MECHANISMS OF CARCINOGENICITY: DISINFECTION BY-PRODUCTS
Report No FR0372

W F Young

Mar 1993

SUMMARY

I BENEFITS

Small differences in water quality standards can result in inordinately large differences in costs for water treatment. Understanding the mechanism of carcinogenicity of disinfection by-products will reduce uncertainties in their risk assessment and enable standards for their presence in drinking water to be set at the most appropriate level. This will enable identification of by-products of most concern and minimise unnecessary investment in the control of those which do not constitute a significant risk to health.

II OBJECTIVES

  1. To explain the different mechanisms of carcinogenicity and how these effect the derivation of drinking water standards for carcinogenic compounds.

  2. To review the mechanisms of carcinogenicity of key disinfection by-products.

  3. To report on the results of recent practical work undertaken, as part of this contract, to elucidate the mechanism of carcinogenicity of bromate.

III REASONS

Previous reviews of disinfection by-products have identified a number that may be of concern on the basis of their frequency of occurrence and evidence for potential adverse effects on humans, in particular carcinogenicity.

There is likely to be increasing regulation of many of these by-products. The mechanism of carcinogenicity will affect the approach taken in deriving standards and will have a significant effect on the numerical standards which emerge.

It is therefore important to determine the mechanisms of carcinogenicity of key disinfection by-products in order that meaningful health-based standards can be derived.

IV CONCLUSIONS

  1. Some chemical contaminants found in water can cause cancer in laboratory animals.

  2. For the purposes of regulating chemical contaminants in drinking water it can be considered that there are two mechanisms by which chemicals cause cancer. Correspondingly, there are two approaches to deriving regulatory values for carcinogens, depending on the mechanism by which they cause cancer. One uses mathematical models, the other uses uncertainty factors.

  3. Regulations determined by mathematical models for extrapolating cancer risk from high to low levels of exposure usually result in more stringent regulatory values than those determined by applying an uncertainty factor to a threshold dose.

  4. It is important to determine the mechanism of carcinogenicity for carcinogens in order to reduce uncertainties in risk assessment and improve the quality of regulatory standards. However, unless there is good evidence to indicate otherwise, regulatory authorities tend to use mathematical models for quantifying cancer risks.

  5. Bromate has been shown to cause cancer in rats and, at present, the World Health Organisation (WHO) have indicated that, to ensure protection of health, they would use a mathematical model for determining a guideline value in drinking water of 3 g l-1. Nevertheless they recognise that its mechanism of carcinogenicity is uncertain and that this cautionary approach may be inappropriate. However, due to limitations in available analytical methods, a provisional drinking water guideline of 25 g l-1 has been recommended on the basis of analytical capability.

  6. The practical study, undertaken at Birmingham University, indicates that bromate causes indirect DNA damage which is likely to exhibit a threshold dose, and therefore supports the use of uncertainty factors in deriving a regulatory value. This work su ggests that the cautionary approach proposed by WHO may be inappropriate for bromate.

  7. Results of this and any future studies should be disseminated to a wider expert audience in order to ensure they are given due consideration in the event of health-based guidelines being developed for bromate in drinking water.

V RESUME OF CONTENTS

For the purposes of regulating chemical contaminants in drinking water it can be considered that there are two mechanisms by which chemicals can cause cancer, `genotoxic' and `non-genotoxic'.

For genotoxic chemicals which react directly with DNA (the genetic material within the cell), there is assumed to be no threshold dose and therefore there is a theoretical risk of cancer at any level of exposure. Regulatory bodies usually use mathematical models to calculate the concentration of a contaminant associated with a particular level of risk which is considered 'negligible' or `acceptable'. The mathematical models used in the process have many conservative assumptions built in and will usually overestimate the true risk, which could be zero.

For non-genotoxic chemicals which are thought to have a threshold dose or exposure level below which there is no risk of cancer, regulatory bodies usually apply a suitable uncertainty or `safety' factor to a no effect level in human or animal studies. These factors will be derived by experienced toxicologists and will benefit from their expert judgement.

The approach to deriving standards can have a significant impact on the regulatory level, with the former approach generally giving lower values. Non-genotoxic carcinogens are of considerably less concern than genotoxic carcinogens and should be treated as such.

Several disinfection by-products have been shown to cause cancer in laboratory animals. The disinfection by-products of most concern appear to be bromodichloromethane (BDCM), the chloroacetic acids and bromate. Bromate has been shown to cause cancer in rats and, at present, the World Health Organisation (WHO) is classifying it as a `genotoxic' carcinogen and is using a mathematical model to derive a guideline value. However, the mechanism of carcinogenicity is not clear and it has been recognised by WHO that it may exhibit a threshold, in which case this approach may be inappropriate. The practical work indicates that bromate does not cause direct DNA damage and is likely to have a threshold. This supports the use of uncertainty factors in deriving a regulatory value. This approach generally results in less stringent standards and therefore, if adopted by WHO, is likely to result in any future health-based regulatory value being less stringent than the value of 3 g l-1 indicated previously.

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