Table 5.
NTP studies where at least one sex had MNCL classified as clear evidence of carcinogenicity.
| Two-year study highlights | Overall MNCL incidencesa | MNCL historical control data | Authors’ commentary |
|---|---|---|---|
| 2,2-Bis(bromomethyl)-1,3-propanediol (NTP TR 452) | |||
| This dietary administration study started in March 1989 with a high-dose male stop-study group. There were epithelial tumors in several tissues in rats and mice. There was an increase in tunica vaginalis mesotheliomas in male rats and increased incidence of MNCL. Oral cavity and esophageal tumors were present in female rats. Harderian gland and lung tumors were present in treated B6C3F1 mice. | F 15/50 (30%), 13/51 (25%), 19/53 (36%), 19/52 (37%)M 27/51 (53%), 29/53 (55%), 40/51 (78%), 34/55 (62%), 25/60 (42% – stop exposure group) | (Not provided in TR)M 48.9% ± 8.8% (range 32–62%) | The MNCL response in the top two doses of the main study was significantly different by the life table test and, therefore, MNCL was listed as part of the clear evidence of carcinogenicity in male rats. It is noted that only the mid-dose exceed the historical control range and MNCL was not increased in the stop exposure group of males. |
| C.I. Direct Blue 15 (NTP TR 397) | |||
| Drinking water study started in 1983 with 9 and 15-month interim sacrifices and with 22-month final sacrifice due to excessive mortality. Multisite positive carcinogen in both sexes including skin, Zymbal’s gland, liver, oral cavity, intestine, etc. MNCL was listed as clear evidence of carcinogenicity in females and as may have been related to chemical treatment in males. There was no study in mice. | F 7/50(14%), 13/35(37%), 27/65(42%), 15/50(30%)M 17/50(34%), 19/35(54%), 28/65(43%), 20/50(40%) | F 20% ± 8% (range 6–40%)M 37% ± 16% (range 10–72%) | Overall incidences within historical control ranges for both sexes. Life table statistical flags are significant. Competing risks from multiple fatal neoplasms. The wide historical control range in males makes that response uncertain. Contribution of MNCL to NTP conclusions of clear evidence in females and equivocal evidence in males is questionable. |
| Furan (NTP TR 402) | |||
| This corn oil gavage study started in June 1982 and included a high-dose stop-exposure. There was a high incidence of liver cholangiocarcinoma in the stop study as well as the main study. MNCL was listed as clear evidence of carcinogenicity in both sexes. There were hepatocellular and adrenal tumors in treated B6C3F1 mice. | F 8/50 (16%), 9/50 (18%), 17/50 (34%), 21/50 (42%)M 8/50 (16%), 11/50 (22%), 17/50 (34%), 25/50 (50%) | F 26.8% ± 7% (range 16–38%)M 21.3% ± 8.9% (range 4–38%) | The MNCL response exceeded the historical control range in at least one treated group in both sexes but was close to the upper historical control limit in females. There was a clear dose-response for MNCL in both sexes consistent with the NTP call of clear evidence of carcinogenicity. |
| Gallium arsenide (NTP TR 492) | |||
| There was good survival in this inhalation study that started in September 1993. There were no neoplastic effects in males. There were lung and adrenal tumors in addition to MNCL classified as clear evidence of carcinogenicity in females. There were no neoplastic effects in B6C3F1 mice. | F 22/50 (44%), 21/50 (42%), 18/50 (36%), 33/50 (66%)M 19/50 (38%), 28/50 (56%), 33/60 (66%), 28/50 (56%) | F 35.0% ± 5.9% (range 24–47%)M 58.0% ± 8.0% (range 42–70%) | The incidence of MNCL in females exceeded the historical control range only at the high dose and statistical significance was only p = 0.021 for this group by the poly 3 test. The control incidence of MNCL in males was unusually low and the incidence in the exposed males was within the historical control range. The call of clear evidence of carcinogenicity in females is questionable. |
| Glycidol (NTP TR374) | |||
| Water gavage study started in 1981. Multisite positive carcinogen in both sexes including mesothelioma, mammary gland neoplasia, glioma, oral mucosa tumors, intestine tumors, etc. Early deaths due to fatal neoplasms. MNCL in females listed as part of clear evidence of carcinogenicity. Multisite neoplasia in male and female B6C3F1 mice. | F 13/50 (26%), 14/50 (28%), 20/50 (40%)M 25/50 (50%), 33/50 (66%), 21/50 (42%) | F 20% ± 8% (range 6–40%)M 37% ± 16% (range 10–72%) | Overall incidences of MNCL within historical control ranges for both sexes. Competing risks from multiple fatal neoplasms. There was discussion of the MNCL response during the peer review. The contribution of MNCL to the NTP conclusion of clear evidence in female rats is questionable. |
| o-Nitroanisole (NTP TR 416) | |||
| This dietary study was started in September 1984 and included a stop-exposure group with interim sacrifices. While the stop study had urinary and intestinal epithelial neoplasia, the only tumor response in the main study was MNCL. The study was classified as clear evidence of carcinogenicity in both sexes of rats based on the combination of the main and stop studies. Liver tumors were present in the treated B6C3F1 mice. | F 14/50 (28%), 11/50 (22%), 14/50 (28%), 26/50 (52%)M 26/50 (52%), 25/50 (50%), 42/50 (84%), 34/50 (68%) | F 26.6% ± 8.8% (range 14–36%)M 48.1% ± 7/7% (range 32–62%) | This is the first NTP study where the combined results of the main and stop studies were used to classify the carcinogenic response. There was discussion during the peer review that the MNCL should be considered some evidence in males and equivocal evidence in females. Life table statistics are not highly convincing. Ultimately, the peer review supported the NTP call of clear evidence of carcinogenicity for MNCL. |
| Mirex (NTP TR 313) | |||
| First dietary study started in June 1977. Second dietary study at higher doses started in females 6 months later. Results combined from the two studies. Good survival. NTP reported clear evidence of carcinogenicity in males based on liver, kidney and adrenal responses and clear evidence of carcinogenicity in females based on liver and MNCL. There was no corresponding B6C3F1 mouse study. | F 14/104(13%), 8/52 (15%), 11/52 (21%), 14/52 (27%), 18/52 (35%), 27/104 (26%), 14/52 (27%)M 16/52 (31%), 17/52 (33%), 15/52 (29%), 22/52 (42%), 21/52 (40%), 10/53 (19%) | F 19% ± 7% (range 6–38%)M 29% ± 12% (range 10–60%) | MNCL response was weak in females without an early response and this was noted during the peer review. In the first study, the female MNCL was considered lethal while in the second study the female MNCL was considered incidental. Statistical flags are low and not convincing. |
| Tetrachloroethylene (NTP TR311) | |||
| Inhalation study started in 1981. Reduced survival in males exposed to highest concentration may have been due to MNCL. NTP reported clear evidence of carcinogenicity in male rats based on MNCL and renal tubular neoplasms and some evidence of carcinogenicity in female rats based on MNCL. B6C3F1 mice had treatment-related increased hepatocellular neoplasia. | F 18/50(36%), 30/50(60%), 29/50(58%)M 28/50(56%), 37/50(74%), 37/50(74%) | F 29% ± 6% (range 22–35%)(Laboratory)F 19% ± 7% (range 6–38%)(NTP)M 47% ± 15% (range 32–68%)(Laboratory)M 29% ± 12% (range 10–60%)(NTP) | The frequency distribution of MNCL stages 1, 2 and 3 was similar and not statistically significant among the controls and exposed rats. Comments during the NTP peer review regarding concerns about the high laboratory control rates of MNCL in this study were made suggesting conclusions regarding MNCL are questionable for both sexes. |
| Tetrafluoroethylene (NTP TR 450) | |||
| This inhalation study, started in June 1988, resulted in liver and kidney neoplasms in both sexes along with MNCL as clear evidence of carcinogenicity in females and equivocal evidence regarding MNCL in males. There was reduced body weight gain and increased early mortality for both sexes at the high concentration. Both sexes of treated B6C3F1 mice had liver neoplasms. | F 16/50 (32%), 31/50 (62%), 23/50 (46%), 36/50 (72%)M 34/50 (68%), 43/50 (86%), 38/50 (76%), 31/50 (62%) | F 42.0% ± 7.2% (range 30–54%)(Laboratory)40.1% ± 7.2% (range 30–54%) (NTP)56.0% ± 8.7% (range 38–66%) (Laboratory)54.4% ± 8.7% (range 34–66%) (NTP) | The control incidence of MNCL in males slightly exceeded the laboratory historical control. There was a clear increased incidence of MNCL at the low- and mid-concentrations in both sexes. The male response was considered uncertain due to the high control incidence. The female MNCL response is consistent with clear evidence of carcinogenicity. |
TR: NTP Technical Report; M: Male; F: Female; MNCL: Mononuclear cell leukemia.
a = Tumor incidences arranged starting with controls and progressing through increased doses.