5
Health-Effect Studies of Reuse Systems

While there is a general lack of toxicological and epidemiological data regarding potable reuse (see Chapter 4), a handful of such studies have specifically explored the public health implications of direct and indirect potable reuse. This chapter reviews six such health-effect studies conducted at operational or proposed planned potable reuse projects. Table 5-1 summarizes information from these studies. Most of the studies sought to analyze and compare the toxicological properties of reclaimed water to those of the current drinking water supply.

Windhoek is the only city in the world that has implemented direct potable reuse. The facility has operated since 1968 and has been the subject of epidemiological studies. In Denver, Colorado, direct reuse was studied extensively from about 1968 to 1992, but not adopted. In a related vein, a U.S. Army Corps of Engineers study was conducted in the early 1980s to assess the feasibility of using the wastewater-contaminated Potomac Estuary as a potential drinking water source for Washington, D.C. San Diego, California, and Tampa, Florida, have both conducted feasibility studies on adding reclaimed water to their surface water supplies and are moving toward implementation. Finally, California's Orange and Los Angeles counties, which have had operational indirect potable reuse systems in place for over 30 years, conducted a series of studies from 1975 to 1987 on the health effects of ground water recharge using reclaimed water.



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--> 5 Health-Effect Studies of Reuse Systems While there is a general lack of toxicological and epidemiological data regarding potable reuse (see Chapter 4), a handful of such studies have specifically explored the public health implications of direct and indirect potable reuse. This chapter reviews six such health-effect studies conducted at operational or proposed planned potable reuse projects. Table 5-1 summarizes information from these studies. Most of the studies sought to analyze and compare the toxicological properties of reclaimed water to those of the current drinking water supply. Windhoek is the only city in the world that has implemented direct potable reuse. The facility has operated since 1968 and has been the subject of epidemiological studies. In Denver, Colorado, direct reuse was studied extensively from about 1968 to 1992, but not adopted. In a related vein, a U.S. Army Corps of Engineers study was conducted in the early 1980s to assess the feasibility of using the wastewater-contaminated Potomac Estuary as a potential drinking water source for Washington, D.C. San Diego, California, and Tampa, Florida, have both conducted feasibility studies on adding reclaimed water to their surface water supplies and are moving toward implementation. Finally, California's Orange and Los Angeles counties, which have had operational indirect potable reuse systems in place for over 30 years, conducted a series of studies from 1975 to 1987 on the health effects of ground water recharge using reclaimed water.

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--> Toxicology Studies The studies conducted at the six projects varied from simple two-test studies to more comprehensive evaluations. The studies and their main findings are described briefly below; Table 5-1 provides further details. Potomac Estuary Experimental Water Treatment Plant In 1980, the U.S. Army Corps of Engineers began a two-year testing program of the Potomac Estuary Experimental Water Treatment Plant (EEWTP). Influent to the EEWTP was a 1:1 blend of estuary water and nitrified secondary effluent from the Blue Plains Wastewater Treatment Plant, which treats municipal wastewater from Washington, D.C. The blended water received further treatment by aeration, coagulation, flocculation, sedimentation, pre-disinfection, filtration, carbon adsorption, and post-disinfection. Short-term in vitro tests (specifically, the Ames Salmonella/microsome test and a mammalian cell transformation test) were run on the EEWTP's blended influent, its effluent, and product water from three local conventional water treatment plants. For the toxicological parameters measured, the study found the EEWTP product water comparable to the finished waters from the local water treatment plants (James M. Montgomery, 1983). However, a National Research Council review panel (NRC, 1984) did not concur with this conclusion, because of the limited toxicological tests that were conducted. Orange and Los Angeles Counties Health-Effect Study The only toxicological study conducted to date on an operating indirect potable reuse project was performed as part of a five-year health-effect study, initiated in 1978, that evaluated possible effects resulting from surface spreading of reclaimed water in the Montebello Forebay area of Los Angeles County, California. Since inception of the potable reuse project in 1962, reclaimed water has been blended with local storm water and river water prior to percolation. At the time of the study, reclaimed water supplied about 16 percent of the total inflow to the ground water basin. Disinfected secondary effluent was used for recharge from 1962 to 1977, at which time dual-media filtration was added to the three wastewater treatment plants producing the product water. The toxicological study sought to detect, isolate, characterize, and if possible, trace

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--> TABLE 5-1 Summary of Health-Effect Studies Evaluated Project Types of Water Studied Health-Effect Data Montebello Forebay, Los Angeles County, California (Nellor et al.,1984) Disinfected filtered secondary effluent, storm runoff, and imported river water used for replenishment; also, recovered ground water Toxicology testing: Ames Salmonella test and mammalian cell transformation assay. 10,000 to 20,000x organic concentrates used in Ames test, mammalian cell transformation assays, and subsequent chemical identification. The level of mutagenic activity (in decreasing order) was storm runoff > dry weather runoff > reclaimed water > ground water > imported water. No relation was observed between percent reclaimed water in wells and observed mutagenicity of residues isolated from wells Epidemiology: In the geographical comparison study, the population ingesting recovered water did not demonstrate any measurable adverse health effects. The household survey (women) found no elevated levels of specific illnesses or other differences in measures of general health Denver Potable Water Reuse Demonstration Project (Lauer et al., 1990) Advanced wastewater treatment (AWT) effluent (with ultrafiltration or reverse osmosis) and finished drinking water (current supply) Toxicologic testing: 150 to 500x organic residue concentrates used in 2-year in vivo chronic/carcinogenicity study in rats and mice and reproductive/teratology study in rats. No treatment-related effects observed

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--> Tampa Water Resource Recovery Project (CH2M Hill, 1993; Pereira et al., undated) AWT effluent (using GAC and ozone disinfection) and Hillsborough River water using ozone disinfection (current drinking water supply) Toxicology testing: Up to 1000x organic concentrates used in Ames Salmonella, micronucleus, and sister chromatid exchange tests in three dose levels up to 1000x concentrates. No mutagenic activity was observed in any of the samples. In vivo testing included mouse skin initiation, strain A mouse lung adenoma, 90-day subchronic assay on mice and rats, developmental toxicity study on mice and rats, and reproductive study on mice. All tests were negative, except for some fetal toxicity exhibited in rats, but not mice, for the AWT sample Total Resource Recovery Project, City of San Diego (Western Consortium for Public Health, 1996) AWT effluent (reverse osmosis and GAC) and Miramar raw reservoir water (current drinking water supply) Toxicology testing: 150-600x organic concentrates used in Ames Salmonella test, micronucleus, 6-thioguanine resistance, and mammalian cell transformation. The Ames test showed some mutagenic activity, but reclaimed water was less active than drinking water. The micronucleus test showed positive results only at the high (600x) doses for both treatments. In vivo fish biomonitoring (28-day bioaccumulation and swimming tests) showed no positive results Epidemiology: baseline reproductive health and vital statistics Neural tube defects study: No estimated health risk from chemicals identified based on use of reference doses and cancer potencies

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--> Project Types of Water Studied Health-Effect Data Potomac Estuary Experimental Wastewater Treatment Plant (James M. Montgomery, Inc.,1983) 1:1 blend of estuary water and nitrified secondary effluent, AWT effluent (filtration and GAC), and finished drinking waters from three water treatment plants (current supplies) Toxicology testing: 150x organic concentrates used in Ames Salmonella and mammalian cell transformation tests. Results showed low levels of mutagenic activity in the Ames test, with AWT water exhibiting less activity than finished drinking water. The cell transformation test showed a small number of positive samples with no difference between AWT water and finished drinking water Windhoek, South Africa (Isaacson and Sayed, 1988) AWT effluent (sand filtration, GAC) Toxicological testing: Ames test, urease enzyme activity, and bacterial growth inhibition. In vivo tests include water flea lethality and fish biomonitoring (guppy breathing rhythm) Epidemiology: Study (1976-1983) of cases of diarrheal diseases, jaundice, and deaths. No relationships to drinking water source were found. Because of Windhoek's unique environment and demographics, these results cannot be extrapolated to other populations in industrial countries NOTE: AWT = advanced wastewater treatment; GAC = granular activated carbon.

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--> the origins of previously unidentified carcinogens in the ground water's replenishment sources and well waters. The Ames test and Salmonella tester strains (TA98 and TA100) were used to screen for mutagenic organics in concentrates of reclaimed water (before it was spread), storm water, imported water, and unchlorinated and chlorinated ground water. While 13 of the 56 sample concentrates tested were free of mutagens, at least one mutagenic concentrate was found from each source. Nellor et al. (1984) reported that storm water and reclaimed water yielded the highest levels of mutagenicity, followed by well water and then imported waters. More than half of the mutagens observed appeared to derive from chlorination processes. The potency of the mutagenic responses did not appear to be related to the estimated percentages of reclaimed water at the various wells. The study also compared the mutagenicity of samples of the ground water with mutagenic responses of known compounds and found that the ground water contained low concentrations of individual mutagens. While these tests (gas chromatography-mass spectroscopy (GC-MS) methods) found four identifiable Ames mutagens (fluoranthene, benzo(a)pyrene, N-nitrosomorpholine, and N-nitropiperidine) in 6 of the 34 tested samples, Nellor et al. (1984) concluded that these compounds could not have caused the mutagenicity in all of the samples, because their frequency of occurrence, distribution in the fractions, and concentrations were not consistent with the bioassay results. Further testing by chemical derivation techniques (including negative ion chemical ionization of GC-EIMS fractions and Ames assays of ground water and replenishment water before and after derivation) suggested that epoxides, organic halides, and two classes of electrophiles may have played a part in causing the observed mutagenicity. However, the results were not conclusive because the reactive components appeared only at part-per-trillion levels. The study identified neither the structures of these compounds nor their sources. Since positive chemical identifications of specific mutagens could not be made and many of the estimated concentrations were very low, Nellor et al. concluded that the health significance of epoxides and organic halides at the levels found in the reclaimed waters remains in doubt. They stated that further characterization of the molecular structure and biological effects of the large numbers of apparently mutagenic halogenated organic compounds in the various waters would be necessary to confirm whether those materials pose any health risk. Denver Potable Reuse Demonstration Project The 3.8 x 103 m3/day (1.0 million gallons per day (mgd)) Potable

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--> Water Reuse Demonstration Plant in Denver, Colorado, began operations in 1984. The product water was treated by secondary treatment via biological oxidation, high-pH lime treatment, recarbonation, filtration, ultraviolet radiation, granular activated-carbon adsorption, reverse osmosis, air stripping, ozonation, and chloramination. A small ultrafiltration unit was evaluated as a possible replacement for reverse osmosis. The health-effect studies, serving as a backup to analytical water quality monitoring, were implemented in the project's second year. They sought to evaluate the safety of the resulting product water compared to Denver's current drinking water, which comes from the Foothills Water Treatment Plant (Lauer, 1993). The studies incorporated acute toxicity testing, reproductive and teratogenic effects testing, subchronic toxicity testing, and chronic effects testing on animals. The studies found that the quality of reclaimed water from the Denver Potable Reuse Demonstration Plant equaled or exceeded that of the existing drinking water supply and that it exceeded all federal and state standards for definable constituents (Lauer and Rogers, 1996). In addition, a two-year chronic toxicity/carcinogenicity study, which gave concentrated doses of organic samples to more than 1500 rats over two generations, revealed no toxicologic, carcinogenic, reproductive, or developmental effects. San Diego Total Resources Recovery Project The City of San Diego, California, imports virtually all of its water from other parts of the state, and current supplies are projected to be insufficient to meet future demands. San Diego investigated indirect potable reuse as one measure to help alleviate water shortages in the future. The San Diego Total Resources Recovery Project developed a series of pilot treatment facilities that included primary treatment by rotary disk filter, a 1.9 x 103 m3/day (0.5 mgd) water hyacinth secondary treatment facility, and 190 m3/day (0.05 mgd) advanced wastewater treatment (AWT) facilities. The AWT treatment train included coagulant addition, filtration, disinfection by ultraviolet radiation, reverse osmosis, air stripping via an aeration tower, and granular activated-carbon adsorption. A health-effect study (Western Consortium for Public Health, 1992) compared the reclaimed water quality and its health risks to those of the city's current raw water supply from the Miramar reservoir. The study used four types of bioassay systems to evaluate genetic toxicity and potential cancer-causing effects. The tests used included the Ames test, the micronucleus test, the 6-thioguanine resistance assay, and the mammalian cell transformation assay. Forty-eight water samples collected be-

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--> tween February 1988 and June 1990 were concentrated and then used for these various bioassay systems. In addition to the total concentrate, many of the fractions and a few of the subfractions were also tested. The Ames test, which sought to measure hereditable genetic alterations in special strains of Salmonella, was performed on 23 samples of reclaimed water and 25 samples of Miramar water. It found weak but statistically significant mutagenic activity in a number of the samples from both waters. The Miramar water samples exhibited more mutagenic activity than those from the reclaimed water. The mouse micronucleus assay, which is a short-term assay that assesses genetic damage to the bone marrow of mice exposed to concentrates, was run on seven samples of both waters. It revealed no statistically significant effect in the majority of samples from either water source until the doses of concentrates were raised to near-lethal levels, at which point a possible trend toward increased genetic damage was observed with both reclaimed water and Miramar water. An approximately threefold increase in micronuclei frequency was observed in the two high doses of reclaimed water samples, but was not confirmed by follow-up experiments. The 6-thioguanine resistance assay measures mutagenic inactivation of a certain gene (known as HGPRT) in a cell line established from hamster ovaries. It was run repeatedly on one sample each of whole concentrate from reclaimed water and Miramar water and five fractions, but showed no apparent mutagenic effect. Finally, the mammalian cell transformation assay, which measures the ability of chemicals to induce changes in a certain strain of cells (called C43H10T1/2 cells) that are injected into immunosuppressed mice, was run several times on one sample collected from each water. The Miramar sample produced a strong positive response that appeared to be dose related. However, the response was not observed in two other samples. As a result, the authors suggested that this single positive test was not significant. In sum, the study found that organic extracts from both reclaimed water and Miramar water sources did exhibit some genotoxic activity, primarily in the Ames test and to a lesser extent in the other bioassays. The activity, however, was stronger in the Miramar water than the reclaimed water. The study's authors could or did not identify the reason behind the higher activity in Miramar water; however, they speculated that the greater activity exhibited by Miramar water may reflect differences in composition of original source waters, including chlorination of Miramar water. The report concludes that, based on short-term bioassay results of organic extracts of both reclaimed water and Miramar water,

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--> reclaimed water is unlikely to be more genotoxic or mutagenic than the current raw water supply source for San Diego. Tampa Water Resource Recovery Project In the 1980s, the City of Tampa, Florida, evaluated the acceptability of using reclaimed water to augment Tampa's current water supply from the Hillsborough River. An AWT pilot treatment plant was completed in 1986 and operated from January 1987 through June 1989. Toxicological testing of concentrates was completed in August 1992. Influent to the AWT pilot facility consisted of treated wastewater from the Hookers Point Wastewater Treatment Facility, which provided secondary treatment, filtration, and denitrification. The pilot plant influent was withdrawn prior to disinfection to reduce the concentration of chlorinated organic compounds. The project evaluated four different unit process trains. All of the process trains included preaeration, high-pH lime treatment, recarbonation, gravity filtration, and disinfection with ozone. Three of the trains also included organic removal processes that differed only in selection of the unit process added between gravity filtration and disinfection; one train added granular activated carbon (GAC), one train added reverse osmosis, and one train added ultrafiltration. The pilot plant was originally operated using chlorine as the disinfectant, but results of Ames testing indicated that ozone-disinfected product waters were less mutagenic than chlorine-disinfected product waters. For similar reasons, the treatment train using GAC was selected for toxicological testing based on preliminary screening using the Ames assay. The Hillsborough River water was disinfected with ozone prior to analysis to make it more analogous to the AWT pilot plant product water. Concentrated extracts from both the Hillsborough River water and the reclaimed water were used to create doses for toxicological testing at up to 1000 times the potential human exposure of a 70 kg (154-pound) person consuming 2 liters of water per day. Toxicological tests evaluated mutagenicity, genotoxicity, subchronic toxicity, reproductive effects, and teratogenicity. Four concentrate samples from each of the two waters were tested extensively for mutagenic activity. In all, eight toxicological studies were conducted on the reclaimed water and ozone-disinfected Hillsborough River reference water. These tests evaluated potential genotoxic effects (Ames and sister chromatid assays), carcinogenicity (strain A lung adenoma and SENCAR mice initiation-promotion studies), fetotoxicity (teratology in rats and reproductive effects in mice), and subchronic toxicity (90-day gavage studies in mice and rats). The results were reported

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--> to be uniformly negative for the product water from the AWT pilot plant (Hemmer et al., 1994). Evaluation of Toxicology Studies Do we have sufficient data to indicate that reclaimed wastewater can be reliably used as a source of drinking water? To answer this question, the results of the toxicological studies described above must be examined against the ''decision logic" for which the assay systems they used were designed. Important differences exist among the available toxicological studies regarding the intent and extent of toxicological testing done. The studies fall into three categories: screening and identification studies, surveys of mutagenic activity, and integrated toxicological testing. While several of the studies fit more than one of these categories, it is important to highlight the differences in philosophical approach that these categories represent. Screening and Identification Studies As described in more detail in Chapter 4, screening and identification studies seek to identify specific chemicals in the water sample that could present a hazard to health. This approach is an alternative to exhaustive chemical analyses. The approach does not attempt to measure risk or to be a comprehensive test of potential health effects. Rather, it seeks to identify compounds that could pose major problems at low doses (i.e., potential genotoxic carcinogens). Such an approach assumes that the risks posed by any compounds so identified will receive additional study, either through the literature or by more complete characterization of their toxic effects in systems that would provide an acceptable basis for estimating risk. This use of bioassays for screening is well accepted in the scientific community. Bioassays have been used in most of the world's extensive studies of drinking water, leading to the identification of numerous highly mutagenic chemicals produced in the chlorination of drinking water (Bull and Kopfler, 1991). These chemicals are now receiving the toxicological evaluations they warrant (Bull et al., 1995). The higher-level toxicological evaluations indicate that these chemicals are less important as potential carcinogens than would be anticipated from their mutagenic potency (ILSI, 1995). They present no greater a carcinogenic

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--> risk than do several nonmutagenic compounds, such as dichloroacetate, that are produced at much higher concentrations in chlorinated drinking water (ILSI, 1995). The water reclamation projects reviewed here very rarely took the approach of screening with bioassays and then applying more detailed toxicological evaluations. In fact, this approach was applied only to one aspect of the health-effect study conducted by Orange and Los Angeles Counties (OLAC) (Baird et al., 1980, 1987; Jacks et al., 1983). The bulk of this OLAC work was performed using the Salmonella/microsome assay. The first efforts were directed at simply identifying the relative mutagenic activity of chemicals that could be isolated from differing source waters. Certain of the more mutagenic waters were then fractionated and studied in more detail. While the approach met with some modest success, the mutagenic activity of the fractions was greater than could be accounted for by known mutagens. Part of the discrepancy was probably caused by the reliance on gas chromatography-mass spectrometry (GCMS) as the analytical tool, because most of the chemicals in water, including some that are potent mutagens, cannot be measured with GC-MS. The OLAC study also attempted to use derivatization methods (which use a second chemical to react with and thus detect the target chemical) to detect certain chemical targets (Baird et al., 1987; Jacks et al., 1983). While this test produced some significant modifications of mutagenic activity in some water samples, it revealed no consistent pattern of mutagen reduction. This suggests that the chemicals present in different waters may be of different characters. It is of interest to contrast the inconclusive nature of the OLAC study's results with the progress that has been made in drinking water chlorination. The initial studies of mutagenicity in drinking waters around the world first traced mutagenicity to the process of chlorination; the major mutagenic activity was found to be associated with a very potent mutagen referred to as MX (Meier et al., 1987), which is produced in chlorination. The whole-animal carcinogenesis testing of this chemical recently ended and concluded that MX induces tumors (Tuomisto et al., 1995). However, a recent workshop (ILSI, 1995) focused on the toxicology data for MX and concluded that MX is probably not a major contributor to cancer via drinking water because it is found at extremely low levels in chlorinated drinking waters. Surveys of Mutagenic Activity Other studies used the Salmonella/microsome assay and other tests to simply compare reclaimed wastewater to other drinking water sources.

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--> nificantly higher congenital malformations were observed in one of the control areas. The investigators did not comment on these findings. In the second study, no consistent dose-response relationship was seen between exposure to reclaimed water and illness rates. The incidence of liver cancer was significantly higher (rate ratio = 1.7, 95 percent confidence interval = 1.1-2.7) in the study area that received the highest percentage of reclaimed water. However, no consistent dose-response relationship was observed in liver cancer incidence in the four other study areas that received lower percentages of reclaimed water. The incidence of stomach cancer and all cancers in the two study areas with the least reclaimed water was slightly higher than the rates of those illnesses in the control areas. Mortality from all cancers and from several specific cancers (liver, rectum, stomach, and kidney) was higher in reclaimed water areas compared to the control areas (rate ratios ranging from 1.12 to 1.71). However, most of these rate ratios were not statistically significant, did not show a consistent dose-response relationship, and showed very small magnitudes of differences between the experimental and control groups. The incidence of giardiasis, hepatitis A, and shigellosis was significantly higher in two study areas receiving low to medium percentages of reclaimed water. The infectious disease incidence rates in the study areas with the highest percentages of reclaimed water were either lower than the control areas or only slightly elevated. In both studies, some significantly higher disease and/or mortality rates were observed both in some of the study areas that received reclaimed water and in some of the control areas. In their final interpretation of these results, the investigators considered the overall pattern of the results and whether the association between an exposure and a particular health outcome indicated a causal relationship, using commonly recognized criteria for causality (strength of the relationship, consistency, temporality, biologic gradient or dose-response, plausibility, and coherence). The absence of consistent dose-response relationships for all the elevated health outcomes that were observed in the study was the major argument against a causal association between exposure to reclaimed water and adverse health effects. The investigators concluded that the statistically significant associations that were observed occurred either due to chance, because of the large number of rate ratios that were calculated in the analyses, or due to differences between the exposed and control populations unrelated to the use of reclaimed water. The ecologic study design does not allow investigation of these differences. Examination of the demographic characteristics of the study populations in the second study (from 1990 census information) indicates some differences among groups in ethnicity, education levels, and percentage employed in white-collar occupations. These demographic differences

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--> may affect risk factors for both chronic and acute diseases. The data analyses controlled for age, sex, and ethnicity differences between the reclaimed water areas and the control areas. Strengths and Limitations The major strengths of the OLAC studies are that they had large study populations and examined a large number or health outcomes. These are important features because one would expect the risks associated with reclaimed water exposure, if any, to be low, requiring a large study population to detect them. Also, the possible health risks associated with reclaimed water are undefined and might include both acute and chronic effects from microbial and chemical contaminants. Therefore it is advantageous to examine a broad array of health effects in a single study. The only health outcomes that were not included in these studies were reproductive outcomes (spontaneous abortions, birth defects, and infant mortality), which could be influenced by both acute and chronic exposures to contaminants in drinking water. One additional strength of the second study was that it could examine health effects that may be associated with long-term exposure or historical exposure to reclaimed water, since by the time the study was completed, reclaimed water had been used for about 30 years. Because of the nature of the ecologic study design, both studies were unable to control for personal characteristics that might affect disease rates, such as smoking, diet, alcohol consumption, and occupational exposure. Ecologic studies assume that the study groups are roughly equivalent in all possible risk factors (except for the exposure of interest) for the health outcomes in question. These studies also assume that the exposure of interest will have the same effect on all the study groups (that is, that there will be no effect modification by group) (Sloss et al., 1996). The investigators note that while the quality of the cancer incidence data used in these studies was high (due to a high-quality cancer registry), the quality of the mortality and infectious disease rate data was less than ideal (Sloss et al., 1996). Death certificates may not accurately record the cause of death or place of residence at time of death. The infectious disease surveillance by the Los Angeles County Department of Health Services may not report all diseases with the same accuracy. However, the quality of the health outcome data should be similar for both the exposed and the control populations. Despite the large study populations in these studies, both the number of cancer illnesses over four years and the number of deaths from specific cancers over two years were very low compared to national aver-

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--> ages. This is probably due to the relatively short study periods for these kinds of chronic diseases. Rectal cancer rates were particularly low, with only 36 deaths in the exposed populations and 21 deaths in the control areas from 1989 to 1991. For bladder cancer, there were only 48 deaths in the reclaimed water study areas and 35 deaths in the control areas. Therefore, in this study the risks associated with exposure to reclaimed water cannot be adequately evaluated for several important health outcomes because of the small number of events. Although the overall analyses do not suggest an association between adverse outcomes and reclaimed water in the drinking water supply, the public health significance of no or low rates of incidence, especially for specific outcomes, should always be interpreted in light of the statistical power of a study to detect an elevated risk. This caveat was not mentioned by the investigators. The OLAC studies used a state-of-the-art model based on hydrogeologic and statistical theory to estimate the proportion of reclaimed water in the ground water at various times and locations. Attempts were made to compare estimates derived from the model with levels of constituents actually measured in the water. This model makes several assumptions and may have introduced an unknown amount of measurement error into the exposure estimates. In addition, the broad exposure categories used in these studies may not have been sufficiently different to show a clear dose-response relationship even if one was present. The studies were also unable to estimate actual exposure to reclaimed water based on personal differences in time spent away from home, consumption of bottled water and other beverages, and time lived in study area. The 1980 household survey in the first study indicated that 28 percent of respondents reported buying bottled water and 23 percent reported not drinking tap water (Frerichs, 1984). Given nationwide trends toward increased bottled water consumption during the 1980s, it is likely that the percentage of households using bottled water was higher in the second study. Areas with highly mobile populations present difficulties in assessing long-term health risks. Data on population mobility in the "high reclaimed water" areas from the first study indicated that 40 percent of the population had lived in the same house for less than five years, and this was the most stable population of the four study areas (Frerichs et al., 1982). In the second study, the percentage of persons who had lived in the same house for less than five years ranged from 41 to 53 percent. Although the role of environmental exposures in the development of diseases with long latency periods (such as cancer) is a complex issue, it seems likely that 50 percent or more of the "exposed" study population would not have been exposed to reclaimed water long enough for reclaimed water to have an effect on cancer morbidity and mortality, since

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--> the minimum latency period for many cancers is believed to be about 15 years. The investigators acknowledged that exposure misclassification of people who recently moved into the study area would weaken the estimates of the effect of exposure on diseases with long latency periods (Sloss et al., 1996). Further, out-migration of ''exposed" persons who had lived in the reclaimed water areas for long periods of time would reduce the statistical power of the study. San Diego Feasibility Study A pilot feasibility epidemiology study was conducted as a component of the San Diego Total Resource Recovery Project. The study sought to provide baseline health information on the residents of San Diego County that could be compared to future epidemiologic monitoring of health effects if potable reuse was adopted. This study also evaluated the feasibility, logistics, and cost of collecting various health data. Reproductive health and vital statistics (mortality and selected morbidity) were chosen by the investigators as "biological conditions that offer the most potential as environmental warning systems for environmental contamination" (Western Consortium for Public Health, 1996). Study Design The first element of this study was a survey of reproductive outcomes of women aged 15 to 44 in San Diego County. Telephone interviews were used to screen 19,504 residents for women eligible to participate in the reproductive health survey. From these interviews, approximately 1100 women were interviewed in their homes to collect demographic and health information: age, area of residence, self-perceived health, employment, height and weight, smoking exposures, alcohol consumption, diseases reported, income, ethnicity, and marital status. In addition, data pertaining to pregnancies were collected: weight gained, prenatal care, nausea, exposure to medication, diseases reported, duration, and pregnancy outcome. The second element involved the collection of existing vital and health data routinely reported to San Diego County and the State of California. This included broad and specific mortality data, information on birth outcomes, and incidence of "various potential waterborne diseases" from 1980 through 1989. The third element was a survey of neural tube birth defects using the California Birth Cohort Perinatal Files data from 1978 through 1985. The purpose of this survey was to establish baseline birth defects prevalence information in California as a whole and in San Diego County.

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--> Study Findings This epidemiologic feasibility study was a useful tool to evaluate methods for conducting further epidemiologic research in this field. The investigators concluded that while the vital statistics element was the least expensive component, it did not provide the necessary "precision in terms of data quality to address the health effects of wastewater recycling" (Western Consortium for Public Health, 1996). Instead, they recommended continuation of the neural tube defects study as the most cost-effective and reasonable approach to compare the rate of an appropriate health outcome in San Diego with that in the rest of California. Conclusions and Recommendations Toxicology Studies All six of the planned potable reuse projects reviewed in this chapter attempted to analyze the toxicological properties of reclaimed water. In most studies the testing was limited to mutagenic activity in bacterial systems, usually including at least two strains of the bacteria in the Ames Salmonella test. Some of the studies also used in vitro systems derived from mammalian cells, usually in the form of transformation assays and short-term in vivo clastogenesis assays (i.e., sister chromatid exchanges and micronucleus assays). Two projects employed chronic studies in live mammal systems to assess chronic toxicity, carcinogenicity, reproductive effects, and the potential for such waters to produce birth defects. Overall, the intent of toxicological testing can be grouped into (1) chemical screening and identification studies, (2) surveys of mutagenic activity, and (3) integrated toxicological testing. The application of bioassays for screening and identifying chemicals that exhibit mutagenic activity, a methodology well accepted in the scientific community, was used in most of the more extensive studies. However, further toxicological evaluations are necessary in order to demonstrate whether or not the chemicals so identified have health effects. The interpretation of the results from surveys of mutagenic activity is subject to the same ambiguity identified with other studies that have depended primarily on in vitro test systems. While the studies appeared to show no differences between reclaimed water and the conventional water source, positive results were obtained in screening assays, and there was no attempt to collect data in a system that would allow a rigorous comparison of relative risks associated with these two water sources. Used alone, in vitro mutagenicity testing produces results of unclear meaning, because mutagenic activity alone does not imply carcinogenic

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--> risk to humans. A more accurate determination of health risk requires test systems that can more directly measure a complete range of health hazards and can use procedures for defining dose-response relationships to estimate the risks associated with varying levels of exposure. Such information cannot be derived from in vitro testing alone. Of the toxicological studies, only the Denver and Tampa studies addressed a broad range of toxicological concerns. Those studies suggested that no adverse health effects should be anticipated from the use of Denver's or Tampa's reclaimed water as a source of potable drinking water. However, these studies, drawn from two discrete points in time and conducted only at a pilot plant level of effort, provide a very limited database from which to extrapolate to other locations and times. Because of the high cost and methodological problems inherent in the testing of concentrated samples on rats and mice and because of the difficulty in applying the logic of safety testing to reclaimed water, the strategy set forth by the 1982 National Research Council panel is potentially too costly to implement and will not resolve health-effect questions in a timely manner for an operational potable reuse system. Accordingly, the committee recommends the following: A new, alternative approach, such as the fish system described in this chapter, should be developed and used to continuously test the toxicity of reclaimed water in potable reuse projects. The testing system described here should be viewed as a starting point for an approach that needs to evolve as deficiencies become apparent or as concerns with chemical contaminants focus on new health end points. It should employ a baseline screening test using a whole-animal rather than in vitro approach. The baseline screening tests should be conducted using water samples at ambient concentrations in order to reduce the uncertainty and high costs of using concentrates. The higher exposure possible with fish and the increased statistical power gained from using larger numbers of subjects will tend to offset the losses in sensitivity from not using high doses derived from concentrates. Research efforts should be undertaken to understand the qualitative and quantitative relationships among responses in whole-animal test species, such as fish, and adverse health effects in humans. In vitro short-term testing should be confined to qualitative evaluations of particular toxicological effects found in the product water in order to identify potential sources of contaminants and to guide remedial actions in a more timely manner. Such studies will probably have to employ concentration techniques. For the fish testing system or any other toxicological test system used for reclaimed water, a clear decision path should be followed in

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--> toxicological testing. Testing should be conducted on live animals for a significant period of their lifespan. If an effect is observed in the whole animal, risk should be estimated using general knowledge about the relative sensitivity of the animal and human systems. While these relationships will contain some uncertainties at the outset of testing, it should be possible to obtain refined estimates of the relative human susceptibility if the test parameters are carefully thought out beforehand. More specific research can then be initiated to improve the risk assessment. Notwithstanding the difficulties of testing unknown chemical mixtures in reclaimed water, this decision path is quite viable for investigating certain types of health outcomes or end points if the underlying basis of the response is understood (e.g., endocrine disruption). For some health outcomes, such as carcinogenesis, the mechanism is less well-understood, and it is probable that an observed effect will have to be accepted as implying an impact on human health. The alternative is to identify the specific chemical responsible for the observed effect and to reduce the risk associated with that chemical. The requirements for toxicological testing of water derived from an alternative source should be inversely related to how well the chemical composition of the water has been characterized. If very few chemicals or chemical groups of concern are present, and the chemical composition of the water is well understood, the need for toxicological characterization of the water is low and may be safely neglected altogether. Conversely, if a large fraction of potentially hazardous and toxicologically uncharacterized organic chemicals is present, then toxicological testing will provide an additional assurance of safety. Epidemiology Studies Numerous epidemiologic studies (ecological, case-control, cohort, and outbreak investigations) have examined the relationship between various microbial and chemical contaminants in drinking water and a wide range of acute and chronic health outcomes in populations exposed either to a specific contaminated water supply or to specific types of source waters and treatment processes. However, only three such studies apply to potable reuse of reclaimed water, and only one set of epidemiological studies (Los Angeles County) evaluating the health effects associated with the consumption of reclaimed water has been conducted in a setting that is useful for assessing possible health effects in other parts of the United States or other industrialized countries. These studies have used an ecologic approach, which is appropriate as an initial step when the health risks are unknown or poorly documented, but negative results from such studies do not necessarily prove the safety of reclaimed water

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--> for human consumption. These studies can only be considered as preliminary examinations of the risks of exposure to reclaimed water. The committee recommends that alternative epidemiologic study designs and more sophisticated methods of exposure assessment and outcome measurement be undertaken at a national level to evaluate the potential health risks associated with reclaimed water. Ecologic studies should be conducted in a variety of water reuse situations (e.g., ground water, surface water) in areas with low population mobility. Case-control studies or retrospective cohort studies should be undertaken to provide information on health outcomes and exposure for an individual level while controlling for other important risk factors. Although cohort studies are the most difficult and expensive to perform, this is the only study design that can examine the temporal relationship between exposure to reclaimed water and the development of adverse health effects. Increasing interest in and need for potable water reuse may justify such efforts. References Anders, F., M. Schartl, and A. Branekow. 1984. Xiphophorus as an in vivo model for studies on oncogenes. National Cancer Institute Monograph 65:97-109. Arnold, S. F., D. M. Klotz, B. M. Collins, P. M. Vonier, L. J. Guillette, Jr., and J. A. McLachlan. 1996a. Synergistic activation of estrogen receptor with combinations of environmental chemicals. Science 272:1489-1492. Arnold, S. F., M. K. Robinson, A. C. Notides, L. J. Guillette, Jr., and J. A. McLachlan. 1996b. A yeast estrogen screen for examining the relative exposure of cells to natural and xenoestrogens. Environ. Health Persp. 104:544-548. Ashby, J., and R. W. Tennant. 1988. Chemical structure, Salmonella mutagenicity, and extent of carcinogenesis as indicators of genotoxic carcinogenicity among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutation Research 24:17-115. Bailey, G. S., D. E. Williams, and J. D. Hendricks. 1996. Fish models for environmental carcinogenesis: the rainbow trout. Environ. Health Persp. 104:5-21. Baird, R. B., J. Gute, C. Jacks, R. Jenkins, L. Neisess, B. Scheybeler, R. van Sluis, and W. Yanko. 1980. Health effects of water reuse: a combination of toxicological and chemical methods for assessment. Pp. 925-935 in Jolley, R. L., et al. (eds.) Water Chlorination: Environmental Impact and Health Effects. Vol. 3. Ann Arbor Sci., Ann Arbor, Mich. Baird, R. B., J. P. Gute, C. A. Jacks, L. B. Neisess, J. R. Smyth, and A. S. Walker. 1987. Negative-ion chemical ionization mass spectrometry and Ames mutagenicity tests of granular activated carbon treated waste water. Pp. 641-658 in Suffet, I. H., and M. Maliayandi (eds.) Advances in Chemistry series 214. Organic Pollutants in Water: Sampling, Analysis and Toxicity Testing. Bull, R. J., and F. D. Kopfler. 1981. Toxicological evaluation of risks associated with potable reuse of wastewater. Pp. 2176-2194 in Proceedings of Water Reuse Symposium II Vol. 3, August 23-28, Washington, D.C. Denver, Colo.: American Water Works Association Research Foundation. Bull, R. J., L. S. Birnbaum, K. P. Cantor, J. B. Rose, B. E. Butterworth, R. Pegram, and J. Tuomisto. 1995. Symposium overview: water chlorination: essential process or cancer hazard. Fund. Appl. Toxicol. 28:155-166.

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