may be used to relate carcinogenic potency (P) to body weight (BW). A value of b = 1 corresponds to interspecies extrapolation on the basis of body weight, whereas b = 2/3 corresponds to extrapolation roughly on the basis of body surface area. Travis & White (1988) suggest an intermediate value of b = 3/4 (cf. Watanabe et al., 1992), which corresponds roughly to extrapolation on the basis of metabolic rate (Schmidt-Nielsen, 1984).

Quantitative interspecies extrapolation of measures of carcinogenic potency such as the TD_{50} may also be based on empirical observations of potency in the two target species, provided that the agents of interest are effective in both species. Crouch & Wilson (1979) demonstrated a positive correlation between rats and mice in carcinogenic potency expressed in terms of the slope coefficient ß in the one-hit model in (2.2). Subsequently, Crouch (1983) suggested that interspecies extrapolation of carcinogenic potency would generally be accurate to within a factor of about 4.5.

Gaylor & Chen (1986) compared the relative carcinogenic potency of chemicals in rats, mice, and hamsters based upon the TD_{50}s given by Gold et al. (1984). Since current practice generally is to base risk estimates upon the data set producing the highest cancer risk, the minimum TD_{50} was selected for each chemical in each species for each route of administration. The largest subset of relative potencies was obtained for rats and mice for 190 chemicals administered in the diet. With dose expressed in terms of mg/kg body weight/day, the geometric mean of the ratio of the minimum TD_{50} value for rats relative to that for mice was 0.45. For dose expressed in terms of concentration (ppm) in the diet, however, the mean ratio was 1.3. Using either dose metric, the mean carcinogenic potency of these chemicals in rats and mice agree to within a factor of about two-fold. The ratio R of the TD_{50} values for rats and mice were approximately lognormally distributed, with log_{10}R exhibiting a standard deviation of 0.82; this corresponds to a multiplicative factor of 10^{0.82} ˜ 7-fold. For 4 of the 190 chemicals, the ratios of

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APPENDIX F 141
original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be
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retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution.
may be used to relate carcinogenic potency (P) to body weight (BW). A
value of b = 1 corresponds to interspecies extrapolation on the basis of body
weight, whereas b = 2/3 corresponds to extrapolation roughly on the basis of
body surface area. Travis & White (1988) suggest an intermediate value of b =
3/4 (cf. Watanabe et al., 1992), which corresponds roughly to extrapolation on
the basis of metabolic rate (Schmidt-Nielsen, 1984).
6.1 Extrapolation from Rats to Mice
Quantitative interspecies extrapolation of measures of carcinogenic
potency such as the TD50 may also be based on empirical observations of
potency in the two target species, provided that the agents of interest are
effective in both species. Crouch & Wilson (1979) demonstrated a positive
correlation between rats and mice in carcinogenic potency expressed in terms of
the slope coefficient β in the one-hit model in (2.2). Subsequently, Crouch
(1983) suggested that interspecies extrapolation of carcinogenic potency would
generally be accurate to within a factor of about 4.5.
Gaylor & Chen (1986) compared the relative carcinogenic potency of
chemicals in rats, mice, and hamsters based upon the TD50s given by Gold et al.
(1984). Since current practice generally is to base risk estimates upon the data
set producing the highest cancer risk, the minimum TD50 was selected for each
chemical in each species for each route of administration. The largest subset of
relative potencies was obtained for rats and mice for 190 chemicals
administered in the diet. With dose expressed in terms of mg/kg body weight/
day, the geometric mean of the ratio of the minimum TD50 value for rats
relative to that for mice was 0.45. For dose expressed in terms of concentration
(ppm) in the diet, however, the mean ratio was 1.3. Using either dose metric,
the mean carcinogenic potency of these chemicals in rats and mice agree to
within a factor of about two-fold. The ratio R of the TD50 values for rats and
mice were approximately lognormally distributed, with log10R exhibiting a
standard deviation of 0.82; this corresponds to a multiplicative factor of 100.82
≈ 7-fold. For 4 of the 190 chemicals, the ratios of

OCR for page 141

APPENDIX F 142
original typesetting files. Page breaks are true to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be
About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the
retained, and some typographic errors may have been accidentally inserted. Please use the print version of this publication as the authoritative version for attribution.
the TD50s for rats and mice differed by more than a factor of 100.
Chen & Gaylor (1987) used results from the NCI/NTP Carcinogenesis
Bioassay Program to compare cancer risk estimates for rats relative to those for
mice for chemicals administered orally. The 10-6 RSD was calculated for rats
and mice for those chemicals that showed a dose-response trend in the same sex
at the same tissue/organ site in both species. In all, 69 comparisons of RSDs
between rats and mice for 38 rodent carcinogens were made. The overall
geometric mean of the RSD ratios for rats to mice was 1.27, with dose was
measured in terms of concentration (ppm) in the diet. The logarithms of the
ratios of RSDs were approximately normally distributed with a standard
deviation of 0.79, corresponding to a multiplicative factor of approximately 6-
fold. The RSD ratios varied from 1:51 to 49:1 for the 69 cases. Without the
restriction of tumors at the same sex and site in both species, the geometric
mean of the ratio of the minimum RSDs of rats to mice was 1.38 with a
standard deviation of loge ratios of 0.78. It appears that relative potencies for
rats and mice are generally within a multiplicative factor of 100-fold for rodent
carcinogens. However, McGregor (1992) recently noted that amides and halides
tended to exhibit disparate TD50s in rats and mice.
Bernstein et al. (1985) suggested that this apparent interspecies correlation
in carcinogenic potency simply reflects the corresponding high correlation in
MTDs for rats and mice. This provoked a debate as to the interpretation of these
results on interspecies potency correlation (Crouch et al., 1987; Reith & Starr,
1989b).
Reith & Starr (1989b) obtained a correlation of r = 0.83 on a logarithmic
scale between potency estimates for n = 83 chemicals selected from the CPDB
identified as carcinogens in both rats and mice. (In this analysis, potency was
defined as the slope β in (2.3), calculated using the TD50 values given in the
CPDB.) They argued that the correlations arise from (i) the strong interspecies
correlation between MTDs in chronic bioassays, (ii) the small numbers of
animals used per dose group, and (iii) the narrow range of doses typically
tested. Reith & Starr (1989b) further noted a high correlation for chemicals
testing negative in both species (r = 0.85, n = 51), for chemicals testing positive
in rats but negative in mice (r = 0.55, n = 15), and for chemicals testing negative
in rats but positive in mice (r = 0.68, n = 25). Reith & Starr (1989b) recomputed
these correlations after dividing each poten

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APPENDIX F 143
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cy estimate by the MDT. The largest correlation (r = 0.27) was obtained for
chemicals testing negative in both rats and mice; none of the four recomputed
correlations was significantly greater than zero (p > 0.05).
To further illustrate the correlation in TD50 values for rats and mice,
consider the data on 127 of the 492 rodent carcinogens discussed by Gold et al.
(1989) which are carcinogenic in both species. These data demonstrate a high
correlation between TD50 values for rats and mice (Figure 5), with a Pearson
correlation of 0.808.
This observation may also be derived analytically (annex E). Let us
assume that the MDTs for the rat and mouse carcinogens are both lognormally
distributed, with MTDrats = cMTDmice. (Although Bernstein et al., 1985,
estimate c to be 0.357, the correlation coefficient is independent of c.) Suppose
further that the TD50s for each species are uniformly distributed about the MTD
within the 32-fold range considered by Bernstein et al. (1985), and that, given
the MTDs for each species, the TD50s for rats and mice are statistically
independent. These assumptions lead to a correlation based on equation (E.5) in
annex E of 0.943 for the TD50 values for rats and mice. The assumption of strict
proportionality between MTD rats and MTD mice may be relaxed as discussed
in annex E, leading to a reduced correlation of 0.763.
Shlyakhter et al. (1992) studied the correlation between carcinogenic
potency and the MTD and the correlation between carcinogenic potencies in
rats and mice by computer simulation based upon characteristics of NCI/NTP
carcinogenicity tests. This investigation demonstrated that the observed
correlation between carcinogenic potency and the MTD could, under certain
conditions, produce a correlation which is purely artifactual. However, by
comparison with actual bioassay data it was concluded that the observed
correlation cannot be an artifact of constraints on the data and therefore must
have some biological basis. This suggests that the observed correlation in
carcinogenic potency between rats and mice cannot be attributed solely to
bioassay design (particularly the MTD), so that the correlation is at least partly
attributable to the biological similarity of rodent species.
Freedman et al. (1992) also argue that the correlation in carcinogenic
potency between rats and mice is not entirely tautological. This analysis is
based on a comparison of models for interspecies correlation that are either
entirely artifactual (due to constraints imposed by the MTD) or