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OCR for page 253
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.
Representative terms from entire chapter:
carcinogenic activity
