Consideration of the variability in control tumor incidence data at the Ramazzini Institute in evaluating treatment-related effects following chemical exposure

Abstract

The Ramazzini Institute (RI) has been conducting animal carcinogenicity studies for decades, many of which have been considered by authoritative bodies to determine potential carcinogenicity in humans. Unlike other laboratories, such as the U.S. National Toxicology Program (NTP), the RI does not provide a report or record of historical control data. Transparently documenting historical control data is critical in the interpretation of individual study results within the same laboratory. Historical control data allow an assessment of significant trends, either increasing or decreasing, resulting from changes in laboratory methods or genetic drift. In this investigation: (1) we compiled a dataset of the tumors reported in control groups of Sprague-Dawley rats and Swiss mice based on data included in published RI studies on specific substances, and (2) conducted case studies to compare data from this RI control dataset to the findings from multiple RI studies on sweeteners and corresponding breakdown products. We found considerable variability in the tumor incidence across multiple tumor types when comparing across control groups from RI studies. When compared to the tumor incidence in treated groups from multiple studies, the incidence of some tumors considered to be treatment-related fell within the variability of background incidence from the RI control dataset.

Keywords:

• Aspartame
• sucralose
• formaldehyde
• methyl alcohol
• Ramazzini Institute
• cancer
• historical control

Acknowledgements

The authors acknowledge and appreciate the comments of the Editor and the external reviewers (selected by the Editor) who were anonymous to the authors. Reviewers’ constructive comments helped strengthen the manuscript.

Declaration of interest

Ramboll is a private consulting firm providing services to private and public organizations on toxicology and risk assessment issues.

This project was a concept presented by Ramboll to the American Beverage Association (ABA). This work was supported by ABA, a 501(c)(6) tax-exempt organization; however, no one from ABA was involved in the preparation of the manuscript. ABA’s Dr. Maia Jack, Chief Science and Regulatory Officer, was given the opportunity to review the draft manuscript. The purpose of this review was for the authors to receive input on the clarity of the science presented but not on the interpretation of research results. The researchers’ scientific conclusions and professional judgments were not subject to the funders’ control; the contents of this manuscript reflect solely the view of the authors.

None of the authors received direct compensation from ABA for this project. The project was funded through contracts between ABA and Ramboll. All the scientists of Ramboll (RG, TG, HB, CVL, JR, and HC) involved in the development of the current manuscript were provided salary compensation as part of their employment as consultants.

There are no conflicts of interest for any of the authors to disclose related to the submission of this manuscript. None of the authors are currently engaged to testify as experts on behalf of the sponsors in litigation related to non-sugar sweeteners. It is anticipated that regulatory authorities may consider the contents of this review in making regulatory decisions regarding potential health effects of non-sugar sweeteners.

Notes

1 Number of animals (when reported) with each tumor type within the control group. If the number of animals with a tumor type was not reported, then it was calculated based on the total number of animals and the percent tumor incidence reported in the study.

2 The aspartame dietary concentration of 100,000 ppm exceeds the limit dose for dietary studies recommended by the FDA as reported in “Toxicological Principles for the Safety Assessment of Food Ingredients Redbook 2000 Chapter IV.C.6”.

3 Doses in ppm drinking water were converted using a default daily drinking water intake and body weight for rats of 0.049 L/day and 0.35 kg, respectively.

4 Doses in ppm drinking water were converted assuming 1 ppm = 1 mg/L and using a default daily drinking water intake and body weight for rats of 0.049 L/day and 0.35 kg, respectively.

5 Equivalent doses in units of mg/kg bw/day were not provided by the authors. The equivalent doses provided for the sucralose study were estimated based on the ratio of doses in ppm to doses in mg/kg bw/day provided in the aspartame mouse study (Soffritti et al. 2010).

Additional information

Funding

This work was supported by ABA.