Health risks of micropollutants - the need for a new approach.

Micropollutants in water provide a challenge to both science and society. The final consideration is to understand whether they are harmful to human health or to aquatic life and to determine what actions should be taken. The numbers of substances that are being identified requires a new approach to risk assessment and to solving the problem based on proper prioritisation of the needs for more targeted and multidisciplinary research delivering high quality data. The concept of threshold of toxicological concern has been applied to food and could usefully be applied to water. However, this approach also needs to be combined with practical and pragmatic assessments of the behaviour of substances in water and their removal by drinking water treatment. Such an approach provides a bridge from problem identification to problem solving.

Use of routinely collected data on trihalomethane in drinking water for epidemiological purposes.

OBJECTIVES: To explore the use of routinely collected trihalomethane (THM) measurements for epidemiological studies. Recently there has been interest in the relation between byproducts of disinfection of public drinking water and certain adverse reproductive outcomes, including stillbirth, congenital malformations, and low birth weight. METHOD: Five years of THM readings (1992--6), collected for compliance with statutory limits, were analysed. One water company in the north west of England, divided into 288 water zones, provided 15,984 observations for statistical analysis. On average each zone was sampled 11.1 times a year. Five year, annual, monthly, and seasonal variation in THMs were examined as well as the variability within and between zones. RESULTS: Between 1992 and 1996 the total THM (TTHM) annual zone means were less than half the statutory concentration, at approximately 46 microg/l. Differences in annual water zone means were within 7%. Over the study period, the maximum water zone mean fell from 142.2 to 88.1 microg/l. Mean annual concentrations for individual THMs (microg/l) were 36.6, 8.0, and 2.8 for chloroform, bromodichloromethane (BDCM), and dibromochloromethane (DBCM) respectively. Bromoform data were not analysed, because a high proportion of the data were below the detection limit. The correlation between chloroform and TTHM was 0.98, between BDCM and TTHM 0.62, and between DBCM and TTHM -0.09. Between zone variation was larger than within zone variation for chloroform and BDCM, but not for DBCM. There was only little seasonal variation (<3%). Monthly variation was found although there were no consistent trends within years. CONCLUSION: In an area where the TTHM concentrations were less than half the statutory limit (48 microg/l) chloroform formed a high proportion of TTHM. The results of the correlation analysis suggest that TTHM concentrations provided a good indication of chloroform concentrations, a reasonable indication of BDCM concentrations, but no indication of DBCM. Zone means were similar over the years, but the maximum concentrations reduced considerably, which suggests that successful improvements in treatment have been made to reduce high TTHM concentrations in the area. For chloroform and BDCM, the main THMs, the component between water zones was greater than variation within water zones and explained most of the overall exposure variation. Variation between months and seasons was low and showed no clear trends within years. The results indicate that routinely collected data can be used to obtain exposure estimates for epidemiological studies at a small area level.

Oestrogens and oestrogenic activity in raw and treated water in Severn Trent Water.

Sewage effluent discharged to surface water has been shown to contain human hormones, particularly oestrogens, and synthetic chemicals which may be able to disrupt the endocrine system. Since many surface waters which receive sewage effluent are subsequently used as drinking water sources, it is important to demonstrate that treated drinking water is not contaminated. Oestrogenic activity in rivers and drinking water in the region of Severn Trent Water was studied using a combination of bioassay, to integrate exposure over time, and advanced chemical analysis. There was little or no evidence of substances that were oestrogenic, even in waters receiving significant amounts of sewage effluent. Oestrogenic activity, as measured in the rainbow trout vitellogenin assay, was seen at the Tame/Trent confluence but this activity was relatively weak. There was no activity detected at raw water intakes and no hormones or substances that are oestrogenic were detected in the final drinking water.

Risk assessment case study--chloroform and related substances.

Chlorine, used as an important disinfectant for drinking water, can react with naturally occurring organic matter to form chloroform, bromodichloromethane, chlorodibromomethane and bromoform. Chloroform and other trihalomethanes have been shown to increase tumours of the liver, kidney or large intestine in rats or mice. The risk to man from these contaminants must be assessed carefully since there is considerable benefit associated with the use of chlorine. The weight of evidence suggests that chloroform is non-genotoxic and there are data, for each site, to indicate that tumours only occur at high doses where there is also tissue damage. Bromodichloromethane has also been shown to increase liver and kidney tumours but this and bromoform have been shown to increase large intestinal tumours in rats. The weight of evidence is that they are only weak genotoxins and they do not appear to be active in vivo. It is probable that the mechanism for the liver and kidney tumours is the same as for chloroform but the mechanism for the large intestinal tumours is uncertain. However, the toxicity and carcinogenicity of these substances is profoundly affected by dosing in corn oil. New studies suggest that dosing in drinking water would not result in increases in tumours. The evidence suggests that the use of a threshold approach, based on a tolerable daily intake, would be the most appropriate way of determining safe levels in drinking water.

Chlorination disinfection byproducts in water and their association with adverse reproductive outcomes: a review.

OBJECTIVES AND METHODS: Chlorination has been the major disinfectant process for domestic drinking water for many years. Concern about the potential health effects of the byproducts of chlorination has prompted the investigation of the possible association between exposure to these byproducts and incidence of human cancer, and more recently, with adverse reproductive outcomes. This paper evaluates both the toxicological and epidemiological data involving chlorination disinfection byproducts (DBPs) and adverse reproductive outcomes, and makes recommendations for future research. RESULTS AND CONCLUSIONS: Relatively few toxicological and epidemiological studies have been carried out examining the effects of DBPs on reproductive health outcomes. The main outcomes of interest so far have been low birth weight, preterm delivery, spontaneous abortions, stillbirth, and birth defects--in particular central nervous system, major cardiac defects, oral cleft, and respiratory, and neural tube defects. Various toxicological and epidemiological studies point towards an association between trihalomethanes (THMs), one of the main DBPs and marker for total DBP load, and (low) birth weight, although the evidence is not conclusive. Administered doses in toxicological studies have been high and even though epidemiological studies have mostly shown excess risks, these were often not significant and the assessment of exposure was often limited. Some studies have shown associations for DBPs and other outcomes such as spontaneous abortions, stillbirth and birth defects, and although the evidence for these associations is weaker it is gaining weight. There is no evidence for an association between THMs and preterm delivery. The main limitation of most studies so far has been the relatively crude methodology, in particular for assessment of exposure. RECOMMENDATIONS: Large, well designed epidemiological studies focusing on well defined end points taking into account relevant confounders and with particular emphasis on exposure characterisation are ideally needed to confirm or refute these preliminary findings. In practice, these studies may be impracticable, partly due to the cost involved, but this is an issue that can be put right--for example, by use of subsets of the population in the design of exposure models. The studies should also reflect differences of culture and water treatment in different parts of the world. To identify the specific components that may be of aetiological concern and hence to fit the most appropriate exposure model with which to investigate human exposure to chlorinated DBPs, further detailed toxicological assessments of the mixture of byproducts commonly found in drinking water are also needed.

The toxicity of cyanobacterial toxins in the mouse: I microcystin-LR.

Blooms of cyanobacteria or blue-green algae are known to have caused poisoning in fish, waterfowl, animals and man. One of the toxins responsible for this is the hepatotoxin microcystin-LR which has been found to occur in blooms present intermittently in sources used for domestic water supplies. Three sets of experiments were undertaken to investigate the acute toxicity of microcystin-LR in mice and rats by the oral and intraperitoneal routes, the potential for effects on foetal development in the mouse, and the effects of repeated oral dosing over 13 weeks in the mouse. The results of this work were as follows: (1) Microcystin-LR is 30-100 times less toxic via oral ingestion than via intraperitoneal injection; (2) Microcystin-LR is not a selective developmental toxicant in the mouse. There was a No Observed Adverse Effect Level (NOAEL) of 600 microg kg(-1) bodyweight per day given on days 6-15 of pregnancy for any form of developmental toxicity; (3) There was a clear NOAEL for tissue damage in the liver of 40 microg kg(-1) bodyweight per day of microcystin-LR. Using this data, a value of 1 microg l(-1) microcystin-LR would be an appropriate guideline value for drinking water.

The toxicity of cyanobacterial toxins in the mouse: II anatoxin-a.

Blooms of cyanobacteria are known to have caused poisoning in fish, waterfowl, animals and man. One of the low molecular weight toxins responsible for this is the neurotoxin anatoxin-a which has been detected in reservoirs used for domestic water supplies. While the acute behaviour of this alkaloid is clear, there is uncertainty regarding the effects on man of ingestion of anatoxin-a at low levels over longer periods. In order to assess this risk, a series of in vitro and in vivo experiments were undertaken to investigate the pharmacology, subacute toxicity, and the teratogenicity of anatoxin-a in the mouse. The results of this work were as follows: (1) Pharmacological screening studies confirmed that anatoxin-a is a potent nicotinic agonist which can produce neuromuscular blockade and death by respiratory arrest. Recovery from a single sub-lethal dose is rapid and complete; (2) Repeated sub-lethal oral administration over 28 days in the mouse did not produce any reliable evidence of treatment-related toxicity; (3) From a preliminary screening study anatoxin-a does not appear to be a developmental toxicant in the mouse. These results indicate that a guideline value for anatoxin-a in drinking water of 1 microg l(-1) would provide an adequate margin of safety.

DNA oxidation by potassium bromate; a direct mechanism or linked to lipid peroxidation?

Following incubation of calf thymus DNA with potassium bromate (KBrO3) and glutathione (GSH), a statistically significant increase in the concentration of 8-oxodeoxyguanosine (8-oxodG) relative to deoxyguanosine was measured. This was GSH-dependent and was associated with loss of GSH during incubation. In contrast, 8-oxodG was not found to be elevated significantly in either total tissue DNA or mitochondrial DNA isolated from Sprague-Dawley rat kidney perfused in situ with KBrO3 (5 mM) for 15 min or 1 h. There was also no associated increase in the level of renal lipid peroxidation or reduced or oxidised GSH. Following intraperitoneal administration of KBrO3 to Sprague-Dawley rats, a dose of 100 mg/kg (maximum tolerated) gave evidence for oxidative stress in the kidney at 24 h as indicated by a significant increase in lipid peroxidation (P < 0.05) and oxidised GSH (P < 0.05). This was associated with a greater than 2-fold, significant (P < 0.01) increase in the level of 8-oxodG in kidney total DNA and a 57% (not statistically significant) increase in kidney mitochondrial 8-oxodG. Pretreatment of rats with diethylmaleate (DEM) to deplete GSH, elevated the toxicity of 100 mg/kg KBrO3. However, at a dose of 20 mg/kg, no change in any of the parameters indicative of kidney oxidative stress (including indicators of oxidative DNA damage; 8-oxodG or etheno-DNA adducts, which can be produced by lipid peroxides) was seen either with or without DEM pretreatment with the exception of a small but statistically significant (P < 0.05) increase in mitochondrial 8-oxodG when KBrO3 was given following DEM pretreatment. DNA oxidation in the kidney is therefore not inhibited by GSH depletion (contrasting with in vitro findings) and requires a sustained exposure at a near-toxic concentration of KBrO3 which is associated with lipid peroxidation and GSH oxidation. The results do not support a role, in rat kidney, of a direct, GSH-mediated mechanism for KBrO3-induced DNA oxidation as seen in vitro.

Derivation of acceptable concentrations for the protection of aquatic organisms.

Derivation of quality standards to protect aquatic ecosystems demands a minimum set of toxicity data to allow the risk assessor to take some account of: (1) variable responses to toxicants; (2) variable environmental characteristics; (3) interactions between duration of exposure and effects; and (4) ecological significance of impacts. Extrapolation from limited experimental data to predict a concentration protective in diverse ecosystems can employ either statistical models (consistent but rather rigid and may not protect all species) or empirical factors (more flexible and possibly more protective, but require expert judgment in their application). However derived, quality standards must be tailored to the specific conditions of release and environmental fate which influence a chemical's impact in aquatic ecosystems. It must also be recognised that protection of all individuals and even of all aquatic species may not be achievable or necessary to maintain a healthy ecosystem. Some possible future advances in the determination of water quality standards are suggested.

The impact of inorganic chemicals on water quality and health.

Inorganic substances constitute by far the greatest proportion of chemical contaminants in drinking water. They are present in greatest quantity as a consequence of natural processes but several important contaminants are present as a result of man's activities. Some of the most important even come from the plumbing material through which water is passed. Inorganic contaminants are the most important determinands of acceptability to the consumer, affecting taste, colour and scale deposition on pipes and fittings. They are also demonstrably the most important for health, having both beneficial and adverse effects which have been shown in human populations. This is a brief review of some of the most important inorganic constituents of drinking water covering major elements such as hardness and nitrate and more minor constituents in terms of quantity, such as arsenic, selenium and lead.

Assessment of the human risk associated with the presence of carcinogenic compounds in drinking water.

Both organic and inorganic contaminants which have been implicated in causing cancer in man or, more commonly, in laboratory animals can be found in drinking water. Apart from arsenic there are none for which there is convincing epidemiological evidence of a significant risk to man. However environmental epidemiology is fraught with difficulties. There are also difficulties in interpreting laboratory animal data and extrapolating this to the low concentrations found in drinking water although mathematical models can be very useful if used sensibly. There is a danger that the rather extreme public perception of cancer could lead to over regulation of some contaminants in water, possibly with an increase in risk from other hazards such as microbiological contamination.

Identification and assessment of hazardous compounds in drinking water.

The identification of organic chemicals in drinking water and their assessment in terms of potential hazardous effects are two very different but closely associated tasks. In relation to both continuous low-level background contamination and specific, often high-level, contamination due to pollution incidents, the identification of contaminants is a pre-requisite to evaluation of significant hazards. Even in the case of the rapidly developing short-term bio-assays which are applied to water to indicate a potential genotoxic hazard (for example Ames tests), identification of the active chemicals is becoming a major factor in the further assessment of the response. Techniques for the identification of low concentrations of organic chemicals in drinking water have developed remarkably since the early 1970s and methods based upon gas chromatography-mass spectrometry (GC-MS) have revolutionised qualitative analysis of water. Such techniques are limited to "volatile" chemicals and these usually constitute a small fraction of the total organic material in water. However, in recent years there have been promising developments in techniques for "non-volatile" chemicals in water. Such techniques include combined high-performance liquid chromatography-mass spectrometry (HPLC-MS) and a variety of MS methods, involving, for example, field desorption, fast atom bombardment and thermospray ionisation techniques. In the paper identification techniques in general are reviewed and likely future developments outlined. The assessment of hazards associated with chemicals identified in drinking and related waters usually centres upon toxicology - an applied science which involves numerous disciplines. The paper examines the toxicological information needed, the quality and deployment of such information and discusses future research needs. Application of short-term bio-assays to drinking water is a developing area and one which is closely involved with, and to some extent dependent on, powerful methods of identification. Recent developments are discussed.