Commentary

Abstract

The authors recently assessed the likelihood that lifetime cancer bioassays of aspartame, methanol, and methyl tertiary butyl ether conducted with conventional (not specific pathogen free) Sprague-Dawley rats were compromised by Mycoplasma pulmonis disease. From the tumor data and other information, the authors concluded that the rats used in these bioassays likely had M pulmonis disease and that lesions of the disease were plausibly interpreted as lymphoma. Subsequently, they analyzed the nonneoplastic lesion data from these bioassays for occurrence of inflammatory lesions and found that 2,267 of 2,960 rats (76.6%) were reported to have bronchitis, the signature lesion of M pulmonis disease, and that 633 rats (21.4%) were reported to have otitis, another common lesion of the disease. Also, documentation is now available containing serologic evidence of mycoplasma infection in the rats. In contrast, the reports of 6 National Toxicology Program bioassays based on specific pathogen-free Sprague-Dawley rats listed no instances of bronchitis or otitis. These findings provide substantial additional evidence that the bioassays in question were compromised by M pulmonis disease. Therefore, the reported induction of lymphoma in these studies should not be considered in cancer risk assessments. The authors also found that inflammatory lesions were prevalent in lymph nodes, thymus, pleura, and brain. Finally, they found that of all 328 cases of lymphoimmunoblastic lymphoma affecting the lung (the primary form of lymphoma reported), 218 (66.5%) occurred within the first 104 weeks of the studies, showing that occurrence of such lesions was not due to appearance in rats surviving beyond that interval.

Scientific Considerations for Evaluating Cancer Bioassays Conducted by the Ramazzini Institute

“…The RI has put a greater emphasis than most laboratories on study designs that attempt to reproduce “as much as possible human exposure scenarios” (Soffritti et al 2006a), and this has contributed to differences between the RI and other laboratories in both husbandry and health of experimental animals. In particular, the retention of test animals until death and the use of non–pathogen-free conditions have been noted as concerns (Bailey et al 2012; Bucher 2002; Cruzan 2009; EFSA 2006; Schoeb and McConnell 2011a, 2011b; Schoeb et al 2009). …”

“…The level of inflammatory changes in the lungs of animals in the RI studies has prompted discussions regarding the role of respiratory infections in tumor formation; the ability to discern tumors from inflammatory infiltrates; and the adequacy of RI protocols [Caldwell et al 2008; Cruzan 2009; EFSA 2006, 2009; National Toxicology Program (NTP) 2011; Schoeb and McConnell 2011a, 2011b; Schoeb et al 2009]. …”