Thank you for your letters of January 6 and January 13, 1983, and the specific invitation to comment on Chapter 6 (cancer policy).

Du Pont is a member company of NACA (National Agricultural Chemicals Association) and will defer detailed comment on the Report to the Association. We have, of course, participated in the development of NACA comments.

We will, however, make some general observations in response to your request. The report attempts to establish a direct line in its reasoning to criticize EPA/OPP for its recent handling (1980-2) of pesticide matters, especially on evaluation of carcinogenicity. The report overlooks events which impacted EPA's administration of FIFRA before 1980, such as:

Serious failures in NCI's carcinogenesis evaluation programs
in the early 70's.

Serious scientific criticism of some of NCI's test methods,
e.g. use of mice at MTD dose levels, etc.

Advances by EPA's Cancer Assessment Group (Dr. Roy Albert, NYU),
a non-OPP unit.

The effective operation of the FIFRA Scientific Advisory
Panel (SAP) as a peer review group starting in late 1976.

All of these happenings played a very understandable and considerable role in the evolution of scientific thinking within EPA/OPP/HED.

Under the FIFRA mandate to register useful pesticides that do not "generally cause unreasonable adverse effects", EPA/OPP have worked hard to incorporate the best available scientific reasoning into their risk assessments,

BETTER THINGS FOR BETTER LIVING. THROUGH CHEMISTRY

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and they have done so in a very open manner.

As to weight-of-evidence, these quotes come from the EPA (Russell Train) notice in the May 25, 1976 Federal Register (41, 21402): "Judgements about the weight of evidence involve considerations of the quality and adequacy of the data and kinds of responses induced by the suspect carcinogen. "...the risk estimates should be regarded only as rough indications of effect."

"The summary section on risk assessment should provide a statement which encompasses answers to the following questions: (1) How likely is the agent to be a human carcinogen? (2) If the agent is a human carcinogen, what is the estimated impact on human health?"

Du Pont finds current OPP decision-making to be entirely consistent with Train's clearly enunciated procedure of 1976. We therefore disagree with the conclusions, and most certainly with the implications of the conclusions, in Chapter 6.

In simple terms, EPA's policy since its formation in 1970 has been not to register a pesticide that poses an unreasonable threat as a human oncogen. This is still the policy today. Risk assessment techniques and methods have evolved and improved, but the policy has and should remain the same.

Report.

Du Pont has reviewed the major recommendations made in the Staff
Our comments are attached.

Also attached is an excellent ECETOC monograph which has just become available on the limited subject of rodent liver tumors: "Hepatocarcinogenesis in the Laboratory Rodents: Relevance for Man" (Monograph 4, October, 1982). This document should be useful to Staff in reassessing Chapter 6. For example, we quote from summary on page 49: "Liver tumors are common in untreated laboratory rats and mice and are readily produced in these species by exposure to a wide variety of chemicals. By contrast, they are rare in Western man. Also from mid-page, "Liver tumor incidence may be enhanced either by exposure to genotoxic mutagens or to certain non-genotoxic agents. The former type of activity is generally a matter of greater concern than the latter because it is frequently difficult to identify any reason why low levels of exposure should not carry proportionately low levels of risk. By contrast, for agents acting by non-genotoxic mechanisms and enhancing liver tumor incidence under conditions of high exposure, it is often possible to identify convincing reasons why there should be no risk under conditions of low exposure. Throughout the monograph, therefore, considerable importance is attached to the distinction between genotoxic and non-genotoxic mechanisms."' You asked for comments on whether present EPA decisions might be out-of-step with likely future White House proposals on cancer assessment and policy. We think not. Also, you asked if we felt EPA was making correct decisions at present. We think they are. Not just under the present Administration, but particularly since SAP was put in place in 1976, EPA/OPP has been more and more atune to the thrust of the best scientific thought.

ATTACHMENT

DU PONT COMMENTS ON RECOMMENDATIONS FROM

STAFF REPORT

ISSUE 1 Regulatory Activities

Recommendation. The Agency and Congress should find and implement
expeditiously better ways to satisfy the pest control needs of specialty
crop producers.

Du Pont Comment. Agree.

Recommendation. The Agency and Congress should consider additional modifications in the Section 3 registration process, such as a provisional category of registration, so that a greater percentage of pesticide registrations satisfy federal registration standards.

Du Pont Comment. Agree. In the USA, there is nothing between a Section 5 experimental use permit and a full Section 3 registration. Du Pont agrees that the USA would benefit from a phased registration system as recommended by WHO/FAO and practiced most notably in France, UK, and Australia. This would tend to alleviate some of the pressure on Section 18's on new active ingredients in particular.

Recommendation. The Agency and Congress should develop better ways to
assist states in analyzing and minimizing potential adverse environmental
impacts of pesticides used under Section 18 and Section 24 (c) of FIFRA.

Du Pont Comment. In spite of increased use of Section 18 and 24 (c), Du Pont
is not aware of an actual (as opposed to potential) adverse environmental
impact to date. Nonetheless, we agree that it would be preferable to practice
a phased registration concept rather than the somewhat ad hoc Section 18

as now.

ISSUE 2 - The Tolerance Setting System.

Recommendation. The Agency should proceed expeditiously with its efforts
to revise the tolerance setting system in accordance with the recommendations
of the Scientific Advisory Board.

Du Pont Comment. Du Pont feels the tolerance setting system is taking
undue criticism in the staff study. Although not widely understood by
the public, or even by scientists who may comment without having been directly
involved in `tolerance petition proposals, the system has worked well since
it was established in the early 1950's. It has stood the changes of
scientific advances for 30 years under rapid developments in measuring
pesticide residues, the expansion of pesticides in crop applications, the
complications of transferring federal authority between two agencies, and
the addition of new personnel for administering pesticide crop tolerances.
Except for some areas where further improvements could be made, the original
concepts are still basically sound. More efforts could be devoted to use
of larger crop groupings for tolerances rather than a crop-by-crop establish-
ment. The latter is time-consuming, the added safeguards are questionable,
and the personnel effort needed is hardly warranted because of limited
manpower. Specialty crop tolerances especially could be streamlined to
lower review costs. Improvements in these areas have been proposed and dis-

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cussed for at least 10 years, and the basis for improvement could be
readily incorporated into the existing tolerance setting system.
Du Pont is glad to see that EPA is nearing a final rule on the crop
grouping proposal.

On both the cancer policy issue and the tolerance setting system issue,
we believe it is important to retain flexibility as new research,
improved test methods, and new risk assessment techniques unfold, to
assure that such techniques are judiciously incorporated into the
evaluations of new pesticides. Additionally, the concept of balancing
risk versus benefits must be retained in final regulatory decision-making
processes under FIFRA. EPA should use the best scientific techniques
available. Anything less would not be in the public interest..

Recommendation. The Agency should adequately document and openly
disseminate for scientific review and public discussion the status of
any tolerance setting system problems or issues on all major pesticides.
The information is essential for meaningful public understanding and
oversight of the changes adopted in the system.

Du Pont Comment. Agree, but EPA is already doing this, and doing a
better and better job of it.

Recommendation. The Agency should focus attention immediately on
pesticides with estimated levels of dietary exposure in excess of acceptable
daily intakes; and forego more detailed refinements in tolerance setting
calculations on pesticides with estimated exposure less than half of
acceptable daily intakes until higher priority reviews are completed.

Du Pont Comment. Du Pont agrees. Perhaps this suggestion would be the
best way of prioritorizing the reregistration (Registration standards)
program in the short term. We are not sure, however, but what EPA may already
have this aspect covered. Also, we agree with the EPA comment that exceeding
the calculated TMRC by itself is meaningless. It merely suggests that

the Agency must begin to take a harder look at actual dietary exposures based
on, e.g., market basket surveys.

The Adequacy of Science Underlying Pesticide Safety Evaluations.

Recommendation. The Agency should establish a program in OPP to monitor
the quality of scientific reviews prepared by staff scientists.

Du Pont Comment. Agree; either that or increase the amount of direct
supervision now given to scientific reviewers.

Recommendation. The Agency should give Agency scientists adequate time and technical support to keep current on new experimental and statistical techniques regularly employed in risk assessment.

Du Pont Comment. Agree, but this will require a budget increase for OPP;
perhaps the money should be earmarked specifically for this task.

Recommendation. The Agency should reinstate a jointly funded scientific visitation program, possibly in cooperation with an independent research institution, to encourage dialogue between industry scientists on promising new analytic methods and risk assessment concepts.

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Du Pont Comment. Agree. But again money is needed for OPP budget.

Recommendation. The Agency should strengthen the breath and force of
the laboratory audit program to include periodic evaluations of all
laboratories and timely regulatory and/or enforcement actions. OPP must
also reinforce the institutional credibility of the program so that it
can realistically be expected to detect, and act as a deterent against, shoddy
science.

Du Pont Comment. Agree. Du Pont feels an appropriate audit program is
essential to maintain credibility for both the Agency and the industry.
We recommend that the real scientists in the review branches be made to
participate in this program so that they will both be able to get out
and see the "real world" and to be able to advise audited laboratories
on what they expect when a study comes in.

Agency Efforts to Establish a Policy to Regulate Potentially Carcinogenic Pesticides

Recommendation. The Agency should clearly articulate the cancer policy
principles which now guide Agency decisions.

Du Pont Comment. We feel it is clear already, but obviously the House
Subcommittee staff would like a de novo enunciation of present practice
and policy. Du Pont does not oppose this but suggests that it will
represent a drain on EPA resources and manpower.

Recommendation. The Agency should insure that these principles are under-
stood and followed consistantly throughout the Agency.

Du Pont Comment. Agree in principle. Present sign-off procedure assures it in practice at OPP. They deserve credit rather than criticism.

Recommendation.

The Agency should provide staff level scientists with the time and technical research support to develop institutional expertise on new risk assessment models and concepts.

Du Pont Comment. Agree. We feel EPA is already doing this, but if additional efforts can be made, then of course budgetary increases would be appropriate.

Recommendation. The Agency should be cautious when making scientific
and regulatory decisions on suspect carcinogens, and explain to the public
and the scientific community its justifications for the levels of risks
accepted.

Du Pont Comment. The Agency is already doing a very credible job of
this. The term "be cautious" possibly shows bias on the part of the
House Subcommittee staff, in the sense that they may judge EPA's recent
decisions to be wrong. We are not aware that staff has scientific expertise
to make this judgement in the regulatory context of FIFRA. Also, we do not
believe the interviews and comments presented in staff report represent
the concensus of scientific thought in this country or the world at present.

Recommendation. The Agency should improve considerably through appropriate research the reliability of the Agency's estimates of human exposure to oncogenic pesticides when conducting risk assessments, or in judging whether a risk assessment is necessary.