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September 16, 2005 Statistical Methods for Testing Carcinogenic Potential of New Drugs in Animal Carcinogenicity Studies Hojin Moon, Ph.D. HMoonnctr.fda.gov.

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Presentation on theme: "September 16, 2005 Statistical Methods for Testing Carcinogenic Potential of New Drugs in Animal Carcinogenicity Studies Hojin Moon, Ph.D. HMoonnctr.fda.gov."— Presentation transcript:

1 September 16, 2005 Statistical Methods for Testing Carcinogenic Potential of New Drugs in Animal Carcinogenicity Studies Hojin Moon, Ph.D. HMoonnctr.fda.gov E-mail: HMoon@nctr.fda.govHMoonnctr.fda.govHMoon@nctr.fda.gov September 16, 2005

2 National Center for Toxicological Research, U.S. Food and Drug AdministrationCollaborators Dr. Ralph L. Kodell – DBRA, NCTR, FDA Dr. Ralph L. Kodell – DBRA, NCTR, FDA Dr. Hongshik Ahn – SUNY@Stony Brook Dr. Hongshik Ahn – SUNY@Stony Brook

3 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Animal Carcinogenicity Study Studies are conducted to assess the oncogenic potential of chemicals encountered in food or drugs for the protection of public health Studies often involve a problem of testing the statistical significance of a dose- response relationship among dose (treatment) groups. Various statistical testing methods for a dose- response relationship (Ahn and Kodell, 1998)

4 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Animal Carcinogenicity Study Typical Experimental Design: A zero-dose control and 2 or 3 dose groups 50 or more animals (mice or rats) per sex/group Exposure to a test agent at treatment groups of varying doses for the duration of a study At least 18 months in mice, 24 months in rats (CDER, US FDA in Office of the Federal Register, 1985) Multiple (interval) sacrifices or single terminal sacrifice Age at death (survival time) and status (presence/absence) of specific tumor types

5 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Animal Carcinogenicity Study Methods: Data with cause-of-death information assigned by pathologists (Peto type) Data without cause-of-death information (Poly-k type)

6 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Animal Carcinogenicity Study The statistical analysis of animal carcinogenicity data and the Peto COD controversy are current issues in the government-regulated pharmaceutical industry (Lee et al., 2002; STP Peto Analysis Working Group, 2001, 2002; U.S. FDA, 2001) Town Hall meetings were held in both June 2001 & June 2002 at the annual meetings of the STP to discuss issues surrounding COD assignment and implications for using the Peto test or the alternative Poly-3 test Opinions of a number of statisticians (Lee et al., 2002)

7 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Dose-Related Trend Tests Peto Test (Peto et al., 1980) Recommended by IARC Required for product registration in Europe Commonly used in most pharmaceutical companies Needed COD assigned by pathologists Use of COD information has been controversial: (Lagakos, 1982; Racine-Poon & Hoel, 1984; Lagakos & Louis, 1988; Kodell et al., 1995; Ahn et al., 2000; Moon et al., 2002; Moon et al., 2003)

8 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Dose-Related Trend Tests Modifications of Petos Test The Peto imputed COD test (Moon et al., 2002) No COD required Developed constrained NPMLE method to impute COD Imputation of COD: Solve the constrained NPMLE problem by implementing Newton-based method of Ahn, Moon, Kim and Kodell (2002) The weight-adjusted Peto Test (Moon et al., 2004) Use of Fleming-Harrington type weight adjustment (Fleming & Harrington, 1981) Web-based sample size and power estimator (Moon et al, 2002) http://biostatistics.mdanderson.org/ACSS

9 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Dose-Related Trend Tests Cochran-Armitage Trend Test (Cochran, 1954; Armitage, 1955) To detect linear trend across dose groups in lifetime tumor incidence rates Does not require COD Requires an assumption under H 0 that all animals are at equal risk of developing a tumor over the duration of a study A problem for this test arises from the presence of treatment- induced mortality unrelated to the tumor of interest The CA test is known to be sensitive to increase in treatment lethality and to fail to control the probability of a Type I error (Bailer & Portier, 1988; Mancuso et al., 2002; Moon et al., 2003)

10 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Cochran-Armitage Trend Test Dose Group 12….gTotal # w. T y1y1y1y1 y2y2y2y2…. ygygygygy. # w/o T N 1 - y 1 N 2 - y 2 …. N g – y g N - y. # subjects N1N1N1N1 N2N2N2N2…. NgNgNgNgN The CA test utilizes the tumor data pooled over the study duration for each group Expected # w T in group Dose level in group Under the null hypothesis of equal tumor incidence rates among groups Some treatments shorten overall survival -> decreased risks of tumor onset Survival time is not utilized Observed # w T in group

11 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration The Poly-k Trend Test Appropriate alternative to the Peto-type test No COD required Adopted by NTP as its official test for carcinogenicity Survival-adjusted quantal-response procedure that takes dose-group differences in intercurrent mortality (all deaths other than those resulting from a tumor of interest) into account.

12 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration The Poly-k Trend Test Bailer & Portier (1988) Proposed the Poly-3 test, which made an adjustment of the CA test by using a fractional weighting scheme # at risk in group where (time-at-risk weight for the k th animal in group i) Replace N i with r i in calculating Z CA First mentioned the Poly-k test without specifying how to obtain k Recommended k=3 following evaluation of neoplasm onset time distribution in control F344 rats and B6C3F1 mice (Portier et al., 1986) The Poly-k test with correct k -> Superior operating characteristics to the Poly-3 test

13 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration The Poly-k Trend Test Bieler & Williams (1993) Further modified the CA test by an adjustment of the variance estimation of the test statistic using the delta method (Woodruff, 1971) Showed that the Bailer-Portier Poly-3 test is anticonservative for low tumor incidence rates and for high treatment toxicity Characteristics of the BP Poly-3 test and the BW Poly-3 test can be found in Chen et al. (2000) Objectives The Poly-k statistic: asymptotically normal under H 0 of equal tumor incidence rates among groups (Bieler & Williams, 1993) The Poly-k statistic: asymptotically normal under H 0 of equal tumor incidence rates among groups (Bieler & Williams, 1993) Valid only if the correct value of k is used Valid only if the correct value of k is used Develop the method of bootstrap resampling to estimate the empirical distribution of the test statistic and corresponding critical value of the Poly-k test while taking into account the presence of competing risks Develop the method of bootstrap resampling to estimate the empirical distribution of the test statistic and corresponding critical value of the Poly-k test while taking into account the presence of competing risks

14 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Generalized Poly-k Test Moon et al. (2003) Proposed a method for estimating k for data with interval sacrifices (interim sacrifices and a terminal sacrifice) Estimation of the poly-k based empirical lifetime cumulative tumor incidence rate, a function of k Estimation of cumulative tumor incidence rate (Kodell & Ahn, 1997) Equate two estimate and find k

15 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Generalized Poly-k Test Moon et al. (2005) – Bootstrap-based age- adjusted Poly-k test Improving the Poly-k test for data with a single terminal sacrifice Estimation of k for single sacrifice data is more difficult than that for data with interval sacrifices due to lack of information on tumor development among live animals before the termination of the experiment Propose a method of bootstrap-based age-adjusted resampling to improve the Poly-k test via a modification of the permutation method of Farrar & Crump (1990), which was used for exact statistical tests

16 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Objectives Develop the method of bootstrap resampling to estimate the empirical distribution of the test statistic and corresponding critical value of the Poly-k test while taking into account the presence of competing risks that are possible COD We attempt to keep the CRSR using an age- adjusted resampling scheme as well as to preserve the tumor incidence rates under H 0 and to assess the significance of the Poly-k test

17 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Bootstrap Method X = (x 1, x 2, …, x n ) Data Set T(X)..... Bootstrap X *1 X *2 X *B..... Samples T(X *1 ) T(X *2 ) T(X *B ) BootstrapReplicates 100(1-α) percentile: CR(X) 100(1-α) th percentile: CR(X) Reject H 0 if T(X) CR(X)

18 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Bootstrap Method Suitable for data with the same CRSR When the CRSR is different across dose groups in the original data, the bootstrap samples from the pooled data may not reflect the CRSR of each group, while satisfying the null distribution of equal tumor incidence rate across groups Need to modify the bootstrap method in order to preserve the survival rates in each dose group Develop an age-adjusted scheme

19 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Age-adjusted Bootstrap Scheme X = (x 1, x 2, …, x n ) Data Set T(X) Samples Replicates..... Bootstrap X *1 X *2 X *B..... T(X *1 ) T(X *2 ) T(X *B ) Bootstrap Age-adjusted scheme I(I,m); i=1,….,G; m=1,….,M i 100(1-α) percentile: CR(X); 100(1-α) th percentile: CR(X); Reject H 0 if T(X) CR(X)

20 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example ID Group 1 Group 2 Group 3 Group 4 A74 B145 C176 D185 E243 F300 G316 H324 I340 J341 K343 L345 M351 N385 ….. Death times (in days) in a hypothetical animal carcinogenicity data set with 4 groups

21 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example ID Group 1 Group 2 Group 3 Group 4 A74 B145 C176 D185 E243 F300 G316 H324 I340 J341 K343 L345 M351 N385 ….. Death times (in days) in a hypothetical animal carcinogenicity data set with 4 groups

22 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example ID Group 1 Group 2 Group 3 Group 4 A74 B145 C176 D185 E243 F300 G316 H324 I340 J341 K343 L345 M351 N385 ….. Death times (in days) in a hypothetical animal carcinogenicity data set with 4 groups

23 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example ID Group 1 Group 2 Group 3 Group 4 A74 B145 C176 D185 E243 F300 G316 H324 I340 J341 K343 L345 M351 N385 ….. Death times (in days) in a hypothetical animal carcinogenicity data set with 4 groups

24 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Simulation Study To evaluate the improvement of the proposed test in terms of the robustness to a variety of tumor onset distributions Typical bioassay design according to standard designs of NTP 4 dose groups (dose levels: 0, 1, 2 and 4) of 50 animals each Experimental duration of 2 yrs. A single terminal sacrifice at the end of the experiment

25 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Simulation Study Illustration of illness and death with possible transitions (Kodell & Nelson, 1980) Illustration of illness and death with possible transitions (Kodell & Nelson, 1980) Death from Tumor (T D ) Death from Competing Risks (T 3 ) Tumor (T 1 )Normal

26 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Simulation Study Modeling T 1 : Time to tumor onset S(t) = exp[-θδ(t/t max ) k ] T 2 : Time after onset until death from the tumor Q(t) = exp[-φ( γ 1 t+ γ 2 t γ3 )] T 3 : Time to death from a competing risk The same form as Q(t) φ is selected to reflect tumor lethality T 1 + T 2 = T D : Time to death from the tumor of interest

27 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Simulation Study Tumor onset distributions: Tumor onset distributions: Weibull tumor onset distribution with shape parameter k = 1.5, 3.0 and 6.0 Weibull tumor onset distribution with shape parameter k = 1.5, 3.0 and 6.0 Tumor rates: Tumor rates:.05,.15 and.30 for the control.05,.15 and.30 for the control Size evaluation: Size evaluation: tumor rates are the same across dose groups tumor rates are the same across dose groups Power evaluation: Power evaluation: tumor rates for the highest dose group by 104 weeks: 5, 3 and 2 times the background tumor rates of.05,.15 and.30, respectively tumor rates for the highest dose group by 104 weeks: 5, 3 and 2 times the background tumor rates of.05,.15 and.30, respectively CRSR (from NTP feeding studies, Haseman et al., 1998) CRSR (from NTP feeding studies, Haseman et al., 1998) (.6,.6,.6,.6); (.6,.5,.4,.3); (.6,.6,.5,.2); (.5,.5,.5,.2); (.5,.6,.5,.4); (.5,.7,.6,.4); (.5,.7,.6,.5) (.6,.6,.6,.6); (.6,.5,.4,.3); (.6,.6,.5,.2); (.5,.5,.5,.2); (.5,.6,.5,.4); (.5,.7,.6,.4); (.5,.7,.6,.5) 5000 simulated data sets; α =.05 significance level; 5000 simulated data sets; α =.05 significance level; For each data set, 5000 bootstrap samples For each data set, 5000 bootstrap samples

28 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Simulation Study Size & Power Evaluation with 5000 simulated data sets, 5000 bootstrap samples for each data set and 5% nominal significance level TRCRSRWeibull 1.5Weibull 3.0Weibull 6.0 BNBNBN.3.3.6,.6,.6,.6.053.050.054.050.055.052.5,.5,.5,.2.044.066.044.041.040.021.6,.6,.5,.2.036.072.033.037.033.018.6,.5,.4,.3.047.069.043.045.040.024.5,.6,.5,.4.049.055.050.048.037.5,.7,.6,.4.046.053.048.046.045.036.5,.7,.6,.5.054.050.051.047.054.044.3.3.6,.6,.6,.6.918.934.908.923.893.904.5,.5,.5,.2.837.932.781.847.725.667.6,.6,.5,.2.790.939.734.846.668.638.6,.5,.4,.3.864.938.825.884.773.748.5,.6,.5,.4.886.929.868.895.834.819.5,.7,.6,.4.881.930.856.892.817.810.5,.7,.6,.5.904.927.884.909.859.865

29 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example The 2-yr Gavage Study of Furan The 2-yr Gavage Study of Furan Furan (C 4 H 4 O), a clear and colorless liquid, serves primarily as an intermediate in the synthesis and preparation of numerous organic compounds (NTP, 1993) Furan (C 4 H 4 O), a clear and colorless liquid, serves primarily as an intermediate in the synthesis and preparation of numerous organic compounds (NTP, 1993) Toxicology and carcinogenesis studies were conducted by administering furan in corn oil by gavage to groups of F344/N rats and B6C3F 1 mice of each sex for 2 yrs Toxicology and carcinogenesis studies were conducted by administering furan in corn oil by gavage to groups of F344/N rats and B6C3F 1 mice of each sex for 2 yrs Furan was nominated by the NCI for evaluation of carcinogenic potential due to its large production volume and use, and because of the potential for widespread human exposure to a variety of furan- containing compounds Furan was nominated by the NCI for evaluation of carcinogenic potential due to its large production volume and use, and because of the potential for widespread human exposure to a variety of furan- containing compounds

30 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Example Female F344/N rats Female F344/N rats Evaluation of carcinogenic potential on incidences of cholangiocarcinoma or hepatocellular neoplasms of the liver Evaluation of carcinogenic potential on incidences of cholangiocarcinoma or hepatocellular neoplasms of the liver Groups of 50 rats were administered 2, 4 or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 yrs Groups of 50 rats were administered 2, 4 or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 yrs Male B6C3F 1 mice Male B6C3F 1 mice Evaluation of carcinogenic potential on incidences of adenocarcinoma or alveolar/bronchiolar adenoma of the lung. Evaluation of carcinogenic potential on incidences of adenocarcinoma or alveolar/bronchiolar adenoma of the lung. Groups of 50 mice received doses of 8 or 15 mg/kg furan 5 days per week for 2 yrs Groups of 50 mice received doses of 8 or 15 mg/kg furan 5 days per week for 2 yrs

31 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Data GroupAnimal Tumor Pathology Liver a Vehicle Control1(0), 2(16), 3(0), 4(34) 2 mg/kg1(1), 2(17), 3(1), 4(31) 4 mg/kg1(3), 2(19), 3(3), 4(25) 8 mg/kg1(4), 2(27), 3(6), 4(13) Lung b Vehicle Control1(3), 2(14), 3(4), 4(29) 8 mg/kg1(4), 2(24), 3(3),4(19) 15 mg/kg1(7), 2(23), 3(6), 4(14) a Cholangiocarcinoma or hepatocellular neoplasms of the liver in female F344/N rats b Adenocarcinoma or alveolar/bronchiolar adenoma of the lung in male B6C3F 1 mice

32 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Test results on the carcinogenic activity of furan in female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver (Reject when T(X) CR(X)) mg/kgT(X) a BW CR(X) b Normal CR(X) c Bootstrap Overall4.16171.6449 (p<.001)2.0141 (p<.001) 0,2,42.77051.6449 (p=.003)1.9584 (p=.004) 0,2,84.35591.6449 (p<.001)1.9584 (p<.001) 0,4,83.66321.6449 (p<.001)1.8214 (p<.001) 0,21.46411.6449 (p=.072)1.4625 (p=.040) 0,42.65421.6449 (p=.004)1.5905 (p=.001) 0,83.84201.6449 (p<.001)1.7423 (p<.001) a The BWP3 test statistic obtained from the data b Standard normal critical value at the significance level.05 c Critical value estimated by the 95 th percentile of T(X)s from our method NTP concluded that under the conditions of these 2-yr gavage studies, there was clear evidence of carcinogenic activity of furan in female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver

33 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Test results on the carcinogenic potential of furan on incidences of adenocarcinoma and alveolar/bronchiolar adenoma of the lung in male B6C3F 1 mice (Reject when T(X) CR(X)) mg/kgT(X) a BW CR(X) b Normal CR(X) c Bootstrap Overall1.69951.6449 (p=.045)1.7774 (p=.058) 0,151.68051.6449 (p=.046)1.6938 (p=.052) 0,8.22291.6449 (p=.41)1.9248 (p=.53) a The BWP3 test statistic obtained from the data b Standard normal critical value at the significance level.05 c Critical value estimated by the 95 th percentile of T(X)s from our method Our test results agree with the conclusions from NTP

34 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Significance The statistical analysis of tumorigenicity data from animal bioassays remains an important regulatory issue to FDA and the pharmaceutical industry The present research will build to further refine the Poly- k test in order to make it more broadly competitive with the Peto test The improved Poly-k test for dose-related trend will be robust to a variety of tumor onset distributions. It will control the false positive rate better than the Poly- 3 test, thus having enhanced performance in identifying dose-related trends. With no information on COD or tumor lethality, the improved version can be used confidently when Petos test can not be implemented

35 References Ahn H, Kodell RL (1998). Analysis of long-term carcinogenicity studies. In Design and Analysis of Animal Studies in Pharmaceutical Development, Chow SC, Liu JP (eds). Marcel Dekker, Inc.: New York, 259-289. Armitage P (1955). Tests for linear trends in proportions and frequencies. Biometrics, 11, 375- 386. Bailer AJ, Portier CJ (1988). Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples. Biometrics, 44, 417-431. Bieler GS, Williams RL (1993). Ratio estimates, the delta method, and quantal response tests for increased carcinogenicity. Biometrics, 49, 793-801. Chen JJ, Lin KK, Huque MF, Arani RB (2000). Weighted p-value for animals carcinogenicity trend test. Biometrics, 56, 596-592. Cochran WG (1954). Some methods for strengthening the common x 2 tests. Biometrics, 10, 417- 451. Lee PN, Fry JS, Fairweather WR, Haseman JK, Kodell RL, Chen JJ et al. (2002). Current issues: statistical methods for carcinogenicity studies. Toxicologic Pathology, 30, 403-414. Mancuso JY, Ahn H, Chen JJ, Mancuso JP (2002). Age-adjusted exact trend tests in the event of rare occurrences. Biometrics, 58, 403-412. Moon H, Ahn H, Kodell RL, Lee JJ (2003). Estimation of k for the poly-k test. Statistics in Medicine, 22, 2619-2636. National Toxicology Program (1993). Toxicology and carcinogenesis studies of furan in F344/N rats and B6C3F1 mice (Gavage studies). NTP Technical Report, 402, Research Triangle Park, NC. STP Peto Analysis Working Group (2001). The Society of Toxicological Pathologys position on statistical methods for rodent carcinogenicity studies. Toxicologic Pathology, 29(6), 670-672. STP Peto Analysis Working Group (2002). The Society of Toxicological Pathologys recommendations on rodent carcinogenicity studies. Toxicologic Pathology, 30, 415-418. U.S. FDA (2001). Guidance for industry: statistical aspects of the design, analysis, and interpretation of chronic rodent carcinogenicity studies of pharmaceuticals. Federal Register, 66(89), 23266-23267. Woodruff RS (1971). A simple method for approximating the variance of a complicated estimate. Journal of the American Statistical Association, 66, 411-414.

36 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Ongoing Research Developing improved survival-adjusted statistical tests in long-term tumorigenicity bioassays (NCTR E07171.01) Developing estimators for hazard identification in long- term tumorigenicity bioassays (NCTR E07172.01) Developing statistical procedures for incorporating dose- response-model uncertainty into microbial risk assessment (NCTR E07045.01) Developing statistical tests for distinguishing tumor frequency risks (effect on the number of induced tumors) from tumor latency risks (effect on their times to observation) in mutiple-tumor photococarcinogenicity studies (NCTR E07061.01)

37 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Abstract Researches in carcinogenicity have been actively conducted to understand the carcinogenic potential of chemicals exposed to humans. Long-term and animal-intensive carcinogenic studies have been performed to extrapolate carcinogenic risks in humans from exposure to drugs and food tainted. In this seminar, we discuss recent development of improved survival-adjusted and age-adjusted dose-related trend tests to achieve improved robustness to a variety of tumor onset distributions. We consider extensions of the survival- adjusted Cochran-Armitage test, known as the Poly-k test, to improve the robustness not only to the effects of differential mortality across groups but also to various tumor onset distributions. The Cochran-Armitage test is routinely applied for detecting a linear trend in the incidence of a tumor of interest across dose groups. We examine our recently developed statistical methods with real data sets including National Toxicology Program data sets to evaluate a dose-related trend of a test substance on the incidence of neoplasms.

38 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Animal Carcinogenicity Data from the ED 01 Study - NCTR To find the carcinogenic effect of feeding 2-AAF to female mice (Littlefield et al., 1980) A subset (low dose groups) of data with a single sacrifice was obtained To test dose-related trend of the liver tumor incidence

39 September 16, 2005National Center for Toxicological Research, U.S. Food and Drug Administration Frequency Tabulation of number of mice in the ED 01 study Dose (ppm) NTP intervals (days) Fatal tumors assigned by pathologists Natural Death Sacrifice With tumor Without tumor Tumor present No tumor present 00-36400900 365-546001500 547-644113400 645-72611607137 300-364001700 365-546024200 547-644166700 645-726278422279 350-36401900 365-546333100 547-644115500 645-726018018192 450-36400700 365-546111300 547-644354300 645-726236619132


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