Health Risk Assessment of Drinking Water Contaminants in Canada ...

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May 29, 1997 - Kannan Krishnan,*,1 Joel Paterson,† and David T. Williams‡. *Département de ... current approaches of Health Canada to the risk as-.
REGULATORY TOXICOLOGY AND PHARMACOLOGY ARTICLE NO.

26, 179–187 (1997)

RT971151

Health Risk Assessment of Drinking Water Contaminants in Canada: The Applicability of Mixture Risk Assessment Methods Kannan Krishnan,*,1 Joel Paterson,† and David T. Williams‡ *De´partement de Me´decine du Travail et d’Hygie`ne du Milieu, Faculte´ de Me´decine, Universite´ de Montre´al, CP 6128, Succursale A, Montre´al, Quebec H3C 3J7, Canada; †Drinking Water Section, Monitoring and Criteria Division, Environmental Health Directorate, Health Canada, Postal Locator 0802A, Tunney’s Pasture, Ottawa, Ontario K1A 0L2, Canada; and ‡Environmental Chemistry Section, Monitoring and Criteria Division, Environmental Health Directorate, Health Canada, Postal Locator 0800C, Tunney’s Pasture, Ottawa, Ontario K1A 0L2, Canada Received May 29, 1997

The objectives of this article are: (i) to review the current approaches of Health Canada to the risk assessment of drinking water contaminants, and (ii) to examine the applicability of mixture risk assessment methods to drinking water contaminants. Health Canada’s current approaches to drinking water risk assessment, like those of many regulatory agencies, focus almost solely on the effects of individual chemicals. As such, no formal method is currently used for developing mixtures guidelines or for modifying guidelines of individual chemicals to account for the possibility of the occurrence of interactions (supraadditive or infraadditive). Recent interest in the risk assessment of mixtures, at least in part, stems from concerns over the potential health risks of mixtures of very commonly occurring compounds in Canadian drinking water supplies, namely the disinfection byproducts. Before any mixtures methods can be considered for incorporation into Health Canada’s current approaches to the risk assessment of drinking water contaminants, it is essential to consider the limitations and data requirements of the various mixture risk assessment methods (i.e., whole mixture approach, similar mixture approach, components-based approaches, interactions-based assessment). Among the existing mixture risk assessment methods, the componentsbased and interactions-based approaches could be applicable to drinking water contaminants. Specifically, among the components-based approaches, dose-addition, response-addition, and the toxic equivalency factor approaches are the most applicable ones for drinking water contaminants. Until an interactions-based, mechanistic risk assessment approach (e.g., physiological model-based approach) becomes available for routine use, the components-based approaches remain the default methods for consideration. Progress in the development and validation of an interactions-based risk 1

To whom all correspondence should be addressed.

assessment methodology should facilitate a more realistic assessment of risk due to drinking water contaminants without increasing the levels of uncertainty in risk estimates above those associated with existing single-chemical methods. q 1997 Academic Press

INTRODUCTION

Health Canada is the agency responsible for recommending guidelines for drinking water contaminants in Canada. Published in 1969, the Canadian Drinking Water Standards and Objectives contained healthbased standards and recommended limits for 25 chemical parameters (Department of National Health and Welfare, 1969). Although potential long-term effects on human health and total environmental exposure to the specified toxicants were considered, no formal approach was outlined for the derivation of these limits. Nearly 30 years later, the Federal–Provincial Subcommittee on Drinking Water has published health-based maximum acceptable concentrations (MACs) for 60 chemical substances in the sixth edition of the Guidelines for Canadian Drinking Water Quality (Health Canada, 1996). Also, to ensure consistency and transparency in the risk assessment process the approach followed for the derivation of drinking water guidelines for chemicals has been published in the supporting documentation to the guidelines (Health Canada, 1995). The existing approaches to the derivation of drinking water guidelines (Health Canada, 1995) are under periodic review. The applicability of mixture risk assessment methods to drinking water contaminants is one of the areas currently under consideration by Health Canada. Recent interest in the risk assessment of mixtures stems, at least in part, from concerns over the potential health risks of mixtures of very commonly occurring compounds in Canadian drinking water supplies, namely the disinfection by-products (DBPs). The

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0273-2300/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.

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TABLE 1 Criteria for Classification of Carcinogenicity (Health Canada, 1995) Group I II III IV V

Description Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Probably not carcinogenic to humans Inadequate data for evaluation

objectives of this article are (i) to review the current approaches of Health Canada to the risk assessment of drinking water contaminants, and (ii) to examine the applicability of the existing mixture risk assessment methods to drinking water contaminants in Canada, with particular emphasis on methods that could be used to assess the health risks of DBP mixtures. HEALTH CANADA’S CURRENT APPROACHES

Under Health Canada’s current approaches to the derivation of drinking water guidelines, the potential for drinking water contaminants to affect human health is assessed using data from toxicological studies conducted with laboratory animals, epidemiological studies of human populations, and clinical case reports. Effects reported in such studies are generally classified as organ-specific, neurological/behavioral, reproductive, teratological, and oncogenic/carcinogenic/mutagenic. The potential for a chemical to cause effects in the latter group forms the basis for determining the type of approach to be followed in the development of a MAC. Each drinking water contaminant is classified into one of five groups (Table 1) following a careful examination of available data from toxicological, epidemiological, and other available studies (Health Canada, 1995). For chemicals that are considered to be carcinogenic, i.e., those that are classified as Group I (carcinogenic to humans) and Group II (probably carcinogenic to humans), the effect in question, carcinogenesis, is generally assumed to be a nonthreshold phenomenon; i.e., there is a probability of harm at any level of exposure. MACs are developed for Group I and Group II chemicals by extrapolating from the dose–response relationship observed at the higher levels of exposure used in experimental studies to the low exposure levels believed to be associated with essentially negligible levels of risk. The robust linear extrapolation model (Krewski et al., 1991) is applied to data on tumor incidences considered most relevant for the human health risk assessment in order to derive a MAC with an upper 95% confidence limit for lifetime cancer risk between 1005 and 1006. In addition, if justified based on pharmacokinetic and metabolism data, a surface area correction is

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applied to account for differences in metabolic rates between humans and experimental animals (Health Canada, 1995). MACs for Group I and Group II chemicals must be achievable using available water treatment technology at a reasonable cost and must be reliably measured by available analytical methods. If limitations in treatment or analytical methodology result in a MAC which is associated with a cancer risk greater than the essentially negligible range, an interim maximum acceptable concentration (IMAC) is established until methodological improvements are made. Chemicals which are thought to have an exposure level below which adverse effects are unlikely to occur (i.e., a threshold) include those classified in Groups III (possibly carcinogenic to humans), IV (probably not carcinogenic to humans), and V (inadequate data for evaluation). For a chemical classified in any one of these three groups, a tolerable daily intake (TDI) is developed by dividing the no-observed-adverse-effect level (NOAEL) for the effect most relevant to the health risk assessment by an uncertainty factor. Uncertainty factors generally vary from 1 to 5000 and are used to account for variations due to intra-/interspecies extrapolation, nature and severity of the effect, adequacy of the study, use of a lowest-observed-adverse-effect level instead of a NOAEL, potential for interaction with other chemicals, and dietary requirements in the case of essential nutrients. An additional uncertainty factor of 1 to 10 can be applied to account for limited evidence of carcinogenicity in the case of Group III chemicals (Health Canada, 1995). When appropriate data exist on other sources of exposure (e.g., air, food, soil), a proportion of the TDI can be allocated to drinking water for the calculation of the MAC. In the absence of such data, a default proportional allocation of 20% is used. The proportion of the TDI allocated to drinking water is then used with the average daily drinking water intake (1.5 L) of a 70-kg adult or the average daily drinking water intake and body weight for the most sensitive subpopulation to derive the MAC. Similar to the approach for Group I and Group II chemicals, IMACs are established when calculated MACs are not currently achievable or reliably measurable due to the need for improved treatment or analytical technologies. Health Canada’s current approaches to drinking water risk assessment, like those of many regulatory agencies, focus almost solely on the effects of individual chemicals. There is no formal method for developing mixtures guidelines or modifying guidelines for individual chemicals to account for the possibility that enhanced (e.g., synergism) or decreased (e.g., antagonism) risk, or even a simple addition of risks could result from simultaneous exposure to two or more chemicals. The only documented approach to dealing with chemical mixtures is the option of incorporating

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an additional uncertainty factor into the TDI calculations for a threshold chemical when data indicating a potential for enhanced toxicity following interaction with other chemicals are available (Health Canada, 1995). The emphasis on the single-chemical approach to risk assessment is not surprising given that the vast majority of experimental studies have been conducted with single compounds and there is a paucity of relevant data on potential interactions between chemicals commonly occurring in drinking water. The only formal mixture-based approach described in the Guidelines for Canadian Drinking Water Quality is one which is intended to be applied to radiological rather than chemical contaminants in drinking water. The guidelines state that ‘‘where two or more radionuclides that affect the same organ or tissue are found to be present in drinking water, the following relationship should be satisfied:

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TABLE 2 Examples of Disinfection By-products Analyzed in 1993 National Survey of Canadian Drinking Water (Williams et al. 1997)

C1 C2 Ci / / rrr õ 1, MAC1 MAC2 MACi

Trihalomethanes Chloroform (CHCl3) Bromodichloromethane (CHBrCl2) Chlorodibromomethane (CHBr2Cl) Bromoform (CHBr3) Haloacetic acids Monochloroacetic acid (CH2ClCOOH) Dichloroacetic acid (CHCl2COOH) Trichloroacetic acid (CCl3COOH) Monobromoacetic acid (CH2BrCOOH) Dibromoacetic acid (CHBr2COOH) Haloacetonitriles Dichloroacetonitrile (CHCl2CN) Trichloroacetonitrile (CCl3CN) Bromochloroacetonitrile (CHBrClCN) Dibromoacetonitrile (CHBr2CN) 1,1-Dichloro-2-propanone (CHCl2COCH3) 1,1,1-Trichloro-2-propanone (CCl3COCH3) Chloral hydrate (CCl3CH(OH)2) Chloropicrin (CCl3NO2)

where C1 , C2 , and Ci are the observed concentrations, and MAC1 , MAC2 , and MACi are the maximum acceptable concentrations for each contributing radionuclide (Health Canada, 1995). However, in recent years there has been increasing concern from both regulatory agencies and researchers that single-chemical approaches may not provide satisfactory estimations of total risk (e.g., Seed et al., 1995). For example, the U.S. EPA has recognized the need for approaches to mixtures risk assessment and has taken the step of publishing guidelines for the risk assessment of chemical mixtures which may be applied to drinking water or other sources of exposure (U.S. EPA, 1986). Health Canada (1994) has outlined several methods for dealing with simple chemical mixtures in the approach to the human health risk assessment of priority substances under the Canadian Environmental Protection Act. While Health Canada has yet to adopt a formal methodology for chemical mixtures in drinking water, interest in the potential applicability of such methods has increased as a result of research on DBPs. Chlorine or other disinfectants can react with naturally occurring organic matter in water to produce a whole range of DBPs. The nature and concentrations of the resulting DBPs have been shown to be dependent on factors such as the bromide ion concentration, disinfectant dose and residual, pH, temperature, and the concentration and nature of the organic precursors in the raw water (Pourmoghaddas et al., 1993; Summers et al., 1993; Symons et al., 1993). The concentration of individual DBPs also varies throughout the year and within the distribution system. The consumer is potentially exposed to complex and changing mixtures of DBPs in drinking water.

Table 2 lists some of the most commonly occurring DBPs which were analyzed in a recent national survey of 53 sites across Canada (Williams et al., 1997). At most sites, the trihalomethanes (THMs) were some of the most prominent DBPs found with mean distribution system concentrations ranging from 9.9 to 33.4 mg/ L in winter and 32.8 to 66.7 mg/L in the summer (i.e., total THMs), depending on the treatment techniques used. The highest total THM concentration recorded for a single water supply was 342.4 mg/L. Chloroform represented the greatest percentage (ú90%) of the total THMs, except at a few sites where the concentrations of the bromine-containing THMs increased due to the presence of higher bromide ion concentration in the raw water supplies (Williams et al., 1997). The THMs are the only type of DBPs for which a Canadian drinking water guideline exits, (i.e., IMAC, 100 mg/L). The THM IMAC applies to the sum of all four brominated and chlorinated THMs (Table 2), but was actually based on the risks associated with chloroform as a nonthreshold carcinogen (Health Canada, 1993). This can be thought of as an indicator chemical approach to mixtures risk assessment; chloroform is the THM of greatest concern, so a guideline developed for this compound will be protective with respect to the other THMs (Health Canada, 1993). This is in keeping with the wealth of health effects data (especially carcinogenicity data) available for chloroform verses the other THMs at the time of the guideline development and the fact that chloroform is the THM most often present and generally found in the highest concentrations in water supplies (Health Canada, 1993). While not necessarily following an indicator chemical

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approach, the U.S. EPA has proposed that the four THMs be grouped under a total THMs maximum contaminant level (MCL) (80 mg/L) under the proposed Disinfectants and Disinfection By-products Rule of the National Primary Drinking Water Regulations (U.S. EPA, 1994b). However, recent studies indicating that chloroform may induce cancer by a nongenotoxic/-cytotoxic mechanism and that the brominated THMs may present a concern equal to or greater than chloroform (Bull et al., 1995) raise the question as to whether consideration should be given to approaches that could account for the combined effects and potential interactions of the THMs. The World Health Organization (WHO) has attempted to account for the combined effects of THMs by developing guidelines for each of the four THMs and suggesting that ‘‘for authorities wishing to establish a total THM standard to account for additive toxicity, the following fractionation approach could be taken’’: CCHBr3 CCHBr2Cl CCHBrCl2 CCHCl3 / / / õ 1, GVCHBr3 GVCHBr2Cl GVCHBrCl2 GVCHCl3 where C Å concentration and GV Å guideline value. This is actually a dose-addition approach and while it represents a step toward the use of more formalized mixture risk assessment methods, it is not without limitations. Inherent to this method are the assumptions that the THMs induce a common toxic effect by the same mechanism of action and they behave as dilutions of each other (WHO, 1993). This may be an oversimplification given current data on the mechanism of action of THMs and the fact that the guidelines for bromodichloromethane and chloroform were based on the occurrence of renal tumors in carcinogenicity assays using male mice and rats, respectively, whereas the guidelines for bromoform and dibromochloromethane were based on NOAELs for liver histopathology in 90day studies using rats (WHO, 1993). Further complicating the risk assessment picture are the potential health risks presented by another major group of DBPs, the haloacetic acids (HAAs). For a number of sites in the recent Canadian national survey, total HAA levels equaled or exceeded total THM levels. Mean distribution system dichloroacetic acid (DCA) concentrations ranged from 4.6 to 15.6 mg/L in winter to 11.4 to 19.0 mg/L in summer with concentrations as high as 120.1 mg/L for one of the water supplies sampled. The corresponding trichloroacetic acid (TCA) concentrations were 4.1 to 56.7 mg/L in winter, 21.4 to 48.9 mg/L in summer, and a peak of 473.1 mg/L for one of the water supplies sampled. Distribution system levels of monobromoacetic acid (MBA, õ0.01 to 9.2 mg/L) and dibromoacetic acid (DBA, õ0.01 to 1.9 mg/L) were much lower than DCA or TCA levels. The mixed HAAs (i.e., containing both chlorine and bromine) were not deter-

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mined because of a lack of standards but were likely to be very low (Williams et al., 1997). The ability of both DCA and TCA to produce hepatotoxicity and hepatocarcinogenicity in rodents has led the WHO to establish provisional guidelines of 50 and 100 mg/L for DCA and TCA, respectively (WHO, 1993). Whereas the U.S. EPA has proposed an ‘‘HAA5’’ MCL of 60 mg/L covering monochloroacetic acid, DCA, TCA, MBA, and DBA (U.S. EPA, 1994b), Health Canada is currently in the initial stages of developing a guideline for the HAAs. The proposed U.S. EPA HAA5 MCL is intended to account for the combined risks from five different HAAs with particular emphasis on DCA and TCA (U.S. EPA, 1994b). However, mechanistic data indicating that DCA produces hepatomegaly with extensive glycogen accumulation and vacuolization, whereas TCA appears to act primarily as a peroxisome proliferator (Bull et al., 1995), raises some questions about combining the risks of DCA and TCA on the basis of simple dose or response addition. Further clouding the issue are studies which suggest that some of the brominated and mixed HAAs may also induce hepatic tumors in rodents, possibly via mechanisms different from those of DCA and TCA, and that DCA and TCA can affect the metabolism of THMs (Bull et al., 1995). The other DBPs listed in Table 2 were also frequently detected in the recent Canadian national survey, but their concentrations were an order of magnitude lower than those of the THMs and HAAs (Williams et al., 1997). The low concentrations and the limited healtheffects databases for most of these compounds make it tempting to downplay their impact on the overall health risk from DBP mixtures. However, for one of these chemicals, chloral hydrate (CH), levels recorded in the Canadian national survey, although generally lower than those of the THMs and HAAs, exceeded the current WHO guideline (10 mg/L—provisional) in some cases (WHO, 1993; Williams et al., 1997). As Seed and colleagues (1995) have suggested, what constitutes a ‘‘low’’ level of a mixture component should be defined with respect to its threshold (e.g., its NOAEL) because additive, synergistic, and antagonistic interactions may occur when mixture components are present at levels equal to or greater than their respective thresholds. Given the range of DBPs which may be present in water due to commonly used treatment techniques, exposure to mixtures of these chemicals can be considered a reality for consumers of treated water. It follows that methods which account for the effects of simultaneous exposure to mixtures of DBPs or other chemicals on the overall health risk could improve the credibility and defensibility of current drinking water risk assessments. However, before any mixtures methods can be considered for incorporation into Health Canada’s current approaches to the risk assessment of drinking wa-

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ter contaminants, it is essential that their limitations be clearly identified. The limiting data requirements and sources of uncertainty must be carefully weighed for each mixture risk assessment method under consideration. In the sections that follow, the currently available methods for mixture risk assessment (whole-mixture approach, similar-mixture approach, components-based approaches, interactions-based assessment approaches) are evaluated for their applicability to drinking water contaminants as a function of these criteria. WHOLE-MIXTURE APPROACH

The whole-mixture approach considers the chemical mixture as a single entity; thus, the health risk assessment for the chemical mixture is conducted the same way as it is done for an individual chemical (Mumtaz et al., 1993). The sole data required to apply this risk assessment method relate to the dose–response of the whole mixture in animals or humans. In principle, the risk estimates obtained using this method should account for the occurrence of interactions among components since the whole mixture is tested. As such, the estimates may be more protective of human health (by accounting for the modulation of toxicity, if any, due to interactions between the mixture components) than the estimates based on individual chemicals. However, a major source of uncertainty for this method is the lack of knowledge of mixture components. Assessments are conducted without knowledge of the concentration ratios of the components, the mechanism of action of the components, the existence of any synergistic or antagonistic interactions, or whether the toxicity of the mixture is dominated by one or a limited number of components. Since the mixture components could vary with time or location, any drinking water limits derived with this method would only be applicable to situations where the profile of water contaminants resulting from a specific process is fairly consistent. The inherent difficulty in generating the required dose–response data for mixtures of drinking water contaminants as a function of the temporal and spatial variations in their composition limits the general utility of this method. Therefore, the whole-mixture approach is unlikely to be useful as a practical approach for drinking water contaminants due to the problem of trying to generate situation-specific dose– response data and the general lack of a mechanistic basis (i.e., assessing the risks of a mixture without any knowledge of mixture components). COMPARATIVE POTENCY APPROACH

This approach involves developing human risk estimates for a chemical mixture by performing a comparative assessment of responses obtained in laboratory assays with that of another mixture for which a human

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health risk assessment has been conducted (Lewtas et al., 1983; Schoney and Margosches, 1989). Apparently, the data required for using this assessment approach relate to the dose–response information for a particular adverse effect in humans for one or more ‘‘similar’’ mixtures. Risk estimates obtained with this method account for the occurrence of interactions among components, if any, since the whole mixture is used in experimental studies. However, since this approach estimates the risk for a specific toxicological endpoint, it may not provide an adequate appraisal of the overall health risks associated with the mixture in question. Further, the dose–response data for similar, chemically characterized mixtures in humans is rarely available. Until such data are available for a wide range of mixtures, the comparative potency approach is unlikely to be routinely applicable for drinking water contaminants. The applicability of this method is also in question, with respect to most drinking water contaminants, because of the high probability of temporal and spatial variations of the mixture constituents. COMPONENT-BASED APPROACHES

The component-based approaches rely on the relative or absolute toxicity information available for mixture constituents, and use them in a framework that does not account for the possible interactions among them. In other words, these risk assessment approaches assume that the shape of the dose–response curve for each component is not altered by the other components present in the mixture. There are four commonly used component-based approaches, namely, indicator chemical, dose addition, response addition, and toxic equivalency factor. Indicator Chemical Approach This approach involves the conduct of risk assessment of only a single-mixture component that is suspected to account for most of the toxicity—qualitatively (toxicological activity) and quantitatively (in terms of percentage by volume or weight of the mixture). When using this approach to develop concentration limits for drinking water contaminants, only the dose–response information for the most active mixture component is required. This approach suffers from the obvious uncertainty that the other mixture components may also induce toxic effects either on an individual basis or following an interaction with the indicator chemical. This approach has sometimes been used in the past for the health risk assessment of contaminated waste sites and drinking water (e.g., chloroform in the case of THMs). The number of chemicals for which risk is assessed may differ from one mixture to another. But the concept is the same. The chemicals chosen for the assessment are assumed to be responsible for the per-

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ceived risk associated with the mixture. This approach is somewhat risky due to the possibility that even a single chemical, not included in the assessment, present at very low concentrations may be responsible, directly or indirectly, for the actual risks. This approach can still be applied for recommending concentration limits for drinking water contaminant mixtures when there is convincing evidence to suggest the absence of adverse toxicological interactions between the indicator chemical(s) and all other inert or weakly active components in the mixture. However, such comprehensive, supporting information is rarely available. Dose Addition and Response Addition The dose-addition and response-addition approaches account for the individual toxicological activity of all components of a mixture. The dose-addition approach generally assumes that the constituents behave as if they are dilutions of each other. This approach involves the calculation of a hazard index (HI), which is the sum of the ratios of actual or anticipated exposure concentrations to the concentration limit for each of the mixture components (U.S. EPA, 1986). When the calculated HI value for a mixture exceeds 1, it represents a concern of health risk similar to that raised by an individual chemical exceeding its concentration limit by the same extent. The response- or effects-addition approach involves the summation of excess risks attributed to each of the mixture constituents. As such, this approach is applied when the concentrations of mixture components (acting via a nonthreshold mechanism) are within the linear range of the dose–response curve. The dose- and response-addition approaches have been recommended for use in the risk assessment of mixtures of systemic toxicants and carcinogens (U.S. EPA, 1986), and as such may be applied for establishing concentration limits for drinking water contaminant mixtures, with the understanding that potential interactions are not accounted for in this process. These approaches cannot be used when the unit risk (for carcinogens) and concentration limits (for systemic toxicants) have not been established for the individual chemicals that constitute the mixture. Toxic Equivalency Factor When the components of a mixture are congeners or isomers of a chemical, the toxic equivalency factor (TEF) approach may be applied. The TEF is the ratio of the potency of a given isomer to the ‘‘signature or reference’’ isomer in a particular assay (Safe, 1990). This procedure converts all isomers into equivalents of the most potent isomer, sums them to get an equivalent total dose in terms of the most potent isomer, and uses the dose–response data for this isomer to yield estimates of potential risk for the mixture. The data re-

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quired for this approach include the TEFs for all mixture components and in vivo dose–response data for the reference isomer. The TEF approach is conceptually similar to the dose-addition approach, except that only the exposure concentration (expressed as equivalents of reference isomer) and concentration limit for the most active mixture component are used. The TEF approach also assumes absence of interactions among the isomers/congeners. This is of particular concern given the fact that isomeric forms may compete for metabolism and receptor-binding sites, thus potentially leading to interactive effects (e.g., Rao and Unger, 1995). The TEF approach could be applicable for regulating drinking water contaminant mixtures when there is appropriate dose-response and mechanistic data (Putzrath, 1997), and convincing evidence to suggest the absence of adverse toxicological interactions among the isomers at relevant concentrations. INTERACTIONS-BASED RISK ASSESSMENT APPROACHES

The fundamental concern with both the whole-mixture-based and component-based risk assessment methods is their inability to explicitly account for the potential occurrence of toxic interactions among components. It is common knowledge that chemicals may interact with each other, resulting in altered toxic responses (Krishnan and Brodeur, 1991). Despite reports of the occurrence of several supraadditive toxicological interactions in animals and humans (Krishnan and Brodeur, 1991, 1994), a risk assessment methodology that permits the quantitative consideration of the interactions among components of chemical mixtures does not exist. A scientifically sound risk assessment procedure for chemical mixtures should consider the potential modulation of the dose–response curves of components present in a mixture. To date, two EPA offices (Environmental Criteria and Assessment Office (ECAO) and Office of Pollution Prevention and Toxics (OPPT)) have attempted to develop methods for considering the available data on binary chemical interactions in the mixture risk assessment process. Whereas the ECAO team developed an interaction matrix method for use with systemic toxicants (Mumtaz and Durkin, 1993), the OPPT group has developed an interaction-weighting ratio method for carcinogens (Woo et al., 1994). The methodological details, advantages and limitations of these empirical approaches can be found elsewhere (Mumtaz and Durkin, 1993; Woo et al., 1994; Krishnan and Paterson, 1997). These approaches can generate index values that are greater or less than those generated by the default approaches (dose addition/response addition). Due to the incomplete consideration of interactions (with no quantitative evaluation of the dose-, species-, and route-dependency), these methods are likely to generate risk

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estimates (quantitatively different from those obtained with simple dose-/response-addition methods) that may not be representative of the actual risks. Further, the fact that only binary and not higher-order interactions are considered suggests that these approaches, in their present form, are unlikely to be of use in developing defensible concentration limits for chemical mixtures. The critical extrapolations (high dose to low dose, route to route, rodents to humans, binary to multichemical mixtures) essential for considering data on chemical interactions within the mixture risk assessment process can be conducted using mechanism-based models. A potentially useful approach in this context is physiologically based modeling. The physiological model is a scientifically sound, mechanistic tool that is increasingly finding use in health risk assessment procedures for the conduct of extrapolations of the uptake, metabolism, tissue dose, receptor interaction, and tissue responses in laboratory animals and humans. Due to the very nature of this modeling framework, the biokinetics and effects of multiple chemicals within the organism and their interactions (toxicokinetic/toxicodynamic) can be simulated as long as the user has the knowledge of plausible/proven mechanisms. Recently, Tardif et al. (1997) demonstrated the feasibility of predicting the change in toxicokinetics of the components of complex mixtures solely by incorporating mechanistic data on binary interactions within physiological models. This modeling approach provides a basis for predicting the change in toxicological outcome during combined exposure to chemicals. However, for achieving this ultimate objective, we require information on both (i) the mechanisms of all plausible binary interactions involving components of a mixture, and (ii) the toxic moieties of each of the mixture components. Once the quantitative relationship between the incidence of an adverse effect and the tissue dose of the toxic moiety is established, by simulating the change in tissue dose of the toxic moiety during combined exposures, the ensuing change in toxicity can be predicted. Due to the mechanistic basis, this approach also allows the species, route, dose, and scenario extrapolations of the interactions to determine the threshold of interactions, and the extent of interactions when they are anticipated to occur in humans (Krishnan and Pelekis, 1995; Tardif et al., 1995, 1997; Pelekis and Krishnan, 1997). The risk estimates for mixtures, obtained using the physiological modeling approach, may be greater or less than those obtained based on individual chemicals, depending upon the outcome of the interactions among mixture components. The impact of spatial and temporal variations in the concentrations of mixture constituents can be examined by simulation with validated models, during the establishment and implementation of limits for drinking water contaminants. The limitations of this method include the need for physiologically based pharmacokinetic models for individual chemi-

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cals, knowledge of plausible/proven mechanisms of binary chemical interactions in a mixture, and the uncertainty associated with model parameters. These aspects have been addressed recently by Krewski et al. (1995), Poulin and Krishnan (1996, 1997), Pelekis and Krishnan (1997), and Pelekis et al. (1997). Even though the current efforts focus on pharmacokinetic interaction mechanisms, the pharmacodynamic interactions can also be modeled in this framework if sufficient data are available. In summary, among the existing mixture risk assessment methods, the components-based and interactionsbased approaches could be applicable to drinking water contaminants. Specifically, among the componentsbased approaches, the dose-addition, response-addition, and the TEF approaches are the most applicable ones for drinking water contaminants. Until an interactions-based mechanistic risk assessment method (e.g., physiological model-based approach) becomes validated and available for routine use, there is no choice but to use the components-based approaches as a default. The application of these methods is appropriate only when the absence of significant interactions among the components at the human exposure level is demonstrated or assumed. The extent to which this might be true with the various chemical mixtures is not known. The preferred strategy should be to develop a feasible, mechanistic modeling approach since it could allow us to quantitatively account for the occurrence of interactions and variability of mixture composition, when deriving drinking water limits. Typical chemical mixtures of immediate concern for guideline development are the DBPs. The following section considers the potential strategies for the assessment of DBP mixtures using the various approaches discussed above. STRATEGIES FOR THE RISK ASSESSMENT OF DBP MIXTURES

In the context of health risk assessment of DBPs, there is a need to consider the risks due to a wide range of compounds occurring in a multitude of combinations in treated water supplies. Even though there have been some recent regulatory initiatives and new data on several families of compounds, the traditional risk assessment processes as followed by many regulatory agencies have emphasized the THMs as the DBPs of greatest concern. The simplest mixture-based approach would be to consider only the mixture constituent (i.e., chloroform) that is assumed/proven to be qualitatively and quantitatively important, as per the past approaches followed by Health Canada and the U.S. EPA. Qualitative importance arises from the possibility that chloroform is responsible for most of the activity/toxicity of the mixture, and quantitative importance is associated with

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the fact that this constituent is found in greatest concentrations. The logical alternative to the use of the indicator chemical method would be to consider dose/response additivity. Here, the potential risks associated with all mixture components are accounted for, assuming the absence of interactions among them, as has been recommended by the WHO for those jurisdictions wishing to establish a combined THM guideline (WHO, 1993). However, the ideal methodology should not only account for the risk due to all THMs, HAAs, and other critical DBPs but also the result of potential interactions among them. Unfortunately, (i) potential interactions among THMs are only beginning to be investigated (Keegan et al., 1997), (ii) limited data are available on the interactions between HAAs and THMs (Davis, 1992), and (iii) there are no data available on the potential interactions involving other DBPs in drinking water. Since the physiological modeling approach has been shown to be able to predict consequences in complex mixtures based only on data from binary chemical interactions (Krishnan and Pelekis, 1995; Tardif et al., 1997), it may be worthwhile to evaluate the possible interactions, for example, among THMs and HAAs, and their influence on the risk estimates using this approach. A suggested working strategy for the development of physiological modeling approach to the assessment of DBP mixtures would involve: (1) the construction of dose–response curves for each of the principal components of DBP mixtures based on relevant tissuedose surrogates (using PBPK models), (2) a study of the potential metabolic interactions between THMs, and between THMs and HAAs, and their effect on the modulation of the tissue-dose surrogates in animals and humans, and (3) use of these data to estimate quantitative risk for human exposure to these chemicals present as a mixture, by computer simulation. This integrated approach would indicate the exposure concentrations of each chemical (in comparison to its drinking water guideline), at which significant interactions can be anticipated to occur during mixed exposures. Finally, the potential impact of temporal and spatial variations in the concentrations of one or more THMs and HAAs in the mixture on the predicted risk estimates can be evaluated by Monte Carlo simulation. Such an approach would be a useful first step toward establishing the combined risks associated with commonly occurring mixtures in drinking water. Progress along these lines should facilitate a more realistic assessment of risk due to drinking water contaminants without increasing the levels of uncertainty in risk estimates above those associated with existing single-chemical methods. REFERENCES Bull, R. J., Birnbaum, L. S., Cantor, K. P., Rose, J. B., Butterworth, B. E., Pegram, R., and Tuomisto, J. (1995). Water chlorination:

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Essential process or cancer hazard? Fundam. Appl. Toxicol. 28, 155–166. Davis, M. F. (1992). Dichloroacetic acid and trichloroacetic acid increase chloroform toxicity. J. Toxicol. Environ. Health 37, 139– 148. Department of National Health and Welfare (1969). Canadian Drinking Water Standards and Objectives 1968. Department of National Health and Welfare, Ottawa. Health Canada (1993). Guidelines for Canadian Drinking Water Quality. Supporting Documentation, Part II, Trihalomethanes. Environmental Health Directorate, Ottawa. Health Canada (1994). Canadian Environmental Protection Act. Human Health Risk Assessment for Priority Substances. DSS Catalogue No. En40-215/41E, Supply and Services Canada, Ottawa. Health Canada (1995). Guidelines for Canadian Drinking Water Quality. Supporting Documentation, Part I, Approach to the Derivation of Drinking Water Guidelines. Environmental Health Directorate, Ottawa. Health Canada (1996). Guidelines for Canadian Drinking Water Quality, 6th ed. H48-10/1996E, Canada Communication Group— Publishing, Ottawa. [Prepared by the Federal–Provincial Subcommittee on Drinking Water of the Federal–Provincial Committee on Environmental and Occupational Health.] Keegan, T. E., Pegram, P. A., and Simmons, J. E. (1997). Assessment of the hepatotoxic interaction between chloroform and bromodichloromethane by dose addition and response addition. Fundam. Appl. Toxicol. 36(Suppl.), 153. Krewski, D., Gaylor, D., and Szyskowicz, M. (1991). A model-free approach to low dose extrapolation. Environ. Health Perspect. 90, 279–285. Krewski, D., Yang, W., Bartlett, S., and Krishnan, K. (1995). Uncertainty, sensitivity and variability analyses in physiological pharmacokinetic models. J. Biopharm. Stat. 5, 245–271. Krishnan, K., and Brodeur, J. (1991). Toxicological consequences of combined exposure to environmental pollutants. Arch. Complex Environ. Stud. 3(3), 1–106. Krishnan, K., and Brodeur, J. (1994). Toxic interactions among solvents and environmental pollutants: Corroborating laboratory observations with human experience. Environ. Health Perspect. 102(Suppl. 9), 11–17. Krishnan, K., and Pelekis, M. (1995). Hematotoxic interactions: Occurrence, mechanisms and predictability. Toxicology 105, 355– 364. Krishnan, K., and Paterson, J. (1997). Methods for the health risk assessment of chemical mixtures. (submitted). Lewtas, J., Nesnow, S., and Albert, Re. (1993). A comparative potency method for cancer risk assessment: Clarification of the rationale, theoretical basis, and application to diesel particulate emissions. Risk Anal. 3, 133–137. Mumtaz, M. M., Sipes, I. G., Clewell, H. J., and Yang, R. S. H. (1993). Risk assessment of chemical mixtures: Biological and toxicological issues. Fundam. Appl. Toxicol. 21, 258–269. Mumtaz, M. M., and Durkin, P. R. (1993). A weight-of-evidence scheme for assessing interactions in chemical mixtures. Toxicol. Ind. Health 8, 377–406. Pelekis, M., Krewski, D., and Krishnan, K. (1997). Physiologicallybased algebraic expressions for predicting steady-state toxicokinetics of inhaled vapors. Toxicol. Methods, (in press). Pelekis, M. L., and Krishnan, K. (1997). Assessing the relevance of rodent data on chemical interactions for health risk assessment purposes: A case study with dichloromethane–toluene mixtures. Regul. Toxicol. Pharmacol. 25, 79–86. Poulin, P., and Krishnan, K. (1996). Molecular structure based prediction of partition coefficients of organic chemicals for physiological pharmacokinetic models. Toxicol. Methods 6, 117–137.

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DRINKING WATER GUIDELINES FOR CHEMICAL MIXTURES Poulin, P., and Krishnan, K. (1997). Molecular structure-based modeling of the pharmacokinetics of highly metabolized chemicals. Fundam. Appl. Toxicol. 36(Suppl.), 28. Pourmoghaddas, H., Stevens, A. A., Kinman, R. N., Dressman, R. C., Moore, L. A., and Ireland, J. C. (1993). Effect of bromide ion on formation of HAAs during chlorination. Am. Water Works Assoc. J. 85(1), 82–87. Putzrath, R.M. (1997). Estimating relative potency for receptor-mediated toxicity: Reevaluating the toxic equivalency factor model. Regul. Toxicol. Pharmacol. 25, 68–78. Rao, V. R., and Unger, A. (1995). Development of a risk assessment model for mixtures of dioxin congeners based on their competitive binding to the Ah receptor. Environ. Carcinog. Ecotoxicol. Rev. C13, 53–74. Safe, S. (1990). Polychlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans and related compounds: Environmental and mechanistic considerations which support the development of toxic equivalency factors (TEFs). CRC Crit. Rev. Toxicol. 21, 51–88. Schoeny, R. S., and Margosches, E. (1989). Evaluating comparative potencies: Developing approaches to risk assessment of chemical mixtures. Toxicol. Ind. Health 5, 825–837. Seed, J., Brown, R. P., Olin, S. S., and Foran, J. A. (1995). Chemical mixtures; current risk assessment methodologies and future directions. Regul. Toxicol. Pharmacol. 22, 76–94. Summers, R. S., Benz, M. A., Shukairy, H. M., and Cummings, L. (1993). Effect of separation processes on the formation of brominated THMs. Am. Water Works Assoc. J. 85, 88–95. Symons, S. M., Krasner, S. W., Simms, L. A., and Sclimenti, M. (1993). Measurement of THM and precursor concentrations revisited: The effect of bromide ion. Am. Water Works Assoc. J. 85, 51– 62.

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Tardif, R., Lapare´, S., Charest-Tardif, G., Brodeur, J., and Krishnan, K. (1995). Physiologically-based modeling of the toxicokinetic interaction between toluene and xylene in humans. Risk Anal. 15, 335–342. Tardif, R., Charest-Tardif, G., Brodeur, J., and Krishnan, K. (1997). Physiologically based pharmacokinetic modeling of a ternary mixture of alkyl benzenes in rats and humans. Toxicol. Appl. Pharmacol. 144, 120–134. U.S. Environmental Protection Agency (U.S. EPA) (1986). Guidelines for Health Risk Assessment of Chemical Mixtures. Fed. Regist. 51, 34014–34025. U.S. Environmental Protection Agency (U.S. EPA) (1994a). Final Draft for the drinking water criteria document on chlorinated acids/aldehydes/ketones/alcohols, March 31, 1994. U.S. EPA, Washington, DC. [Prepared by Clement International Corporation for Health and Ecological Criteria Division, Office of Science and Technology, Office of Water.] U.S. Environmental Protection Agency (U.S. EPA) (1994b). National primary drinking water regulations: Disinfections and disinfectant byproducts: Propose rule (40 CFR Parts 141 and 142). Fed. Regist. 59, 38668. Williams, D. T., Lebel, G. L., and Benoit, F. M. (1997). Disinfection by-products in Canadian Drinking Water. Chemosphere 34, 299– 316. Woo, Y. T., Di Carlo, J., Arcos, J. C., Argus, M. F., Polansky, G., and Dubose, J. (1994). Assessment of carcinogenic hazard of chemical mixtures through analysis of binary chemical interaction data. Environ. Health Perspect. 102(Suppl. 9), 113–118. World Health Organization (WHO). (1993). Guidelines for DrinkingWater Quality, 2nd ed, Vol. 1, Recommendations. World Health Organization, Geneva.

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