Table 7.
Occurrence of MNCL in NTP studies with at least one sex classified as equivocal evidence of carcinogenicity.
| Two-year study highlights | Overall MNCL incidencesa | MNCL historical control data | Authors’ commentary |
|---|---|---|---|
| Acetaminophen (NTP TR 394) | |||
| Survival was similar among all groups in an acetaminophen 2-year study started in December 1982 at dietary concentrations of 0, 600, 3000 and 6000 ppm. The incidence of MNCL was increased in female acetaminophen groups. There was no evidence of carcinogenicity in male rats or in B6C3F1 male and females. | F 9/50 (18%), 17/50 (34%), 15/50 (30%), 24/50 (48%)M 27/50 (54%), 26/50 (52%), 24/50 (48%), 20/50 (40%) | F 16.5% ± 7/9% (range 6–28%) (Lab)F 20.8% ± 8.1% (range 6–40%) (NTP)M Not provided in TR | High dose MNCL response was considered equivocal evidence of carcinogenicity in females during NTP formal public peer review due to uncertainty that increased incidence was due to acetaminophen exposure. Lack of leukemic response in other rat studies including a F344 rat study with acetaminophen exposures up to 13,000 ppm is noted in NTP Technical Report 394. |
| Alpha-Methylstyrene (NTP TR 543) | |||
| This inhalation study was started in 2001. There were increased kidney tumors in males with equivocal evidence of carcinogenicity for MNCL. No increase in tumors was seen in females. B6C3F1 mice had increased liver tumors. | F 18/50 (36%), 21/50 (42%), 21/50 (42%), 22/50 (44%)M 26/50 (52%), 32/50 (64%), 29/50 (58%), 38/50 (76%) | F Not provided in TRM 47.1% ± 10.3% (range 32–66%) | No recorded comments on MNCL were documented during the formal public peer review where the focus was on kidney tumors. The male MNCL response is primarily a high-dose effect. |
| Ampicillin trihydrate (NTP TE 318) | |||
| This corn oil gavage study was started in 1980. There was good survival in both sexes and in mice. There was equivocal evidence of carcinogenicity in male rats based on pheochromocytomas and a marginal increase in MNCL. Female rats and B6C3F1 mice had no evidence of carcinogenicitiy. | F 14/50 (28%), 18/50 (36%), 13/50 (26%)M 5/5 (10%), 14/50 (28%), 13/50 (26%) | F Not provided in TRM 14% ± 8% (range 2–28%) (NTP) | There was considerable discussion regarding the MNCL during the formal publc peer review raising concern about how to classify the MNCL response. Ultimately a consensus vote supported equivocal evidence of carcinogenicity for the male rats. It is noted that the incidences of MNCL in males are within the historical control range. |
| Benzophenone (NTP TR 533) | |||
| In this dosed-feed study started in 1999, there was early mortality in high-dose males. There was an increase in renal tubular tumors in males. MNCL was considered equivocal evidence of carcinogenicity in both sexes. Mice had liver tumors (males) and histiocytic sarcoma (females). | F 19/50 (38%), 25/50 (50%), 30/50 (60%), 29/50 (58%)M 27/50 (54%), 41/50 82%), 39/50 (78%), 24/50 (48%) | F 24.6% ± 9.5% (range 12–38%)M 49.1% ± 11.9% (range 30–68%) | The extent of organ involvement with MNCL increased with dose in females and decreased with dose in males. It was noted during the formal public peer review that the incidences of MNCL in control and treated rats was unusually high. |
| Chlorinated paraffins (NTP TR 308) | |||
| This corn oil gavage was started in 1980. There was decreased body weight and survival in male and female rats. Liver, thyroid and kidney tumor responses were present in both sexes of rats and B6C3F1 mice. | F 11/50 (22%), 22/50 (44%), 16/50 (32%)M 7/50 (14%), 12/50 (24%), 14/50 (28%) | F 12% ± 6% (range 4–20%) (Lab)18% ± 9% (range 4–42%) (NTP)M 6% ± 6% (range 2–18%) (Lab)14% ± 8% (range 2–28%) (NTP) | The study was classified as clear evidence of carcinogenicity while the MNCL response was equivocal evidence of carcinogenicity with indication that it may have been related to treatment. It was recommended that the fact that the maximum tolerated dose was exceeded should be mentioned in the technical report abstract. |
| Chlorinated water (TR 392) | |||
| This drinking water study was started in 1985 with MNCL as the only tumor response attributed to treatment, seen in female rats and considered equivocal evidence of carcinogenicity. B6C3F1 mice had no evidence of carcinogenicity. | F 8/50 (16%), 7/50 (14%), 19/51 (37%), 16/50 (32%)M 25/51 (49%), 25/51 (49%), 27/50 (54%), 29/51 (57%) | F 25% ± 6.1% (range 14–36%) (NTP Feed studies)26% ± 8.5% (range 16–33%) (NTP drinking water studies)M Not provided in TR | There was considerable discussion during the formal public peer review with suggestions to downgrade the call to no evidence of carcinogenicity. However, that motion was defeated in the final voting and equivocal evidence of carcinogenicity was listed in the technical report. |
| Chloraminated water (TR 392) | |||
| This drinking water was started in 1985 and run along with the chlorinated water study (same TR 392). MNCL in female rats was the only response and was called equivocal evidence of carcinogenicity. | F 8/50 (16%), 11/50 (22%), 15/50 (30%), 16/50 (32%)M 25/51 (49%), 26/50 (52%), 29/51 (57%), 30/50 (60%) | F 25% ± 6.1% (range 14–36%) (NTP Feed studies)26% ± 8.5% (range 16–33%) (NTP drinking water studies)M Not provided in TR | The study is even less convincing than the chlorinated water study with all responses falling within the historical control range. A concern is with the high and variable incidence of MNCL in historic controls and the fact that study incidences were within the historic control range. The final call was equivocal evidence of carcinogenicity for MNCL in female rats. |
| C.I. Acid Red 114 (NTP TR 405) | |||
| This dose water study started in 1983 had early mortality due to multiple tumor sites in both sexes. MNCL in female was listed as an uncertain finding (equivocal evidence) regarding carcinogenicity. No mouse study was done. | F 12/50 (24%), 13/35 (37%), 18/65 (28%), 5/50 (10%)M 20/50 (40%), 20/35 (57%), 37/65 (57%), 12/50 (24%) | F 25% ± 6.3% (range 14–36%)M Not provided in TR | Most of the discussion during the peer review indicated a consideration that MNCL should be listed as a tumor response. Hence, it was listed as uncertain (equivocal evidence) evidence of carcinogenicity. It is noted that the incidences fall within or are just above (37% versus 36%) the historical control range. Early mortality was due to toxicity and not MNCL. |
| Diallylphthalate (NTP TR 284) | |||
| There was good survival in this rat only corn oil gavage study started in 1980. No evidence of carcinogenicity in male rats. | F 15/50 (30%), 15/43 (35%), 25/49 (51%)M 13/50 (26%), 12/50 (24%), 14/50 (28%) | F 29% ± 13% (range 16–42%) (Lab)16% ± 9% (range 2–42%) (NTP)M Not provided in TR | This study was called some evidence of carcinogenicity based on MNCL but was downgraded to equivocal evidence during the formal public peer review based on variability in the control incidence and difficulty in definitively diagnosing this lesion. |
| 3,3′-Dimethylbenzidine dihydrochloride (NTP TR 390) | |||
| This was a drinking water study started in 1983 that lasted only 14 months due to mortality. Multiple tumor sites in male and female rats were documented. There was no concurrent B6C3F1 mouse study. | F 1/60 (2%), 3/45 (7%), 6/75 (8%), 4/60 (7%)M 0/60 (0%), 1/44 (2%), 1/75 (1%), 1/60 (2%). | F No historical control data for 14-month intervalM No historical control data for 14-month interval. | The frequency of MNCL is low since it is a late occurring disease in control as well as in treated rats. However, the TR speculates that MNCL may have been related to treatment (equivocal evidence of carcinogenicity) based on its possible early occurrence in treated females. |
| Dimethyl methylphosphonate (NTP TR 323) | |||
| This corn oil gavage study was started in 1981. Significant weight loss and decreased survival were present at the high-dose with clear evidence of carcinogenicity based on renal tumors in male and no evidence of carcinogenicity in female rats. The male B6C3F1 mouse study was inadequate and the female mice had no evidence of carcinogenicity. | F 10/50 (20%), 9/50 (18%), 12/50 (24%)M 10/50(20%), 11/50 (22%), 17/50 (34%) | F Not provided in TRM 19% ± 9% (range 4–28%) (Lab)14% ± 8% (range 2–28%) (NTP) | The increased incidence of MNCL in males was not considered part of the clear evidence call as noted during the formal public peer review and would probably fall into the category of equivocal evidence of carcinogenicity but was not indicated in the technical report. The majority of the MNCL cases were at stage 3. |
| Indium Phosphide (NTP TR 499) | |||
| This inhalation study was started in 1996 producing lung and adrenal tumors in both sexes. MNCL was an uncertain finding in male and female rats. Lung and liver tumors were seen in treated B6C3F1 mice. | F 14/50 (28%), 21/50 (42%), 14/50 (28%), 24/50 (48%)M 16/50 (32%), 23/50 (46%), 29/50 (58%), 25/50 (50%) | F 29.1% ± 8.5% (range 16–42%)M 43.5% ± 9.6% (range 32–54%) | There was no discussion of MNCL during the peer review. The TR report commented that the occurrence of MNCL in both sexes suggests equivocal evidence of carcinogenicity. |
| 4-Methylimidazole (NTP TR 535) | |||
| This dosed feed study started in 2000 and there was equivocal evidence of carcinogenicity in female rats based on MNCL as the only response in rats. B6C3F1 mice had increased lung tumors. | F 9/50 (18%), 7/50 (14%), 16/50 (32%), 20/50 (40%)M 15/50 (30%), 18/50 (36%), 22/50 (44%), 20/50 (40%) | F 23.8% ± 9.1% (range 12–38%)M 46.8% ± 13.0% (range 30–68%) | MNCL was discussed during the formal public peer review and ultimately considered equivocal evidence of carcinogenicity. The female MNCL response was one tumor outside the control range. |
| Methyl isobutyl ketone (NTP TR 538) | |||
| This inhalation study started in 2000 resulted in kidney tumors in males and possible kidney tumors in females. Males had equivocal evidence of MNCL. B6C3F1 mice had increased liver tumors. | F 14/50 (28%), 21/50 (42%), 12/50 (24%), 16/50 (32%)M 25/50 (50%), 26/50 (52%), 32/50 (64%), 35/50 (70%) | F Not provided in TRM 47.1% ± 10.3% (range 32–66%) | No recorded comment on MNCL during the formal public peer review. |
| Pyridine (NTP TR 470) | |||
| This is a dosed water study started in 1991 with some evidence of carcinogenicity in males based on kidney tumors and with MNCL as the only response in females. Liver tumors were increased in male and female B6C3F1 mice. | F 12/50 (24%), 16/50 (32%), 22/50 (44%), 23/50 (46%)M 29/50 (58%), 32/50 (64%), 26/50 (52%), 27/50 (54%) | F 30.9% ± 10.0% (range 16–44%)M Not provided in TR | Female incidences of MNCL were mostly within historical control range with the high-dose just outside that range. The control incidence in a concurrent dosed water study at the same lab was 38%. |
| Tris(2-chloroethyl) phosphate (NTP TR391) | |||
| Survival in high dose males and females was reduced in this 2-year corn oil gavage study. Renal tubular neoplasms were increased in both sexes. Slight increases in MNCL and thyroid follicular neoplasms (equivocal evidence) were seen in both sexes. There was an interim sacrifice at 66 weeks. Male B6C3F1 had a marginal increase in neoplasms. | F 14/50(28%), 16/50(32%), 20/50(40%)M 5/50(10%), 14/50(28%), 13/50(26%) | F 15.3 ± 10.6%% (range 0–38%) (NTP)M 14.9 ± 10.8% (range 0–44%) (NTP) | NTP concluded clear evidence of carcinogenicity based on renal neoplasms and equivocal evidence based on MNCL using a life table statistical test. In males, there was a lower than expected control incidence of MNCL. In females, the MNCL incidence was marginal and restricted to the high dose group. |
TR: NTP Technical Report; M: Male; F: Female; MNCL: Mononuclear cell leukemia.
a = Tumor incidences arranged starting with controls and progressing through increased doses.