To the Editor:
I was pleased to read the article on early diagnosis of oral and oropharyngeal squamous cancers by Mashberg and Samit in the November/December issue.1 In the past I have read other articles about the use of toluidine blue intraorally and was disappointed to learn that my oral surgeon acquaintances were not using this diagnostic method. In addition they could give me no lead as to how this material could be obtained.
After reading the article by Mash-berg and Samit, I decided to pursue this matter with a local pathology laboratory, which provided me with the Material Data Safety Sheet for toluidine blue. The Material Data Safety Sheet indicates that toluidine blue is “probably toxic by ingestion.” I wrote a letter to a manufacturer of toluidine blue and received a letter in response indicating that based on the Material Safety Data Sheet, it is certain that the dye can be harmful. The letter added that their company's products are strictly for in vitro use and stated that in vivo use is not appropriate and may be harmful to patients.2 I was hoping that some light might be shed on the safety of this material or perhaps another source or dilution might be suggested.
The following is submitted to allay Dr. Wilhelmsen's concerns about the toxicity of toluidine blue (TB) as related to our article in CA. Historical and current in vivo animal and human studies on the use of TB, also known as tolonium chloride, clearly show that doses of 100 to 1,000 times that used in our regimen have no observable toxic effect.
TB was marketed as Blutene Chloride Tablets by Abbott Laboratories, holder of an approved Food and Drug Administration new drug application (NDA no. 8–683 ). The product was distributed in 100-mg tablets and was recommended for use in the control of uterine bleeding in doses of 100 to 300 mg daily. Approval was withdrawn in 1968 because of a lack of substantial evidence of its efficacy, not for lack of safety.1 By comparison, the use of TB as a rinse or application, according to our regimen,2 results in infrequent exposure to a maximum of 10 ml of a one-percent solution (100 mg) for a brief time, most of which is expectorated. Less than 10 mg is absorbed in the average 70-kg patient. Our previous publication2 evaluating TB as a cancer diagnostic cites and details the various animal and human studies and the use of TB in oral (100 to 300 mg for hypermenorrhea) and intravenous doses (3 to 5 mg/kg for parathyroid identification) in far greater doses than our regimen, without evidence of toxicity.
We cited multiple reports of the use of TB in the diagnosis and biopsy site selection of squamous malignancies of the head and neck and cervix, none of which reported or implied any toxic effects. In our use of TB rinse and application in hundreds of patients, no toxic effect was observed. A more recent study supports the use of a one-percent TB solution as a useful adjunct for the discovery of occult carcinomas of the esophagus during panendoscopic evaluation of patients with squamous cancer of the head and neck.3
Zila Pharmaceuticals, to which one of us (Arthur Mashberg) acts as a consultant on the use of TB, has an FDA investigational new drug clearance and is conducting multicenter clinical studies based on studies by one of us (AM) of the use of toluidine blue rinse as an adjunct to clinical impressions in the diagnosis of squamous carcinoma in a high-risk population. Zila has submitted further evidence to the FDA of lack of toxicity. In experimental studies, TB was administered to male and female rats at dosage level of 0, 10, and 100 mg/kg and did not produce any mortalities or adverse effects on body weight gain, feed consumption, and hematologic or biochemical values. Histopathologic examination revealed no abnormalities or lesions. All tissue examined were within normal limits. The low dose used in the study was 100 times the expected exposure of TB as used in our regimen. The high dose of 100 mg/kg represents about 1,000 times the expected dose of .09 mg/kg.
Pending FDA approval, TB is not yet available in the United States for commercial distribution as a diagnostic. Currently, it is usually compounded as a one-percent solution, in multidose amounts, by institutional pharmacies (i.e., federal hospitals, universities, etc.) on prescription from the clinician.