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This volume of the IARC Monographs provides evaluations of the carcinogenicity of hydrochlorothiazide, voriconazole, and tacrolimus.
Hydrochlorothiazide is a prescription-only thiazide diuretic primarily used to treat essential hypertension. It is present in single-ingredient pills as well as in single-pill combinations, which include other antihypertensives (mostly, angiotensin receptor blockers). Although hydrochlorothiazide has increasingly been replaced by newer medications, it remains a commonly prescribed drug because of the high prevalence of hypertension worldwide. The use of single-pill combinations is greater in most high-income countries than in many low- and middle-income countries.
Voriconazole is a broad-spectrum triazole antifungal medication that is used to treat invasive aspergillosis and other serious fungal infections, which are especially common in transplant recipients. Voriconazole is approved in most countries worldwide for use in adults and children aged 2 years and older. Voriconazole is also used for prophylaxis of invasive fungal infections in high-risk transplant recipients. Use is higher in high-income than in middle-income countries.
Tacrolimus is an immunosuppressive medication that is mainly used to reduce the risk of organ rejection in adult and paediatric transplant recipients, and for the prevention of graft-versus-host disease after allogeneic haematopoietic stem cell transplantation. Because systemic tacrolimus is mainly used for solid-organ transplant recipients, the worldwide prevalence of exposure in the general population tracks with the prevalence of transplantation in each country. Topical tacrolimus is indicated as second-line therapy for atopic dermatitis and vitiligo, as an alternative to first-line treatment with topical corticosteroids.
For these three agents, exposure might also occur via the environment or occupation, although it is expected to be magnitudes lower than that from medications.
An IARC Monographs Working Group reviewed evidence from epidemiological studies, cancer bioassays in experimental animals, and mechanistic studies to assess the carcinogenic hazard to humans of exposure to these agents and concluded that hydrochlorothiazide, tacrolimus, and voriconazole are all carcinogenic to humans (Group 1).
ANNEX 1. Supplementary material for Section 1, Exposure Characterization
These supplementary tables are available online only. They were produced in draft form by the Working Group and were subsequently fact-checked, but not edited.
Please report any errors to imo@iarc.who.int.
Hydrochlorothiazide
Voriconazole
Tacrolimus
ANNEX 2. Supplementary material for hydrochlorothiazide, Section 2, Cancer in humans
ANNEX 3. Supplementary material for Section 2, Cancer in humans
These supplementary figures are available online only.
Please report any errors to imo@iarc.who.int.
Fig. S2.1 Directed acyclic graph to illustrate key confounding considerations of the Working Group regarding the association between hydrochlorothiazide and squamous cell carcinoma of the skin in studies of cancer in humans
Fig. S2.1 Simplified directed acyclic graph to illustrate the Working Group’s considerations of potential confounding by indication in studies on voriconazole use and risk of squamous cell carcinoma of the skin
Fig. S2.2 Simplified directed acyclic graph to illustrate the Working Group’s considerations of selection bias in studies on voriconazole use and squamous cell carcinoma of the skin
Fig. S2.8 Funnel plot for voriconazole use (ever or long-term use versus never use) and risk of squamous cell carcinoma of the skin
Fig. S2.9 Funnel plot for voriconazole use and basal cell carcinoma of the skin restricted to ever-versus-never use (or similar)
ANNEX 4. Supplementary material for Section 4, Mechanistic Evidence
These supplementary tables are available online only.
Please report any errors to imo@iarc.who.int.
Table S4.10 End-points relevant to oxidative stress in experimental systems in vivo exposed to tacrolimus
Table S4.11 Suppression of oxidative stress in experimental systems in vivo exposed to tacrolimus
Table S4.12 Effects of selected agents on tacrolimus-induced oxidative stress in experimental systems in vivo
Table S4.14 Effects of selected agents on tacrolimus-induced oxidative stress in experimental systems in vitro
These supplementary online-only tables contain summaries of the findings (including the assay name, the corresponding key characteristic, the resulting “hit calls” both positive and negative, and any reported caution flags) for those chemicals evaluated in the present volume that have been tested in high-throughput screening assays performed by the United States Environmental Protection Agency (US EPA) and the United States National Institutes of Health. The results were generated by the Working Group using the software “kc-hits” (key characteristics of carcinogens – high-throughput screening discovery tool) available from https://gitlab.com/i1650/kc-hits.git (Reisfeld et al., 2022), using the US EPA Toxicity Forecaster (ToxCast) assay data and the curated mapping of key characteristics to assays available at the time of the evaluations performed for IARC Monographs Volume 137. Data were available for hydrochlorothiazide, voriconazole, and tacrolimus.
Please report any errors to imo@iarc.who.int.
1. Hydrochlorothiazide: ToxCast/Tox21 assay results mapped to the key characteristics of carcinogens
2. Voriconazole: ToxCast/Tox21 assay results mapped to the key characteristics of carcinogens
3. Tacrolimus: ToxCast/Tox21 assay results mapped to the key characteristics of carcinogens
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