Table 4.
NCI/NTP F344 rat studies with a positive leukemia response started and evaluated prior to introduction of NTP levels of evidence of carcinogenicity.
| Two-year study highlights | Overall MNCL incidencesa | MNCL historical control data | Authors’ commentary |
|---|---|---|---|
| Allyl Isovalerate (NTP TR 253) | |||
| This corn oil gavage study started in 1979 and there was good survival and body weight gain in rats. Marginal increases in pancreatic acinar and preputial tumors were present in treated males along with an increase in MNCL. No increased incidence of tumors was seen in female rats or male B6C3F1 mice. Treated female B6C3F1 mice had increased incidence of lymphoma. | F 4/50 (8%), 6/50 (12%), 8/50 (16%)M 1/50 (2%), 4/50 (8%), 7/50 (14%) | 13.2% (range 2–42%)49.6% (range 2–24%) | There was discussion during the peer review regarding how biologically relevant the leukemia response was and debate regarding which of several different historical controls should be used in the evaluation. It is noted that the incidences of MNCL are unusually low in all groups and within the laboratory historical control range. |
| 2-Amino-5-nitrothiazole (NTP TR 053) | |||
| There was dose-related early mortality in rats in this dosed-feed study. A mixture of hematopoietic neoplasms was present in male and female rats but only considered a positive response in males. According to the TR, there was no clear evidence of carcinogenicity in female rats or in either sex of B6C3F1 mice. | All lymphomas/leukemias combined.F 2/24 (8%), 9/24 (37%), 11/24 (46%), 1/24 (4%)M 13/50 (26%), 19/50 (38%), 28/49 (57%) | No historical control data provided in TR. | The leukemia was consistent with MNCL. There was a marginally significant trend for leukemia but no significant pairwise statistical flag for MNCL. During the 1978 peer review, it was suggested that the male response might be within normal statistical variation. It is not clear why the female response was not regarded as positive. |
| Butyl benzyl phthalate (NTP TR 213) | |||
| This is the first of two dietary studies. This study was considered inadequate for male rats due to toxicity and early mortality. Female rats had a marginally increased incidence of MNCL as the only tumor response. There was no increased in tumor incidences in B6C3F1 mice. | F 7/49 (14%), 7/49 (14%), 18/50 (36%)M Study inadequate | 19% (range 12–24%) | Peer reviewed in December 1978. Study repeated starting in 1989 (TR 458) using same or higher doses. In the repeat study there was an increase in pancreatic acinar tumors but no increase in MNCL. MNCL incidences – [F 21/50 (42%), 20/50 (40%), 21/50 (42%), 19/50 (38%); M 31/50 (62%), 28/50 (56%), 34/50 (68%), 30/50 (60%)]. We note the high background incidence of MNCL in this second study. |
| 3,3′-Dimethoxybenzidine-4,4′-diisocyanate (NTP TR 128) | |||
| Test agent was administered by gavage and then followed by dosed-feed. Exposure was for 78 weeks plus 26 weeks without treatment. There was dose-related increased mortality in both sexes. The increased incidence of leukemia/malignant lymphoma was present along with skin and Zymbal gland tumors, and endometrial stromal polyps in treated rats. The B6C3F1 mouse study was negative for carcinogenicity. | F 1/20 (5%), 8/50 (16%), 13/48 (27%)M 0/20 (0%), 19/50 (38%), 17/50 (34%) | No historical control data provided in TR | The leukemia was morphologically characteristic of MNCL. The lymphoma diagnoses were also consistent with MNCL. The low leukemia incidence and small group size of the controls is noted. The 1978 peer review comments were supportive of the leukemia/malignant lymphoma diagnoses. |
| Lasiocarpine (NTP TR 039) | |||
| In this dosed-feed study, there was significant dose-related mortality in male and female rats. Liver angiosarcomas and hepatocellular tumors were treatment-related in both sexes. The leukemia was diagnosed as granulocytic leukemia. Lymphoma/leukemia was increased in low and mid-dose female rats. There was no associated mouse study. | Lymphoma/leukemia combinedF 2/24 (8%), 9/24 (37%), 11/24 (46%), 1/23 (4%)M 3/24 (12%), 3/24 (12%), 11/24 (46%), 7/24 (29%) | No historical control data provided in TR | Slides were not available to determine if the leukemia was consistent with MNCL. During the 1977 peer review by the Data Evaluation/Risk Assessment Subgroup of the Clearinghouse on Environmental Carcinogens, it was pointed out that the incidence of leukemia in treated rats was approximately the same as in female controls in a contemporary study of hexa-chlorophene. The small experimental group size was noted. |
| 2,4,6-Trichlorophenol (NTP TR 155) | |||
| This was a dosed-feed study with good survival but lower body weight in treated rats. The leukemia in male rats was described a monocytic with mature and blast forms. Liver tumors were increased in treated B6C3F1 mice. | F 3/20 (15%), 11/50 (22%), 11/50 (22%)M 4/20 (20%), 25/50 (50%), 29/50 (58%) | No historical control data provided in TR | The monocytic leukemia was confirmed to the characteristic of MNCL. The study summary noted a large number of circulating monocytes in male and female rats. |
TR: NTP Technical Report; M: Male; F: Female; MNCL: Mononuclear cell leukemia.
a = Tumor incidences arranged starting with controls and progressing through increased doses.