The Toxicology of Hydroquinone — Relevance to Occupational and Environmental Exposure

Abstract

Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is p...

Hypothesis: Phenol and hydroquinone derived mainly from diet and gastrointestinal flora activity are causal factors in leukemia

“…24,32 Phenol and hydroquinone produce genetic damage of the type found in leukemia Quinones derived from phenol, catechol, hydroquinone and 1,2,4-benzenetriol cause various forms of genetic damage Leukemia including chromosome breakage and aneuploidy. 26,33 Aneuploidy is the loss or gain of whole chromosomes and is a frequent clonal aberration in leukemia. Common aneuploidies include trisomy of chromosome 8 and monosomy of chromosomes 5 and 7.…”

Cigarette Smoke-Related Hydroquinone Induces Filamentous Actin Reorganization and Heat Shock Protein 27 Phosphorylation through p38 and Extracellular Signal-Regulated Kinase 1/2 in Retinal Pigment Epithelium

“…HQ is an oxidant of special relevance due to its presence not only in cigarette smoke but also in processed foods, plastic containers, and atmospheric pollutants as well as its widespread occurrence in nature. 16,17 Detectable levels of HQ have been measured in the plasma of many nonsmoker individuals living a Western life style. 16 We embrace the pathogenic paradigm based on the response-to-injury hypothesis, which proposes that sub-RPE deposits originate from RPE-derived cell membrane blebs 18,19 induced by chronic nonlethal injury to the RPE in response to oxidative damage.…”

Pharmaceutical and Clinical Assessment of Hydroquinone Ointment Prepared by Extemporaneous Nonsterile Compounding.

“…Recent studies suggested the possibility of serious adverse events associated with HQ, 1,[8][9][10] and various types of skinlightening agents have been proposed including gentisic acid analogues, 9) HQ glucosides 11) and tert-butyl HQ. 12) New protocols or formulation methods have also been proposed using all-trans retinoic acid, kojic acid and hydrocortisone.…”

“…1,9) Recent investigations have suggested the nephrotoxicity, mutagenicity or carcinogenicity of HQ. 1,[8][9][10] However, the adverse events associated with external OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, whereas higher incidences have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. 1) In Japan, HQ formulations are not commercially available and have been prepared by extemporaneous nonsterile compounding in hospitals with various prescriptions without sufficient experimental evidence providing justification for the prescriptions.…”

“…HQ is susceptible to acid-base and oxidation-reduction matrix to form various chemical structures including p-BQ. 1) p-BQ is thought to be potentially important for the action of HQ in biological systems, 1) and is expected to be responsible for the chromatic aberration of HQ ointment.…”