8

III.

A.

USE OF QUANTITATIVE RISK ASSESSMENT METHODS HAS PROVIDED THE
AGENCY WITH ANOTHER REGULATORY TOOL TO ESTIMATE LEVELS
OF RISK

Use of Risk Extrapolation Models and Interpretation of Calculated
Risk Factors

The difficulty in resolving the problem of quantitative relationship between the amounts of a chemical that causes cancer in laboratory animals and the amount required to do the same in a given human population is universally recognized.

A 1975 NAS/NRC report stated "in the absence of countervailing
evidence for the specific agent in question, it appears reasonable
to assume that the lifetime cancer incidence induced by chronic
exposure in man can be approximated by the lifetime incidence
induced by similar exposure in laboratory animals at the same
total dose per body weight."(23) The use of additional safety
factors in arriving at acceptable human exposure levels rest, at
least tacitly, on the assumption of the existence of a threshold
dose below which no adverse effects will occur. Or, at least, that
the degree of risks will be reduced to a sufficiently low level as
to be acceptable to society. In theory, a single molecule of a
carcinogenic agent could lead to cancer. Although many scientists
agree that a safe level probably exists for such materials, there
is currently insufficient conclusive information available to
define such a level. This uncertainty as to the low dose effects
of carcinogenic agents has resulted in the application of
mathematical models to evaluate such risks at levels far below
those attained experimentally.

The present Draft Report correctly points out the legislative
justification for determination of risk and OPP's present and
projected use of mathematical equations to assist in quantitative
risk assessment estimates. Of importance is the fact that many of
these mathematical models will fit the same animal data equally
well, yet give widely different risk factors due to the inclusion
of a number of scientifically unconfirmed assumptions. (24) "The
chief criticism of the model-fitting approach and a valid one
is that the shape of the dose-response curve at low doses is
impossible to determine experimentally, and different models,
fitted to experimental carcinogenicity data, often lead to vastly
different estimates of low-dose risks. Perhaps this difficulty
could be mitigated by admitting that we don't know how to protect
human health to the levels of 10-6 or 10-5 lifetime risks and to
begin paying more attention to comparisons of carcinogenic
potencies rather than absolute levels of risks."(25) Because of
the wide uncertainties inherent in the design and application of
these various mathematical models, the EPA application of the risk
factors developed from such exercises has been viewed as general
ranges of potential risk rather than a finite conclusion of a safe
dose to man.

28-401 - 84 - 34

9

Thus, mathematically-derived risk factors can and should be used to rank our level of concern over cancer-producing substances of varying potency(26). The converse, e.g., absolution of such values as definitive risks, cannot be scientifically supported. We agree with the subcommittee report that SUCH PROCEDURES CONTINUE TO HOLD PROMISE IN PROVIDING AN ORDERLY AND SYSTEMATIC APPROACH TO TOLERANCE DETERMINATION. WE FURTHER BELIEVE THAT THE CURRENT EPA APPROACH IN USE OF SUCH RISK FACTORS TO BE A PRACTICAL MEANS FOR ESTABLISHING TOLERANCE AND SOCIALLY PRUDENT.

B. Use of a Safety Factor for Non-genotoxic Agents

It is clear that there should be greater concern with the more potent compounds that demonstrate significant carcinogenic activity [genotoxic agents] than non-genotoxic agents that produce tumors only at near-toxic doses (8, 27). While the use of mathematical modeling may be appropriate for potent genotoxic agents, the use of such procedures for substances which may induce tumors through non-genotoxic mechanisms is not considered warranted (24). Typically, such agents elicit clearly-defined dose-response curves and well established no-effect levels experimentally.

Thus, particularly in the case of non-genotoxic agents, it is quite possible that a qualitatively based (but conservative) pragmatic approach could provide a more realistic margin of safety than scientifically uncertain, but mathematically sound,

extrapolation.

Because of the uncertainty as to the low-dose effects (threshold concept) of carcinogenic agents, the use of safety factors of 3 orders of magnitude has been advocated for both genotoxic and non-genotoxic agents (5, 28). Thus, the CAG proposal to use a 1000-fold safety factor only for non-genotoxic carcinogens cited in the Draft Report calls for the use of safety factors quite similar to safety factors previously considered sufficient to prevent substantial risk to ALL classes of carcinogenic agents.

2/17/83

REFERENCES

1.

de Serres, F.J. 1977. J. Environ. Path. & Tox. 1:43-48.

3.

4.

5.

6.

7.

8.

9.

10.

Task Force of Past Presidents (Society of Toxicology), 1982.
Fundamen. Appl. Toxicol. 2(3):101-107.

Weil, C.S. 1972. Toxicol. Appl. Pharmacol. 21:454-463.
Annonymous. 1979. IARC Scientific Publication No. 25:
Carcinogenic Risks Strategies For Intervention, Discussion
Synopsis on Measurement of Carcinogenic Risks, pp. 229-233.
Lyon, France.

D'Aguano, W. 1973. Section 8: Interpretation of Test
Results in Terms of Carcinogenic Potential to the Test
Animal: The Regulatory Point of View in Carcinogenesis
Testing of Chemicals ed. L. Goldberg, CRC Press, Cleveland
Ohio. 144 pp.

Deichmann, W.B. and MacDonald, W.E. 1979. "Organochlorine Pesticides and Liver Cancer Deaths in the United States, 1930-1972." Dev. Toxicol. Environ. Sci. 4:147-173.

European Chemical Industry Ecology & Toxicology Centre,
Monograph No. 4. "Hepatocarcinogenesis in Laboratory
Rodents: Relevance For Man." October 1982.

Clayson, D.B. 1977. J. Environ. Path. & Tox. 1:31-40
Muller, H.J. 1927. Science 66:84.

11. Auerbach, C. and J.M. Robson. 1946. Nature 157:302.

12.

13.

14.

15.

Miller, E.C. and J.A. Miller in Hiatt, H.H. et al. (ed.)
Origins of Human Cancer. Vol. 4 Cold Spring Harbor
Laboratory, New York, 1977.

Ames, B.N. et al. 1975. Mut. Res. 31:347-364.

Office of

Asher, I.M. and Zervos, C. (ed.) Symposium on Structural
Correlates of Carcinogenesis and Mutagenesis.
Science, FDA, Rockville, Md., 1978.

Mulvihill, J.J. 1977. Genetics of Human Cancer. New York,

20.

21.

22.

Brit. J. Cancer

Carcinogenesis: A
588 pp.

Comprehensive Survey, Volume 2, Raven Press.

Bourdeau, P. et al. 1979. IARC Scientific Publication No. 25. IARC, Lyon, France.

Squire, R.A. 1981. Science 214:877-880.

Snee, R.D. and Parks, C.N. in Quantitative Risk Assessment,
A.I.H.C. 1982.

23. NAS/NRC Environmental Studies Board. 1975 Washington, D.C. National Academy of Sciences. 438 pp.

24.

25.

26.

27.

28.

Munro, I.C. and Krewski, D.R. 1981. Fd. Cosmet. Toxicol.

19:549-560.

Crump, K. 1982. Science 219:236-7.

NAS. 1979. Committee for Study on Saccharin and Food
Safety Policy. Part 2. Washington.

Shank, R.C. and Barrows, L.R. in Health Risk
Analysis, P.J. Walsh (ed.) Franklin Institute Press.
Philadelphia. 1981.

Truhant, R. 1979 IARC Scientific Publication No. 25.

Ibid.

2

Stauffer Stauffer Chemical Company

CHEMICALS

Westport, Connecticut 06880 / Tel. (203) 222-3000/ Cable "Staufchem"

March 4, 1983

The Honorable George E. Brown, Jr., Chairman
Subcommittee on Department Operations,

Research, and Foreign Agriculture

Room 1301

Longworth House Office Building

U.S. House of Representatives
Washington, D.C. 20515

Dear Mr. Brown:

We are pleased to provide you with comments for the record on the recent hearings on the subject of the draft report "Regulatory Procedures and Public Health Issues in EPA's Office of Pesticide Programs". We support the Subcommittee's efforts to understand the complex scientific and regulatory issues that are related to the registration and regulation of pesticides in the United States.

Stauffer has been involved in the registration of pesticide products for over 25 years. It has been our experience that the key to an objective and sound registration procedure is a competent, well-trained scientific review staff. We support NACA's position that EPA should make available funds to hire and train scientists to review the highly sophisticated and complex data related to toxicology, chemistry, ecological and environmental fate of pesticide products. EPA scientists should have the opportunity to review and discuss with their peers the complicated issues that are involved in the technical data they must judge. The scientific staff should be provided the incentive to attend scientific meetings at appropriate intervals so that they can keep up with the state of the art in their professions. Also, the scientific staff should have ready access to a library that stores credible scientific journals, reference books, and other technical materials. Stauffer cannot say what is adequate funding but we think Congress and the EPA should provide adequate funds for employment of a well-trained scientific staff. This, in our view, is in the best interests of the public and the industry.

The FIFRA Scientific Advisory Panel has been an effective consulting and peer review arm for EPA. At present, this Panel is not operating because funds are not available. Stauffer strongly recommends a reauthorization for full funding of their well-respected independent panel of recognized scientists.