This volume of the IARC Monographs provides an assessment of the carcinogenicity of 14 drugs and herbal products.

The IARC Monographs Working Group relied on epidemiological studies to evaluate the carcinogenic hazard to humans exposed to the drugs digoxin (widely prescribed for the treatment of chronic heart failure), pioglitazone (used for the treatment of type 2 diabetes mellitus), and hydrochlorothiazide (used to treat hypertension). Other agents evaluated included the drugs primidone, sulfasalazine, pentosan polysulfate sodium, and triamterene, and five herbal products (or their components): Aloe vera whole leaf extract, goldenseal root powder, Ginkgo biloba leaf extract, kava extract, and pulegone. In view of the limited agent-specific information available from epidemiological studies, assessments of these agents relied mainly on carcinogenicity bioassays to reach conclusions as to the carcinogenic hazard to exposed humans.

Contents

• NOTE TO THE READER
• List of Participants
• PREAMBLE
• GENERAL REMARKS
• ALOE VERA
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Analysis
    • 1.3. Use
    • 1.4. Production, sales, and consumption
    • 1.5. Occupational exposure
    • 1.6. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Studies of carcinogenicity
    • 3.2. Photo-co-carcinogenicity studies
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Toxic effects and other mechanistic data
    • 4.4. Other mechanistic data
    • 4.5. Susceptibility
    • 4.6. Mechanisms of carcinogenesis
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• GOLDENSEAL
  • 1. Exposure Data
    • 1.1. Identification of the agent and its major constituents
    • 1.2. Analysis
    • 1.3. Use
    • 1.4. Production, sales, and consumption
    • 1.5. Occupational exposure
    • 1.6. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptibility
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• GINKGO BILOBA
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Analysis
    • 1.3. Uses
    • 1.4. Production, sales, and consumption
    • 1.5. Occupational exposure
    • 1.6. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Background
    • 2.2. Randomized controlled trial
    • 2.3. Case–control studies
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptibility
    • 4.5. Mechanisms of carcinogenesis
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• KAVA
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Analysis
    • 1.3. Use
    • 1.4. Production, sales, and consumption
    • 1.5. Occupational exposure
    • 1.6. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenesis
    • 4.4. Susceptibility
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• PULEGONE
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Production and use
    • 1.3. Occurrence and exposure
    • 1.4. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data
    • 4.4. Susceptibility
    • 4.5. Mechanistic consideration
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• METHYLENE BLUE
  • 1. Exposure Data
    • 1.1. Chemical and physical data
    • 1.2. Analysis
    • 1.3. Production and use
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other relevant mechanisms
    • 4.4. Susceptible populations
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• PRIMIDONE
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Analysis
    • 1.3. Production and use
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Cohort studies
    • 2.2. Nested case–control studies
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenesis
    • 4.4. Susceptible populations
    • 4.5. Mechanistic consideration
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• SULFASALAZINE
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Production
    • 1.3. Occurrence and exposure
    • 1.4. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Background
    • 2.2. Longitudinal, cohort, and nested case–control studies
    • 2.3. Case–control studies
    • 2.4. Meta-analysis
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
    • 3.3. Studies of co-carcinogenicity
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptible populations
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• PENTOSAN POLYSULFATE SODIUM
  • 1. Exposure Data
    • 1.1. Chemical and physical data
    • 1.2. Analysis
    • 1.3. Production
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptible populations
    • 4.5. Mechanistic consideration
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• TRIAMTERENE
  • 1. Exposure Data
    • 1.1. Chemical and physical data
    • 1.2. Analysis
    • 1.3. Production and use
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Background
    • 2.2. Triamterene and cancer of the breast
    • 2.3. Combined use of triamterene and hydrochlorothiazide, and cancer of the lip
    • 2.4. The drug class including triamterene and cancer of the breast or colorectum
  • 3. Cancer in Experimental Animals
    • 3.1. Mouse
    • 3.2. Rat
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptibility
    • 4.5. Mechanistic consideration
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• HYDROCHLOROTHIAZIDE
  • 1. Exposure Data
    • 1.1. Identification of the agent
    • 1.2. Analysis
    • 1.3. Production and use
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Cancers of the lip and skin
    • 2.2. Renal cell carcinoma
    • 2.3. Other cancers
  • 3. Cancer in Experimental Animals
    • 3.1. Oral administration
    • 3.2. Coexposure with modifying agents
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptibility
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• PIOGLITAZONE AND ROSIGLITAZONE
  • 1. Exposure Data
    • 1.1. Chemical and physical data on pioglitazone
    • 1.2. Analysis of pioglitazone
    • 1.3. Production and use of pioglitazone
    • 1.4. Occurrence and exposure to pioglitazone
    • 1.5. Regulations and guidelines for pioglitazone
    • 1.6. Chemical and physical data on rosiglitazone
    • 1.7. Analysis of rosiglitazone
    • 1.8. Production and use of rosiglitazone
    • 1.9. Occurrence and exposure to rosiglitazone
    • 1.10. Regulations and guidelines for rosiglitazone
  • 2. Cancer in Humans
    • 2.1. Cancer of the bladder
    • 2.2. Cancer of the liver
    • 2.3. Cancer of the colorectum
    • 2.4. Cancer of the lung
    • 2.5. Cancer of the prostate
    • 2.6. Cancer of the breast
    • 2.7. Other site-specific cancers
  • 3. Cancer in Experimental Animals
    • 3.1. Pioglitazone
    • 3.2. Rosiglitazone
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism, and excretion of pioglitazone
    • 4.2. Absorption, distribution, metabolism, and excretion of rosiglitazone
    • 4.3. Genetic and related effects
    • 4.4. Other mechanistic data
    • 4.5. Susceptibility
    • 4.6. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• DIGOXIN
  • 1. Exposure Data
    • 1.1. Chemical and physical data
    • 1.2. Analysis
    • 1.3. Production and use
    • 1.4. Occurrence and exposure
    • 1.5. Regulations and guidelines
  • 2. Cancer in Humans
    • 2.1. Cancer of the breast
    • 2.2. Cancers of the uterus and ovary
    • 2.3. Cancer of the prostate
    • 2.4. Non-Hodgkin lymphoma
    • 2.5. Other cancer sites
  • 3. Cancer in Experimental Animals
  • 4. Mechanistic and Other Relevant Data
    • 4.1. Absorption, distribution, metabolism and excretion
    • 4.2. Genetic and related effects
    • 4.3. Other mechanistic data relevant to carcinogenicity
    • 4.4. Susceptibility
    • 4.5. Mechanistic considerations
  • 5. Summary of Data Reported
    • 5.1. Exposure data
    • 5.2. Human carcinogenicity data
    • 5.3. Animal carcinogenicity data
    • 5.4. Mechanistic and other relevant data
  • 6. Evaluation
    • 6.1. Cancer in humans
    • 6.2. Cancer in experimental animals
    • 6.3. Overall evaluation
  • References
• LIST OF ABBREVIATIONS

This publication represents the views and expert opinions of an IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, which met in Lyon, 4-11 June 2013

Lyon, France - 2016

IARC MONOGRAPHS

In 1969, the International Agency for Research on Cancer (IARC) initiated a programme on the evaluation of the carcinogenic risk of chemicals to humans involving the production of critically evaluated monographs on individual chemicals. The programme was subsequently expanded to include evaluations of carcinogenic risks associated with exposures to complex mixtures, lifestyle factors and biological and physical agents, as well as those in specific occupations. The objective of the programme is to elaborate and publish in the form of monographs critical reviews of data on carcinogenicity for agents to which humans are known to be exposed and on specific exposure situations; to evaluate these data in terms of human risk with the help of international working groups of experts in carcinogenesis and related fields; and to indicate where additional research efforts are needed. The lists of IARC evaluations are regularly updated and are available on the Internet at http://monographs.iarc.fr/.

This programme has been supported since 1982 by Cooperative Agreement U01 CA33193 with the United States National Cancer Institute, Department of Health and Human Services. Additional support has been provided since 2014 by Employment and Social Innovation “EaSI” (2014–2020) (for further information please consult: http://ec.europa.eu/social/easi), and since 1992 by the United States National Institute of Environmental Health Sciences, Department of Health and Human Services. The contents of this volume are solely the responsibility of the Working Group and do not necessarily represent the official views of the United States National Cancer Institute, the United States National Institute of Environmental Health Sciences, the United States Department of Health and Human Services, or the European Commission.

Published by the International Agency for Research on Cancer,
150 cours Albert Thomas, 69372 Lyon Cedex 08, France
©International Agency for Research on Cancer, 2016
Online publication, 15 September 2015

Distributed by WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; email: tni.ohw@sredrokoob).

Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved.

Corrigenda to the IARC Monographs are published online at http://monographs.iarc.fr/ENG/Publications/corrigenda.php.

Corrigenda to Volume 108. (PDF, 83K)

To report an error, please contact: rf.crai@omitide

• Co-funded by the European Union

The International Agency for Research on Cancer welcomes requests for permission to reproduce or translate its publications, in part or in full. Requests for permission to reproduce or translate IARC publications – whether for sale or for non-commercial distribution – should be addressed to the IARC Communications Group at: publications@iarc.fr.

The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city, or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.

The IARC Monographs Working Group alone is responsible for the views expressed in this publication.