The predominant source of human exposure to radio frequency radiation (RFR) occurs through usage of cellular phone handsets. The Food and Drug Administration nominated cell phone RFR emission for toxicology and carcinogenicity testing in 1999. At that time, animal experiments were deemed crucial because meaningful human exposure health data from epidemiological studies were not available. Male and female B6C3F1/N mice were exposed to time-averaged whole-body specific absorption rates of 0 (sham control), 5, 10, or 15 W/kg Global System for Mobile Communications (GSM)- or Code Division Multiple Access (CDMA)-modulated cell phone RFR at 1,900 MHz for 28 days or 0, 2.5, 5, or 10 W/kg GSM- or CDMA-modulated cell phone RFR for up to 2 years. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes and leukocytes, brain cells, and liver cells.
GSM
Twenty-eight-day study
Groups of 10 male and 10 female mice were housed in specially designed reverberation chambers and received whole-body exposures to GSM-modulated cell phone RFR at power levels of 0 (sham control), 5, 10, or 15 W/kg, for up to 18 hours and 20 minutes per day, 5 or 7 (last week of study) days per week for at least 28 days with continuous cycling of 10 minutes on and 10 minutes off during the exposure periods. The sham control animals were housed in reverberation chambers identical to those used for the exposed groups, but were not exposed to cell phone RFR; a shared group of unexposed mice of each sex served as sham controls for both cell phone RFR modulations. All mice survived to the end of the study. Mean body weights of exposed groups of males and females were similar to the sham controls. There were no exposure-related clinical signs, differences in organ weights, or histopathologic findings. Differences in body temperatures between the exposed groups and the sham control group were not considered to be related to cell phone RFR exposure.
Two-year study
Groups of 105 male and 105 female mice were housed in reverberation chambers and received whole-body exposures to GSM-modulated cell phone RFR at power levels of 0 (sham control), 2.5, 5, or 10 W/kg, 9 hours and 10 minutes per day, 7 days per week for 106 (males) or 108 (females) weeks with continuous cycling of 10 minutes on and 10 minutes off during a period of 18 hours and 20 minutes each day. The sham control animals were housed in reverberation chambers identical to those used for the exposed groups, but were not exposed to RFR; shared groups of unexposed mice of each sex served as sham controls for both RFR modulations. Fifteen mice per group were randomly selected from the core group after 10 weeks of study; 10 of those 15 mice per group were used for interim evaluation at 14 weeks, and five mice per group were used for genetic toxicity testing at 14 weeks. The remaining 90 animals per group were exposed up to 2 years.
At the 14-week interim evaluation in the 2-year study, mean body weights of exposed groups of males and females were similar to those of the sham controls. There were no changes to the hematology variables attributable to GSM RFR exposure. Differences in organ weights were not associated with histopathologic findings and were not considered related to exposure. In males, there were no exposure-related effects on reproductive organ weights, testis spermatid concentrations, caudal epididymal sperm concentrations, or sperm motility. In females, there were no exposure-related effects on estrous cycle length, number of cycling females, or relative amount of time spent in the estrous stages.
In the 2-year study, percent survival was significantly higher for the 5 W/kg males than the sham control group. Survival of the other exposed groups of males and females was generally similar to that of the sham controls. Mean body weights of exposed groups of males and females were similar to those of the sham controls throughout the study.
The combined incidences of fibrosarcoma, sarcoma, or malignant fibrous histiocytoma of the skin were increased in 5 and 10 W/kg males, although not significantly or in a SAR-related manner; however, the incidences exceeded the overall historical control ranges for malignant fibrous histiocytoma. In the lung, there was a significant positive trend in the incidences of alveolar/ bronchiolar adenoma or carcinoma (combined) in males. Compared to the sham controls, all exposed groups of females had increased incidences of malignant lymphoma and the incidences in the 2.5 and 5 W/kg groups were significantly increased. The sham control group had a low incidence of malignant lymphoma compared to the range seen in historical controls.
There were no nonneoplastic lesions that were considered related to exposure to GSM-modulated cell phone RFR.
CDMA
Twenty-eight-day study
Groups of 10 male and 10 female mice were housed in reverberation chambers and received whole-body exposures to CDMA-modulated cell phone RFR at power levels of 0 (sham control), 5, 10, or 15 W/kg, for up to 18 hours and 20 minutes per day, 5 or 7 (last week of study) days per week for at least 28 days with continuous cycling of 10 minutes on and 10 minutes off during the exposure periods. The sham control animals were housed in reverberation chambers identical to those used for the exposed groups, but were not exposed to RFR; a shared group of unexposed mice of each sex served as sham controls for both RFR modulations. All mice survived to the end of the study. Mean body weights of exposed groups of males and females were similar to the sham controls. There were no exposure-related clinical signs, differences in organ weights, or histopathologic findings. Differences in body temperatures between the exposed groups and the sham control group were not considered to be related to RFR exposure.
Two-year study
Groups of 105 male and 105 female mice were housed in reverberation chambers and received whole-body exposures to CDMA-modulated cell phone RFR at power levels of 0 (sham control), 2.5, 5, or 10 W/kg, 9 hours and 10 minutes per day, 7 days per week for 106 (males) or 108 (females) weeks with continuous cycling of 10 minutes on and 10 minutes off during a period of 18 hours and 20 minutes each day. The sham control animals were housed in reverberation chambers identical to those used for the exposed groups, but were not exposed to RFR; shared groups of unexposed mice of each sex served as sham controls for both RFR modulations. Fifteen mice per group were randomly selected from the core group after 10 weeks of study; 10 of those 15 mice per group were used for interim evaluation at 14 weeks, and five mice per group were used for genetic toxicity testing at 14 weeks. The remaining 90 animals per group were exposed up to 2 years.
At the 14-week interim evaluation of the 2-year study, mean body weights of exposed groups of males and females were similar to those of the sham controls. There were no changes to the hematology variables attributable to CDMA-modulated RFR exposure. Differences in organ weights in male mice were not associated with histopathologic findings and were not considered related to exposure; there were no significant changes in organ weights in females. In males, there were no exposure-related effects on reproductive organ weights, testis spermatid concentrations, caudal epididymal sperm concentrations, or sperm motility. In females, there were no exposure-related effects on estrous cyclicity. Compared to the sham controls, there were statistically significant differences for extended estrous in the 2.5 W/kg group and extended diestrus in the 5 W/kg group; however, these changes were considered sporadic due to the lack of an exposure-related response. In the kidney of 10 W/kg females, there was a significantly increased incidence of minimal to mild interstitial lymphocytic cellular infiltration.
Percent survival was significantly higher in 2.5 W/kg males compared to that in the sham controls in the 2-year study. Survival of males and females in all other exposed groups was generally similar to that of the sham controls. Mean body weights of exposed groups of males and females were similar to those of the sham controls throughout the study.
There was a significantly increased incidence of hepatoblastoma in 5 W/kg males. Compared to the sham controls, the incidences of malignant lymphoma were increased in all exposed groups of females, and the increase was significant in the 2.5 W/kg group. As noted for the GSM study, the shared sham control group had a low incidence of malignant lymphoma compared to the range observed in historical controls.
There were no nonneoplastic lesions that were considered related to exposure to CDMA-modulated cell phone RFR.
Genetic toxicology
Comet assay
As part of the 14-week interim evaluation, samples of frontal cortex, hippocampus, cerebellum, liver, and blood leukocytes were evaluated for DNA damage using the comet assay (two sexes, two RFR modulations, and five tissues per animal). Samples of peripheral blood from these same animals were also evaluated for chromosome damage in the micronucleus assay. Results in the comet assay are based on the 100-cell scoring approach that was standard at the time of the study; data obtained using a second 150-cell scoring approach, recommended in a recently adopted international guideline for the in vivo comet assay, are noted for the few instances where results differed between the two methods. Significant increases in DNA damage were observed in cells of the frontal cortex of male mice exposed to both modulations, GSM and CDMA. No other tissues showed evidence of an exposure-related effect in male mice. In female mice exposed to the CDMA modulation, significant increases in DNA damage were seen in blood leukocytes at all three exposure levels using both scoring approaches. No statistically significant increases in percent comet tail DNA were observed in any of the samples from female mice exposed to the GSM modulation with the 100-cell scoring method. Scoring 150 cells resulted in a significant response in liver of female mice exposed to CDMA; a similar pattern of response was seen with the 100-cell scoring method, but none of the increases were significant.
Micronucleus assay
No significant increases in micronucleated red blood cells or changes in the percentage of immature erythrocytes among total erythrocytes were observed in the peripheral blood of mice of either sex exposed to either modulation of RFR.
Conclusions
Under the conditions of these 2-year studies, there was equivocal evidence of carcinogenic activity (see a summary of the peer review panel comments and the public discussion on this Technical Report in Appendix L) of GSM-modulated cell phone RFR at 1,900 MHz in male B6C3F1/N mice based on the combined incidences of fibrosarcoma, sarcoma, or malignant fibrous histiocytoma in the skin and the incidences of alveolar/ bronchiolar adenoma or carcinoma (combined) in the lung. There was equivocal evidence of carcinogenic activity of GSM-modulated cell phone RFR at 1,900 MHz in female B6C3F1/N mice based on the incidences of malignant lymphoma (all organs). There was equivocal evidence of carcinogenic activity of CDMA-modulated cell phone RFR at 1,900 MHz in male B6C3F1/N mice based on the incidences of hepatoblastoma of the liver. There was equivocal evidence of carcinogenic activity of CDMA-modulated cell phone RFR at 1,900 MHz in female B6C3F1/N mice based on the incidences of malignant lymphoma (all organs).
Exposure to GSM- or CDMA-modulated cell phone RFR at 1,900 MHz did not increase the incidence of any nonneoplastic lesions in male or female B6C3F1/N mice.
National Toxicology Program (NTP). 2018. NTP technical report on the toxicology and carcinogenesis studies in B6C3F1/N mice exposed to whole-body radio frequency radiation at a frequency (1,900 MHz) and modulations (GSM and CDMA) used by cell phones. Research Triangle Park, NC: National Toxicology Program. Technical Report 596. https://doi.org/10.22427/NTP-TR-596