Assessment of the cancer potential of methanol

Abstract

There are no published cancer studies of methanol-exposed cohorts. Genotoxicity studies do not suggest carcinogenic activity from methanol exposure. Oncogenicity studies of methanol were conducted by inhalation for approximately 20 hrs/day at up to 1000 ppm in F344 rats and B6C3F1 mice (NEDO), and by incorporation into drinking water at up to 20,000 ppm in Sprague-Dawley rats (Ramazzini Foundation, by Soffritti et al.). No increased neoplasms were found in the NEDO rat and mouse inhalation studies, even at air levels (up to 1000 ppm for >19 hours/day, 7 days/week) that caused 10-fold increased blood methanol levels. The maximum dose level was 600 mg/kg/day. The breakdown of methanol to formaldehyde in rats is saturated at doses above 600 mg/kg according to Horton et al. Thus, higher inhalation exposure concentrations are not expected to lead to tumors in rats or mice. In the Soffritti et al. study there was excessive early mortality, and lung pathology (inflammation, dysplasia, or neoplasm) was present in 87-94% of those dying anytime in the study. Soffritti et al. reported lympho-immunoblastic lymphoma. There are no historical control data to which this study can be compared because this diagnosis is not used by any other pathologist in animal studies. Lung infections probably played a role in formation of the lesions called lympho-immunoblastic lymphoma in the Ramazzini methanol study. The data from genotoxicity studies, the inhalation and drinking water oncogenicity studies of methanol in rats and mice, and mode of action considerations support a conclusion that methanol is not likely to be carcinogenic in humans.

Scientific Considerations for Evaluating Cancer Bioassays Conducted by the Ramazzini Institute

“…The spontaneous (control) rate of these tumors in RI Sprague-Dawley rats has been reported to be higher than in Sprague-Dawley rats from other sources (Cruzan 2009). Using the meta-regression technique of Sidik and Jonkman (2005), we performed an analysis of past RI studies (see Supplemental Material, Table S1) and identified a significant association between spontaneous lymphoma/leukemia rates and year of study publication for both males and females ( p < 0.001).…”

“…Concurrent RI studies have at times shared controls (Belpoggi et al 1995; Cruzan 2009), with RI publications indicating that such shared controls have been concurrent with, housed in the same facility as, and age-, strain- and colony-matched to treatment groups (Maltoni et al 1986, 1999; Soffritti et al 2002c, 2006a). U.S. EPA testing guidelines require (U.S.…”

“…Reporting variability across RI bioassays and the lack of a single SOP can lead to uncertainty regarding study details. For example, it is not always clear from the individual study reports whether RI used study-specific, concurrent matched controls or common controls across multiple studies (Cruzan 2009). The EFSA (2006) noted deviations in OECD guidelines with respect to the RI aspartame study (e.g., a lack of a complete analysis of the test substance, no clear information on the stability of the substance, a lack of clinical observations, a lack of hematological assays, a lack of serology, and limited histopathology reports).…”

“…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]. …”

Mycoplasma Pulmonis and Lymphoma in a Methanol Bioassay

“…9 We consider it in the public interest to promote resolution of the scientific questions that have been raised about the methanol and other bioassays. 2,4,[6][7][8][10][11][12][13]15,16 We therefore obtained the results of the slide review from the National Institute of Environmental Health Sciences via a Freedom of Information Act request and analyzed them for differences between the NTP pathologists' diagnoses and those of the study pathologist. We tabulated diagnoses of lymphoma, leukemia, and histiocytic sarcoma in thymus, lung, liver, spleen, and lymph nodes and inflammatory lesions in the nose, lung, and ear.…”