Table 8.
NTP studies that had a Leydig cell tumor response.
| Two-year study highlights | Overall incidencesa | Historical control data | Authors’ commentary |
|---|---|---|---|
| Cumene (NTP TR 452) | |||
| Inhalation exposure to cumene was started in June 2001. There was clear evidence of carcinogenicity for nose and kidney and equivocal evidence of carcinogenicity for LCT. Lung, spleen and thyroid tumor responses were present in male B6C3F1 mice. | 36/50 (72%), 38/50 (76%), 40/50 (80%), 46/50 (92%) | Mean 76.8% ± 5.9% (range 66–84%) | The judgment that the LCT response represents equivocal evidence of carcinogenicity is reasonable in that there is a clear dose response. Furthermore, the incidence of LC hyperplasia was increased in the low- and intermediate-dose groups, and the severity was increased in the high-dose group. |
| Ethylbenzene (NTP TR 466) | |||
| This inhalation study was started in March 1990 and had a reduced survival in high-dose males. There was clear evidence of carcinogenicity based on kidney neoplasms. The Leydig cell tumor response was also listed as clear evidence. Male B6C3F1 mice had an increase in lung tumors. | 36/50 (72%), 33/50 (66%), 40/50 (80%), 44/50 (88%) | Mean 68.7% ± 8.7% (range 54–83%) | An increase incidence of unilateral and bilateral a Leydig cell tumors was slightly above the historical control in the highest concentration. There was no treatment-related increase in Leydig cell hyperplasia. At best, the Leydig cell tumor response should more appropriately be consistent with equivocal evidence of carcinogenicity |
| Isoprene (NTP TR 486) | |||
| This inhalation study was started in June 1993. Clear evidence of carcinogenicity was identified for mammary and kidney tumors in addition to Leydig cell tumors. There was no accompanying mouse carcinogenicity study. | 33/50 (66%), 37/50 (74%), 44/50 (88%), 48/50 (96%) | Mean 69.4% ± 9.7% (range 46–83%) | Although the concurrent control is unusually low, the mid- and high-dose responses are robust. Leydig cell proliferation was present in a previously published 26-week study supporting the clear evidence of carcinogenicity call for the Leydig cell tumor response. |
| Kava Kava (NTP TR 571) | |||
| Kava kava extract was administered by corn oil gavage in a study that started in August 2004. There were no tumor responses in male, aside from the equivocal evidence of carcinogenicity for LCTs. Male B6C3F1 mice had an increase in liver hepatoblastomas. | 37/49 (76%), 44/50 (88%), 49/50 (98%), 46/50 (92%) | Mean 88.4% ± 8.6% (range 76–94%) | The equivocal evidence of carcinogenicity for LCTs in this study was associated with a reduced latency and a dose-related decrease in Leydig cell hyperplasia. These observations suggest early conversion of hyperplasia to adenoma. It is noted that the control incidence is the lowest recorded for corn oil gavage studies. |
| Leucomalachite Green (NTP TR 527) | |||
| The dietary study of leucomalachite green was started in November 1998. Treatment in males was associated with equivocal evidence of carcinogenicity for thyroid and Leydig cell tumors with treatment-related decreases in pituitary adenomas and MNCL. There was no accompanying mouse study. | 37/48 (77%), 42/47 (89%), 43/48 (90%), 45/47 (96%) | Mean 85.7% (range 69–90%) | The incidence of bilateral interstitial cell tumors was increased in treated rats removed from study prior to the terminal sacrifice. The call of equivocal evidence of carcinogenicity for ICT is reasonable. |
| Tetrafluoroethylene (NTP TR 450) | |||
| This inhalation study, started in June 1988, resulted in clear evidence of liver and kidney carcinogenesis and equivocal evidence of carcinogenesis for MNCL in males. There was reduced body weight and early mortality at the highest concentration. Bothe sexes of treated B6C3F1 mice had liver neoplasms. | 39/50 (78%), 40/50 (80%), 48/50 (96%), 47/50 (94%) | Mean 68.7% ± 8.7% (range 54–83%) | The Leydig cell tumor response may have been related to treatment (equivocal evidence of carcinogenicity) but it is noted that the control incidence is within the historical control range. There was no treatment-related increase in Leydig cell hyperplasia or adenoma at a 15-month interim sacrifice. |
| Tetralin (NTP TR 561) | |||
| This inhalation study started in June 2003. There was some evidence of carcinogenicity based on kidney tumors and equivocal evidence of carcinogenicity for LCTs. There was no evidence of carcinogenicity in male B6C3F1 mice. | 29/50 (58%), 39/50 (78%), 31/50 (62%), 41/50 (82%) | Mean 71.7% ± 8.5% (range 58–84%) | There was some discussion during the formal public peer review where it was pointed out that all of the LCT responses are within the historical control range. The judgment that the response is equivocal evidence of carcinogenicity for LCTs is based primarily on statistical evaluation. Since the concurrent control incidence of LCTs is the lowest observed in inhalation studies, the judgment of equivocal evidence of carcinogenicity for LCTs is questionable. |
TR: NTP Technical Report; M: Male; F: Female; LCT: Leydig cell tumor; MNCL: Mononuclear cell leukemia.
a = Tumor incidences arranged starting with controls and progressing through increased doses.