Affiliations of authors: P. F. Coogan, L. Rosenberg, J. R. Palmer, S. Shapiro, Slone Epidemiology Unit, Boston University School of Medicine, Brookline, MA; B. L. Strom, Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, and Division of General Internal Medicine of the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia; A. G. Zauber, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; P. D. Stolley, Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore.
Correspondence to: Patricia F. Coogan, Sc.D., Slone Epidemiology Unit, Boston University School of Medicine, 1371 Beacon St., Brookline, MA 02446 (e-mail: pcoogan{at}slone.bu.edu).
Phenolphthalein was the main component in numerous over-the-counter laxatives, including Ex-Lax and Feen-A-Mint, for most of the 20th century. The U.S. Food and Drug Administration (FDA) classified phenolphthalein as "safe and effective" in 1975 (1). However, in 1997, the FDA proposed that phenolphthalein be reclassified as "not generally recognized as safe and effective" (2) after a 2-year feeding study in rodents found increased incidences of neoplasms of the ovary, adrenal gland, kidney, and hematopoietic system in treated animals (3). Subsequently, most phenolphthalein-containing laxatives were voluntarily withdrawn from the market in the United States. Phenolphthalein has also been found to be genotoxic (3), to cause oxidative damage (4), and to bind to estrogen receptors (5).
The only data on laxative use and human cancers indicate that use is unrelated to the risk of large-bowel cancer (612). We used data collected in a hospital-based, casecontrol surveillance study of medication use to evaluate the relationship between phenolphthalein laxative use and the risk of cancers, both at sites for which animal studies have raised suspicions and at other sites with sufficient numbers for analysis.
Data were collected during the period from 1976 through 1999 from patients 2179 years old who were admitted to hospitals in Baltimore (MD), Boston (MA), New York (NY), or Philadelphia (PA). Nurse interviewers administered questionnaires to obtain demographic information and reproductive and medical histories. Phenolphthalein use was elicited by questions about use of laxatives and other drugs for the bowel. For each episode of use, the drug name and duration, timing, and frequency of use were recorded. Details of the diagnoses were abstracted from discharge summaries and pathology reports. Ninety-six percent of the patients approached for an interview participated.
The study was approved by the Institutional Review Boards of all participating institutions. All subjects gave written informed consent.
The 18 163 case patients had a primary cancer at one of 16 sites that had been diagnosed within the year before admission to the hospital and no history of cancer other than nonmelanoma skin cancer. The 16 sites or types of cancer and numbers of case patients were as follows: breast, 6199; lung, 1687; colon, 1555; melanoma, 1466; prostate, 1081; rectum, 934; endometrium, 794; leukemia, 735; ovary, 728; bladder, 551; pancreas, 523; non-Hodgkin's lymphoma, 488; bone and connective tissue, 485; kidney, 461; stomach, 262; and esophagus, 214. Control patients were 12 204 patients who had been admitted to the hospital for one of the following nonmalignant conditions that we judged to be unrelated to the use of laxatives: trauma (5881), acute infection (2670), or orthopedic conditions (3653). None of the control patients had a history of cancer other than nonmelanoma skin cancer.
Use of phenolphthalein was defined as any use for at least 3 continuous months, starting at least 2 years before admission to the hospital. The frequency of use of phenolphthalein among people who reported use for at least 3 months (283 case patients and 236 control patients) was as follows: daily use, 5%; use 16 days per week, 22%; use 14 days per month, 18%; occasional (sporadic) use, 40%; and variable (fluctuating) use, 15%. Individuals for whom the 3-month period of use occurred completely within the 2 years before admission were excluded because such use might not have antedated the occurrence of the cancer and might also have been affected by symptoms of the illness. Subjects who used laxatives for fewer than 3 months were included in the reference category with never users.
Unconditional multiple logistic regression analysis was used to estimate odds ratios (ORs) for each cancer type for use of phenolphthalein relative to never use of any laxative (13), and 95% test-based confidence intervals (CIs) were calculated (14) (Table 1). Indicator terms were included for sex, age, study center, interview year, education, race, and religion. ORs for cancers of the breast, endometrium, and ovary were also adjusted for use of oral contraceptives and female hormones and for menopausal status. Crude and adjusted ORs were substantially similar (data not shown). Other risk factors for the cancers under consideration, notably cigarette smoking, alcohol consumption, and, for women, reproductive factors, were not associated with laxative use. ORs from models that included these variables were not changed for any site (data not shown).
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To check for a possible reporting or selection bias, we assessed the ORs for each cancer site for use of laxatives other than phenolphthalein [or anthraquinones, which were not commonly used in this population and may also be genotoxic (15)] relative to never use of any laxative (Table 1). Other laxative use was defined as use for 3 consecutive months starting at least 2 years before admission. All ORs for the use of other laxatives were compatible with 1.0 except for the OR for stomach cancer (OR = 2.0; 95% CI = 1.13.6); for heavy users of laxatives (at least once per week for at least 2 years), the OR for stomach cancer, based on seven case users, was 1.7 (95% CI = 0.73.9). Controlling for anthraquinone use did not influence the results.
Our data suggest that the use of phenolphthalein laxatives does not increase the risk of cancer types implicated in animal studies (i.e., ovarian cancer, kidney cancer, leukemia, and lymphoma) or at other sites. While the ORs for 3 or more months of phenolphthalein use were reduced for some cancer sites, the ORs approached 1.0 when heavier use (i.e., at least once a week for a least 2 years) was considered. It is unlikely that selection or reporting bias explains the reductions: The fact that ORs among users of other laxatives, which have not been linked to cancer risk, were also compatible with 1.0 suggests that neither bias was operating. If nondifferential misclassification of laxative use was masking true increases in cancer risk, we would expect to see increases in ORs for the category of "heavier" use; however, these ORs were compatible with 1.0. The nonstatistically significant twofold increase in the OR for colon cancer among heavier users was based on only 11 case users and is likely to reflect random variation around the null.
In the animal studies that raised concerns about phenolphthalein, rodents were given much higher doses of the agent than are commonly used by humansfrom 10 to 1000 times the human dose, in terms of mg/m2 of body surface area (2)although, in one study (16), thymic lymphomas were observed in mice at doses only three times human exposures. In our data, the majority of laxative users reported occasional use. Thus, although we can state that phenolphthalein laxatives as used in this population were not associated with increased risk of cancer, our data cannot address the effect of their very heavy use or abuse.
NOTES
Supported by Public Health Service grant R01CA45762 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Additional support was provided by grant FD-U-000082 from the U.S. Food and Drug Administration.
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Manuscript received May 15, 2000; revised September 6, 2000; accepted September 13, 2000.
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