toxicology of a compound and people who can say something

about the techniques of cost-benefit evaluation in public application.

Having said all of that, I have to revert to one theme that is somewhat dis-

couraging. I am not sure that it will make the slighest difference. The issue
-?7-

that has shaken me to the core, because it does have deep religious overtones,
is recombinant DNA. Here I was a protagonist. I was not sitting on the side-
lines. I was an investigator who devoted all of my scientific life to laying the
groundwork for these investigations. I can hardly claim a purity of motive

in wanting to see the effective utilization of that particular technology. But I

_ have been very reluctant to get into the middle of that fray because, to be

very frank with you, I couldn't find a way to bring a cost-risk benefit analysis
into that picture. I had no way to estimate the risks. I got off on my own
intuitions . I can offer all kinds of reasons why there are many, many other
things going on in the world that are far riskier than what is involved here.
But I had no way to articulate that in a clear-cut, rational analytical framework.
I haven't heard that very much from my colleagues either. I think we have to
own up to that. Also, one thing that was never stated clearly enough was

the benefit side of these kinds of investigations. And there I have gone
"gung-ho" to try to articulate the very important fruits of research in that

particular area.

I honestly and earnestly believe that the risks have been vastly exaggerated.
I indeed can point to many many things far more consequential, like letting
anyone in this auditorium who shows signs of sneezing. There is always the
possibility of some epidemic disease being initiated by such an individual.
You have no way to estimate the risk if that will happen tomorrow and that
the world's population will be decimated as a result of your carelessness in

letting that person come into the room. I am quite serious. I think you can
-28~

make just as strong a chain of argument about those possibilities and historical
precedence about the Great Plague and so forth as you can about any of the

other areas of discussion.

However, they defy rigorous analysis at the present time and I think we have

to be getting on to a somewhat different track in dealing with them. That track,

I suppose, has a great deal to do with instilling public confidence in the integrity
of your motives and your approach and a great many other things, some of

which have been very badly fumbled by my colleagues in this particular arena.
For example, you don't start out an honest effort in this direction by making it

a media event to begin with. That has predictable consequences of the kind that

in fact have come to fruit.

Well, I have offered some propositions, not very strong on substance, but I
think at least I have conveyed the notion that we are all on the same leaky boat,

a notion I think we need to share with the much broader community.