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BThe Carcinogenic Activity Indicator CAI's FROM ANIMAL DATA A Carcinogenic Activity Indicator, as defined and used in this report, is: c _ Excess percentage of subjects in which tumors are observed Lifetime dose (in m moles/kg of body weight) CAN'S should be determined and expressed with confidence intervals derived from the experimental errors inherent in all the variables used in the calculation. CAYS are not absolute estimates of the carcinogenic potency of compounds; rather they vary, depending upon the conditions or parameters that characterize the study from which they were derived. CAT values are basically intended to be used for comparisons between compounds. The more the study parameters characterizing CA' values for different compounds agree, the more likely it is that the CAIN can be validly compared. Parameters that require specification include species of animal (and, for certain species, the strain within the species), route of administration, and approximate tumor excess level (this last to compensate for nonlinearities of dose-response curves). This list of parameters is not, however, necessarily sufficient. For example, sex may also be a determinant of the electiveness of a substance in inducing cancer; in such cases it would also be an appropriate parameter. Also, CAI values 253

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254 Appendix B may be calculated for a specific organ site or for all tumors. Ideally, CAT comparisons would be restricted to relative incidence rates at the same organ sites. If this is done, the organ site becomes another parameter of the CA' value; comparisons of CAN'T for different compounds would have to consider whether the compounds are equally specific to the same target organ. In practice, however, the Committee feels that with appropriate caution aggregate totals of tumors also can be scientifically compared. As-we better understand the process of carcinogenesis, additional parameters may require specification. The excess percentage of subjects in which tumors are observed (in the numerator of the equation) is a measure of the proportion of the tumor response in the experimental group attributable to the test substance. Several considerations must be made in determining this value (see Appendix C). Allowance must be made for tumors in the control group. If the tumor incidence in the control group is excessively high, CAT calculations are highly constrained. In determining an error estimate, group sizes and the tumor incidence in the control group must be considered (e.g., with Abbott's correction, Abbott 1925~. The forgoing presupposes that experiments are performed with nearly complete survival until a terminal sacrifice. In experiments where animals die spontaneously or where there has been excessive mortality prior to a terminal sacrifice, appropriate actuarial methods must be used to determine incidences of excess tumors. The dose to which the tumor response is compared (the denominator of the equation) is in millimoles per kilogram of body weight integrated over the lifetime of the animal. The expression of the dose in this form is partially a matter of convenience and partially related to the compound chosen for illustration in this report, i.e., chlorobenzilate (see Chapter 7~. The essential point is that the dose should be comparable between compounds, thus necessitating conversion to millimoles rather than grams or milligrams. To over some basis for comparisons between species, the dose must be normalized to body weight of the animal. The total integrated dose over the lifetime of the animal was chosen in preference to dose rate (e.g., millimoles per kilogram per day) because of the discontinuous schedule of dosage in the most sensitive study of chlorobenzilate. If dose is integrated over a lifetime, attention must be given to the dosing schedule: certainly equivalent doses given in the first and last 10 percent of an animal's lifetime would be expected to give different results. Similarly, single doses are likely to give results different from fractionated doses. Alternative CAT values could be constructed compar- ing substances on the basis of other measures of dose, e.g., millimoles per

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Appendix B 255 square meter of surface area per day. Again, when making comparisons of carcinogenic activity between compounds, it is most critical that appropriate judgment be given to selecting CAT values with comparable test parameters and reasonable biological similarities. CAI's FOR HUMANS In order to use the CAl comparisons derived from animal data to provide indications of the relative carcinogenic potential of the same compounds in humans, a number of assumptions must be invoked. The following four assumptions, for example, will justify statements about the relative dangers of two compounds, for convenience called pesticide i and pesticidej, in humans: 1. The ratio of CAI'S in animals for pesticide i and pesticide j is the same at all levels of dosage (D). Algebraically stated, CAIa ~D') cAIa j( D I) CAIa ( D2) CAIa (D2) for all Do and D2 greater than zero, where CMat (D) denotes the cut for pesticide i in experimental animals at dose level D, and similarly for pesticide j. The assumption asserts nothing about the shapes of the individual dose-response curves, but it does state that they will be parallel if plotted on logarithmic scales. 2. For any dose level, D, the ratio of the CAI'S that would be observed in experimental animals is the same as the ratio of the CAN'S that would be observed in humans. Algebraically, CAIa ( D ) CAIa J( D ) = CAIh ( D ) D ~ O. CAIh ( D ) The subscript h is introduced here to denote CAT values that pertain to humans. Algebraically, these two assumptions imply that CAIh ( D ) CAIh (D) CAIa ( D O) ~- CAIa ( D o) , D ~ O.

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256 where Do now denotes the observed experimental dose. Appendix B 3. For low doses to which humans are typically exposed, the incidence of excess tumors induced by pesticides is in the same proportion as their CAI'S. Algebraically, I h ~ D ~ CAIh ~ D ~ Ih j(D) cAIh (D) = where D is a small positive dose level and Ih (D) is the excess incidence of cancers induced in humans by dose D of pesticide i, and similarly for pesticidej. 4. For a restricted range of doses, the incidence of tumors induced in humans by a pesticide is proportional to the dose. Algebraically, Ih i`D' D D 1 I i(D~) Dot, r ~ Do where r is any number greater than zero. Together, these four assumptions permit the calculation of equivalent doses from experimentally observed CAN'T. By virtue of the first three assumptions, for any low dose, Di, to which humans are typically exposed, Ih'~Dl) . Ih (D1) Invoking the last assumption, Ih i ~D) = = CAIa ~ Do) CAIa ~ Do) 9 D CAIa i(Do) i D1 CAI iced ~ Ih (D1) provided that D/Di is not outside the designated range. Now choose D so that Ihi (~D) is equal to Ih* (`D~`J. Then D is the dose of pesticide j that is equivalent to the prescribed dose Di of pesticide i and, cancelling,

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Appendix B 257 D D CAIa ( D a) CAIa (Do) e That is, the ratio of the equivalent doses of the two pesticides is the reciprocal of the ratio of their observed CAN'T, provided the ratio so found is within the range for which the proportional response relationship is believed to hold. None of these assumptions can be expected to apply precisely in practice. In fact we are not aware of any hard experimental evidence that supports them. Yet they, or assumptions of comparable strength, must be invoked whenever the results of bioassays are used to compare the potencies in humans of different compounds. The above assumptions appear to be plausible approximations for compounds whose chemical and biological properties are not excessively dissimilar. It is, perhaps, an indication of the poverty of our understanding that there is virtually no empirical evidence to indicate the circumstances under which these assumptions are or are not acceptable. The assumptions described above have some theoretical implications. For example, it can be shown that assumption (1) is inconsistent with the popular "one-hit model," which implies the rather different potency index employed by Meselson and Russell (19774. There is no particular reason, aside from pedagogical convenience, for accepting the one-hit model. (For some empirical evidence on the validity of the one-hit model, see Ashley 1969.) The Committee therefore recommends the definition of the CAT that has been proposed above. In view of the strong assumptions that have to be invoked, the CAT, like all other simple measures of carcinogen~city, must be interpreted with caution and discretion. Nevertheless, with the present state of our understanding, there is no scientifically warranted indicator of the hazards of being exposed to a carcinogen that can obviate the need for making assumptions as strong as these or stronger. REFERENCES Abbott, W.S. (1925) A method of computing the effectiveness of an insecticide. Journal of Economic Entomology 18:26~267. Ashley, D.J.B. (1969) The two 'hit' and multiple 'hit' theory of carcinogenesis. British Journal of Cancer 23:313-328. Meselson, M.S. and K. Russell (1977) Comparison of carcinogensis and mutagenesis potency. Pages 1473-1481, Book C, Origin of Human Cancer, edited by H.H. Hiatt, J.D. Watson, and J.A. Winsten. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory.