LITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY

J.E.A. Leakey; W.T. Allaben; J.K. Dunnick; F.W. Lee; S.M. Lewis; P.C. Howard; C.C. Weis; D.D. Paine; S.M. Billedeau; B.R. Brown; J.P Freeman; J. Moody; L.K. Schoenbachler; P.H. Siitonen; S.J. Culp; J.M. Fowler; R.D. Smith; S. Appana; S.J. Baek; R.P. Felton; B.T. Thorn; C.J. Cain; J.W. Carson; A. Matson; K.A. Carroll; S.H. Green; P.W. Mellick; G.R. Olson; A.R. Warbritton; L.P. Wiley; M.H. Hamlin, II; J.F. Hardisty; R.A. Miller; J.F. Hardisty; J.M. Cullen; S.A. Elmore; D.E. Malarkey; P.W. Mellick; R.A. Miller; G.R. Olson; P.C. Howard; W.T. Allaben; N.J. Walker; J.R. Bucher; S.R. Gunnels; L.M. Harper; E.S. Rathman; D.C. Serbus

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Leakey JEA, Allaben WT, Dunnick JK, et al. NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2013 Oct.

Cover of NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study)

NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53^tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet].

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APPENDIX GLITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY

Background

The study design consisted of three different dosing regimens: (1) 30-week continuous dosing consisting of two dose groups (0/0/0 and 240/120/240 mg AZT/kg body weight per day); (2) 45-week continuous dosing consisting of four dose groups (0/0/0, 80/40/80, 160/80/160 and 240/120/240 mg/kg per day); and (3) 45-week stop-study (0/0 and 240/40 mg/kg per day). There were 24 to 27 animals per sex per dose group.

Female C3H/HeNTac wild-type mice were mated with male homozygous, p53-null C57BL/6(N12)Trp53^(−/−) mice in order to produce heterozygous F1 p53^+/− offspring. Each male was mated consecutively with up to six females. The pregnant females were randomized to the treatment groups and heterozygous F1 p53^+/− mice were bred into the study. The mice were dosed by gavage. The pregnant females were dosed daily from gestational day (GD) 12 through GD 18. On postnatal day (PND) 1, heterozygous F1 p53^+/− mice were culled to six pups (three males and three females where possible) and postnatal dosing was initiated. The pups were dosed with half the adult dose in half the dosing volume, except in the 45-week stop-study where pups received one-sixth of the maternal dose in half the dose volume. Pups from the same litters could be utilized for the 30- and 45-week continuous dosing studies, because they used the same dosing regimen. Different litters were used for the 45-week stop-study. Pups were weighed and dosed as a litter (i.e. each pup received a dose calculated from the total weight of the litter divided by the number of surviving pups in that litter) from PND 1 through PND 10 for the 30-week and 45-week continuous dosing studies and from PND 1 through PND 8 (with either vehicle or 40 mg/kg) for the 45-week stop-study. For the continuous dosing studies, the pups were individually weighed and administered the same adult dose as their mother from PND 11 onwards. Pups used for the 45-week stop-study were not dosed after PND 8.

The heterozygous F1 p53^+/− mice were weaned on PND 21 and assigned to either stay on study or to be culled on PND 28 for genotoxicity evaluations (see Appendix B). In general, either one or two mice of each sex from the same litter were assigned to each study; however, in certain cases three or four pups had to be assigned in order to provide sufficient mice to complete the dose group. The litter and sire assignments of all pups assigned to the three studies are shown in Tables G1 and G2. The primary experimental unit in this study was the heterozygous F1 p53^+/− pup. However, because the male C57BL/6(N12)Trp53^(−/−) mice used in these studies sired multiple litters and more than one pup per litter was loaded into the studies, two potential clustering factors existed: common litter origin and common sire. While all pups within a litter received the same treatment (i.e. litter implies treatment group), pups from the same sire were not restricted to the same litter (i.e. sire does not imply treatment group).

Additional analyses were performed as outlined below to determine whether these clustering factors had any significant influence on the outcome of the survival, body weight, and pathology evaluations in the three studies.

Methods

Survival

A proportional hazards model (Cox, 1972) was run by Sex and Group using Days-On-Study, the censor flag, and AZT dose as the predictor. For the 45-week continuous dosing study, a linear trend estimate was formed using contrasts.

The proportional hazards assumption was checked using the method of Lin et al. (1993). The litter or sire effect clustering was adjusted for by using the aggregated sandwich estimate of variance (Lin and Wei, 1989; Binder, 1992). Ties were handled by Efron’s (1977) method.

All tests of interest were single degree-of-freedom tests and were transformed into estimate ± standard error and given a Z-score testing against zero and a single-sided P value following NTP convention of appending an “N” for negative dose effects.

Three sex × group × dose combinations had no dead/moribund events: 0/0/0 mg/kg males in the 30-week study, 240/120/240 mg/kg females in the 30-week study, and 160/80/160 mg/kg males in the 45-week study. To facilitate convergence for the analyses involving these combinations, an augmented dataset was created by adding a dummy event at the study termination time for each combination and weighting the observation as one-tenth of an observation. Actual observations were weighted as a full observation.

Body Weight

A repeated measures model with a heterogeneous autoregressive covariance structure was used for the analyses of body weight unadjusted for litter or sire (Appendix D). The repeated measures model refers to the fact that multiple observations were taken on the same animal over time and that the observations for this animal are likely to be more alike than those between two different animals. The design within dosing regimen and sex was a one-way repeated measures model with AZT dose as the fixed effect and time as the repeated measures variable. Testing for an overall linear or quadratic dose trend was accomplished using contrasts. Dunnett’s tests (Dunnett, 1955) on AZT dose were computed for each time point. These tests compared each dosed group with the vehicle control group and made an adjustment for the fact that several comparisons were being carried out concurrently. Summary statistics for the animals’ body weights (in grams) are presented by sex, time (in weeks), and AZT dose (in order to compare dose effects) for each dosing regimen.

The body weight data for each animal were rasterized to evenly-spaced time points (every week) via locally weighted scatterplot smoothing scoring (Cleveland, 1979; Cleveland et al., 1988). This process reduces the number of time points for the mixed-effects model, reduces the effects of outliers, and creates a grid of regularly spaced time points. The scored data were then treated as primary data for the mixed-effects model.

This study needed to correct for possible correlation among littermates and it was long enough to demonstrate variance heterogeneity over time. Therefore, a choice was necessary because of the difficulty in simultaneously adjusting for litters and for variance heterogeneity. The analysis opted to keep litter-adjustments and to estimate the model at each time point. These models were run separately for each sex. The model treated body weight as a function of treatment group. Observations within each litter (dam- or sire-determined) were presumed to be correlated at a given time point. Since separate analyses were performed at each time point, the variance was allowed to change.

In order to better summarize the results, a two-stage analysis was also conducted for each sex × study duration combination on two aspects of the growth curves: early growth rate (slope between 2 and 5 weeks for all studies) and late growth rate (slope between 38 and 44 weeks for the 45-week studies and slope between 23 and 29 weeks for the 30-week study). These analyses determined whether there were any treatment-related effects on early growth or late growth.

Dunnett’s method was used to compare dose levels to control within each drug combination at each age. A polynomial contrast was used to test for linear trend with dose at each age. Contrasts were used to compare drug combinations within dose levels at each age.

Pathology

For neoplastic lesions, the Poly-k method of Bailer and Portier (1988) as modified by Bieler and Williams (1993) and NIEHS (continuity correction) was used to analyze age-adjusted incidence. For liver neoplasms in male mice, a k=5 analysis was run in addition to the standard k=3 analysis because comparison between the neoplasm incidences at 30 weeks and 45 weeks suggested a steeper tumor progression curve for heterozygous F1 p53^+/− mice than for B6C3F1 mice that are used in 2-year carcinogenicity studies.

Bieler and Williams (1993), in the derivation of their variance correction, used the fact that the Cochran-Armitage test can be envisioned as a binomial-weighted regression. Beginning with a regression paradigm with binomial weights, this framework can be generalized and the Cochran-Armitage test can be viewed as a generalized linear model (GLIM) with binomial variation and an identity link function. If this analysis is performed with Poly-k weights, the resulting analysis can be used with more complex designs, including litter correlations and factorial effects as well as alternative link functions.

Correlation among littermates (litter adjusted) was achieved by using the GLIM described above with estimation using generalized estimating equations (GEE) (Liang and Zeger, 1986) and an exchangeable correlation among littermates. Sire-adjusted analyses were generated in the same manner differing only in the specification of the correlation group variable.

It should be noted that the implementation details of this method are different from the Bieler and Williams variance-adjusted Poly-k test (Bieler and Williams, 1993). Particularly, the variance is not quantal adjusted and all comparisons are estimated within a single analysis of variance model rather than multiple regression models. Suitable contrasts were used to test the relevant hypotheses. One-sided results were generated and, per NTP custom, an “N” was appended to indicate negative trends. Since the variance structure is group specific rather than estimated from the null hypothesis, uniform treatment groups were dealt with by adding an uncorrelated dummy lesion observation to all groups (if necessary for any group) with value=0.005 and Poly-3 weight=0.005.

The presented results include the usual unadjusted Bieler and Williams’ quantal-adjusted Poly-3, Poly-3 weighted binomial/identity-link GLIM with litter-adjusted GEE correlation, and Poly-3 weighted binomial/identity-link GLIM with sire-adjusted GEE correlation.

For nonneoplastic lesions, the Poly-k method was used with k=3 to analyze age-adjusted incidences and the nonzero severity score averages were computed. The cluster-adjusted models were used here, also. In addition, to incorporate lesion severity scores, the distribution-free (but unadjusted for age) method of Jonckheere (1954) and Terpstra (1952) was used to compute monotonic trend tests, and the method of Shirley (1977) as modified by Williams (1986) was used to compute comparisons to the vehicle controls (JT/SW). No attempt was made to adjust JT/SW for correlation among clusters.

Results

Survival

In the 30-week study, dosed male mice exhibited significantly greater hazard compared to the 0/0/0 mg/kg group, indicated by five early deaths or moribund animals in the 240/120/240 mg/kg group relative to no early deaths or moribund animals in the 0/0/0 mg/kg group. Malignant lymphoma was present in three of the five early removals. Cluster analyses for litter or sire effects did not alter the empirical variance or its significance (Table G3).

There is no indication that AZT significantly increased the hazard in female mice dosed continuously with 240/120/240 mg/kg until 30 weeks, in male or female mice dosed continuously with 80/40/80, 160/80/160, or 240/120/240 mg/kg until 45 weeks, or in male or female mice dosed with 240/40 mg/kg until PND 8 and killed at 45 weeks. Cluster analyses for litter or sire effects did not alter the empirical variance or significance of any of these dose groups (Tables G3, G4, and G5).

Two AZT dose groups demonstrated significantly smaller hazard than the vehicle control group: 30-week study females administered 240/120/240 mg/kg (Table G3) and 45-week study males administered 160/80/160 mg/kg (Table G4). As before, this was due to the lack of failures in these AZT-dosed groups in this study and not to any other distinction. It seems unlikely that AZT serves any protective function and the result is more likely due to chance.

The linear trend tests performed for the 45-week study males were significant (Table G4). This was due to the zero failures in the 160/80/160 mg/kg males; if this cell is ignored then no significant trends are apparent. For the 45-week stop-study, there was no significant dose effect on survival in either male or female mice with or without adjustment for litter or sire clustering (Table G5).

The results tend to indicate that intralitter correlation with regards to survival is either not present or is negative. In any case, merely using the empirical variance estimator caused far more impact than the actual aggregation over dams (litters) or sires.

Body Weight

The unadjusted body weight tables are shown in Appendix D. The two adjusted analyses (data not shown) were generally identical to the unadjusted analysis (Appendix D).

Pathology

The following results refer to the litter-adjusted analyses unless otherwise stated. Liver hepatocellular adenoma was the only non-systemic neoplasm found to occur within male mice in sufficient quantity to justify analysis. Hepatocellular carcinoma was also found in males (although in insufficient numbers to justify its own analysis). Therefore, the hepatocellular adenoma or carcinoma pool was also analyzed. The only neoplasm found within female mice in sufficient quantity to justify analysis was the systemic lesion malignant lymphoma.

Neoplasms

Generally, the adverse dose-response effects in males were not very notable with the exception of incidences of hepatocellular adenoma.

For males in the 45-week study, significant positive trends occurred in the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined), and the incidences of these lesions in the 240/120/240 mg/kg group were significantly increased relative to the 0/0/0 mg/kg group (Table G7). Using k=5 rather than k=3 for the Poly-k survival adjustment did not alter the significance of the tumor incidence increases. Incidences of benign neoplasms (in all organs) showed a significant positive dose trend but no individual dose group incidence differed significantly from that in the 0/0/0 mg/kg group. Adjusting the data for intralitter correlation did not substantially change the conclusions, and in these tumor pools, the estimated correlation was negative or nearly zero. P values were decreased slightly for the litter-adjusted and sire-adjusted Poly-3 tests relative to those of the naive Poly-3 test.

In the 30-week study, incidences (in all organs) of malignant lymphoma, malignant neoplasms, and benign and malignant neoplasms (combined) were significantly increased in 240/120/240 mg/kg males compared to those in the 0/0/0 mg/kg group (Table G6). The naive analysis did not find the incidence of malignant lymphoma to be significantly increased.

No significant dose effects were found in 45-week stop-study males (Table G8).

Generally, the adverse dose-response effects in females were not very notable. For females in the 45-week study, significant positive trends occurred in the incidences (in all organs) of malignant lymphoma and malignant neoplasms found (Table G10), and the incidence of malignant lymphoma in the 240/120/240 mg/kg group was significantly increased compared to that in the 0/0/0 mg/kg group. Using the naive analysis, there was no significant trend in the incidences of malignant neoplasms and, although there was a positive trend in the incidences of malignant lymphoma, the incidence in the 240/120/240 mg/kg group did not differ from that in the 0/0/0 mg/kg group.

No significant dose effects were found in females in the 30-week study (Table G9) or 45-week stop-study (Table G11).

Nonneoplastic Lesions

In general, AZT administration significantly increased the incidence or severity of few nonneoplastic lesions when analyzed by naive Poly-3 tests not adjusting for litter or sire correlation. Adjusting for either litter or sire increased the number of significantly increased nonneoplastic lesion incidences.

In males, positive dose effects were found in the 45-week study in the incidences of preputial gland degeneration and hyperplasia of the cecum when adjusted for litter or sire effects but not with the naive Poly-3 analysis (Table G13). The sire-adjusted analysis also showed the incidence of cellular infiltration of the kidney in 45-week 80/40/80 mg/kg males to be significantly increased, although this result was inconsistent with the (nonsignificant) dose trend in this study and with the significantly decreased incidence in the 30-week study (Table G12). There were several other decreases in the incidences of nonneoplastic lesions, which differed in significance between the naive and adjusted evaluations; details appear in Tables G12 through G14. Generally, the adverse dose responses were not very notable.

In females, the only positive dose effects found were in the 45-week study, including increased incidences of cerebral mineralization, myeloid cell bone marrow hyperplasia, cellular infiltration of the pancreas, and tension lipidosis of the liver (Table G16). These increases were significant when adjusted for litter or sire effects but not with the naive Poly-3 analysis. The only notable positive dose effect seen in 30-week study females was a significant increase in the litter-adjusted incidence of cecum hyperplasia (Table G15). There were several other decreases in the incidences of nonneoplastic lesions, which differed in significance between the naive and adjusted evaluations; details appear in Tables G15 through G17. Generally, the adverse dose responses were not very notable.

Conclusions

The use of common sires and more than one pup per litter to populate dose groups did not confound the sensitivity of these studies. There appeared to be a slightly negative, rather than positive, correlation between littermates and pathologic endpoints. This suggests that in these mice, which are derived from inbred parent strains, the epigenetic effects of intrauterine position override genetic differences between litters.

Table G1Distribution of Male Heterozygous F1 p53^+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Animal Number	Dam UIN^a	Sire UIN^b	Litter UIN^b	Lesion^c	Duration^d	Dose^e
426	7F000000316	7E000000019	7G000001650	Pc	1	0/0
578	7F000000316	7E000000019	7G000001650	L	1	0/0
598	7F000000315	7E000000019	7G000001700	LgA	1	0/0
597	7F000000315	7E000000019	7G000001700		1	0/0
625	7F000000346	7E000000019	7G000001782		1	0/0
618	7F000000346	7E000000019	7G000001782		1	0/0
575	7F000000309	7E000000033	7G000001635		1	0/0
574	7F000000309	7E000000033	7G000001635		1	0/0
599	7F000000310	7E000000033	7G000001721	L	1	0/0
600	7F000000310	7E000000033	7G000001721		1	0/0
629	7F000000351	7E000000033	7G000001818		1	0/0
628	7F000000351	7E000000033	7G000001818		1	0/0
587	7F000000327	7E000000034	7G000001666		1	0/0
588	7F000000327	7E000000034	7G000001666	LgA	1	0/0
576	7F000000320	7E000000037	7G000001642		1	0/0
577	7F000000320	7E000000037	7G000001642		1	0/0
626	7F000000326	7E000000046	7G000001796		1	0/0
585	7F000000325	7E000000049	7G000001659	L	1	0/0
586	7F000000325	7E000000049	7G000001659		1	0/0
635	7F000000345	7E000000052	7G000001849		1	0/0
647	7F000000322	7E000000053	7G000001856		1	0/0
648	7F000000322	7E000000053	7G000001856		1	0/0
652	7F000000360	7E000000055	7G000001880		1	0/0
653	7F000000360	7E000000055	7G000001880	HA	1	0/0
611	7F000000324	7E000000019	7G000001738		1	240/40
612	7F000000324	7E000000019	7G000001738		1	240/40
646	7F000000336	7E000000019	7G000001871		1	240/40
645	7F000000336	7E000000019	7G000001871	L	1	240/40
488	7F000000199	7E000000022	7G000001393		1	240/40
565	7F000000323	7E000000028	7G000001673	L	1	240/40
564	7F000000323	7E000000028	7G000001673		1	240/40
593	7F000000306	7E000000031	7G000001707	L	1	240/40
634	7F000000352	7E000000033	7G000001852	Lym	1	240/40
643	7F000000352	7E000000033	7G000001852	Lym	1	240/40
566	7F000000319	7E000000037	7G000001679		1	240/40
567	7F000000319	7E000000037	7G000001679		1	240/40
581	7F000000312	7E000000039	7G000001695		1	240/40
582	7F000000312	7E000000039	7G000001695		1	240/40
568	7F000000321	7E000000041	7G000001686	Lc	1	240/40
580	7F000000321	7E000000041	7G000001686	Lc	1	240/40
605	7F000000317	7E000000048	7G000001728	L	1	240/40
549	7F000000317	7E000000048	7G000001728	S	1	240/40
644	7F000000341	7E000000052	7G000001865		1	240/40
656	7F000000356	7E000000053	7G000001893	L	1	240/40
657	7F000000356	7E000000053	7G000001893		1	240/40
651	7F000000357	7E000000056	7G000001886		1	240/40
655	7F000000357	7E000000056	7G000001886		1	240/40
664	7F000000338	7E000000056	7G000001899		1	240/40
665	7F000000338	7E000000056	7G000001899		1	240/40
269	7F000000194	7E000000017	7G000001150		2	0/0/0
432	7F000000194	7E000000017	7G000001150		3	0/0/0
517	7F000000177	7E000000017	7G000001446		3	0/0/0
516	7F000000177	7E000000017	7G000001446		3	0/0/0
295	7F000000116	7E000000019	7G000000539		3	0/0/0
394	7F000000347	7E000000019	7G000001752		2	0/0/0
393	7F000000347	7E000000019	7G000001752		2	0/0/0
332	7F000000161	7E000000022	7G000000609		3	0/0/0
210	7F000000123	7E000000023	7G000000478		2	0/0/0
493	7F000000123	7E000000023	7G000000478		3	0/0/0
294	7F000000125	7E000000024	7G000000522	OS	3	0/0/0
212	7F000000125	7E000000024	7G000000522		2	0/0/0
279	7F000000231	7E000000025	7G000001563		2	0/0/0
515	7F000000171	7E000000026	7G000001461	HA	3	0/0/0
514	7F000000171	7E000000026	7G000001461	L	3	0/0/0
469	7F000000135	7E000000029	7G000000542	Lym	3	0/0/0
213	7F000000135	7E000000029	7G000000542		2	0/0/0
348	7F000000225	7E000000029	7G000000636		3	0/0/0
230	7F000000225	7E000000029	7G000000636		2	0/0/0
293	7F000000144	7E000000033	7G000000484		3	0/0/0
211	7F000000144	7E000000033	7G000000484		2	0/0/0
395	7F000000350	7E000000033	7G000001765		2	0/0/0
396	7F000000350	7E000000033	7G000001765		2	0/0/0
350	7F000000120	7E000000036	7G000000672		3	0/0/0
386	7F000000197	7E000000037	7G000000791		3	0/0/0
256	7F000000197	7E000000037	7G000000791		2	0/0/0
349	7F000000132	7E000000038	7G000000642		3	0/0/0
231	7F000000132	7E000000038	7G000000642		2	0/0/0
415	7F000000261	7E000000038	7G000000796	OS	3	0/0/0
355	7F000000142	7E000000041	7G000000680		3	0/0/0
232	7F000000142	7E000000041	7G000000680	L	2	0/0/0
278	7F000000229	7E000000041	7G000001546		2	0/0/0
539	7F000000229	7E000000041	7G000001546		3	0/0/0
277	7F000000229	7E000000041	7G000001546		2	0/0/0
254	7F000000147	7E000000042	7G000000768		2	0/0/0
375	7F000000147	7E000000042	7G000000768	S	3	0/0/0
284	7F000000223	7E000000042	7G000001571		2	0/0/0
280	7F000000223	7E000000042	7G000001571		2	0/0/0
457	7F000000152	7E000000044	7G000000627		3	0/0/0
226	7F000000152	7E000000044	7G000000627	L I	2	0/0/0
374	7F000000153	7E000000045	7G000000731		3	0/0/0
255	7F000000153	7E000000045	7G000000731		2	0/0/0
417	7F000000170	7E000000045	7G000000853		3	0/0/0
263	7F000000170	7E000000045	7G000000853		2	0/0/0
356	7F000000156	7E000000046	7G000000694	Lf	3	0/0/0
233	7F000000156	7E000000046	7G000000694		2	0/0/0
416	7F000000146	7E000000047	7G000000804		3	0/0/0
257	7F000000146	7E000000047	7G000000804		2	0/0/0
357	7F000000166	7E000000049	7G000000701		3	0/0/0
234	7F000000166	7E000000049	7G000000701		2	0/0/0
630	7F000000339	7E000000053	7G000001745	L	3	0/0/0
631	7F000000339	7E000000053	7G000001745		3	0/0/0
557	7F000000364	7E000000056	7G000001945		2	0/0/0
558	7F000000364	7E000000056	7G000001945		2	0/0/0
323	7F000000158	7E000000019	7G000000587		3	80/40/80
324	7F000000158	7E000000019	7G000000587		3	80/40/80
547	7F000000208	7E000000019	7G000001556	L	3	80/40/80
306	7F000000118	7E000000020	7G000000490		3	80/40/80
305	7F000000118	7E000000020	7G000000490		3	80/40/80
494	7F000000149	7E000000022	7G000001198		3	80/40/80
428	7F000000149	7E000000022	7G000001198	Lf	3	80/40/80
427	7F000000149	7E000000022	7G000001198	Lc	3	80/40/80
316	7F000000126	7E000000024	7G000000566		3	80/40/80
309	7F000000126	7E000000024	7G000000566		3	80/40/80
307	7F000000127	7E000000025	7G000000529		3	80/40/80
308	7F000000127	7E000000025	7G000000529		3	80/40/80
543	7F000000205	7E000000034	7G000001518		3	80/40/80
480	7F000000205	7E000000034	7G000001518		3	80/40/80
402	7F000000244	7E000000035	7G000000812		3	80/40/80
401	7F000000244	7E000000035	7G000000812		3	80/40/80
450	7F000000201	7E000000038	7G000001579	Lym	3	80/40/80
362	7F000000137	7E000000039	7G000000777	LgA	3	80/40/80
361	7F000000137	7E000000039	7G000000777		3	80/40/80
171	7F000000243	7E000000041	7G000001512		3	80/40/80
541	7F000000196	7E000000042	7G000001498		3	80/40/80
542	7F000000196	7E000000042	7G000001498		3	80/40/80
511	7F000000220	7E000000043	7G000001476		3	80/40/80
512	7F000000220	7E000000043	7G000001476		3	80/40/80
510	7F000000220	7E000000043	7G000001476	StA	3	80/40/80
444	7F000000246	7E000000048	7G000001437	Nb	3	80/40/80
509	7F000000246	7E000000048	7G000001437	L Lym	3	80/40/80
328	7F000000157	7E000000019	7G000000595	L	3	160/80/160
330	7F000000157	7E000000019	7G000000595		3	160/80/160
320	7F000000145	7E000000020	7G000000572		3	160/80/160
321	7F000000145	7E000000020	7G000000572		3	160/80/160
298	7F000000121	7E000000022	7G000000498	L	3	160/80/160
299	7F000000121	7E000000022	7G000000498		3	160/80/160
410	7F000000232	7E000000022	7G000000836	L	3	160/80/160
409	7F000000232	7E000000022	7G000000836		3	160/80/160
412	7F000000210	7E000000025	7G000000848		3	160/80/160
411	7F000000210	7E000000025	7G000000848		3	160/80/160
379	7F000000224	7E000000028	7G000000752		3	160/80/160
380	7F000000224	7E000000028	7G000000752		3	160/80/160
551	7F000000200	7E000000028	7G000001595		3	160/80/160
358	7F000000190	7E000000029	7G000000666	Lym	3	160/80/160
337	7F000000190	7E000000029	7G000000666	L	3	160/80/160
531	7F000000215	7E000000036	7G000001454		3	160/80/160
530	7F000000215	7E000000036	7G000001454		3	160/80/160
433	7F000000233	7E000000039	7G000001158	L	3	160/80/160
434	7F000000233	7E000000039	7G000001158		3	160/80/160
335	7F000000162	7E000000047	7G000000653		3	160/80/160
334	7F000000162	7E000000047	7G000000653		3	160/80/160
381	7F000000164	7E000000048	7G000000740		3	160/80/160
382	7F000000164	7E000000048	7G000000740		3	160/80/160
424	7F000000173	7E000000048	7G000000862		3	160/80/160
413	7F000000173	7E000000048	7G000000862	L	3	160/80/160
336	7F000000165	7E000000049	7G000000664		3	160/80/160
633	7F000000343	7E000000055	7G000001810		3	160/80/160
344	7F000000216	7E000000019	7G000000689	L	3	240/120/120
314	7F000000117	7E000000020	7G000000554	L	3	240/120/120
219	7F000000117	7E000000020	7G000000554	OS \|	2	\| 240/120/120
482	7F000000160	7E000000020	7G000000602		3	240/120/120
223	7F000000160	7E000000020	7G000000602		2	\| 240/120/120
675	7F000000218	7E000000022	7G000000658		3	240/120/120
342	7F000000184	7E000000023	7G000000616		3	240/120/120
227	7F000000184	7E000000023	7G000000616		2	240/120/120
241	7F000000185	7E000000024	7G000000784		2	240/120/120
389	7F000000185	7E000000024	7G000000784		3	240/120/120
322	7F000000167	7E000000025	7G000000581		3	240/120/120
368	7F000000186	7E000000025	7G000000746		3	240/120/120
315	7F000000130	7E000000026	7G000000557		3	240/120/120
220	7F000000130	7E000000026	7G000000557		2	240/120/120
343	7F000000222	7E000000026	7G000000619	L	3	240/120/120
240	7F000000222	7E000000026	7G000000619		2	240/120/120
262	7F000000203	7E000000026	7G000000820		2	240/120/120
421	7F000000203	7E000000026	7G000000820	Lf	3	240/120/120
313	7F000000134	7E000000028	7G000000514	SfS	3	240/120/120
218	7F000000134	7E000000028	7G000000514		2	240/120/120
312	7F000000136	7E000000029	7G000000505		3	240/120/120
285	7F000000193	7E000000033	7G000001613	Nb	2	240/120/120
243	7F000000112	7E000000034	7G000000717	Ac	2	240/120/120
365	7F000000112	7E000000034	7G000000717		3	240/120/120
367	7F000000113	7E000000035	7G000000773		3	240/120/120
463	7F000000211	7E000000035	7G000000843	Lym	2	240/120/120
422	7F000000211	7E000000035	7G000000843	L	3	240/120/120
366	7F000000119	7E000000036	7G000000706	Nb	3	240/120/120
481	7F000000119	7E000000036	7G000000706	Lym	2	240/120/120
456	7F000000122	7E000000037	7G000000723	L	3	240/120/120
242	7F000000122	7E000000037	7G000000723		2	240/120/120
271	7F000000175	7E000000037	7G000001470		2	240/120/120
272	7F000000175	7E000000037	7G000001470		2	240/120/120
465	7F000000175	7E000000037	7G000001470	Lym	2	240/120/120
273	7F000000175	7E000000037	7G000001470		2	240/120/120
524	7F000000139	7E000000038	7G000001421		3	240/120/120
523	7F000000139	7E000000038	7G000001421		3	240/120/120
270	7F000000236	7E000000039	7G000001428		2	240/120/120
522	7F000000236	7E000000039	7G000001428	L	3	240/120/120
521	7F000000236	7E000000039	7G000001428		3	240/120/120
288	7F000000245	7E000000039	7G000001618	L	2	240/120/120
553	7F000000245	7E000000039	7G000001618	L	3	240/120/120
476	7F000000150	7E000000043	7G000000765	Lym	3	240/120/120
265	7F000000179	7E000000043	7G000000829		2	240/120/120
423	7F000000179	7E000000043	7G000000829	L	3	240/120/120
504	7F000000230	7E000000043	7G000001625	L	3	240/120/120
261	7F000000151	7E000000044	7G000000758		2	240/120/120
388	7F000000151	7E000000044	7G000000758		3	240/120/120
441	7F000000340	7E000000053	7G000001834		2	240/120/120
442	7F000000340	7E000000053	7G000001834		2	240/120/120
439	7F000000342	7E000000055	7G000001825		2	240/120/120
452	7F000000342	7E000000055	7G000001825		2	240/120/120
501	7F000000354	7E000000056	7G000001841		2	240/120/120

a: UIN = unique identification number
b: Adjacent cells within a column with the same shading share the same UIN number.
c: Ac = Astrocytoma; HA = Harderian gland adenoma; L = Liver, hepatocellular adenoma; Lc = Liver, hepatocellular carcinoma; LgA = Lung, adenoma; Lf = Liver, basophilic focus; Lym = Malignant lymphoma; L Lym= Liver, hepatocellular adenoma + Malignant lymphoma; Nb = Neuroblastoma; OS = Osteosarcoma; Pc = Pancreas, carcinoma; S = Sarcoma; SfS = Skin, fibrosarcoma; StA = Stomach, adenocarcinoma
d: Duration 1, 2, and 3, designate the 45-week stop-study, 30-week study, and 45-week study, respectively; shading highlights nonconsecutive durations
e: AZT dose is presented as mg/kg body weight per day

Table G2Distribution of Female Heterozygous F1 p53^+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Animal Number	Dam UIN	Sire UIN	Litter UIN^b	Lesion^c	Duration^d	Dose^e
569	7F000000316	7E000000019	7G000001650		1	0/0
570	7F000000316	7E000000019	7G000001650		1	0/0
571	7F000000315	7E000000019	7G000001700	Up	1	0/0
572	7F000000315	7E000000019	7G000001700	OTm	1	0/0
573	7F000000346	7E000000019	7G000001782		1	0/0
579	7F000000346	7E000000019	7G000001782		1	0/0
589	7F000000309	7E000000033	7G000001635		1	0/0
590	7F000000309	7E000000033	7G000001635		1	0/0
591	7F000000310	7E000000033	7G000001721		1	0/0
592	7F000000310	7E000000033	7G000001721		1	0/0
601	7F000000351	7E000000033	7G000001818		1	0/0
602	7F000000351	7E000000033	7G000001818		1	0/0
603	7F000000327	7E000000034	7G000001666		1	0/0
604	7F000000327	7E000000034	7G000001666		1	0/0
608	7F000000320	7E000000037	7G000001642	Oc	1	0/0
619	7F000000320	7E000000037	7G000001642		1	0/0
620	7F000000326	7E000000046	7G000001796	MA	1	0/0
621	7F000000326	7E000000046	7G000001796		1	0/0
622	7F000000326	7E000000046	7G000001796		1	0/0
623	7F000000325	7E000000049	7G000001659		1	0/0
624	7F000000325	7E000000049	7G000001659		1	0/0
627	7F000000345	7E000000052	7G000001849		1	0/0
636	7F000000345	7E000000052	7G000001849		1	0/0
637	7F000000322	7E000000053	7G000001856		1	0/0
649	7F000000360	7E000000055	7G000001880		1	0/0
654	7F000000360	7E000000055	7G000001880		1	0/0
390	7F000000324	7E000000019	7G000001738		1	240/40
556	7F000000324	7E000000019	7G000001738		1	240/40
559	7F000000336	7E000000019	7G000001871		1	240/40
560	7F000000336	7E000000019	7G000001871		1	240/40
561	7F000000323	7E000000028	7G000001673		1	240/40
562	7F000000323	7E000000028	7G000001673		1	240/40
563	7F000000306	7E000000031	7G000001707		1	240/40
583	7F000000306	7E000000031	7G000001707		1	240/40
584	7F000000306	7E000000031	7G000001707	Lk	1	240/40
594	7F000000352	7E000000033	7G000001852		1	240/40
595	7F000000319	7E000000037	7G000001679		1	240/40
596	7F000000319	7E000000037	7G000001679		1	240/40
606	7F000000308	7E000000038	7G000001714	Up	1	240/40
607	7F000000308	7E000000038	7G000001714	US	1	240/40
610	7F000000312	7E000000039	7G000001695	Ac	1	240/40
613	7F000000321	7E000000041	7G000001686		1	240/40
638	7F000000321	7E000000041	7G000001686		1	240/40
639	7F000000317	7E000000048	7G000001728		1	240/40
640	7F000000341	7E000000052	7G000001865		1	240/40
641	7F000000341	7E000000052	7G000001865		1	240/40
642	7F000000356	7E000000053	7G000001893		1	240/40
650	7F000000356	7E000000053	7G000001893		1	240/40
658	7F000000357	7E000000056	7G000001886		1	240/40
659	7F000000357	7E000000056	7G000001886		1	240/40
666	7F000000338	7E000000056	7G000001899		1	240/40
667	7F000000338	7E000000056	7G000001899		1	240/40
173	7F000000194	7E000000017	7G000001150		2	0/0/0
209	7F000000194	7E000000017	7G000001150	S	3	0/0/0
289	7F000000177	7E000000017	7G000001446		3	0/0/0
290	7F000000177	7E000000017	7G000001446		3	0/0/0
291	7F000000116	7E000000019	7G000000539		3	0/0/0
215	7F000000347	7E000000019	7G000001752		2	0/0/0
214	7F000000347	7E000000019	7G000001752		2	0/0/0
216	7F000000161	7E000000022	7G000000609		2	0/0/0
292	7F000000161	7E000000022	7G000000609		3	0/0/0
333	7F000000123	7E000000023	7G000000478		3	0/0/0
217	7F000000123	7E000000023	7G000000478		2	0/0/0
351	7F000000125	7E000000024	7G000000522		3	0/0/0
222	7F000000125	7E000000024	7G000000522		2	0/0/0
235	7F000000128	7E000000025	7G000000548		2	0/0/0
236	7F000000231	7E000000025	7G000001563		2	0/0/0
238	7F000000231	7E000000025	7G000001563		2	0/0/0
237	7F000000231	7E000000025	7G000001563		2	0/0/0
353	7F000000171	7E000000026	7G000001461		3	0/0/0
352	7F000000171	7E000000026	7G000001461		3	0/0/0
354	7F000000225	7E000000029	7G000000636		3	0/0/0
239	7F000000144	7E000000033	7G000000484		2	0/0/0
360	7F000000144	7E000000033	7G000000484		3	0/0/0
249	7F000000350	7E000000033	7G000001765		2	0/0/0
376	7F000000120	7E000000036	7G000000672	OL	3	0/0/0
250	7F000000120	7E000000036	7G000000672		2	0/0/0
377	7F000000197	7E000000037	7G000000791		3	0/0/0
251	7F000000197	7E000000037	7G000000791	Usp	2	0/0/0
252	7F000000261	7E000000038	7G000000796		2	0/0/0
378	7F000000261	7E000000038	7G000000796		3	0/0/0
253	7F000000142	7E000000041	7G000000680		2	0/0/0
400	7F000000142	7E000000041	7G000000680		3	0/0/0
414	7F000000229	7E000000041	7G000001546		3	0/0/0
268	7F000000229	7E000000041	7G000001546		2	0/0/0
266	7F000000229	7E000000041	7G000001546		2	0/0/0
431	7F000000147	7E000000042	7G000000768		3	0/0/0
274	7F000000147	7E000000042	7G000000768		2	0/0/0
446	7F000000192	7E000000042	7G000001497	Mth	3	0/0/0
276	7F000000223	7E000000042	7G000001571		2	0/0/0
275	7F000000223	7E000000042	7G000001571	MA	2	0/0/0
281	7F000000152	7E000000044	7G000000627		2	0/0/0
513	7F000000152	7E000000044	7G000000627		3	0/0/0
282	7F000000153	7E000000045	7G000000731		2	0/0/0
518	7F000000153	7E000000045	7G000000731		3	0/0/0
519	7F000000170	7E000000045	7G000000853		3	0/0/0
283	7F000000170	7E000000045	7G000000853	ip	2	0/0/0
399	7F000000156	7E000000046	7G000000694		2	0/0/0
520	7F000000156	7E000000046	7G000000694		3	0/0/0
443	7F000000146	7E000000047	7G000000804	Lym	2	0/0/0
538	7F000000146	7E000000047	7G000000804		3	0/0/0
464	7F000000166	7E000000049	7G000000701		2	0/0/0
540	7F000000166	7E000000049	7G000000701		3	0/0/0
552	7F000000339	7E000000053	7G000001745	OS	3	0/0/0
632	7F000000339	7E000000053	7G000001745		3	0/0/0
300	7F000000158	7E000000019	7G000000587		3	80/40/80
301	7F000000158	7E000000019	7G000000587		3	80/40/80
302	7F000000208	7E000000019	7G000001556	LgA	3	80/40/80
303	7F000000118	7E000000020	7G000000490		3	80/40/80
304	7F000000118	7E000000020	7G000000490		3	80/40/80
326	7F000000149	7E000000022	7G000001198		3	80/40/80
317	7F000000149	7E000000022	7G000001198		3	80/40/80
325	7F000000149	7E000000022	7G000001198		3	80/40/80
363	7F000000126	7E000000024	7G000000566		3	80/40/80
364	7F000000126	7E000000024	7G000000566	Usp	3	80/40/80
403	7F000000127	7E000000025	7G000000529		3	80/40/80
429	7F000000127	7E000000025	7G000000529		3	80/40/80
445	7F000000244	7E000000035	7G000000812	OS	3	80/40/80
430	7F000000244	7E000000035	7G000000812	OS	3	80/40/80
451	7F000000201	7E000000038	7G000001579	Sh	3	80/40/80
483	7F000000137	7E000000039	7G000000777		3	80/40/80
505	7F000000137	7E000000039	7G000000777		3	80/40/80
506	7F000000243	7E000000041	7G000001512		3	80/40/80
507	7F000000243	7E000000041	7G000001512		3	80/40/80
508	7F000000196	7E000000042	7G000001498		3	80/40/80
529	7F000000196	7E000000042	7G000001498		3	80/40/80
544	7F000000220	7E000000043	7G000001476		3	80/40/80
545	7F000000220	7E000000043	7G000001476	Sp	3	80/40/80
546	7F000000246	7E000000048	7G000001437		3	80/40/80
548	7F000000246	7E000000048	7G000001437	KA	3	80/40/80
550	7F000000246	7E000000048	7G000001437		3	80/40/80
673	7F000000246	7E000000048	7G000001437		3	80/40/80
296	7F000000157	7E000000019	7G000000595		3	160/80/160
297	7F000000157	7E000000019	7G000000595		3	160/80/160
318	7F000000145	7E000000020	7G000000572	OS	3	160/80/160
319	7F000000145	7E000000020	7G000000572	HA	3	160/80/160
327	7F000000121	7E000000022	7G000000498		3	160/80/160
331	7F000000121	7E000000022	7G000000498		3	160/80/160
338	7F000000232	7E000000022	7G000000836		3	160/80/160
339	7F000000232	7E000000022	7G000000836		3	160/80/160
340	7F000000210	7E000000025	7G000000848	AA	3	160/80/160
341	7F000000210	7E000000025	7G000000848		3	160/80/160
359	7F000000224	7E000000028	7G000000752		3	160/80/160
383	7F000000224	7E000000028	7G000000752		3	160/80/160
384	7F000000200	7E000000028	7G000001595		3	160/80/160
385	7F000000190	7E000000029	7G000000666	ScC	3	160/80/160
404	7F000000190	7E000000029	7G000000666		3	160/80/160
405	7F000000215	7E000000036	7G000001454		3	160/80/160
406	7F000000215	7E000000036	7G000001454		3	160/80/160
407	7F000000233	7E000000039	7G000001158	OS Lym	3	160/80/160
408	7F000000233	7E000000039	7G000001158		3	160/80/160
435	7F000000162	7E000000047	7G000000653		3	160/80/160
425	7F000000162	7E000000047	7G000000653		3	160/80/160
436	7F000000164	7E000000048	7G000000740	MA	3	160/80/160
458	7F000000164	7E000000048	7G000000740		3	160/80/160
462	7F000000173	7E000000048	7G000000862		3	160/80/160
532	7F000000173	7E000000048	7G000000862		3	160/80/160
533	7F000000165	7E000000049	7G000000664		3	160/80/160
609	7F000000343	7E000000055	7G000001810	MA	3	160/80/160
221	7F000000216	7E000000019	7G000000689		2	240/120/120
310	7F000000216	7E000000019	7G000000689		3	240/120/120
311	7F000000117	7E000000020	7G000000554	MA	3	240/120/120
224	7F000000160	7E000000020	7G000000602	1	2	240/120/120
329	7F000000160	7E000000020	7G000000602	Lym	3	240/120/120
345	7F000000218	7E000000022	7G000000658		3	240/120/120
225	7F000000218	7E000000022	7G000000658		2	240/120/120
346	7F000000184	7E000000023	7G000000616		3	240/120/120
347	7F000000185	7E000000024	7G000000784		3	240/120/120
228	7F000000185	7E000000024	7G000000784		2	240/120/120
369	7F000000167	7E000000025	7G000000581	Lym	3	240/120/120
229	7F000000167	7E000000025	7G000000581		2	240/120/120
244	7F000000186	7E000000025	7G000000746		2	240/120/120
370	7F000000186	7E000000025	7G000000746		3	240/120/120
371	7F000000130	7E000000026	7G000000557		3	240/120/120
245	7F000000130	7E000000026	7G000000557		2	240/120/120
372	7F000000222	7E000000026	7G000000619		3	240/120/120
246	7F000000222	7E000000026	7G000000619		2	240/120/120
373	7F000000203	7E000000026	7G000000820		3	240/120/120
247	7F000000203	7E000000026	7G000000820		2	240/120/120
387	7F000000134	7E000000028	7G000000514		3	240/120/120
418	7F000000136	7E000000029	7G000000505		3	240/120/120
248	7F000000349	7E000000031	7G000001757		2	240/120/120
419	7F000000112	7E000000034	7G000000717		3	240/120/120
258	7F000000112	7E000000034	7G000000717		2	240/120/120
259	7F000000113	7E000000035	7G000000773		2	240/120/120
420	7F000000113	7E000000035	7G000000773		3	240/120/120
447	7F000000211	7E000000035	7G000000843		3	240/120/120
260	7F000000211	7E000000035	7G000000843		2	240/120/120
448	7F000000119	7E000000036	7G000000706	OS	3	240/120/120
264	7F000000119	7E000000036	7G000000706	SbC	2	240/120/120
449	7F000000122	7E000000037	7G000000723	SfS	3	240/120/120
267	7F000000122	7E000000037	7G000000723		2	240/120/120
453	7F000000175	7E000000037	7G000001470	Lym	3	240/120/120
525	7F000000139	7E000000038	7G000001421		3	240/120/120
497	7F000000139	7E000000038	7G000001421		3	240/120/120
527	7F000000236	7E000000039	7G000001428	Ost	3	240/120/120
526	7F000000236	7E000000039	7G000001428		3	240/120/120
528	7F000000245	7E000000039	7G000001618		3	240/120/120
286	7F000000245	7E000000039	7G000001618		2	240/120/120
287	7F000000318	7E000000041	7G000001802	Lym	2	240/120/120
391	7F000000318	7E000000041	7G000001802		2	240/120/120
554	7F000000150	7E000000043	7G000000765		3	240/120/120
555	7F000000179	7E000000043	7G000000829		3	240/120/120
392	7F000000179	7E000000043	7G000000829		2	240/120/120
674	7F000000230	7E000000043	7G000001625	Sh	3	240/120/120
397	7F000000230	7E000000043	7G000001625		2	240/120/120
398	7F000000311	7E000000049	7G000001769		2	240/120/120
437	7F000000340	7E000000053	7G000001834		2	240/120/120
438	7F000000342	7E000000055	7G000001825		2	240/120/120
440	7F000000342	7E000000055	7G000001825		2	240/120/120
503	7F000000354	7E000000056	7G000001841		2	240/120/120
502	7F000000354	7E000000056	7G000001841	S	2	240/120/120

a: UIN = unique identification number
b: Adjacent cells within a column with the same shading share the same UIN number.
c: AA = Adrenal cortex adenoma; Ac = Astrocytoma; HA = Harderian gland adenoma; Ip = Intestine, polyp; KA = Renal tubule adenoma; LgA = Lung, adenoma; Lk = Leukemia, granulocytic; Lym = Malignant lymphoma; MA = Mammary gland adenocarcinoma; Mth = Malignant mesothelioma; Oc = Ovary, carcinoma; OL = Ovary, luteoma; OS = Osteosarcoma; Ost = Osteoma; OS Lym = Osteosarcoma + Malignant lymphoma; OTm = Ovary, malignant teratoma; S = Sarcoma; SbC = Skin, basal cell carcinoma; ScC = Skin, squamous cell carcinoma; SfS = Skin, fibrosarcoma; Sh = Sarcoma, histiocytic; Sp = Stomach, papilloma; Up = Uterus, polyp; Usp = Uterus, stomal polyp; US = Uterus, sarcoma
d: Duration 1, 2, and 3, designate the 45-week stop-study, 30-week study, and 45-week study, respectively; shading highlights nonconsecutive durations
e: AZT dose is presented as mg/kg body weight per day

Table G3Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT^a

	0/0/0 mg/kg vs. 240/120/240 mg/kg
Male
Hazard Ratio^b	6174.4%
Independence	4.1 ± 3.2
	P=0.097
Empirical Variance - Naive	4.1 ± 1.1
	P≤0.001^***
Correlation within Dam/Litter	4.1 ± 1.0
	P≤0.001^***
Correlation within Sire	4.1 ± 1.1
	P≤0.001^***
Female
Hazard Ratio	3.3%
Independence	−3.4 ± 3.2
	P=0.143N
Empirical Variance - Naive	−3.4 ± 1.2
	P=0.002N^**
Correlation within Dam/Litter	−3.4 ± 1.2
	P=0.002N^**
Correlation within Sire	−3.4 ± 1.2
	P=0.002N^**

**: Significantly different (P≤0.01) by the Cox (1972) proportional hazard model
***: P≤0.001
a: The results are presented for the naive model assuming pup independence, an empirical variance model, an empirical variance model aggregated over litters, and an empirical variance model aggregated over sires. A lower P value in a dosed group is indicated by N.
b: The Hazard Ratio represents the treatment group hazard relative to 0/0/0 mg/kg group. The ratio for the 0/0/0 mg/kg group is always 100%.

Table G4Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT^a

	0/0/0 mg/kg	80/40/80 mg/kg	160/80/160 mg/kg	240/120/240 mg/kg
Male
Hazard Ratio^b	–	217.1%	3.1%	169.4%
Independence	−3.2 ± 3.5	0.8 ± 0.7	−3.5 ± 3.2	0.5 ± 0.7
	P=0.180N^c	P=0.136	P=0.139N	P=0.234
Empirical Variance - Naive	−3.2 ± 1.8	0.8 ± 0.7	−3.5 ± 1.2	0.5 ± 0.7
	P=0.039N^*	P=0.137	P=0.001N^**	P=0.233
Correlation within Dam/Litter	−3.2 ± 1.4	0.8 ± 0.7	−3.5 ± 0.9	0.5 ± 0.7
	P=0.013N^*	P=0.128	P≤0.001N^***	P=0.235
Correlation within Sire	−3.2 ± 1.4	0.8 ± 0.7	−3.5 ± 0.9	0.5 ± 0.8
	P=0.013N^*	P=0.135	P≤0.001N^***	P=0.252
Female
Hazard Ratio	–	130.3%	96.5%	202.0%
Independence	1.1 ± 1.6	0.3 ± 0.8	0.0 ± 0.8	0.7 ± 0.7
	P=0.246	P=0.364	P=0.483N	P=0.160
Empirical Variance - Naive	1.1 ± 1.6	0.3 ± 0.8	0.0 ± 0.8	0.7 ± 0.7
	P=0.244	P=0.364	P=0.482N	P=0.158
Correlation within Dam/Litter	1.1 ± 1.5	0.3 ± 0.7	0.0 ± 0.8	0.7 ± 0.7
	P=0.235	P=0.349	P=0.482N	P=0.151
Correlation within Sire	1.1 ± 1.3	0.3 ± 0.7	0.0 ± 0.7	0.7 ± 0.6
	P=0.196	P=0.350	P=0.480N	P=0.135

*: Significantly different (P≤0.05) by the Cox (1972) proportional hazard model
**: P≤0.01
***: P≤0.001
a: The results are presented for the naive model assuming pup independence, an empirical variance model, an empirical variance model aggregated over litters, and an empirical variance model aggregated over sires.
b: The Hazard Ratio represents the treatment group hazard relative to the 0/0/0 mg/kg. The ratio for the 0/0/0 mg/kg group is always 100%.
c: P values for the 0/0/0 mg/kg group represent linear dose trends and not the Cox estimate which is implicitly zero for this group. A negative trend or a lower P value in a dosed group is indicated by N.

Table G5Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT^a

	0/0 mg/kg vs. 240/40 mg/kg
Male
Hazard Ratio^b	293.8%
Independence	1.1 ± 1.2
	P=0.175
Empirical Variance - Naive	1.1 ± 1.1
	P=0.173
Correlation within Dam/Litter	1.1 ± 1.1
	P=0.167
Correlation within Sire	1.1 ± 1.2
	P=0.178
Female
Hazard Ratio	306.1%
Independence	1.1 ± 1.2
	P=0.166
Empirical Variance - Naive	1.1 ± 1.1
	P=0.164
Correlation within Dam/Litter	1.1 ± 1.1
	P=0.157
Correlation within Sire	1.1 ± 1.1
	P=0.159

a: The results are presented for the naive model assuming pup independence, an empirical variance model, an empirical variance model aggregated over litters, and an empirical variance model aggregated over sires.
b: The Hazard Ratio represents the treatment group hazard relative to the 0/0 mg/kg group. The ratio for the 0/0 mg/kg group is always 100%.

Table G6Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	240/120/240 mg/kg
Liver: Hepatocellular Adenoma
Overall rate^a	1/27 (3.7%)	1/26 (3.8%)
Adjusted rate^b	1/27.0 (3.7%)	1/22.8 (4.4%)
Terminal rate^c	1/27 (3.7%)	1/21 (4.8%)
First incidence (days)	217 (T)	213 (T)
Poly-3 test^d		0.722
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	3.8%	4.5%
Litter-adjusted Poly-3 test		0.451
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	3.6%	4.4%
Sire-adjusted Poly-3 test		0.446
Liver: Hepatocellular Adenoma or Carcinoma
Overall rate	1/27 (3.7%)	1/26 (3.8%)
Adjusted rate	1/27.0 (3.7%)	1/22.8 (4.4%)
Terminal rate	1/27 (3.7%)	1/21 (4.8%)
First incidence (days)	217 (T)	213 (T)
Poly-3 test		0.722
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	3.8%	4.5%
Litter-adjusted Poly-3 test		0.451
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	3.6%	4.4%
Sire-adjusted Poly-3 test		0.446
All Organs: Malignant Lymphoma
Overall rate	0/27 (0.0%)	3/26 (11.5%)
Adjusted rate	0/27.0 (0.0%)	3/25.2 (11.9%)
Terminal rate	0/27 (0.0%)	0/21 (0.0%)
First incidence (days)	—^e	84
Poly-3 test		0.102
Litter-adjusted correlation	−0.21
Litter-adjusted Poly-3 rate	0.0%	14.4%
Litter-adjusted Poly-3 test		0.005^**
Sire-adjusted correlation	−0.05
Sire-adjusted Poly-3 rate	0.0%	12.0%
Sire-adjusted Poly-3 test		0.016^*
All Organs: Osteosarcoma
Overall rate	0/27 (0.0%)	1/26 (3.8%)
Adjusted rate	0/27.0 (0.0%)	1/22.8 (4.4%)
Terminal rate	0/27 (0.0%)	1/21 (4.8%)
First incidence (days)	—	213 (T)
Poly-3 test		0.467
Litter-adjusted correlation	0.03
Litter-adjusted Poly-3 rate	0.0%	4.5%
Litter-adjusted Poly-3 test		0.155
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	0.0%	4.4%
Sire-adjusted Poly-3 test		0.148
All Organs: Benign Neoplasms
Overall rate	1/27 (3.7%)	1/26 (3.8%)
Adjusted rate	1/27.0 (3.7%)	1/22.8 (4.4%)
Terminal rate	1/27 (3.7%)	1/21 (4.8%)
First incidence (days)	217 (T)	213 (T)
Poly-3 test		0.722
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	3.8%	4.5%
Litter-adjusted Poly-3 test		0.451
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	3.6%	4.4%
Sire-adjusted Poly-3 test		0.446
All Organs: Malignant Neoplasms
Overall rate	0/27 (0.0%)	6/26 (23.1%)
Adjusted rate	0/27.0 (0.0%)	6/25.2 (23.8%)
Terminal rate	0/27 (0.0%)	2/21 (9.5%)
First incidence (days)	—	-84
Poly-3 test		0.008^**
Litter-adjusted correlation	−0.15
Litter-adjusted Poly-3 rate	0.0%	23.5%
Litter-adjusted Poly-3 test		<0.001^***
Sire-adjusted correlation	−0.04
Sire-adjusted Poly-3 rate	0.0%	23.3%
Sire-adjusted Poly-3 test		0.001^**
All Organs: Benign or Malignant Neoplasms
Overall rate	1/27 (3.7%)	7/26 (26.9%)
Adjusted rate	1/27.0 (3.7%)	7/25.2 (27.8%)
Terminal rate	1/27 (3.7%)	3/21 (14.3%)
First incidence (days)	217 (T)	84
Poly-3 test		0.017^*
Litter-adjusted correlation	−0.10
Litter-adjusted Poly-3 rate	3.6%	27.3%
Litter-adjusted Poly-3 test		0.003^**
Sire-adjusted correlation	−0.12
Sire-adjusted Poly-3 rate	3.4%	25.9%
Sire-adjusted Poly-3 test		0.002^**

: (T)Terminal kill
*: Significantly different (P≤0.05) from the 0/0/0 mg/kg group by the Poly-3 test
**: P≤0.01
***: P≤0.001
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill.
e: Not applicable; no neoplasms in animal group

Table G7Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	80/40/80 mg/kg	160/80/160 mg/kg	240/120/240 mg/kg
Liver: Hepatocellular Adenoma
Overall rate^a	3/26 (11.5%)	2/27 (7.4%)	6/27 (22.2%)	9/27 (33.3%)
Adjusted rate^b	3/24.4 (12.3%)	2/22.8 (8.8%)	6/27.0 (22.2%)	9/24.7 (36.5%)
Terminal rate^c	3/24 (12.5%)	2/21 (9.5%)	6/27 (22.2%)	7/22 (31.8%)
First incidence (days)	321 (T)	319 (T)	320 (T)	228
Poly-3 test^d	0.013^*	0.531N	0.288	0.048^*
Poly-5 test	0.013^*	0.536N	0.293	0.047^*
Litter-adjusted correlation	−0.23
Litter-adjusted Poly-3 rate	13.8%	7.2%	22.8%	35.9%
Litter-adjusted Poly-3 test	0.010^*	0.214N	0.168	0.027^*
Sire-adjusted correlation	0.04
Sire-adjusted Poly-3 rate	12.4%	7.9%	21.2%	36.1%
Sire-adjusted Poly-3 test	0.009^**	0.305N	0.119	0.022^*
Liver: Hepatocellular Adenoma or Carcinoma
Overall rate	3/26 (11.5%)	3/27 (11.1%)	6/27 (22.2%)	9/27 (33.3%)
Adjusted rate	3/24.4 (12.3%)	3/22.8 (13.2%)	6/27.0 (22.2%)	9/24.7 (36.5%)
Terminal rate	3/24 (12.5%)	3/21 (14.3%)	6/27 (22.2%)	7/22 (31.8%)
First incidence (days)	321 (T)	319 (T)	320 (T)	228
Poly-3 test	0.019^*	0.634	0.288	0.048^*
Poly-5 test	0.019^*	0.629	0.293	0.047^*
Litter-adjusted correlation	−0.26
Litter-adjusted Poly-3 rate	14.0%	12.0%	22.9%	35.8%
Litter-adjusted Poly-3 test	0.016^*	0.417N	0.174	0.029^*
Sire-adjusted correlation	0.10
Sire-adjusted Poly-3 rate	12.4%	10.9%	19.5%	35.7%
Sire-adjusted Poly-3 test	0.018^*	0.421N	0.167	0.024^*
All Organs: Malignant Lymphoma
Overall rate	1/27 (3.7%)	2/27 (7.4%)	1/27 (3.7%)	1/27 (3.7%)
Adjusted rate	1/25.4 (3.9%)	2/23.5 (8.5%)	1/27.0 (3.7%)	1/24.7 (4.1%)
Terminal rate	0/24 (0.0%)	1/21 (4.8%)	1/27 (3.7%)	0/22 (0.0%)
First incidence (days)	159	217	321 (T)	94
Poly-3 test	0.502N	0.473	0.746N	0.754
Litter-adjusted correlation	0.00
Litter-adjusted Poly-3 rate	3.9%	8.5%	3.7%	4.1%
Litter-adjusted Poly-3 test	0.402N	0.258	0.482N	0.492
Sire-adjusted correlation	0.09
Sire-adjusted Poly-3 rate	3.5%	9.0%	3.5%	3.8%
Sire-adjusted Poly-3 test	0.388N	0.221	0.494N	0.472
All Organs: Osteosarcoma
Overall rate	2/27 (7.4%)	0/27 (0.0%)	0/27 (0.0%)	0/27 (0.0%)
Adjusted rate	2/24.5 (8.2%)	0/22.8 (0.0%)	0/27.0 (0.0%)	0/23.7 (0.0%)
Terminal rate	2/24 (8.3%)	0/21 (0.0%)	0/27 (0.0%)	0/22 (0.0%)
First incidence (days)	319 (T)	—^e	—	—
Poly-3 test	0.050N^*	0.251N	0.214N	0.242N
Litter-adjusted correlation	0.01
Litter-adjusted Poly-3 rate	8.2%	0.0%	0.0%	0.0%
Litter-adjusted Poly-3 test	0.072N	0.072N	0.072N	0.072N
Sire-adjusted correlation	0.00
Sire-adjusted Poly-3 rate	8.2%	0.0%	0.0%	0.0%
Sire-adjusted Poly-3 test	0.067N	0.067N	0.067N	0.067N
All Organs: Benign Neoplasms
Overall rate	4/27 (14.8%)	2/27 (7.4%)	6/27 (22.2%)	9/27 (33.3%)
Adjusted rate	4/24.5 (16.3%)	2/22.8 (8.8%)	6/27.0 (22.2%)	9/24.7 (36.5%)
Terminal rate	4/24 (16.7%)	2/21 (9.5%)	6/27 (22.2%)	7/22 (31.8%)
First incidence (days)	321 (T)	319 (T)	320 (T)	228
Poly-3 test	0.031^*	0.367N	0.430	0.099
Litter-adjusted correlation	0.00
Litter-adjusted Poly-3 rate	16.4%	8.8%	22.2%	36.5%
Litter-adjusted Poly-3 test	0.031^*	0.236N	0.295	0.059
Sire-adjusted correlation	−0.07
Sire-adjusted Poly-3 rate	16.4%	7.4%	20.7%	35.2%
Sire-adjusted Poly-3 test	0.046^*	0.202N	0.328	0.087
All Organs: Malignant Neoplasms
Overall rate	4/27 (14.8%)	6/27 (22.2%)	1/27 (3.7%)	3/27 (11.1%)
Adjusted rate	4/25.4 (15.8%)	6/24.0 (25.0%)	1/27.0 (3.7%)	3/24.7 (12.2%)
Terminal rate	3/24 (12.5%)	3/21 (14.3%)	1/27 (3.7%)	2/22 (9.1%)
First incidence (days)	159	217	321 (T)	94
Poly-3 test	0.176N	0.328	0.155N	0.516N
Litter-adjusted correlation	0.06
Litter-adjusted Poly-3 rate	16.0%	25.0%	3.7%	12.3%
Litter-adjusted Poly-3 test	0.153N	0.226	0.068N	0.356N
Sire-adjusted correlation	0.01
Sire-adjusted Poly-3 rate	15.7%	25.1%	3.6%	12.1%
Sire-adjusted Poly-3 test	0.140N	0.223	0.031N^*	0.361N
All Organs: Benign or Malignant Neoplasms
Overall rate	8/27 (29.6%)	7/27 (25.9%)	7/27 (25.9%)	12/27 (44.4%)
Adjusted rate	8/25.4 (31.5%)	7/24.0 (29.1%)	7/27.0 (25.9%)	12/25.7 (46.8%)
Terminal rate	7/24 (29.2%)	4/21 (19.0%)	7/27 (25.9%)	9/22 (40.9%)
First incidence (days)	159	217	320 (T)	94
Poly-3 test	0.185	0.550N	0.444N	0.205
Litter-adjusted correlation	0.10
Litter-adjusted Poly-3 rate	31.1%	29.6%	25.6%	47.1%
Litter-adjusted Poly-3 test	0.155	0.457N	0.334N	0.123
Sire-adjusted correlation	0.02
Sire-adjusted Poly-3 rate	31.5%	28.3%	25.1%	46.0%
Sire-adjusted Poly-3 test	0.200	0.407N	0.285N	0.188

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test
**: P≤0.01
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-k test accounts for differential mortality in animals that do not reach terminal kill. A negative trend or lower incidence in a dose group is indicated by N.
e: Not applicable; no neoplasms in animal group

Table G8Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

	0/0 mg/kg	240/40 mg/kg
Liver: Hepatocellular Adenoma
Overall rate^a	3/24 (12.5%)	5/25 (20.0%)
Adjusted rate^b	3/23.4 (12.8%)	5/23.5 (21.3%)
Terminal rate^c	3/23 (13.0%)	5/22 (22.7%)
First incidence (days)	317 (T)	317 (T)
Poly-3 test^d		0.352
Poly-5 test		0.350
Litter-adjusted correlation	−0.17
Litter-adjusted Poly-3 rate	12.8%	20.8%
Litter-adjusted Poly-3 test		0.212
Sire-adjusted correlation	−0.10
Sire-adjusted Poly-3 rate	15.2%	22.3%
Sire-adjusted Poly-3 test		0.218
Liver: Hepatocellular Adenoma or Carcinoma
Overall rate	3/24 (12.5%)	7/25 (28.0%)
Adjusted rate	3/23.4 (12.8%)	7/23.5 (29.8%)
Terminal rate	3/23 (13.0%)	7/22 (31.8%)
First incidence (days)	317 (T)	317 (T)
Poly-3 test		0.143
Poly-5 test		0.141
Litter-adjusted correlation	−0.02
Litter-adjusted Poly-3 rate	12.8%	29.8%
Litter-adjusted Poly-3 test		0.076
Sire-adjusted correlation	−0.07
Sire-adjusted Poly-3 rate	12.6%	29.1%
Sire-adjusted Poly-3 test		0.077
All Organs: Malignant Lymphoma
Overall rate	0/24 (0.0%)	2/25 (8.0%)
Adjusted rate	0/23.4 (0.0%)	2/23.7 (8.5%)
Terminal rate	0/23 (0.0%)	1/22 (4.5%)
First incidence (days)	—^e	300
Poly-3 test		0.237
Litter-adjusted correlation	0.77
Litter-adjusted Poly-3 rate	0.0%	7.9%
Litter-adjusted Poly-3 test		0.148
Sire-adjusted correlation	0.13
Sire-adjusted Poly-3 rate		—f
Sire-adjusted Poly-3 test		—
All Organs: Benign Neoplasms
Overall rate	6/24 (25.0%)	5/25 (20.0%)
Adjusted rate	6/23.4 (25.6%)	5/23.5 (21.3%)
Terminal rate	6/23 (26.1%)	5/22 (22.7%)
First incidence (days)	317 (T)	317 (T)
Poly-3 test		0.498N
Litter-adjusted correlation	−0.29
Litter-adjusted Poly-3 rate	26.0%	20.4%
Litter-adjusted Poly-3 test		0.298N
Sire-adjusted correlation	−0.08
Sire-adjusted Poly-3 rate	25.8%	21.1%
Sire-adjusted Poly-3 test		0.317N
All Organs: Malignant Neoplasms
Overall rate	1/24 (4.2%)	5/25 (20.0%)
Adjusted rate	1/24.0 (4.2%)	5/24.0 (20.8%)
Terminal rate	0/23 (0.0%)	3/22 (13.6%)
First incidence (days)	240	281
Poly-3 test		0.093
Litter-adjusted correlation	0.40
Litter-adjusted Poly-3 rate	4.0%	20.2%
Litter-adjusted Poly-3 test		0.076
Sire-adjusted correlation	−0.04
Sire-adjusted Poly-3 rate	4.9%	21.1%
Sire-adjusted Poly-3 test		0.104
All Organs: Benign and Malignant Neoplasms
Overall rate	7/24 (29.2%)	10/25 (40.0%)
Adjusted rate	7/24.0 (29.2%)	10/24.0 (41.7%)
Terminal rate	6/23 (26.1%)	8/22 (36.4%)
First incidence (days)	240	281
Poly-3 test		0.276
Litter-adjusted correlation	0.21
Litter-adjusted Poly-3 rate	28.7%	41.8%
Litter-adjusted Poly-3 test		0.189
Sire-adjusted correlation	−0.02
Sire-adjusted Poly-3 rate	29.5%	41.4%
Sire-adjusted Poly-3 test		0.233

: (T)Terminal kill
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group. The Poly-k test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Not applicable; no neoplasms in animal group
f: Sire-adjusted analysis produced invalid results

Table G9Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	240/120/240 mg/kg
All Organs: Malignant Lymphoma
Overall rate^a	1/27 (3.7%)	1/26 (3.8%)
Adjusted rate^b	1/25.2 (4.0%)	1/26.0 (3.8%)
Terminal rate^c	0/24 (0.0%)	1/26 (3.8%)
First incidence (days)	192	213 (T)
Poly-3 test^d		0.753N
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	4.0%	3.9%
Litter-adjusted Poly-3 test		0.490N
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	3.9%	3.8%
Sire-adjusted Poly-3 test		0.492N
All Organs: Benign Neoplasms
Overall rate	2/27 (7.4%)	0/26 (0.0%)
Adjusted rate	2/24.9 (8.0%)	0/26.0 (0.0%)
Terminal rate	2/24 (8.3%)	0/26 (0.0%)
First incidence (days)	211 (T)	—^e
Poly-3 test		0.225N
Litter-adjusted correlation	−0.11
Litter-adjusted Poly-3 rate	8.2%	0.0%
Litter-adjusted Poly-3 test		0.063N
Sire-adjusted correlation	−0.02
Sire-adjusted Poly-3 rate	8.0%	0.0%
Sire-adjusted Poly-3 test		0.060N
All Organs: Malignant Neoplasms
Overall rate	2/27 (7.4%)	3/26 (11.5%)
Adjusted rate	2/25.2 (7.9%)	3/26.0 (11.5%)
Terminal rate	1/24 (4.2%)	3/26 (11.5%)
First incidence (days)	192	213 (T)
Poly-3 test		0.515
Litter-adjusted correlation	−0.21
Litter-adjusted Poly-3 rate	8.2%	11.8%
Litter-adjusted Poly-3 test		0.327
Sire-adjusted correlation	−0.12
Sire-adjusted Poly-3 rate	7.3%	12.1%
Sire-adjusted Poly-3 test		0.279
All Organs: Benign and Malignant Neoplasms
Overall rate	4/27 (14.8%)	3/26 (11.5%)
Adjusted rate	4/25.2 (15.9%)	3/26.0 (11.5%)
Terminal rate	3/24 (12.5%)	3/26 (11.5%)
First incidence (days)	192	213 (T)
Poly-3 test		0.482N
Litter-adjusted correlation	−0.34
Litter-adjusted Poly-3 rate	15.9%	12.1%
Litter-adjusted Poly-3 test		0.344N
Sire-adjusted correlation	−0.12
Sire-adjusted Poly-3 rate	14.5%	11.1%
Sire-adjusted Poly-3 test		0.353N

: (T)Terminal kill
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Not applicable; no neoplasms in animal group

Table G10Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	80/40/80 mg/kg	160/80/160 mg/kg	240/120/240 mg/kg
All Organs: Histiocytic Sarcoma
Overall rate^a	0/26 (0.0%)	1/27 (3.7%)	0/27 (0.0%)	1/27 (3.7%)
Adjusted rate^b	0/24.5 (0.0%)	1/25.5 (3.9%)	0/25.1 (0.0%)	1/24.4 (4.1%)
Terminal rate^c	0/23 (0.0%)	0/23 (0.0%)	0/24 (0.0%)	0/21 (0.0%)
First incidence (days)	—^e	212	—^f	278
Poly-3 test^d	0.378	0.509	—	0.500
Litter-adjusted correlation	−0.12
Litter-adjusted Poly-3 rate	0.0%	5.0%	0.0%	4.6%
Litter-adjusted Poly-3 test	0.260	0.116	—	0.141
Sire-adjusted correlation	−0.02
Sire-adjusted Poly-3 rate	0.0%	4.2%	0.1%	4.1%
Sire-adjusted Poly-3 test	0.254	0.123	—	0.144
All Organs: Malignant Lymphoma
Overall rate	0/26 (0.0%)	0/27 (0.0%)	1/27 (3.7%)	3/27 (11.1%)
Adjusted rate	0/24.5 (0.0%)	0/24.8 (0.0%)	1/25.1 (4.0%)	3/24.7 (12.2%)
Terminal rate	0/23 (0.0%)	0/23 (0.0%)	1/24 (4.2%)	2/21 (9.5%)
First incidence (days)	—^e	—	322 (T)	241
Poly-3 test	0.020^*	—	0.505	0.115
Litter-adjusted correlation	−0.01
Litter-adjusted Poly-3 rate	0.0%	0.0%	4.0%	12.2%
Litter-adjusted Poly-3 test	0.023^*	—	0.148	0.033^*
Sire-adjusted correlation	−0.03
Sire-adjusted Poly-3 rate	0.0%	0.0%	4.1%	12.1%
Sire-adjusted Poly-3 test	0.018^*	—	0.137	0.032^*
All Organs: Mesothelioma
Overall rate	1/26 (3.8%)	0/27 (0.0%)	0/27 (0.0%)	0/27 (0.0%)
Adjusted rate	1/24.7 (4.0%)	0/24.8 (0.0%)	0/25.1 (0.0%)	0/24.1 (0.0%)
Terminal rate	0/23 (0.0%)	0/23 (0.0%)	0/24 (0.0%)	0/21 (0.0%)
First incidence (days)	291	—	—	—
Poly-3 test	0.186N	0.499N	0.497N	0.506N
Litter-adjusted correlation	0.00
Litter-adjusted Poly-3 rate	4.1%	0.0%	0.0%	0.0%
Litter-adjusted Poly-3 test	0.155N	0.155N	0.155N	0.155N
Sire-adjusted correlation	0.00
Sire-adjusted Poly-3 rate	4.1%	0.0%	0.0%	0.0%
Sire-adjusted Poly-3 test	0.156N	0.156N	0.156N	0.156N
All Organs: Osteosarcoma
Overall rate	1/26 (3.8%)	2/27 (7.4%)	3/27 (11.1%)	1/27 (3.7%)
Adjusted rate	1/24.9 (4.0%)	2/25.2 (7.9%)	3/25.1 (12.0%)	1/24.4 (4.1%)
Terminal rate	0/23 (0.0%)	1/23 (4.3%)	3/24 (12.5%)	0/21 (0.0%)
First incidence (days)	269	282	320 (T)	287
Poly-3 test	0.486	0.504	0.305	0.756
Litter-adjusted correlation	0.32
Litter-adjusted Poly-3 rate	3.2%	6.5%	11.6%	4.3%
Litter-adjusted Poly-3 test	0.323	0.317	0.102	0.423
Sire-adjusted correlation	0.07
Sire-adjusted Poly-3 rate	4.0%	7.4%	11.4%	4.0%
Sire-adjusted Poly-3 test	0.406	0.339	0.120	0.498N
All Organs: Benign Neoplasms
Overall rate	1/26 (3.8%)	4/27 (14.8%)	2/27 (7.4%)	1/27 (3.7%)
Adjusted rate	1/24.5 (4.1%)	4/24.8 (16.1%)	2/25.1 (8.0%)	1/24.1 (4.2%)
Terminal rate	1/23 (4.3%)	4/23 (17.4%)	2/24 (8.3%)	1/21 (4.8%)
First incidence (days)	320 (T)	319 (T)	322 (T)	321 (T)
Poly-3 test	0.452N	0.177	0.509	0.757
Litter-adjusted correlation	−0.06
Litter-adjusted Poly-3 rate	4.0%	15.6%	7.8%	4.4%
Litter-adjusted Poly-3 test	0.361N	0.074	0.284	0.476
Sire-adjusted correlation	−0.05
Sire-adjusted Poly-3 rate	4.2%	15.1%	6.9%	4.2%
Sire-adjusted Poly-3 test	0.339N	0.079	0.342	0.496
All Organs: Malignant Neopl asms
Overall rate	3/26 (11.5%)	3/27 (11.1%)	6/27 (22.2%)	7/27 (25.9%)
Adjusted rate	3/26.0 (11.5%)	3/25.9 (11.6%)	6/25.3 (23.7%)	7/25.6 (27.3%)
Terminal rate	0/23 (0.0%)	1/23 (4.3%)	5/24 (20.8%)	3/21 (14.3%)
First incidence (days)	184	212	298	241
Poly-3 test	0.053	0.663	0.220	0.139
Litter-adjusted correlation	0.02
Litter-adjusted Poly-3 rate	11.5%	11.4%	23.8%	27.3%
Litter-adjusted Poly-3 test	0.036^*	0.494N	0.107	0.066
Sire-adjusted correlation	0.09
Sire-adjusted Poly-3 rate	12.5%	10.4%	21.3%	28.3%
Sire-adjusted Poly-3 test	0.028^*	0.410N	0.127	0.053
All Organs: Benign or Malignant Neoplasms
Overall rate	4/26 (15.4%)	7/27 (25.9%)	8/27 (29.6%)	8/27 (29.6%)
Adjusted rate	4/26.0 (15.4%)	7/25.9 (27.0%)	8/25.3 (31.6%)	8/25.6 (31.2%)
Terminal rate	1/23 (4.3%)	5/23 (21.7%)	7/24 (29.2%)	4/21 (19.0%)
First incidence (days)	184	212	298	241
Poly-3 test	0.105	0.248	0.149	0.154
Litter-adjusted correlation	−0.10
Litter-adjusted Poly-3 rate	15.4%	27.4%	30.9%	31.6%
Litter-adjusted Poly-3 test	0.067	0.123	0.099	0.067
Sire-adjusted correlation	0.06
Sire-adjusted Poly-3 rate	15.8%	26.5%	30.9%	31.8%
Sire-adjusted Poly-3 test	0.080	0.163	0.094	0.074

: (T)Terminal kill
*: Significantly different (P≤0.05) from by the Poly-3 test
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A negative trend or a lower incidence in a dose group is indicated by N.
e: Not applicable; no neoplasms in animal group
f: Value of statistic cannot be computed.

Table G11Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

	0/0 mg/kg	240/40 mg/kg
All Organs: Granulocytic Leukemia
Overall rate^a	0/26 (0.0%)	1/26 (3.8%)
Adjusted rate^b	0/25.5 (0.0%)	1/24.7 (4.1%)
Terminal rate^c	0/25 (0.0%)	1/23 (4.3%)
First incidence (days)	—^e	320 (T)
Poly-3 test^d		0.493
Litter-adjusted correlation	0.02
Litter-adjusted Poly-3 rate	0.0%	4.2%
Litter-adjusted Poly-3 test		0.158
Sire-adjusted correlation	0.01
Sire-adjusted Poly-3 rate	0.0%	4.2%
Sire-adjusted Poly-3 test		0.160
All Organs: Benign Neoplasms
Overall rate	2/26 (7.7%)	1/26 (3.8%)
Adjusted rate	2/25.5 (7.8%)	1/24.7 (4.1%)
Terminal rate	2/25 (8.0%)	1/23 (4.3%)
First incidence (days)	320 (T)	318 (T)
Poly-3 test		0.512N
Litter-adjusted correlation	−0.11
Litter-adjusted Poly-3 rate	7.7%	4.6%
Litter-adjusted Poly-3 test		0.314N
Sire-adjusted correlation	−0.08
Sire-adjusted Poly-3 rate	7.7%	5.5%
Sire-adjusted Poly-3 test		0.368N
All Organs: Malignant Neoplasms
Overall rate	2/26 (7.7%)	3/26 (11.5%)
Adjusted rate	2/26.0 (7.7%)	3/25.1 (11.9%)
Terminal rate	1/25 (4.0%)	2/23 (8.7%)
First incidence (days)	259	260
Poly-3 test		0.484
Litter-adjusted correlation	−0.02
Litter-adjusted Poly-3 rate	7.7%	11.8%
Litter-adjusted Poly-3 test		0.309
Sire-adjusted correlation	0.03
Sire-adjusted Poly-3 rate	8.4%	12.2%
Sire-adjusted Poly-3 test		0.319
All Organs: Benign and Malignant Neoplasms
Overall rate	4/26 (15.4%)	4/26 (15.4%)
Adjusted rate	4/26.0 (15.4%)	4/25.1 (15.9%)
Terminal rate	3/25 (12.0%)	3/23 (13.0%)
First incidence (days)	259	260
Poly-3 test		0.628
Litter-adjusted correlation	0.17
Litter-adjusted Poly-3 rate	15.5%	16.7%
Litter-adjusted Poly-3 test		0.459
Sire-adjusted correlation	0.01
Sire-adjusted Poly-3 rate	15.8%	15.9%
Sire-adjusted Poly-3 test		0.495

: (T)Terminal kill
a: Number of neoplasm-bearing animals/number of animals examined microscopically
b: Poly-3 estimated neoplasm incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Not applicable; no neoplasms in animal group

Table G12Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	240/120/240 mg/kg
Kidney: Cellular Infiltration
Overall rate^a	7/27 (25.9%)	2/26 (7.7%)
Adjusted rate^b	7/27.0 (25.9%)	2/22.8 (8.8%)
Terminal rate^c	7/27 (25.9%)	2/21 (9.5%)
First incidence (days)	212 (T)	213 (T)
Average severity	1.0	1.0
Poly-3 test^d		0.115N
Litter-adjusted correlation	0.34
Litter-adjusted Poly-3 rate	25.5%	9.6%
Litter-adjusted Poly-3 test		0.076N
Sire-adjusted correlation	−0.17
Sire-adjusted Poly-3 rate	30.0%	3.7%
Sire-adjusted Poly-3 test		0.003N^**
SW Test^e		0.040N^*
Lymph Node (Mesenteric): Hyperplasia
Overall rate	19/27 (70.4%)	16/25 (64.0%)
Adjusted rate	19/27.0 (70.4%)	16/23.5 (68.1%)
Terminal rate	19/27 (70.4%)	15/21 (71.4%)
First incidence (days)	212 (T)	125
Average severity	1.9	1.4
Poly-3 test		0.551N
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	70.2%	68.2%
Litter-adjusted Poly-3 test		0.439N
Sire-adjusted correlation	0.02
Sire-adjusted Poly-3 rate	70.2%	68.3%
Sire-adjusted Poly-3 test		0.431N
SW Test		0.045N^*
Salivary Gland: Cellular Infiltration
Overall rate	5/27 (18.5%)	0/26 (0.0%)
Adjusted rate	5/27.0 (18.5%)	0/22.8 (0.0%)
Terminal rate	5/27 (18.5%)	0/21 (0.0%)
First incidence (days)	212 (T)	—^f
Average severity	1.0	^f
Poly-3 test		0.042N^*
Litter-adjusted correlation	−0.12
Litter-adjusted Poly-3 rate	18.6%	0.0%
Litter-adjusted Poly-3 test		0.004N^**
Sire-adjusted correlation	−0.05
Sire-adjusted Poly-3 rate	18.4%	0.0%
Sire-adjusted Poly-3 test		0.003N^**
SW Test		0.011N^*

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or the SW test.
**: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for the differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A lower incidence in the dosed group is indicated by N.
f: Not applicable; no lesions in animal group

Table G13Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	80/40/80 mg/kg	160/80/160 mg/kg	240/120/240 mg/kg
Brain (Cerebrum): Mineralization
Overall rate^a	4/27 (14.8%)	1/27 (3.7%)	2/27 (7.4%)	0/27 (0.0%)
Adjusted rate^b	4/24.5 (16.3%)	1/22.8 (4.4%)	2/27.0 (7.4%)	0/23.7 (0.0%)
Terminal rate^c	4/24 (16.7%)	1/21 (4.8%)	2/27 (7.4%)	0/22 (0.0%)
First incidence (days)	320 (T)	324 (T)	322 (T)	—^f
Average severity	1.0	1.0	1.0	—^f
Poly-3 test^d	0.037N^*	0.195N	0.289N	0.058N
Litter-adjusted correlation	0.00
Litter-adjusted Poly-3 rate	16.3%	4.4%	7.4%	0.0%
Litter-adjusted Poly-3 test	0.027N^*	0.085N	0.164N	0.016N^*
Sire-adjusted correlation	0.02
Sire-adjusted Poly-3 rate	16.3%	4.5%	7.5%	0.0%
Sire-adjusted Poly-3 test	0.045N^*	0.105N	0.192N	0.029N^*
JT/SW Test^e	0.028N^*	0.081N	0.136N	0.016N^*
Large Intestine (Cecum): Hyperplasia
Overall rate	0/26 (0.0%)	2/26 (7.7%)	2/27 (7.4%)	3/25 (12.0%)
Adjusted rate	0/24.4 (0.0%)	2/22.8 (8.8%)	2/27.0 (7.4%)	3/23.0 (13.0%)
Terminal rate	0/24 (0.0%)	2/21 (9.5%)	2/27 (7.4%)	3/22 (13.6%)
First incidence (days)	–	319 (T)	321 (T)	321 (T)
Average severity	–	2.5	2.0	2.0
Poly-3 test	0.080	0.220	0.259	0.103
Litter-adjusted correlation	−0.08
Litter-adjusted Poly-3 rate	0.0%	8.8%	7.5%	12.9%
Litter-adjusted Poly-3 test	0.048^*	0.060	0.062	0.034^*
Sire-adjusted correlation	−0.03
Sire-adjusted Poly-3 rate	0.0%	8.7%	7.5%	13.6%
Sire-adjusted Poly-3 test	0.029^*	0.062	0.062	0.019^*
JT/SW Test	0.059	0.077	0.127	0.056
Kidney: Cellular Infiltration
Overall rate	6/26 (23.1%)	11/27 (40.7%)	6/27 (22.2%)	4/26 (15.4%)
Adjusted rate	6/24.4 (24.6%)	11/23.5 (46.8%)	6/27.0 (22.2%)	4/23.7 (16.9%)
Terminal rate	6/24 (25.0%)	10/21 (47.6%)	6/27 (22.2%)	4/22 (18.2%)
First incidence (days)	318 (T)	217	320 (T)	318 (T)
Average severity	1.0	1.0	1.0	1.3
Poly-3 test	0.151N	0.095	0.550N	0.382N
Litter-adjusted correlation	−0.14
Litter-adjusted Poly-3 rate	24.3%	46.7%	22.6%	17.1%
Litter-adjusted Poly-3 test	0.103N	0.050	0.435N	0.261N
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	24.6%	47.0%	22.5%	17.2%
Sire-adjusted Poly-3 test	0.130N	0.034^*	0.422N	0.275N
JT/SW Test	0.155N	0.914N	0.554N	0.373N
Liver: Cytoplasmic Vacuolization
Overall rate	20/26 (76.9%)	17/27 (63.0%)	23/27 (85.2%)	13/27 (48.1%)
Adjusted rate	20/24.4 (82.1%)	17/22.8 (74.6%)	23/27.0 (85.2%)	13/23.7 (54.9%)
Terminal rate	20/24 (83.3%)	17/21 (81.0%)	23/27 (85.2%)	13/22 (59.1%)
First incidence (days)	318 (T)	317 (T)	318 (T)	318 (T)
Average severity	1.6	1.8	1.5	1.5
Poly-3 test	0.052N	0.392N	0.530	0.036N^*
Litter-adjusted correlation	0.10
Litter-adjusted Poly-3 rate	82.0%	75.0%	85.3%	55.3%
Litter-adjusted Poly-3 test	0.039N^*	0.297N	0.366	0.017N^*
Sire-adjusted correlation	−0.04
Sire-adjusted Poly-3 rate	81.5%	73.5%	85.5%	54.8%
Sire-adjusted Poly-3 test	0.042N^*	0.245N	0.341	0.014N^*
JT/SW Test	0.022N^*	0.343N	0.525N	0.012N^*
Preputial Gland: Degeneration
Overall rate	0/27 (0.0%)	0/26 (0.0%)	0/27 (0.0%)	3/26 (11.5%)
Adjusted rate	0/24.5 (0.0%)	0/22.8 (0.0%)	0/27.0 (0.0%)	3/24.7 (12.2%)
Terminal rate	0/24 (0.0%)	0/21 (0.0%)	0/27 (0.0%)	2/22 (9.1%)
First incidence (days)	—	—	—	94
Average severity	—	—	—	3.0
Poly-3 test	0.017^*	—^g	—	0.115
Litter-adjusted correlation	0.01
Litter-adjusted Poly-3 rate	0.0%	0.0%	0.0%	12.2%
Litter-adjusted Poly-3 test	0.033^*	—	—	0.033^*
Sire-adjusted correlation	0.04
Sire-adjusted Poly-3 rate	—	—	—	—
Sire-adjusted Poly-3 test	—	—	—	—
JT/SW Test	0.009^**	0.500	0.583	0.007^**

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or the JT/SW test
**: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A negative trend or a lower incidence in a dose group is indicated by N.
e: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the Jonckheere/Terpstra monotonic trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A negative trend or a lower incidence in a dose group is indicated by N.
f: Not applicable; no lesions in animal group
g: Value of statistic cannot be computed.

Table G14Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

	0/0 mg/kg	240/40 mg/kg
Liver: Cytoplasmic Vacuolization
Overall rate^a	23/24 (95.8%)	18/25 (72.0%)
Adjusted rate^b	23/23.4 (98.2%)	18/23.5 (76.7%)
Terminal rate^c	23/23 (100.0%)	18/22 (81.8%)
First incidence (days)	294 (T)	317 (T)
Average severity	1.7	1.6
Poly-3 test^d		0.026N^*
Litter-adjusted correlation	0.27
Litter-adjusted Poly-3 rate	98.6%	77.4%
Litter-adjusted Poly-3 test		0.022N^*
Sire-adjusted correlation	−0.10
Sire-adjusted Poly-3 rate	96.3%	74.4%
Sire-adjusted Poly-3 test		0.009N^**
SW Test^e		0.043N^*

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or SW test
**: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A lower incidence in the dosed group is indicated by N.

Table G15Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg
Large Intestine (Cecum): Hyperplasia
Overall rate^a	0/26 (0.0%)	2/26 (7.7%)
Adjusted rate^b	0/24.7 (0.0%)	2/26.0 (7.7%)
Terminal rate^c	0/24 (0.0%)	2/26 (7.7%)
First incidence (days)	—^f	214 (T)
Average severity	—^f	2.0
Poly-3 test^d		0.247
Litter-adjusted correlation	−0.41
Litter-adjusted Poly-3 rate	0.0%	11.2%
Litter-adjusted Poly-3 test		0.042^*
Sire-adjusted correlation	−0.06
Sire-adjusted Poly-3 rate	0.1%	7.9%
Sire-adjusted Poly-3 test		0.060
SW Test^e		0.077
Kidney: Cellular Infiltration
Overall rate	8/26 (30.8%)	3/26 (11.5%)
Adjusted rate	8/24.7 (32.4%)	3/26.0 (11.5%)
Terminal rate	8/24 (33.3%)	3/26 (11.5%)
First incidence (days)	212 (T)	213 (T)
Average severity	1.1	1.0
Poly-3 test		0.070N
Litter-adjusted correlation	0.12
Litter-adjusted Poly-3 rate	31.5%	11.8%
Litter-adjusted Poly-3 test		0.042N^*
Sire-adjusted correlation	−0.04
Sire-adjusted Poly-3 rate	33.3%	11.6%
Sire-adjusted Poly-3 test		0.004N^**
SW Test		0.043N^*
Salivary Gland: Cellular Infiltration
Overall rate	14/26 (53.8%)	7/26 (26.9%)
Adjusted rate	14/24.7 (56.7%)	7/26.0 (26.9%)
Terminal rate	14/24 (58.3%)	7/26 (26.9%)
First incidence (days)	211 (T)	213 (T)
Average severity	1.1	1.1
Poly-3 test		0.028N^*
Litter-adjusted correlation	−0.29
Litter-adjusted Poly-3 rate	57.3%	26.0%
Litter-adjusted Poly-3 test		0.006N^**
Sire-adjusted correlation	−0.10
Sire-adjusted Poly-3 rate	55.5%	26.8%
Sire-adjusted Poly-3 test		0.016N^*
SW Test		0.031N^*

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or SW test
**: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A lower incidence in the dosed group is indicated by N.
f: Not applicable, no lesions in animal group

Table G16Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

	0/0/0 mg/kg	80/40/80 mg/kg	160/80/160 mg/kg	240/120/240 mg/kg
Adrenal Cortex: Subscapular Hyperplasia
Overall rate^a	25/26 (96.2%)	25/27 (92.6%)	27/27 (100.0%)	24/26 (92.3%)
Adjusted rate^b	25/26.0 (96.2%)	25/25.7 (97.5%)	27/27.0 (100.0%)	24/24.7 (97.2%)
Terminal rate^c	22/23 (95.7%)	23/23 (100.0%)	24/24 (100.0%)	21/21 (100.0%)
First incidence (days)	184	212	162	274
Average severity	1.0	1.2	1.2	1.2
Poly-3 test^d	0.432	0.710	0.492	0.727
Litter-adjusted correlation	−0.07
Litter-adjusted Poly-3 rate	95.9%	97.2%	100%	97.2%
Litter-adjusted Poly-3 test	0.322	0.390	0.144	0.392
Sire-adjusted correlation	−0.03
Sire-adjusted Poly-3 rate	96.1%	97.3%	100%	97.2%
Sire-adjusted Poly-3 test	0.332	0.389	0.146	0.402
JT/SW Test⁶	0.108	0.153	0.030^*^f	0.096
Bone Marrow: Myeloid Cell Hyperplasia
Overall rate	0/26 (0.0%)	0/26 (0.0%)	4/26 (15.4%)	1/26 (3.8%)
Adjusted rate	0/24.5 (0.0%)	0/24.8 (0.0%)	4/25.8 (15.5%)	1/24.6 (4.1%)
Terminal rate	0/23 (0.0%)	0/23 (0.0%)	3/24 (12.5%)	0/21 (0.0%)
First incidence (days)	—^g	—	185	50
Average severity	—^g	—	2.5	2.0
Poly-3 test	0.103	—^h	0.061	0.501
Litter-adjusted correlation	−0.08
Litter-adjusted Poly-3 rate	0.0%	0.0%	15.6%	4.0%
Litter-adjusted Poly-3 test	0.020^*	—	0.008^**	0.154
Sire-adjusted correlation	−0.01
Sire-adjusted Poly-3 rate	0.0%	0.0%	15.6%	4.1%
Sire-adjusted Poly-3 test	0.019^*	—	0.013^*	0.139
JT/SW Test	0.079	0.500	0.007^**^f	0.066
Brain (Cerebrum): Mineralization
Overall rate	0/26 (0.0%)	1/27 (3.7%)	4/27 (14.8%)	2/27 (7.4%)
Adjusted rate	0/24.5 (0.0%)	1/24.8 (4.0%)	4/25.1 (15.9%)	2/24.1 (8.3%)
Terminal rate	0/23 (0.0%)	1/23 (4.3%)	4/24 (16.7%)	2/21 (9.5%)
First incidence (days)	—	322 (T)	321 (T)	321 (T)
Average severity	—	1.0	1.0	1.0
Poly-3 test	0.073	0.503	0.058	0.231
Litter-adjusted correlation	−0.13
Litter-adjusted Poly-3 rate	0.0%	3.8%	16.1%	8.6%
Litter-adjusted Poly-3 test	0.020^*	0.151	0.007^**	0.064
Sire-adjusted correlation	−0.07
Sire-adjusted Poly-3 rate	0.0%	4.6%	15.6%	7.9%
Sire-adjusted Poly-3 test	0.021^*	0.109	0.002^**	0.065
JT/SW Test	0.062	0.163	0.015^*^f	0.064
Kidney: Cellular Infiltration
Overall rate	9/26 (34.6%)	6/27 (22.2%)	5/27 (18.5%)	4/27 (14.8%)
Adjusted rate	9/24.5 (36.8%)	6/24.8 (24.2%)	5/25.1 (19.9%)	4/24.5 (16.4%)
Terminal rate	9/23 (39.1%)	6/23 (26.1%)	5/24 (20.8%)	3/21 (14.3%)
First incidence (days)	320 (T)	319 (T)	320 (T)	274
Average severity	1.1	1.2	1.0	1.0
Poly-3 test	0.056N	0.258N	0.158N	0.095N
Litter-adjusted correlation	−0.04
Litter-adjusted Poly-3 rate	36.9%	23.5%	20.0%	16.4%
Litter-adjusted Poly-3 test	0.034N^*	0.129N	0.084N	0.033N^*
Sire-adjusted correlation	0.06
Sire-adjusted Poly-3 rate	36.7%	26.8%	20.5%	16.4%
Sire-adjusted Poly-3 test	0.014N^*	0.175N	0.085N	0.026N^*
JT/SW Test	0.038N^*	0.171N	0.098N	0.048N^*
Liver: Tension Lipidosis
Overall rate	3/26 (11.5%)	5/27 (18.5%)	7/27 (25.9%)	4/27 (14.8%)
Adjusted rate	3/24.5 (12.3%)	5/25.2 (19.9%)	7/25.1 (27.9%)	4/24.1 (16.6%)
Terminal rate	3/23 (13.0%)	4/23 (17.4%)	7/24 (29.2%)	4/21 (19.0%)
First incidence (days)	319 (T)	282	320 (T)	318 (T)
Average severity	1.0	1.6	1.1	1.0
Poly-3 test	0.307	0.367	0.154	0.491
Litter-adjusted correlation	−0.17
Litter-adjusted Poly-3 rate	11.7%	17.9%	28.0%	16.1%
Litter-adjusted Poly-3 test	0.229	0.260	0.047^*	0.328
Sire-adjusted correlation	−0.07
Sire-adjusted Poly-3 rate	11.8%	21.9%	27.3%	16.3%
Sire-adjusted Poly-3 test	0.294	0.149	0.070	0.335
JT/SW Test	0.339	0.203	0.110	0.258
Liver: Cytoplasmic Vacuolization
Overall rate	6/26 (23.1%)	4/27 (14.8%)	3/27 (11.1%)	10/27 (37.0%)
Adjusted rate	6/24.5 (24.5%)	4/24.8 (16.1%)	3/25.3 (11.9%)	10/24.5 (40.9%)
Terminal rate	6/23 (26.1%)	4/23 (17.4%)	2/24 (8.3%)	9/21 (42.9%)
First incidence (days)	320 (T)	317 (T)	298	274
Average severity	1.2	1.0	1.3	1.0
Poly-3 test	0.150	0.354N	0.215N	0.179
Litter-adjusted correlation	−0.11
Litter-adjusted Poly-3 rate	24.8%	15.5%	11.5%	40.2%
Litter-adjusted Poly-3 test	0.147	0.184N	0.092N	0.119
Sire-adjusted correlation	−0.00
Sire-adjusted Poly-3 rate	24.5%	16.0%	11.8%	40.9%
Sire-adjusted Poly-3 test	0.121	0.213N	0.102N	0.104
JT/SW Test	0.152	0.792	0.906	0.163
Pancreas: Cellular Infiltration
Overall rate	0/26 (0.0%)	0/27 (0.0%)	1/27 (3.7%)	3/26 (11.5%)
Adjusted rate	0/24.5 (0.0%)	0/24.8 (0.0%)	1/25.1 (4.0%)	3/23.4 (12.8%)
Terminal rate	0/23 (0.0%)	0/23 (0.0%)	1/24 (4.2%)	3/21 (14.3%)
First incidence (days)	—	—	322 (T)	321 (T)
Average severity	—	—	1.0	1.0
Poly-3 test	0.018^*	—	0.505	0.106
Litter-adjusted correlation	−0.06
Litter-adjusted Poly-3 rate	0.0%	0.0%	4.0%	13.0%
Litter-adjusted Poly-3 test	0.017^*	—	0.148	0.025^*
Sire-adjusted correlation	−0.02
Sire-adjusted Poly-3 rate	0.0%	0.0%	3.9%	12.9%
Sire-adjusted Poly-3 test	0.015^*	—	0.154	0.025^*
JT/SW Test	0.011^*	0.500	0.135	0.017^*
Salivary Gland: Cellular Infiltration
Overall rate	15/26 (57.7%)	14/27 (51.9%)	10/26 (38.5%)	10/27 (37.0%)
Adjusted rate	15/24.9 (60.2%)	14/24.9 (56.2%)	10/24.3 (41.1%)	10/24.7 (40.4%)
Terminal rate	14/23 (60.9%)	13/23 (56.5%)	10/24 (41.7%)	8/21 (38.1%)
First incidence (days)	269	312	320 (T)	274
Average severity	1.2	1.1	1.3	1.0
Poly-3 test	0.058N	0.498N	0.145N	0.131N
Litter-adjusted correlation	0.07
Litter-adjusted Poly-3 rate	59.9%	56.6%	41.0%	40.8%
Litter-adjusted Poly-3 test	0.052N	0.410N	0.084N	0.089N
Sire-adjusted correlation	0.01
Sire-adjusted Poly-3 rate	60.2%	56.3%	41.3%	40.5%
Sire-adjusted Poly-3 test	0.080N	0.399N	0.091N	0.124N
JT/SW Test	0.032N^*	0.250N	0.134N	0.049N^*

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or the JT/SW test
**: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A negative trend or a lower incidence in a dose group is indicated by N.
e: Beneath the 0/0/0 mg/kg group incidence is the P value associated with the Jonckheere/Terpstra monotonic trend test. Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A negative trend or lower incidence in a dose group is indicated by N.
f: The P value from the William’s modified Shirley’s test was significant, but the test violated the monotonic constraint.
g: Not applicable, no lesions in animal group
h: Value of statistic cannot be computed.

Table G17Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

	0/0 mg/kg	240/40 mg/kg
Large Intestine (Cecum): Hyperplasia
Overall rate^a	3/25 (12.0%)	0/26 (0.0%)
Adjusted rate^b	3/25.0 (12.0%)	0/24.7 (0.0%)
Terminal rate^c	3/25 (12.0%)	0/23 (0.0%)
First incidence (days)	318 (T)	—^f
Average severity	2.0	—^f
Poly-3 test^d		0.116N
Litter-adjusted correlation	−0.07
Litter-adjusted Poly-3 rate	12.0%	0.0%
Litter-adjusted Poly-3 test		0.024N^*
Sire-adjusted correlation	−0.11
Sire-adjusted Poly-3 rate	15.1%	0.4%
Sire-adjusted Poly-3 test		<0.001N^***
SW Test^e		0.036N^*
Liver: Cytoplasmic Vacuolization
Overall rate	12/25 (48.0%)	6/26 (23.1%)
Adjusted rate	12/25.0 (48.0%)	6/25.3 (23.7%)
Terminal rate	12/25 (48.0%)	5/23 (21.7%)
First incidence (days)	317 (T)	231
Average severity	1.0	1.0
Poly-3 test		0.064N
Litter-adjusted correlation	0.04
Litter-adjusted Poly-3 rate	48.4%	23.6%
Litter-adjusted Poly-3 test		0.031N^*
Sire-adjusted correlation	0.21
Sire-adjusted Poly-3 rate	54.2%	22.6%
Sire-adjusted Poly-3 test		0.002N^**
SW Test		0.033N^*

: (T)Terminal kill
*: Significantly different (P≤0.05) by the Poly-3 test or SW test
**: P≤0.01
***: P≤0.01
a: Number of lesion-bearing animals/number of animals examined microscopically
b: Poly-3 estimated lesion incidence after adjustment for intercurrent mortality
c: Observed incidence at terminal kill
d: Beneath the dosed group incidence are P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group. The Poly-3 test accounts for differential mortality in animals that do not reach terminal kill. A lower incidence in the dosed group is indicated by N.
e: Beneath the dosed group incidence are the P values corresponding to pairwise comparisons between the 0/0 mg/kg group and that dosed group by William’s modified Shirley’s test. A lower incidence in the dosed group is indicated by N.
f: Not applicable; no lesions in animal group

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Leakey JEA, Allaben WT, Dunnick JK, et al. NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet]. Research Triangle Park (NC): National Toxicology Program; 2013 Oct. APPENDIX G, LITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY.
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LITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY - NTP Genetically Modifie...
LITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY - NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study)
GENETIC TOXICOLOGY - NTP Genetically Modified Model Report on the Toxicology and...
GENETIC TOXICOLOGY - NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study)

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NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet].

APPENDIX GLITTER EFFECTS ON SURVIVAL, BODY WEIGHT, AND PATHOLOGY

Background

Methods

Survival

Body Weight

Pathology

Results

Survival

Body Weight

Pathology

Neoplasms

Nonneoplastic Lesions

Conclusions

Table G1Distribution of Male Heterozygous F1 p53+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Table G2Distribution of Female Heterozygous F1 p53+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Table G3Effect of AZT Dose on Survival of Heterozygous F1 p53+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZTa

Table G4Effect of AZT Dose on Survival of Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZTa

Table G5Effect of AZT Dose on Survival of Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZTa

Table G6Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G7Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G8Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G9Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G10Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G11Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G12Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G13Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G14Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G15Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G16Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G17Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

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NTP Genetically Modified Model Report on the Toxicology and Carcinogenicity Studies of 3’-Azido-3’-Deoxythymidine (CASRN 30516-87-1) in Genetically Modified C3B6.129F1-Trp53^tm1Brd N12 Haploinsufficient Mice (In Utero and Postnatal Gavage Study): NTP GMM 14 [Internet].

Table G1Distribution of Male Heterozygous F1 p53^+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Table G2Distribution of Female Heterozygous F1 p53^+/− Mouse Pups in the In Utero/Postnatal Gavage Studies of AZT

Table G3Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT^a

Table G4Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT^a

Table G5Effect of AZT Dose on Survival of Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT^a

Table G6Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G7Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G8Litter-adjusted Statistical Analysis of Primary Neoplasms in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G9Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G10Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G11Litter-adjusted Statistical Analysis of Primary Neoplasms in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G12Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G13Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G14Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Male Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT

Table G15Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 30-Week In Utero/Postnatal Gavage Study of AZT

Table G16Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Study of AZT

Table G17Litter-adjusted Statistical Analysis of Selected Nonneoplastic Lesions in Female Heterozygous F1 p53^+/− Mice in the 45-Week In Utero/Postnatal Gavage Stop-Study of AZT