Approaches to determining regulatory values for carcinogens with particular reference to bromate.

There are challenges in developing standards for substances that are carcinogenic in laboratory animals. In general, acceptable levels of substances that are shown to act through a mechanism that involves direct genotoxicity are determined by applying a mathematical model to extrapolate the risk at high doses to the risk at low environmental exposures. Most such models assume linearity at the low doses, which is not experimentally verifiable. Levels for substances that act through an indirect mechanism for which there is an experimentally verifiable threshold, such as cytotoxicity and regenerative hyperplasia, are generally determined by applying an uncertainty factor to a no effect level or a benchmark dose. Bromate is a potentially important contaminant in hypochlorite, and also as a consequence of the use of ozone in drinking water treatment. Although it has been used for many years as a flour improver it is known to cause cancers of the kidney, tunica vaginalis testis and thyroid in laboratory rodents. There are species differences in the sensitivity to bromate and differences in the tumours observed. The mechanism by which bromate causes cancer in laboratory animals is uncertain. There is evidence that bromate is a genotoxin but there is also indication that the dose response is not linear at low doses and that bromate may act through an intermediate mechanism. There is also evidence to suggest that bromate may be inactivated by antioxidants in the gastrointestinal tract and blood and so may not reach the sensitive tissues at low doses. Bromate has been considered by WHO, USEPA and Canada with slightly differing outcomes depending on the assumptions made. Because the acceptable levels determined are close to or below the concentrations that can be practically achieved in drinking water, even small differences have become very important. Determining whether it is appropriate to use a linear assumption and which is the most relevant tumour site are important steps in refining the risk assessment to for drinking water disinfection with hypochlorite and ozone.