Hydroquinone: An Evaluation of the Human Risks from its Carcinogenic and Mutagenic Properties

Abstract

The toxicology of hydroquinone has been reviewed on a number of previous occasions. This review targets its potential for carcinogenicity and possible modes of carcinogenic action. The evaluation made by IARC (1999) of its carcinogenic risk to humans was that hydroquinone is not classifiable as to its carcinogenicity to humans (Group 3). This evaluation was based on inadequate evidence in humans and limited evidence in experimental animals. The epidemiological information comes from four cohort studies involving occupational exposures. A cohort of lithographers, some of whom had worked with hydroquinone, had an excess of malignant melanoma based on five cases, but only two of the cases had reported exposure to hydroquinone. In a study of photographic processors the number of exposed individuals was uncertain and the numbers of cases of individual cancer sites were small. In view of the statistical power limitations of these studies for individual diagnostic categories of cancers, they are not considered to be informative with regard to the carcinogenicity of hydroquinone. A cohort of workers with definite and lengthy exposure to hydroquinone, during either its manufacture or its use, had low cancer rates compared with two comparison populations; the reason for the lower than expected rates is unclear. In a motion picture film processing cohort there were significant excess malignancies of the respiratory system among workers engaged in developing, where there was exposure to hydroquinone as well as other chemicals. There was no information on tobacco smoking habits and no dose-response relationship. Hydroquinone has been shown reproducibly to induce benign neoplasms in the kidneys of male F344 rats dosed orally either by gavage (25 and 50 mg/kg body weight) or diet (0.8%). The gavage study has been evaluated in considerable detail. This evaluation showed that all renal tubule adenomas and all cases of renal tubule atypical hyperplasia occurred in areas of severe or end-stage chronic progressive nephropathy and that the neoplasms were not otherwise confined to any particular part of the kidney. It is likely that the mode of carcinogenic action of hydroquinone is exacerbation of this natural disease process. Hydroquinone is mutagenic in vitro and in vivo, having caused genotoxicity or chromosomal aberrations in rodent bone-marrow cells. At least a portion, if not all, of the chromosomal effects are caused by interference by hydroquinone or its metabolites with chromosomal segregation, probably due to interaction with mitotic spindle proteins. However, the dose routes used to demonstrate these effects in almost all of the studies in vivo were intraperitoneal or subcutaneous injection, which were considered inappropriate. There were five studies by the oral route. These included a mouse bone-marrow cell micronucleus test in which a weak, marginally positive response was obtained following a single oral dose of 80 mg/kg body weight. The remaining oral route studies all showed no significant effect. They included a mouse bone-marrow cell micronucleus test in which there was no genotoxic activity after exposure to a diet containing 0.8% hydroquinone for 6 days; two ³²P-post-labeling assays, one with targets of Zymbal gland, liver, and spleen in Sprague-Dawley rats, the other with the kidney as target in F344 rats; and the last oral assay was for 8-hydroxydeoxyguanosine adducts in F344 rat kidney DNA. Thus, the evidence (and the database) for any genotoxic effect in vivo is sparse and none has been observed in kidney. While glutathione conjugates could be responsible for the tumor induction, careful histology seems to show that the most actively toxic of several glutathione compounds tested, 2,3,5-triglutathion-S-yl hydroquinone, targets a very specific region of the kidney, the outer stripe of the outer medulla (OSOM), whereas hydroquinone-associated adenomas are more randomly distributed and occur in the cortex as well as the medulla. A nongenotoxic mode of action that involves exacerbation of a spontaneously occurring rodent renal disease, chronic progressive nephropathy (CPN), is proposed and evaluated. This disease is particularly prominent in male rats and the evidence is consistent with an absence of any human counterpart; therefore, the increased incidence of renal tubule adenomas in hydroquinone-dosed male rats is without human consequence.

Key words :

• Chronic Progressive Nephropathy
• Human Kidney
• Hydroquinone
• IPCS Framework
• Metabolism
• Mutagens
• Rodent Carcinogens

Notes

¹This reference is to an abstract of a meeting presentation, but the more complete information is available from the Hydroquinone Group—see Acknowledgements

²P1 originates at the glomerulus and consists of about half of the pars convoluta (convoluted tubule); P2 consists of the remainder of the convoluted tubule and the beginning of the pars recta; P3 is the remainder of the pars recta. P1 and P2 are cortical, although P2 intrudes slightly into the medulla, while P3 is located in the OSOM and medulla