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[Federal Register: March 31, 1998 (Volume 63, Number 61)]



[Proposed Rules]               



[Page 15673-15692]



From the Federal Register Online via GPO Access [wais.access.gpo.gov]



[DOCID:fr31mr98-42]







      







[[Page 15673]]







_______________________________________________________________________







Part IV























Environmental Protection Agency























_______________________________________________________________________















40 CFR Parts 141 and 142















National Primary Drinking Water Regulations: Disinfectants and 



Disinfection Byproducts Notice of Data Availability; Proposed Rule











[[Page 15674]]















ENVIRONMENTAL PROTECTION AGENCY







40 CFR Parts 141 and 142







[WH-FRL-5988-7]







 



National Primary Drinking Water Regulations: Disinfectants and 



Disinfection Byproducts Notice of Data Availability







AGENCY: U.S. Environmental Protection Agency (USEPA).







ACTION: Notice of data availability; request for comments.







-----------------------------------------------------------------------







SUMMARY: In 1994 USEPA proposed a Stage 1 Disinfectants/Disinfection 



Byproducts Rule (D/DBP) to reduce the level of exposure from 



disinfectants and disinfection byproducts (DBPs) in drinking water 



(USEPA, 1994a). This Notice of Data Availability summarizes the 1994 



proposal and a subsequent Notice of Data Availability in 1997 (USEPA, 



1997a); describes new data that the Agency has obtained and analyses 



that have been completed since the 1997 Notice of Data Availability; 



requests comments on the regulatory implications that flow from the new 



data and analyses; and requests comments on several issues related to 



the simultaneous compliance with the Stage 1 DBP Rule and the Lead and 



Copper Rule. USEPA solicits comment on all aspects of this Notice and 



the supporting record. The Agency also solicits additional data and 



information that may be relevant to the issues discussed in the Notice.



    The Stage 1 D/DBP rule would apply to community water systems and 



nontransient noncommunity water systems that treat their water with a 



chemical disinfectant for either primary or residual treatment. In 



addition, certain requirements for chlorine dioxide would apply to 



transient noncommunity water systems because of the short-term health 



effects from high levels of chlorine dioxide.



    Key issues related to the Stage 1 D/DBP rule that are addressed in 



this Notice include the establishment of Maximum Contaminant Level 



Goals for chloroform, dichloroacetic acid, chlorite, and bromate and 



the Maximum Residual Disinfectant Level Goal for chlorine dioxide.







DATES: Comments should be postmarked or delivered by hand on or before 



April 30, 1998. Comments must be received or post-marked by midnight 



April 30, 1998.







ADDRESSES: Send written comments to DBP NODA Docket Clerk, Water Docket 



(MC-4101); U.S. Environmental Protection Agency; 401 M Street, SW., 



Washington, DC 20460. Comments may be hand-delivered to the Water 



Docket, U.S. Environmental Protection Agency; 401 M Street, SW., East 



Tower Basement, Washington, DC 20460. Comments may be submitted 



electronically to owdocket@epamail.epa.gov.







FOR FURTHER INFORMATION CONTACT: For general information contact, the 



Safe Drinking Water Hotline, Telephone (800) 426-4791. The Safe 



Drinking Water Hotline is open Monday through Friday, excluding Federal 



holidays, from 9:00 a.m. to 5:30 p.m. Eastern Time. For technical 



inquiries, contact Dr. Vicki Dellarco, Office of Science and Technology 



(MC 4304) or Mike Cox, Office of Ground Water and Drinking Water (MC 



4607), U.S. Environmental Protection Agency, 401 M Street SW., 



Washington DC 20460; telephone (202) 260-7336 (Dellarco) or (202) 260-



1445 (Cox).







SUPPLEMENTARY INFORMATION:



    Regulated entities. Entities potentially regulated by the Stage 1 



D/DBP rule are public water systems that add a disinfectant or oxidant. 



Regulated categories and entities include:







------------------------------------------------------------------------



                                                Examples of regulated   



                 Category                             entities          



------------------------------------------------------------------------



Public Water System.......................  Community and nontransient  



                                             noncommunity water systems 



                                             that add a disinfectant or 



                                             oxidant.                   



State Governments.........................  State government offices    



                                             that regulate drinking     



                                             water.                     



------------------------------------------------------------------------







    This table is not intended to be exhaustive, but rather provides a 



guide for readers regarding entities likely to be regulated by this 



action. This table lists the types of entities that EPA is now aware 



could potentially be regulated by this action. Other types of entities 



not listed in this table could also be regulated. To determine whether 



your facility may be regulated by this action, you should carefully 



examine the applicability criteria in Sec. 141.130 of the proposed rule 



(USEPA, 1994a). If you have questions regarding the applicability of 



this action to a particular entity, contact one of the persons listed 



in the preceding FOR FURTHER INFORMATION CONTACT section.



    Additional Information for Commenters. Please submit an original 



and three copies of your comments and enclosures (including 



references). The Agency requests that commenters follow the following 



format: Type or print comments in ink, and cite, where possible, the 



paragraph(s) in this Notice to which each comment refers. Commenters 



should use a separate paragraph for each method or issue discussed. 



Electronic comments must be submitted as a WP5.1 or WP6.1 file or as an 



ASCII file avoiding the use of special characters. Comments and data 



will also be accepted on disks in WordPerfect in 5.1 or WP6.1 or ASCII 



file format. Electronic comments on this Notice may be filed online at 



many Federal Depository Libraries. Commenters who want EPA to 



acknowledge receipt of their comments should include a self-addressed, 



stamped envelope. No facsimiles (faxes) will be accepted.



    Availability of Record. The record for this Notice, which includes 



supporting documentation as well as printed, paper versions of 



electronic comments, is available for inspection from 9 to 4 p.m. 



(Eastern Time), Monday through Friday, excluding legal holidays, at the 



Water Docket, U.S. EPA Headquarters, 401 M. St., S.W., East Tower 



Basement, Washington, D.C. 20460. For access to docket materials, 



please call 202/260-3027 to schedule an appointment.







Abbreviations Used in This Notice







AWWA: American Water Works Association



AWWARF: AWWA Research Foundation



BAT: Best Available Technology



BDCM: Bromodichloromethane



CMA: Chemical Manufacturers Association



CWS: Community Water System



DBCM: Dibromochloromethane



DBP: Disinfection Byproducts



D/DBP: Disinfectants and Disinfection Byproducts



DCA: Dichloroacetic Acid



ED<INF>10</INF>: Maximum likelihood estimate on a dose associated with 



10% extra risk



EPA: United States Environmental Protection Agency



ESWTR: Enhanced Surface Water Treatment Rule



FACA: Federal Advisory Committee Act



GAC: Granular Activated Carbon



HAA5: Haloacetic Acids (five)



HAN: Haloacetonitrile



ICR: Information Collection Rule



ILSI: International Life Sciences Institute



IESTWR: Interim Enhanced Surface Water Treatment Rule



IRFA: Initial Regulatory Flexibility Analysis



LCR: Lead and Cooper Rule



LED<INF>10</INF>: Lower 95% confidence limit on a dose associated with 



10% extra risk



LMS: Linear Multistage Model



LOAEL: Lowest Observed Adverse Effect Level



LTESTWR: Long-Term Enhanced Surface Water Treatment Rule







[[Page 15675]]







MCL: Maximum Contaminant Level



MCLG: Maximum Contaminant Level Goal



M-DBP: Microbial and Disinfectants/Disinfection Byproducts



mg/L: Milligrams per liter



MoE: Margin of Exposure



MRDL: Maximum Residual Disinfectant Level



MRDLG: Maximum Residual Disinfectant Level Goal



MTD: Maximum Tolerated Dose



NIPDWR: National Interim Primary Drinking Water Regulation



NOAEL: No Observed Adverse Effect Level



NODA: Notice of Data Availability



NPDWR: National Primary Drinking Water Regulation



NTNCWS: Nontransient Noncommunity Water System



NTP: National Toxicology Program



PAR: Population Attributable Risk



PQL: Practical Quantitation Limit



PWS: Public Water System



q1 *: Cancer Potency Factor



RFA: Regulatory Flexibility Act



RfD: Reference Dose



RIA: Regulatory Impact Analysis



RSC: Relative Source Contribution



SAB: Science Advisory Board



SBREFA: Small Business Regulatory Enforcement Fairness Act



SDWA: Safe Drinking Water Act, or the ``Act,'' as amended in 1986 and 



1996



SWTR: Surface Water Treatment Rule



TCA: Trichloroacetic Acid



TOC: Total Organic Carbon



TTHM: Total Trihalomethanes



TWG: Technical Working Group







Table of Contents







I. Introduction and Background



    A. 1979 Total Trihalomethane MCL



    B. Statutory Authority



    C. Regulatory Negotiation Process



    D. Overview of 1994 DBP Proposal



    1. MCLGs/MCLs/MRDLGs/MRDLs



    2. Best Available Technologies



    3. Treatment Technique



    4. Preoxidation (Predisinfection) Credit



    5. Analytical Methods



    6. Effect on Small Public Water Systems



    E. Formation of 1997 Federal Advisory Committee



II. Significant New Epidemiology Information for the Stage 1 



Disinfectants and Disinfection Byproducts Rule



    A. Epidemiological Associations Between the Exposure to DBPs in 



Chlorinated Water and Cancer



    1. Assessment of the Morris et al. (1992) Meta-Analysis



    a. Poole Report



    b. EPA's Evaluation of Poole Report



    c. Peer Review of Poole Report and EPA's Evaluation



    2. New Cancer Epidemiology Studies



    3. Quantitative Risk Estimation for Cancers From Exposure to 



Chlorinated Water



    4. Peer-Review of Quantitative Risk Estimates



    5. Summary of Key Observations



    6. Requests for Comments



    B. Epidemiological Associations Between Exposure to DBPs in 



Chlorinated Water and Adverse Reproductive and Developmental Effects



    1. EPA Panel Report and Recommendations for Conducting 



Epidemiological Research on Possible Reproductive and Developmental 



Effects of Exposure to Disinfected Drinking Water



    2. New Reproductive Epidemiology Studies



    3. Summary of Key Observations



    4. Request for Comments



III. Significant New Toxicological Information for the Stage 1 



Disinfectants and Disinfection Byproducts



    A. Chlorite and Chlorine Dioxide



    1. 1997 CMA Two-Generation Reproduction Rat Study



    2. External Peer Review of the CMA Study



    3. MCLG for Chlorite: EPA's Reassessment of the Noncancer Risk



    4. MRDLG for Chlorine Dioxide: EPA's Reassessment of the 



Noncancer Risk



    5. External Peer Review of EPA's Reassessment



    6. Summary of Key Observations



    7. Request for Comments



    B. Trihalomethanes



    1. 1997 International Life Sciences Institute Expert Panel 



Conclusions for Chloroform



    2. MCLG for Chloroform: EPA's Reassessment of the Cancer Risk



    a. Weight of the Evidence and Understanding of the Mode of 



Carcinogenic Action



    b. Dose-Response Assessment



    3. External Peer Review of EPA's Reassessment



    4. Summary of Key Observations



    5. Requests for Comments



    C. Haloacetic Acids



    1. 1997 International Life Sciences Institute Expert Panel 



Conclusions for Dichloroacetic Acid (DCA)



    2. MCLG for DCA: EPA's Reassessment of the Cancer Hazard



    3. External Peer Review of EPA's Reassessment



    4. Summary of Key Observations



    5. Requests for Comments



    D. Bromate



    1. 1998 EPA Rodent Cancer Bioassay



    2. MCLG for Bromate: EPA's Reassessment of the Cancer Risk



    3. External Peer Review of EPA's Reassessment



    4. Summary of Key Observations



    5. Requests for Comments



IV. Simultaneous Compliance Considerations: D/DBP Stage 1 Enhanced 



Coagulation Requirements and the Lead and Copper Rule



V. Compliance with Current Regulations



VI. Conclusions



VII. References







I. Introduction and Background







A. 1979 Total Trihalomethane MCL







    USEPA set an interim maximum contaminant level (MCL) for total 



trihalomethanes (TTHMs) of 0.10 mg/L as an annual average in November 



1979 (USEPA, 1979). There are four trihalomethanes (chloroform, 



bromodichloromethane, chlorodibromomethane, and bromoform). The interim 



TTHM standard applies to any PWS (surface water and/or ground water) 



serving at least 10,000 people that adds a disinfectant to the drinking 



water during any part of the treatment process. At their discretion, 



States may extend coverage to smaller PWSs. However, most States have 



not exercised this option. About 80 percent of the PWSs, serving 



populations of less than 10,000, are served by ground water that is 



generally low in THM precursor content (USEPA, 1979) and which would be 



expected to have low TTHM levels even if they disinfect.







B. Statutory Authority







    In 1996, Congress reauthorized the Safe Drinking Water Act. Several 



of the 1986 provisions were renumbered and augmented with additional 



language, while other sections mandate new drinking water requirements. 



As part of the 1996 amendments to the Safe Drinking Water Act, USEPA's 



general authority to set a Maximum Contaminant Level Goal (MCLG) and a 



National Primary Drinking Water Regulation (NPDWR) was modified to 



apply to contaminants that ``may have an adverse effect on the health 



of persons'', that are ``known to occur or there is a substantial 



likelihood that the contaminant will occur in public water systems with 



a frequency and at levels of public health concern'', and for which 



``in the sole judgement of the Administrator, regulation of such 



contaminant presents a meaningful opportunity for health risk reduction 



for persons served by public water systems' (1986 SDWA Section 1412 



(b)(3)(A) stricken and amended with 1412(b)(1)(A)).



    The Act also requires that at the same time USEPA publishes an 



MCLG, which is a non-enforceable health goal, it also must publish a 



NPDWR that specifies either a maximum contaminant level (MCL) or 



treatment technique (Sections 1401(1), 1412(a)(3), and 1412 (b)(4)B)). 



USEPA is authorized to promulgate a NPDWR ``that requires the use of a 



treatment technique in lieu of establishing a MCL,'' if the Agency 



finds that ``it is not economically or technologically feasible to 



ascertain the level of the contaminant'' (1412(b)(7)(A)).



    The 1996 Amendments also require USEPA to promulgate a Stage 1 



disinfectants/disinfection byproducts (D/DBP) rule by November 1998. In







[[Page 15676]]







addition, the 1996 Amendments require USEPA to promulgate a Stage 2 D/



DBP rule by May 2002 (Section 1412(b)(2)(C)).







C. Regulatory Negotiation Process







    In 1992 USEPA initiated a negotiated rulemaking to develop a D/DBP 



rule. The negotiators included representatives of State and local 



health and regulatory agencies, public water systems, elected 



officials, consumer groups and environmental groups. The Committee met 



from November 1992 through June 1993.



    Early in the process, the negotiators agreed that large amounts of 



information necessary to understand how to optimize the use of 



disinfectants to concurrently minimize microbial and DBP risk on a 



plant-specific basis were unavailable. Nevertheless, the Committee 



agreed that USEPA should propose a D/DBP rule to extend coverage to all 



community and nontransient noncommunity water systems that use 



disinfectants. This rule proposed to reduce the current TTHM MCL, 



regulate additional disinfection byproducts, set limits for the use of 



disinfectants, and reduce the level of organic compounds from the 



source water that may react with disinfectants to form byproducts.



    One of the major goals addressed by the Committee was to develop an 



approach that would reduce the level of exposure from disinfectants and 



DBPs without undermining the control of microbial pathogens. The 



intention was to ensure that drinking water is microbiologically safe 



at the limits set for disinfectants and DBPs and that these chemicals 



do not pose an unacceptable risk at these limits.



    Following months of intensive discussions and technical analysis, 



the Committee recommended the development of three sets of rules: a 



staged D/DBP Rule (proposal: 59 FR 38668, July 29, 1994), an 



``interim'' Enhanced Surface Water Treatment Rule (IESWTR) (proposal: 



59 FR 38832, July 29, 1994), and an Information Collection Rule (final 



61 FR 24354, May 14, 1996). The IESWTR would only apply to systems 



serving 10,000 people or more. The Committee agreed that a ``long-



term'' ESWTR (LTESWTR) would be needed for systems serving fewer than 



10,000 people when the results of more research and water quality 



monitoring became available. The LTESWTR could also include additional 



refinements for larger systems.







D. Overview of 1994 DBP Proposal







    The proposed D/DBP Stage 1 rule addressed a number of complex and 



interrelated drinking water issues. The proposal attempted to balance 



the control of health risks from compounds formed during drinking water 



disinfection against the risks from microbial organisms (such as 



Giardia lamblia, Cryptosporidium, bacteria, and viruses) to be 



controlled by the IESWTR.



    The proposed Stage 1 D/DBP rule applied to all community water 



systems (CWSs) and nontransient noncommunity water systems (NTNCWSs) 



that treat their water with a chemical disinfectant for either primary 



or residual treatment. In addition, certain requirements for chlorine 



dioxide would apply to transient noncommunity water systems because of 



the short-term health effects from high levels of chlorine dioxide. 



Following is a summary of key components of the 1994 proposed Stage 1 



D/DBP rule.



1. MCLGs/MCLs/MRDLGs/MRDLs



    EPA proposed MCLGs of zero for chloroform, bromodichloromethane, 



bromoform, bromate, and dichloroacetic acid and MCLGs of 0.06 mg/L for 



dibromochloromethane, 0.3 mg/L for trichloroacetic acid, 0.04 mg/L for 



chloral hydrate, and 0.08 mg/L for chlorite. In addition, EPA proposed 



to lower the MCL for TTHMs from 0.10 to 0.080 mg/L and added an MCL for 



five haloacetic acids (i.e., the sum of the concentrations of mono-, 



di-, and trichloroacetic acids and mono-and dibromoacetic acids) of 



0.060 mg/L. EPA also, for the first time, proposed MCLs for two 



inorganic DBPs: 0.010 mg/L for bromate and 1.0 mg/L for chlorite.



    In addition to proposing MCLGs and MCLs for several DBPs, EPA 



proposed maximum residual disinfectant level goals (MRDLGs) of 4 mg/L 



for chlorine and chloramines and 0.3 mg/L for chlorine dioxide. The 



Agency also proposed maximum residual disinfectant levels (MRDLs) for 



chlorine and chloramines of 4.0 mg/L, and 0.8 mg/L for chlorine 



dioxide. MRDLs protect public health by setting limits on the level of 



residual disinfectants in the distribution system. MRDLs are similar in 



concept to MCLs--MCLs set limits on contaminants and MRDLs set limits 



on residual disinfectants in the distribution system. MRDLs, like MCLs, 



are enforceable, while MRDLGs, like MCLGs, are not enforceable.



2. Best Available Technologies



    EPA identified the best available technology (BAT) for achieving 



compliance with the MCLs for both TTHMs and HAA5 as enhanced 



coagulation or treatment with granular activated carbon with a ten 



minute empty bed contact time and 180 day reactivation frequency 



(GAC10), with chlorine as the primary and residual disinfectant. The 



BAT for achieving compliance with the MCL for bromate was control of 



ozone treatment process to reduce formation of bromate. The BAT for 



achieving compliance with the chlorite MCL was control of precursor 



removal treatment processes to reduce disinfectant demand, and control 



of chlorine dioxide treatment processes to reduce disinfectant levels. 



EPA identified BAT for achieving compliance with the MRDL for chlorine, 



chloramine, and chlorine dioxide as control of precursor removal 



treatment processes to reduce disinfectant demand, and control of 



disinfection treatment processes to reduce disinfectant levels.



3. Treatment Technique



    EPA proposed a treatment technique that would require surface water 



systems and groundwater systems under the direct influence of surface 



water that use conventional treatment or precipitative softening to 



remove DBP precursors by enhanced coagulation or enhanced softening. A 



system would be required to remove a certain percentage of total 



organic carbon (TOC) (based on raw water quality) prior to the point of 



continuous disinfection. EPA also proposed a procedure to be used by a 



PWS not able to meet the percent reduction, to allow them to comply 



with an alternative minimum TOC removal level. Compliance for systems 



required to operate with enhanced coagulation or enhanced softening was 



based on a running annual average, computed quarterly, of normalized 



monthly TOC percent reductions.



4. Preoxidation (Predisinfection) Credit



    The proposed rule did not allow PWSs to take credit for compliance 



with disinfection requirements in the SWTR/IESWTR prior to removing 



required levels of precursors unless they met specified criteria. This 



provision was modified by the 1997 Federal Advisory Committee (see 



below).



5. Analytical Methods



    EPA proposed nine analytical methods (some of which can be used for 



multiple analyses) to ensure compliance with proposed MRDLs for 



chlorine, chloramines, and chlorine dioxide. EPA proposed methods for 



the analysis of TTHMs, HAA5, chlorite, bromate and total organic 



carbon.



6. Effect on Small Public Water Systems



    The Regulatory Flexibility Act (RFA), as amended by the Small 



Business







[[Page 15677]]







Regulatory Enforcement Fairness Act (SBREFA), requires federal 



agencies, in certain circumstances, to consider the economic effect of 



proposed regulations on small entities. The agency must assess the 



economic impact of a proposed rule on small entities if the proposal 



will have a significant economic impact on a substantial number of 



small entities. Under the RFA, 5 U.S.C. 601 et seq., an agency must 



prepare an initial regulatory flexibility analysis (IRFA) describing 



the economic impact of a rule on small entities unless the agency 



certifies that the rule will not have a significant impact.



    In the l994 D/DBP and IESWTR proposals, EPA defined small entities 



as small PWSs--serving 10,000 or fewer persons--for purposes of its 



regulatory flexibility assessments under the RFA. EPA certified that 



the IESWTR will not have a significant impact on a substantial number 



of small entities, and prepared an IRFA for the DBP proposed rule. EPA 



did not, however, specifically solicit comment on that definition. EPA 



will use this same definition of small PWSs in preparing the final RFA 



for the Stage 1 DBP rule. Further, EPA plans to define small entities 



in the same way in all of its future drinking water rulemakings. The 



Agency solicited public comment on this definition in the proposed 



National Primary Drinking Water Regulations: Consumer Confidence 



Reports, 63 FR 7606, at 7620-21, February 13, 1998.







E. Formation of 1997 Federal Advisory Committee







    In May 1996, the Agency initiated a series of public informational 



meetings to exchange information on issues related to microbial and D/



DBP regulations. To help meet the deadlines for the IESWTR and Stage 1 



D/DBP rule established by Congress in the 1996 SDWA Amendments and to 



maximize stakeholder participation, the Agency established the 



Microbial and Disinfectants/Disinfection Byproducts (M-DBP) Advisory 



Committee under the Federal Advisory Committee Act (FACA) on February 



12, 1997, to collect, share, and analyze new information and data, as 



well as to build consensus on the regulatory implications of this new 



information. The Committee consists of 17 members representing USEPA, 



State and local public health and regulatory agencies, local elected 



officials, drinking water suppliers, chemical and equipment 



manufacturers, and public interest groups.



    The Committee met five times, in March through July 1997, to 



discuss issues related to the IESWTR and Stage 1 D/DBP rule. Technical 



support for these discussions was provided by a Technical Work Group 



(TWG) established by the Committee at its first meeting in March 1997. 



The Committee's activities resulted in the collection, development, 



evaluation, and presentation of substantial new data and information 



related to key elements of both proposed rules. The Committee reached 



agreement on the following major issues that were discussed in the 1997 



NODA (USEPA, 1997a): (1) Maintaining the proposed MCLs for TTHMs, HAA5 



and bromate; (2) modifying the enhanced coagulation requirements as 



part of DBP control; (3) including a microbial bench marking/profiling 



to provide a methodology and process by which a PWS and the State, 



working together, assure that there will be no significant reduction in 



microbial protection as the result of modifying disinfection practices 



in order to meet MCLs for TTHM and HAA5; (4) credit for compliance with 



applicable disinfection requirements should continue to be allowed for 



disinfection applied at any point prior to the first customer, 



consistent with the existing Surface Water Treatment Rule; (5) 



modification of the turbidity performance requirements and requirements 



for individual filters; (6) issues related to the MCLG for 



Cryptosporidium; (7) requirements for removal of Cryptosporidium; and 



(8) provision for conducting sanitary surveys.







II. Significant New Epidemiology Information for the Stage 1 



Disinfectant and Disinfection Byproducts Rule







    The preamble to the 1994 proposed rule provided a summary of the 



health criteria documents for the following DBPs: Bromate; chloramines; 



haloacetic acids and chloral hydrate; chlorine; chlorine dioxide, 



chlorite, and chlorate; and trihalomethanes (USEPA, 1994a). The 



information presented in 1994 was used to establish MCLGs and MRDLGs. 



On November 3, 1997, the EPA published a Notice of Data Availability 



(NODA) summarizing new information that the Agency has obtained since 



the 1994 proposed rule (USEPA, 1997a). The following sections briefly 



discuss additional information received and analyzed since the November 



1997 NODA. This new information concerns the following: (1) Recently 



published epidemiology studies examining the relationship between 



exposure to contaminants in chlorinated surface water and adverse 



health outcomes; (2) an assessment of the Morris et. al. (1992) meta-



analysis of the epidemiology studies published prior to 1996; (3) 



recommendations made by an International Life Science Institute (ILSI) 



expert panel on the application of the USEPA Proposed Guidelines for 



Carcinogen Assessment (USEPA, 1996b) to data sets for chloroform and 



dichloroacetic acid; and (4) new laboratory animal studies on bromate 



and chlorite (also applicable to chlorine dioxide risk). This Notice 



presents the conclusions of these supplemental analyses as well as 



their implications for MCLGs, MCLs, MRDLGs, and MRDLs. The new 



documents are included in the Docket for this action.



    As a result of this new information, the EPA requests comment on 



the following: (1) Revisions to estimates of potential cancer cases 



that can be attributed to exposure from DBPs in chlorinated surface 



water (USEPA, 1998a); (2) revisions to the noncancer assessment for 



chlorite and chlorine dioxide (USEPA, 1998b); (3) revisions to the 



cancer quantitative risks for chloroform (USEPA, 1998c); (4) updates on 



the cancer assessment for bromate (USEPA, 1998d); and (5) updates on 



the hazard characterization for dichloroacetic acid (USEPA, 1998e).



    As in 1994, the assessment of public health risks from chlorination 



of drinking water currently relies on inherently difficult and 



incomplete empirical analysis. On one hand, epidemiologic studies of 



the general population are hampered by difficulties of design, scope, 



and sensitivity. On the other hand, uncertainty is involved in using 



the results of high dose animal toxicological studies of a few of the 



numerous byproducts that occur in disinfected drinking water to 



estimate the risk to humans from chronic exposure to low doses of these 



and other byproducts. In addition, such studies of individual 



byproducts cannot characterize the entire mixture of disinfection 



byproducts in drinking water. Nevertheless, while recognizing the 



uncertainties of basing quantitative risk estimates on less than 



comprehensive information regarding overall hazard, EPA believes that 



the weight-of-evidence represented by the available epidemiological and 



toxicological studies on DBPs and chlorinated surface water continues 



to support a hazard concern and a protective public health approach to 



regulation.







A. Epidemiologic Associations Between Exposure to DBPs in Chlorinated 



Water and Cancer







    The preamble to the 1994 proposed rule discussed several cancer 



epidemiology studies that had been conducted over the past 20 years to







[[Page 15678]]







examine the association between exposure to chlorinated water and 



cancer (USEPA, 1994a). At the time of the 1994 proposed rule, there was 



disagreement among the members of the Negotiating Committee on the 



conclusions that could be drawn from these studies. Some members of the 



Committee felt that the cancer epidemiology data, taken in conjunction 



with the results from toxicological studies, provided ample and 



sufficient weight of evidence to conclude that exposure to DBPs in 



drinking water could result in increased cancer risk at levels 



encountered in some public water supplies. Other members of the 



Committee concluded that the cancer epidemiology studies on the 



consumption of chlorinated drinking water to date were insufficient to 



provide definitive information for the regulation. As a response, EPA 



agreed to pursue additional research to reduce the uncertainties 



associated with these data and to better characterize and project the 



potential human cancer risks associated with the exposure to 



chlorinated water. To implement this commitment, EPA sponsored an 



expert panel to review the state of cancer epidemiology research 



(USEPA, 1994b). As discussed in the 1997 NODA, EPA has implemented 



several of the panel's recommendations for short-and long-term research 



to improve the assessment of risks, using the results from cancer 



epidemiology studies.



    The 1994 proposed rule also presented the results of a meta-



analysis that pooled the relative risks from ten cancer epidemiology 



studies in which there was a presumed exposure to chlorinated water and 



its byproducts (Morris et al., 1992). A conclusion of this meta-



analysis was a calculated upper bound estimate of approximately 10,000 



cases of rectal and bladder cancer cases per year that could be 



associated with exposure to chlorinated water and its byproducts in the 



United States. The ten studies included in the meta-analysis had 



methodological issues and significant design differences. There was 



considerable debate among the members of the Negotiating Committee on 



the extent to which the results of this meta-analysis should be 



considered in developing benefit estimates associated with the proposed 



rule. Negotiators agreed that the range of possible risks attributed to 



chlorinated water should consider both toxicological data and 



epidemiological data, including the Morris et al. (1992) estimates. No 



consensus, however, could be reached on a single likely risk estimate.



    For purposes of estimating the potential benefits from the proposed 



rule, EPA used a range of estimated cancer cases that could be 



attributed to exposure to chlorinated waters of less than 1 cancer case 



per year up to 10,000 cases per year. The less than 1 cancer case per 



year was based on toxicology (the maximum likelihood cancer risk 



estimate calculated from animal assay data for THMs). The 10,000 cases 



per year was based on epidemiology (estimates from the Morris et al. 



(1992) meta-analysis).



1. Assessment of the Morris et al. (1992) Meta-Analysis



    Based on the recommendations from the 1994 expert panel on cancer 



epidemiology, EPA completed an assessment of the Morris et al. (1992) 



meta-analysis which comprises three reports: (1) A Report completed for 



EPA which evaluated the Morris et al. (1992) meta-analysis (Poole, 



1997); (2) EPA's assessment of the Poole report (USEPA, 1998f); and (3) 



a peer review of the Poole report and EPA's assessment of the Poole 



report (USEPA, 1998g). Each of these documents is briefly discussed 



below. The full reports together with Dr. Morris's comments on the 



Poole Review (Morris, 1997) can be found in the docket for this Notice.



    a. Poole Report. A report was prepared for EPA which made 



recommendations regarding whether the data used by Morris et al. (1992) 



should be aggregated into a single summary estimate of risk. The report 



also commented on the utility of the aggregated estimates for risk 



assessment purposes (Poole, 1997). This report was limited to the 



studies available to Morris et al. (1992) plus four additional studies 



that EPA requested to be included (Ijsselmuiden et al., 1992; McGeehin 



et al., 1993; Vena et al., 1993; and King and Marrett, 1996). Poole 



observed that there was considerable heterogeneity among the data and 



that there was evidence of publication bias within the body of 



literature. When there is significant heterogeneity among studies, 



aggregation of the results into a single summary estimate may not be 



appropriate. Publication bias refers to the situation where the 



literature search and inclusion criteria for studies used for the meta-



analysis indicate that the sample of studies used is not representative 



of all the research (published and unpublished) that has been done on a 



topic. In addition, Poole found that the aggregate estimates reported 



by Morris et al. (1992) were sensitive to small changes in the analysis 



(e.g., addition or deletion of a single study). Based on these 



observations, Poole recommended that the cancer epidemiology data 



considered in his evaluation should not be combined into a single 



summary estimate and that the data had limited utility for risk 



assessment purposes. Many of the reasons cited by Poole for why it was 



not appropriate to combine the studies into a single point estimate of 



risk were noted in the 1994 proposal (Farland and Gibb, 1993; Murphy, 



1993; and Craun, 1993).



    b. EPA's Evaluation of Poole Report. EPA reviewed the conclusions 



from the Poole report and generally concurred with Poole's 



recommendations (USEPA, 1998f). EPA concluded that Poole presented 



reasonable and supportable evidence to suggest that the work of Morris 



et al. (1992) should not be used for risk assessment purposes without 



further study and review because of the sensitivity of the results to 



analytical choices and to the addition or deletion of a single study. 



EPA agreed that the studies were highly heterogeneous, thus undermining 



the ability to combine the data into a single summary estimate of risk.



    c. Peer Review of Poole Report and EPA's Evaluation. The Poole 



report and EPA's evaluation were reviewed by five epidemiologic experts 



from academia, government, and industry (EPA, 1998g). Overall, these 



reviewers agreed that the Poole report was of high quality and that he 



had used defensible assumptions and techniques during his analysis. 



Most of the reviewers concluded that the report was correct in its 



assessment that these data should not be combined into a single summary 



estimate of risk.



2. New Cancer Epidemiology Studies



    Several cancer epidemiological studies examining the association 



between exposure to chlorinated surface water and cancer have been 



published subsequent to the 1994 proposed rule and the Morris et al. 



(1992) meta-analysis (McGeehin et al., 1993; Vena et al. 1993; King and 



Marrett, 1996; Doyle et al., 1997; Freedman et al., 1997; Cantor et al, 



1998; and Hildesheim et al., 1998). These studies, with the exception 



of Freedman et al. (1997), were described in the ``Summaries of New 



Health Effects Data'' (USEPA, 1997b) that was included in the docket 



for the 1997 NODA.



    In general, the new studies cited above are better designed than 



the studies published prior to the 1994 proposal. The newer studies 



generally include incidence cases of disease, interviews with the study 



subjects and better exposure assessments. Based on the entire cancer 



epidemiology database, bladder cancer studies provide







[[Page 15679]]







better evidence than other types of cancer for an association between 



exposure to chlorinated surface water and cancer. EPA believes the 



association between exposure to chlorinated surface water and colon and 



rectal cancer cannot be determined at this time because of the limited 



data available for these cancer sites (USEPA, 1998a).



3. Quantitative Risk Estimation for Cancers From Exposure to 



Chlorinated Water



    Under Executive Order 12866 (58 FR 51735, October 4, 1993), the EPA 



must conduct a regulatory impact analysis (RIA). In the 1994 proposal, 



EPA used the Morris et al. (1992) meta-analysis in the RIA to provide 



an upper-bound estimate of 10,000 possible cancer cases per year that 



could be attributed to exposure to chlorinated water and its associated 



byproducts. EPA also estimated that an upper bound of 1200-3300 of 



these cancer cases per year could be avoided if the requirements for 



the Stage 1 DBP rule were implemented (USEPA, 1994a). EPA acknowledged 



the uncertainty in these estimates, but believed they were the best 



that could be developed at the time.



    Based on the evaluations cited above, EPA does not believe it is 



appropriate to use the Morris et al. (1992) study as the basis for 



estimating the potential cancer cases that could be attributed to 



exposure to DBPs in chlorinated surface water. Instead, EPA is 



providing for comment an analysis based on a more traditional approach 



for estimating the potential cancer risks from exposure to DBPs in 



chlorinated surface water that does not rely on pooling or aggregating 



the epidemiologic data into a single summary estimate. Based on a 



narrower set of improved studies, this approach utilizes the population 



attributable risk (PAR) concept and presents a range of potential risks 



and not a single point estimate. As discussed below, there are a number 



of uncertainties associated with the use of this approach for 



estimating potential risks. Therefore, EPA requests comments on both 



the PAR methodology as well as on the assumptions upon which it is 



based.



    Epidemiologists use PAR to quantify the fraction of the disease 



burden in a population (e.g., cancer) that could be eliminated if the 



exposure was absent (e.g., DBPs in chlorinated water) (Rockhill, et 



al., 1998). PARs provide a perspective on the potential magnitude of 



risk associated with various exposures. The concept of PAR is known by 



many names (e.g, attributable fraction, attributable proportion, 



etiologic fraction). For this Notice, the term PAR will be used to 



avoid confusion. A range of PARs better captures the heterogeneity of 



the risk estimates than a single point estimate.



    In the PAR analysis of the cancer epidemiology data and the 



development of the range of potential cancer cases attributable to 



exposure to DBPs in chlorinated surface water, EPA recognizes that a 



causal relationship between chlorinated surface water and bladder 



cancer has not yet been demonstrated by epidemiology studies. However, 



several studies have suggested a weak association in various subgroups. 



EPA presents potential cancer case estimates as upper bounds of 



suggested risk as part of the Agency's analysis of potential costs and 



benefits associated with this rule. EPA focused its current evaluation 



on bladder cancer because the number of quality studies that are 



available for other cancer sites such as colon and rectal cancers are 



very limited.



    EPA estimated PARs for the best bladder cancer studies that 



provided enough information to calculate a PAR (USEPA, 1998a). In 



addition, EPA selected studies for inclusion in the quantitative 



analysis if they met all three of the following criteria: (1) The study 



was a population based case-control or cohort study conducted to 



evaluate the relationship between exposure to chlorinated drinking 



water and incidence cancer cases, based on personal interviews (no 



cohort studies were found that met all 3 criteria); (2) the study was 



of high quality and well designed (e.g., good sample size, high 



response rate, and adjusted for confounding factors); and (3) the study 



had adequate exposure assessments (e.g., residential histories, actual 



THM data). Based on the above selection criteria, five bladder cancer 



studies were selected for estimating PARs: Cantor et al., 1985; 



McGeehin et al. 1993; King and Marrett, 1996; Freedman et al., 1997; 



and Cantor et al., 1998. PARs were derived for two exposure categories: 



years of exposure to chlorinated surface water; and THM levels and 



years of chlorinated surface water exposure.



    The PARs from the five bladder cancer studies for the two exposure 



categories ranged from 2-17%. The uncertainties associated with these 



PAR estimates are large as expected, due to the common prevalence of 



both the disease (bladder cancer) and exposure (chlorinated drinking 



water). Based on 54,500 expected new bladder cancer cases in the U.S., 



as projected by NCI (1998) for 1997, the upper bound estimate of the 



number of potential bladder cancer cases per year potentially 



associated with exposure to DBPs in chlorinated surface water was 



estimated to be 1100-9300.



    EPA made several important assumptions when evaluating the 



application of the PAR range of estimated bladder cancer cases from 



these studies to the U.S. population. They include the following: (i) 



The study population selected for each of the cancer epidemiology 



studies are reflective of the entire U.S. population that develops 



bladder cancer; (ii) the percentage of bladder cancer cases exposed to 



DBPs in the reported studies are reflective of the bladder cancer cases 



exposed to DBPs in the U.S. population; (iii) the levels of DBP 



exposure in the bladder studies are reflective of the DBP exposure in 



the U.S. population; and (iv) the possible relationship between 



exposure to DBPs in chlorinated surface water and bladder cancer is 



causal.



    EPA believes that these assumptions would not be appropriate for 



estimating the potential upper bound cancer risk for the U.S. 



population based on a single study. However, the Agency believes that 



these assumptions are appropriate given the number of studies used in 



the PAR analysis and for gaining a perspective on the range of possible 



upper bound risks that can be used in establishing a framework for 



further cost-benefit analysis. In addition, EPA believes these 



assumptions are appropriate given the SDWA mandate that ``drinking 



water regulations be established if the contaminant may have an adverse 



effect on the health of persons'' (SDWA--Section 1412(b)(1)A). Because 



of this mandate, EPA believes that when the scientific data indicates 



there may be causality, such an analytical approach is appropriate. EPA 



believes the assumption of a potential causal relationship is supported 



by the weight-of-evidence from toxicology and epidemiology. Toxicology 



studies have shown several individual DBPs to be carcinogenic and 



mutagenic, while the epidemiology data have shown weak associations 



between several cancer sites and exposure to chlorinated surface water.



    EPA notes and requests comment on the following additional issues 



associated with basing an estimate of the potential bladder cancer 



cases that can be attributed to DBPs in chlorinated surface water from 



the five studies selected for this analysis. The results generally 



showed weak statistical significance and were not always consistent 



among the studies. For example, some reviewers believe that two studies 



showed statistically significant effects only for male smokers, while 



two other studies showed higher effects for non-smokers.







[[Page 15680]]







One study showed a significant association with exposure to chlorinated 



surface water but not chlorinated ground water, while another showed 



the opposite result. Furthermore, two studies which examined the 



effects of exposure to higher levels of THMs failed to find a 



significant association between level of THMs and cancer. The Agency 



notes that it is not necessary that statistical significance be shown 



in order to conduct a PAR analysis as was stated by peer-reviewers of 



this analysis.



4. Peer-Review of Quantitative Risk Estimates



    The quantitative cancer risks estimated from the five epidemiology 



studies derived through the calculation of individual PARs has 



undergone external peer review by three expert epidemiologists (USEPA, 



1998a). Two peer reviewers concurred with the decision to derive a PAR 



range. This approach was deemed more appropriate than the selection of 



a single study or aggregation of study results. One reviewer indicated 



significant reservations with this approach based not on the method, 



but the inconclusivity of the epidemiology database and stated that it 



was premature to perform a PAR analysis because it would suggest that 



the epidemiological information is more consistent and complete than it 



actually is. To better present the degree of variability, this reviewer 



suggested an alternative approach that involves a graphical 



presentation of the individual odds ratios and their corresponding 



confidence intervals. Two reviewers agreed that there is not enough 



information to present an estimate of the PAR for colon and rectal 



cancer.



    EPA understands the issues raised regarding the use of PARs and 



recognizes there may be controversy on using this approach with the 



available epidemiology data. However, as stated above, EPA believes the 



PAR approach is a useful tool for estimating the potential upper bound 



risk for use in developing the regulatory impact analysis. EPA agrees 



with two of the reviewers that there is not enough information to 



present an estimate of colon and rectal risk at this time using a PAR 



approach.



5. Summary of Key Observations



    The 1994 proposal included a meta-analysis of 10 cancer 



epidemiology studies that provided an estimate of the number of bladder 



and rectal cancer cases per year that could be attributed to 



consumption of chlorinated water and its associated byproducts (Morris 



et al., 1992). Based on the evaluations previously described, EPA does 



not believe it is appropriate to use the Morris et al. (1992) study as 



the basis for estimating the potential cancer cases that could be 



attributed to exposure to DBPs in chlorinated surface water. Instead, 



EPA has focused on a smaller set of higher quality studies and 



performed a PAR analysis to estimate the potential cancer risks from 



exposure to DBPs in chlorinated surface water that does not rely on 



pooling or aggregating the data into a single summary estimate, as was 



done by Morris et al. (1992). EPA focused the current evaluation on 



bladder cancer because there are more appropriate studies of higher 



quality available upon which to base this assessment than for other 



cancer sites. It was decided to present the potential number of cancer 



cases as a range instead of a single point estimate because this would 



better represent the uncertainties in the risk estimates. The number of 



potential bladder cancer cases per year that could be associated with 



exposure to DBPs in chlorinated surface water is estimated to be an 



upper bound range of 1100-9300 per year.



    In the PAR analysis of the cancer epidemiology data and the 



development of the range of potential cancer cases attributable to 



exposure to DBPs in chlorinated surface water, EPA presents the 



estimates as upper bounds of any suggested risk. As was debated during 



the 1992-1993 M/DBP Regulatory Negotiation process, EPA believes that 



there are insufficient data to conclusively demonstrate a causal 



association between exposure to DBPs in chlorinated surface water and 



cancer. EPA recognizes the uncertainties of basing quantitative 



estimates using the current health database on chlorinated surface 



waters and has identified a number of issues that must be considered in 



interpreting the results of this analysis. Nonetheless, the Agency 



believes that the overall weight-of-evidence from available 



epidemiologic and toxicologic studies on DBPs and chlorinated surface 



water continues to support a hazard concern and thus, a prudent public 



health protective approach for regulation.



6. Requests for Comments



    EPA is not considering any changes to the recommended regulatory 



approach contained in the 1994 proposal, and discussed further in the 



1997 NODA, based on the upper bound risk analysis issues discussed 



above. Nonetheless, EPA requests comments on the conclusions from the 



Poole report (Poole, 1997), EPA's assessment of the Poole report (EPA, 



1998f), the peer-review of the Poole report and EPA's assessment of the 



Poole report (EPA, 1998g); and Dr. Morris comments on the Poole review 



(Morris, 1997). EPA also requests comments on its quantitative analysis 



(PAR approach) to estimate the upper bound risks from exposure to DBPs 



in chlorinated surface water, the methodology for estimating the number 



of cancer cases per year that could be attributed to exposure to DBPs 



in chlorinated surface water, and any alternative approaches for 



estimating the upper bound estimates of risk. In particular, EPA 



requests comment on the extent to which the approach used in the PAR 



analysis addresses the concerns identified by Poole and others 



regarding the earlier Morris meta-analysis. EPA also requests comments 



on the peer review of the PAR analysis.







B. Epidemiologic Associations Between Exposure to DBPs in Chlorinated 



Water and Adverse Reproductive and Developmental Effects







    The 1994 proposed rule discussed several reproductive epidemiology 



studies. At the time of the proposal, it was concluded that there was 



no compelling evidence to indicate a reproductive and developmental 



hazard due to exposure to chlorinated water because the epidemiologic 



evidence was inadequate and the toxicological data were limited. In 



1993, an expert panel of scientists was convened by the International 



Life Sciences Institute to review the available human studies for 



developmental and reproductive outcomes and to provide research 



recommendations (USEPA/ILSI, 1993). The expert panel concluded that the 



epidemiologic results should be considered preliminary given that the 



research was at a very early stage (USEPA/ILSI, 1993; Reif et al., 



1996). The 1997 NODA and the ``Summaries of New Health Effects Data'' 



(USEPA, 1997b) presented several new studies (Savitz et al., 1995; 



Kanitz et al. 1996; and Bove et al., 1996) that had been published 



since the 1994 proposed rule and the 1993 ILSI panel review. Based on 



the new studies presented in the 1997 NODA, EPA stated that the results 



were inconclusive with regard to the association between exposure to 



chlorinated waters and adverse reproductive and developmental effects 



(62 FR 59395)







[[Page 15681]]







1. EPA Panel Report and Recommendations for Conducting Epidemiological 



Research on Possible Reproductive and Developmental Effects of Exposure 



to Disinfected Drinking Water



    EPA convened an expert panel in July 1997 to evaluate epidemiologic 



studies of adverse reproductive or developmental outcomes that may be 



associated with the consumption of disinfected drinking water published 



since the 1993 ILSI panel review. A report was prepared entitled ``EPA 



Panel Report and Recommendations for Conducting Epidemiological 



Research on Possible Reproductive and Developmental Effects of Exposure 



to Disinfected Drinking Water'' (USEPA, 1998h). The 1997 expert panel 



was also charged to develop an agenda for further epidemiological 



research. The 1997 panel concluded that the results of several studies 



suggest that an increased relative risk of certain adverse outcomes may 



be associated with the type of water source, disinfection practice, or 



THM levels. The panel emphasized, however, that most relative risks are 



moderate or small and were found in studies with limitations of their 



design or conduct. The small magnitude of the relative risk found may 



be due to one or more sources of bias, as well as to residual 



confounding (factors not identified and controlled). Additional 



research is needed to assess whether the observed associations can be 



confirmed. The panel considers a recent study by Waller et al. (1998), 



discussed below, to provide a strong basis for further research. This 



study was funded in part by EPA as an element of the research program 



agreed to as part of the 1992/1993 negotiated M/DBP rulemaking.



2. New Reproductive Epidemiology Studies



    Three new reproductive epidemiology studies have been published 



since the 1997 NODA. The first study (Klotz and Pyrch, 1998) examined 



the potential association between neural tube defects and certain 



drinking water contaminants, including some DBPs. In this case-control 



study, births with neural tube defects reported to New Jersey's Birth 



Defects Registry in 1993 and 1994 were matched against control births 



chosen randomly from across the State. Birth certificates were examined 



for all subjects, as was drinking water data corresponding to the 



mother's residence in early pregnancy. The authors reported elevated 



odds ratios (ORs), generally between 1.5 and 2.1, for the association 



of neural tube defects with TTHMs. However, the only statistically 



significant results were seen when the analysis was isolated to those 



subjects with the highest THM exposures (greater than 40 ppb) and 



limited to those subjects with neural tube defects in which there were 



no other malformations (odds ratio 2.1; 95% confidence interval 1.1-



4.0). Neither HAAs or haloacetonitriles (HANs) showed a clear 



relationship to neural tube defects but monitoring data on these DBPs 



were more limited than for THMs. Nitrates were not observed to be 



associated with neural tube defects. Certain chlorinated solvent 



contaminants were also studied but occurrence levels were too low to 



assess any relationship to neural tube defects. This study is available 



in the docket for this NODA. Although EPA has not completed its review 



of the study, the Agency is proceeding on the premise that this study 



will add to the weight-of-evidence concerning the potential adverse 



reproductive health effects from DBPs, but will not by itself provide 



sufficient evidence for further regulatory actions.



    Two studies looked at early term miscarriage risk factors. The 



first of these studies (Waller et al., 1998) examined the potential 



association between early term miscarriage and exposure to THMs. The 



second study (Swan et al., 1998) examined the potential association 



between early term miscarriage and tap water consumption. Both studies 



used the same group of pregnant women (5,144) living in three areas of 



California. They were recruited from the Santa Clara area, the Fontana 



area in southern California, or the Walnut Creek area. The women were 



all members of the Kaiser Permanente Medical Care Program and were 



offered a chance to participate in the study when they called to 



arrange their first prenatal visit. In the Waller et al. (1998) study, 



additional water quality information from the women's drinking water 



utilities were obtained so that THM levels could be determine. The Swan 



et al. (1998) study provided no quantitative measurements of THMs (or 



DBPs), and thus, provided no additional information on the risk from 



chlorination byproducts. Because of this, only the Waller et al. (1998) 



study is summarized below.



    In the Waller et al. (1998) study, utilities that served the women 



in this study were identified. Utilities' provided THM measurements 



taken during the time period participants were pregnant. The TTHM level 



in a participant's home tap water was estimated by averaging water 



distribution system TTHM measurements taken during a participants first 



three months of pregnancy. This ``first trimester TTHM level'' was 



combined with self reported tap water consumption to create a TTHM 



exposure level. Exposure levels of the individual THMs (e.g., 



chloroform, bromoform, etc.) were estimated in the same manner. Actual 



THM levels in the home tap water were not measured.



    Women with high TTHM exposure in home tap water (drinking five or 



more glasses per day of cold home tap water containing at least 75 ug 



per liter of TTHM) had an early term miscarriage rate of 15.7%, 



compared with a rate of 9.5% among women with low TTHM exposure 



(drinking less than 5 glasses per day of cold home tap water or 



drinking any amount of tap water containing less than 75 ug per liter 



of TTHM). An adjusted odds ratio for early term miscarriage of 1.8 (95% 



confidence interval 1.1-3.0) was determined.



    When the four individual trihalomethanes were studied, only high 



bromodichloromethane (BDCM) exposure, defined as drinking five or more 



glasses per day of cold home tap water containing <gr-thn-eq>18 ug/L 



bromodichloromethane, was associated with early term miscarriage. An 



adjusted odds ratio for early term miscarriage of 3.0 (95% confidence 



interval 1.4-6.6) was determined.



3. Summary of Key Observations



    The Waller et al. (1998) study reports that consumption of tapwater 



containing high concentrations of THMs, particularly BDCM, is 



associated with an increased risk of early term miscarriage. EPA 



believes that while this study does not prove that exposure to THMs 



causes early term miscarriages, it does provide important new 



information that needs to be pursued and that the study adds to the 



weight-of-evidence which suggests that exposure to DBPs may have an 



adverse effect on humans.



    EPA has an epidemiology and toxicology research program that is 



examining the relationship between DBPs and adverse reproductive and 



developmental effects. In addition to conducting scientifically 



appropriate follow-up studies to see if the observed association in the 



Waller et al. (1998) study can be replicated elsewhere, EPA will be 



working with the California Department of Health Services to improve 



estimates of exposure to DBPs in the existing study population. A more 



complete DBP exposure data base is being developed by asking water 



utilities in the study area to provide additional information, 



including levels of other types of DBPs (e.g., haloacetic







[[Page 15682]]







acids). These efforts will help further assess the significance of the 



Waller et al. (1998) study, associated concerns, and how further 



follow-up work can best be implemented. EPA will collaborate with the 



Centers for Disease Control and Prevention (CDC) in a series of studies 



to evaluate if there is an association between exposure to DBPs in 



drinking water and birth defects. The Agency is also involved in a 



collaborative testing program with the National Toxicology Program 



(NTP) under which several individual DBPs have been selected for 



reproductive and developmental screening tests. Finally, EPA is 



conducting several toxicology studies on DBPs other endpoints of 



concern including examining the potential effects of BDCM on male 



reproductive endpoints. This information will be used in developing the 



Stage 2 DBP rule. In the meantime, the Agency plans to proceed with the 



1994 D/DBP proposal for tightening the control for DBPs.



4. Requests for Comments



    EPA is not considering any changes to the recommended regulatory 



approach contained in the 1994 proposal, and discussed further in the 



1997 NODA, based on the new reproductive epidemiology studies discussed 



above. Nonetheless, EPA requests comments on the findings from the 



Klotz, et al. (1998) and Waller et al. (1998) study and EPA's 



conclusions regarding the studies.







III. Significant New Toxicological Information for the Stage 1 



Disinfectants and Disinfection Byproducts







    The 1997 NODA reviewed new toxicological information that became 



available for several of the DBPs after the 1994 proposal (USEPA, 1997a 



and b). In that Notice, it was pointed out that several forthcoming 



reports were not available in time for consideration during the 1997 



FACA process. Reports now available include a two-generation 



reproductive rat study of sodium chlorite sponsored by the Chemical 



Manufacturer Association (CMA, 1996); an EPA two-year cancer rodent 



study of bromate (DeAngelo et al., 1998); and the International Life 



Sciences Institute (ILSI) expert panel report of chloroform and 



dichloroacetic acid (ILSI, 1997). These reports are discussed below, as 



well as EPA's analyses and conclusions based on this new information.







A. Chlorite and Chlorine Dioxide







    The 1994 proposal included an MCLG of 0.08 mg/L and an MCL of 1.0 



mg/L for chlorite. The proposed MCLG was based on an RfD of 3 mg/kg/d 



estimated from a lowest-observed-adverse-effect-level (LOAEL) for 



neurodevelopmental effects identified in a rat study by Mobley et al. 



(1990). This determination was based on a weight of evidence evaluation 



of all the available data at that time (USEPA, 1994a). An uncertainty 



factor of 1000 was used to account for inter- and intra-species 



differences in response to toxicity (a factor of 100) and a factor of 



10 for use of a LOAEL. The EPA proposed rule also included an MRDLG of 



0.3 mg/L and an MRDL of 0.8 mg/L for chlorine dioxide. The proposed 



MRDLG was based on a RfD of 3 mg/kg/d estimated from a no-observed-



adverse-effect-level (NOAEL) for developmental neurotoxicity identified 



from a rat study (Orme et al., 1985; see USEPA, 1994a). This 



determination was based on a weight of evidence evaluation of all the 



available data at that time (USEPA, 1994a). An uncertainty factor of 



300 was applied that was composed of a factor of 100 to account for 



inter- and intra-species differences in response to toxicity and a 



factor of 3 for lack of a two-generation reproductive study necessary 



to evaluate potential toxicity associated with lifetime exposure. To 



fill this important data gap, the Chemical Manufacturers Associations 



(CMA) agreed to conduct a two-generation reproductive study in rats. 



Sodium chlorite was used as the test compound. It should be noted that 



data on chlorite are relevant to assessing the risks of chlorine 



dioxide because chlorine dioxide rapidly disassociates to chlorite (and 



chloride) (USEPA, 1998b). Therefore, the new CMA two-generation 



reproductive chlorite study will be considered in assessing the risks 



for both chlorite and chlorine dioxide.



    Since the 1994 proposal, CMA has completed the two-generation 



reproductive rat study (CMA, 1996). EPA has reviewed the CMA study and 



has completed an external peer review of the study (EPA, 1997c). In 



addition, EPA has reassessed the noncancer health risk for chlorite and 



chlorine dioxide considering the new CMA study (USEPA, 1998b). This 



reassessment has been peer reviewed (USEPA, 1998b). Based on this 



reassessment, EPA is considering changing the proposed MCLG for 



chlorite from 0.08 mg/L to 0.8 mg/L based on the NOAEL identified from 



the new CMA study. Since data on chlorite are considered relevant to 



chlorine dioxide risks and the two generation reproduction data gap has 



been filled, EPA is also considering changing the proposed MRDLG for 



chlorine dioxide from 0.3 mg/L to 0.8 mg/L. The basis for these changes 



are discussed below.



1. 1997 CMA Two-Generation Reproduction Rat Study



    The CMA two-generation reproductive rat study was designed to 



evaluate the effects of chlorite (sodium salt) on reproduction and pre- 



and post-natal development when administered orally via drinking water 



for two successive generations (CMA, 1996). Developmental 



neurotoxicity, hematological, and clinical effects were also evaluated 



in this study.



    Sodium chlorite was administered at 0, 35, 70, and 300 ppm in 



drinking water to male and female Sprague Dawley rats (F<INF>0</INF> 



generation) for ten weeks prior to mating. Dosing continued during the 



mating period, pregnancy and lactation. Reproduction, fertility, 



clinical signs, and histopathology were evaluated in F<INF>0</INF> and 



F<INF>1</INF> (offspring from the first generation of mating) males and 



females. F<INF>1</INF> and F<INF>2</INF> (offspring from the



second 



generation of mating) pups were evaluated for growth and development, 



clinical signs, and histopathology. In addition, F<INF>1</INF> animals 



from each dose group were assessed for neurotoxicity (e.g., 



neurohistopathology, motor activity, learning ability and memory 



retention, functional observations, auditory startle response). Limited 



neurotoxicological evaluations were conducted on F<INF>2</INF> pups.



    The CMA report concluded that there were no treatment related 



effects at any dose level for systemic, reproductive/developmental, and 



developmental neurological end points. The report indicates that there 



were small statistically significant decreases in the maximum response 



to auditory startle response in the F<INF>1</INF> animals at the mid 



and high dose (70 and 300 ppm); this neurological effect was not 



considered to be toxicologically significant. A reduction in pup weight 



and decreased body weight gain through lactation in the F<INF>1</INF> 



and F<INF>2</INF> animals and a decrease in body weight gain in the 



F<INF>2</INF> males at 300 ppm were noted. Decreases in liver weight in 



F<INF>0</INF> and F<INF>1</INF> animals, as well as reductions in



red 



blood cell indices in F<INF>1</INF> animals at 300 ppm and 70 ppm were 



noted. Minor hematological effects were found in F<INF>1</INF> females 



at 35 ppm. CMA concluded that the effects noted above were not 



clinically or toxicologically significant. A NOAEL of 300 ppm was 



identified in the CMA report for reproductive toxicity and for 



developmental neurotoxic effects, and a NOAEL of 70 ppm for 



hematological effects. EPA disagrees with the CMA conclusions regarding 



the NOAEL of 300 ppm for the reproductive and







[[Page 15683]]







developmental neurological effects for this study as discussed below.



2. External Peer Review of the CMA Study



    EPA has evaluated the CMA 2-generation reproductive study and 



concluded that the study design was consistent with EPA testing 



guidelines (USEPA, 1992). Additionally, an expert peer review of the 



CMA study was conducted and indicated that the study design and 



analyses were adequate (USEPA, 1997c). Although the study design was 



considered adequate and consistent with EPA guidelines, the peer review 



pointed out some limitations in the study (USEPA, 1997c). For example, 



developmental neurotoxicity evaluations were conducted after exposure 



ended at weaning. This is consistent with EPA testing guidelines and 



should potentially detect effects on the developing central nervous 



system. Nevertheless, the opportunity to detect neurological effects 



due to continuous or lifetime exposure may be reduced. The peer review 



generally questioned the CMA conclusions regarding the NOAELs for this 



study and indicated that the NOAEL should be lower than 300 ppm. The 



majority of peer reviews recommended that the NOAEL for reproductive/



developmental toxicity be reduced to 70 ppm given the treatment related 



effects found at 300 ppm, and that the NOAEL for neurotoxicity be 



reduced to 35 ppm based on significant changes in the maximum responses 



in startle amplitude and absolute brain weight at 70 and 300 ppm. The 



reviewers indicated that a NOAEL was not observed for hematological 



effects and noted that the CMA conclusion for selecting the 70 ppm 



NOAEL for the hematology variables needs to be explained further.



3. MCLG for Chlorite: EPA's Reassessment of the Noncancer Risk



    EPA has determined that the NOAEL for chlorite should be 35 ppm (3 



mg/kg/d chlorite ion, rounded) based on a weight of evidence approach. 



The data considered to support this NOAEL are summarized in USEPA 



(1998b) and included the CMA study as well as previous reports on 



developmental neurotoxicity (USEPA, 1998b). The NOAEL of 35 ppm (3 mg/



kg/d chlorite ion) is based on the following effects observed in the 



CMA study at 70 and 300 ppm chlorite: Decreases in absolute brain and 



liver weight, and lowered auditory startle amplitude. Decreases in pup 



weight were found at the 300 ppm and thus a NOAEL of 70 ppm for 



reproductive effects is considered appropriate (USEPA, 1998b). Although 



70 ppm appears to be the NOAEL for hemolytic effects, the NOAEL and 



LOAEL are difficult to discern for this endpoint given that minor 



changes were reported at 70 and 35 ppm. EPA considers the basis of the 



NOAELs to be consistent with EPA risk assessment guidelines (USEPA, 



1991, 1998i, 1996a). Furthermore, a NOAEL of 35 ppm is supported by 



effects (particularly neurodevelopmental effects) found in previously 



conducted studies of chlorite and chlorine dioxide (USEPA, 1998b).



    An RfD of 0.03 mg/kg/d is estimated using a NOAEL of 3 mg/kg/d and 



an uncertainty factor of 100 to account for inter- and intra-species 



differences. The revised MCLG for chlorite is calculated to be 0.8 mg/L 



by assuming an adult tap water consumption of 2 L per day for a 70 kg 



adult and using a relative source contribution of 80% (because most 



exposure to chlorite is likely to come from drinking water):



[GRAPHIC] [TIFF OMITTED] TP31MR98.024







Therefore, EPA is considering an increase in the proposed MCLG for 



chlorite from 0.08 mg/L to 0.8 mg/L. A more detailed discussion of this 



assessment is included in the docket for this Notice (USEPA, 1998b).



4. MRDLG for Chlorine Dioxide: EPA's Reassessment of the Noncancer Risk



    EPA believes that data on chlorite are relevant to assessing the 



risk of chlorine dioxide because chlorine dioxide rapidly disassociates 



to chlorite (and chloride) (USEPA, 1998b). Therefore, the findings from 



the 1997 CMA two-generation reproductive study on sodium chlorite 



should be considered in a weight of evidence approach for establishing 



the MRDLG for chlorine dioxide. Based on all the available data, 



including the CMA study, a dose of 3 mg/kg/d remains as the NOAEL for 



chlorine dioxide (USEPA, 1998b). The MRDLG for chlorine dioxide is 



increased 3 fold from the 1994 proposal since the CMA 1997 study was a 



two-generation reproduction study. Using a NOAEL of 3 mg/kg/d and 



applying an uncertainty factor of 100 to account for inter- and intra-



species differences in response to toxicity, the revised MRDLG for 



chlorine dioxide is calculated to be 0.8 mg/L. This MRDLG takes into 



account an adult tap water consumption of 2 L per day for a 70 kg adult 



and applies a relative source contribution of 80% (because most 



exposure to chlorine dioxide is likely to come from drinking water):



[GRAPHIC] [TIFF OMITTED] TP31MR98.025







EPA is considering revising the MRDLG for chlorine dioxide from 0.3 mg/



L to 0.8 mg/L. A more detailed discussion of this assessment can be 



found in the docket for this Notice (USEPA, 1998b).



5. External Peer Review of EPA's Reassessment



    Three external experts have reviewed the EPA reassessment for 



chlorite and chlorine dioxide (see USEPA, 1998b). Two of the three 



reviewers generally agreed with EPA conclusions regarding the 



identified NOAEL of 35 ppm for neurodevelopmental toxicity. The other 



reviewer indicated that the developmental neurological results from the 



CMA study were transient, too inconsistent, and equivocal to identify a 



NOAEL. EPA believes that although different responses were found for 



startle response (as indicated by measures of amplitude, latency, and 



habituation), this is not unexpected given that these measures examine 



different aspects of the nervous system, and thus can be differentially 



affected. Although no neuropathology was observed in the CMA study, 



neurofunctional (or neurochemical)







[[Page 15684]]







changes such as startle responses can indicate potential neurotoxicity 



without neuropathological effects. Furthermore, transient effects are 



considered an important indicator of neurotoxicity as indicated in EPA 



guidelines (USEPA, 1998i). EPA maintains that the NOAEL is 35 ppm (3 



mg/kg/d) from the CMA chlorite study based on neurodevelopmental 



effects as well as changes in brain and liver weight. This conclusion 



is supported by previous studies on chlorite and chlorine dioxide 



(USEPA, 1998b). Other comments raised by the peer reviewers concerning 



improved clarity and completeness of the assessment were considered by 



EPA in revising the assessment document on chlorite and chlorine 



dioxide.



6. Summary of Key Observations



    EPA continues to believe that chlorite and chlorine dioxide may 



have an adverse effect on the public health. EPA identified a NOAEL of 



35 ppm for chlorite based on neurodevelopmental effects from the 1997 



CMA two-generation reproductive study, which is supported by previous 



studies on chlorite and chlorine dioxide. In addition, EPA identified a 



NOAEL of 70 ppm for reproductive/developmental effects and hemolytic 



effects. EPA considers this study relevant to assessing the risk to 



chlorine dioxide. Based on the EPA reassessment, EPA is considering 



adjusting the MCLG for chlorite from 0.08 mg/L to 0.8 mg/L. Because 



data on chlorite are considered relevant to chlorine dioxide risks, EPA 



is considering adjusting the MRDLG for chlorine dioxide from 0.3 mg/L 



to 0.8 mg/L. The MRDL for chlorine dioxide would remain at 0.8 mg/L. 



The MCL for chlorite would remain at 1.0 mg/L because as noted in the 



1994 proposal, 1.0 mg/L for chlorite is the lowest level achievable by 



typical systems using chlorine dioxide and taking into consideration 



the monitoring requirements to determine compliance. In addition, given 



the margin of safety that is factored into the estimation of the MCLG, 



EPA believes that 1.0 mg/L will be protective of public health. It 



should be noted that the MCLG and MRDLG presented for chlorite and 



chlorine dioxide are considered to be protective of susceptible groups, 



including children given that the RfD is based on a NOAEL derived from 



developmental testing, which includes a two-generation reproductive 



study. A two-generation reproductive study evaluates the effects of 



chemicals on the entire developmental and reproductive life of the 



organism. Additionally, current methods for developing RfDs are 



designed to be protective for sensitive populations. In the case of 



chlorite and chlorine dioxide a factor of 10 was used to account for 



variability between the average human response and the response of more 



sensitive individuals.



7. Requests for Comments



    Based on the recent two-generation reproductive rat study for 



chlorite (CMA, 1996), EPA is considering revising the MCLG for chlorite 



from 0.08 mg/L to 0.8 mg/L and the MRDLG for chlorine dioxide from 0.3 



mg/L to 0.8 mg/L. EPA requests comments on these possible changes in 



the MCLGs and on EPA's assessment of the CMA report.







B. Trihalomethanes







    The 1994 proposed rule included an MCL for TTHM of 0.08 mg/L. MCLGs 



of zero for chloroform, BDCM and bromoform were based on sufficient 



evidence of carcinogenicity in animals. The MCLG of 0.06 mg/L for 



dibromochloromethane (DBCM) was based on observed liver toxicity from a 



subchronic study and limited animal evidence for carcinogenicity. As 



stated in the 1997 NODA, several new studies have been published on 



bromoform, BDCM, and chloroform since the 1994 proposal. The 1997 NODA 



concluded that the new studies on THMs contribute to the weight-of-



evidence conclusions reached in the 1994 proposed rule, and that the 



new studies are not anticipated to change the proposed MCLGs for BDCM, 



DBCM, and bromoform. Since the 1997 NODA, the EPA has evaluated the 



significance of an ILSI panel report on the cancer risk assessment for 



chloroform. EPA has conducted a reassessment of chloroform (USEPA, 



1998c), considering the ILSI report. The EPA reassessment of chloroform 



has been peer reviewed (USEPA, 1998c). Based on EPA's reassessment, the 



Agency is considering changing the proposed MCLG for chloroform from 



zero to 0.3 mg/L.



1. 1997 International Life Sciences Institute Expert Panel Conclusions 



for Chloroform



    In 1996, EPA co-sponsored an ILSI project in which an expert panel 



was convened and charged with the following objectives: (i) Review the 



available database relevant to the carcinogenicity of chloroform and 



DCA, excluding exposure and epidemiology data; (ii) consider how end 



points related to the mode of carcinogenic action can be applied in the 



hazard and dose-response assessment; (iii) use guidance provided by the 



1996 EPA Proposed Guidelines for Carcinogen Assessment to develop 



recommendations for appropriate approaches for risk assessment; and 



(iv) provide a critique of the risk assessment process and comment on 



issues encountered in applying the proposed EPA Guidelines (ILSI, 



1997). The panel was made up of 10 expert scientists from academia, 



industry, government, and the private sector. It should be emphasized 



that the ILSI report does not represent a risk assessment, per se, for 



chloroform (or DCA) but, rather, provides recommendations on how to 



proceed with a risk assessment for these two chemicals.



    To facilitate an understanding of the ILSI panel recommendations 



for the dose-response characterization of chloroform, the EPA 1996 



Proposed Guidelines for Carcinogen Risk Assessment must be briefly 



described. For a more detail discussion of these guidelines, refer to 



USEPA (1996b).



    The EPA 1996 Proposed Guidelines for Carcinogen Risk Assessment 



describes a two-step process to quantifying cancer risk (USEPA, 1996b). 



The first step involves modeling response data in the empirical range 



of observation to derive a point of departure. The second step is to 



extrapolate from this point of departure to lower levels that are 



within the range of human exposure. A standard point of departure was 



proposed as the lower 95% confidence limit on a dose associated with 



10% extra risk (LED<INF>10</INF>). Based on comments from the public 



and the EPA's Science Advisory Board, the central or maximum likelihood 



estimate (i.e., ED<INF>10</INF>) is also being considered as a point of 



departure. Once the point of departure is identified, a straight-line 



extrapolation to the origin (i.e., zero dose, zero extra risk) is 



conducted as the linear default approach. The linear default approach 



would be considered for chemicals in which the mode of carcinogenic 



action understanding is consistent with low dose linearity or as a 



science policy choice for those chemicals for which the mode of action 



is not understood.



    The EPA 1996 Proposed Guidelines for Carcinogen Risk Assessment are 



different from the 1986 guidelines approach that applied the linearized 



multi-stage model (LMS) to extrapolate low dose risk. The LMS approach 



under the 1986 guidelines was the only default for low dose 



extrapolation. Under the 1996 proposed guidelines both linear and 



nonlinear default approaches are available. The nonlinear approach 



applies a margin of exposure (MoE) analysis rather than estimating the 



probability of effects at low doses. In order to use the nonlinear 



default, the agent's mode of action in causing tumors must be 



reasonably understood.







[[Page 15685]]







The MoE analysis is used to compare the point of departure with the 



human exposure levels of interest (i.e., MoE = point of departure 



divided by the environmental exposure of interest). The key objective 



of the MoE analysis is to describe for the risk manager how rapidly 



responses may decline with dose. A shallow slope suggests less risk 



reduction at decreasing exposure than does a steep one. Information on 



factors such as the nature of response being used for the point of 



departure (i.e., tumor data or a more sensitive precursor response) and 



biopersistence of the agent are important considerations in the MoE 



analysis. A numerical default factor of no less than 10-fold each may 



be used to account for human variability and for interspecies 



differences in sensitivity when humans may be more sensitive than 



animals.



    The ILSI expert panel considered a wide range of information on 



chloroform including rodent tumor data, metabolism/toxicokinetic 



information, cytotoxicity, genotoxicity, and cell proliferation data. 



Based on its analysis of the data, the panel concluded that the weight 



of evidence for the mode of action understanding indicated that 



chloroform was not acting through a direct DNA reactive mechanism. The 



evidence suggested, instead, that exposure to chloroform resulted in 



recurrent or sustained toxicity as a consequence of oxidative 



generation of highly tissue reactive and toxic metabolites (i.e., 



phosgene and hydrochloric acid (HCl)), which in turn would lead to 



regenerative cell proliferation. Oxidative metabolism was considered by 



the panel to be the predominant pathway of metabolism for chloroform. 



This mode of action was considered to be the key influence of 



chloroform on the carcinogenic process. The ILSI report noted that the 



weight-of-evidence for the mode of action was stronger for the mouse 



kidney and liver responses and more limited, but still supportive, for 



the rat kidney tumor responses.



    The panel viewed chloroform as a likely carcinogen to humans above 



a certain dose range, but considered it unlikely to be carcinogenic 



below a certain dose range. The panel indicated that ``This mechanism 



is expected to involve a dose-response relationship which is nonlinear 



and probably exhibits an exposure threshold.'' The panel, therefore, 



recommended the nonlinear default or margin of exposure approach as the 



appropriate one for quantifying the cancer risk associated with 



exposure to chloroform.



2. MCLG for Chloroform: EPA's Reassessment of the Cancer Risk



    In the 1994 proposed rule, EPA classified chloroform under the 1986 



EPA Guidelines for Carcinogen Risk Assessment as a Group B2, probable 



human carcinogen. This classification was based on sufficient evidence 



of carcinogenicity in animals. Kidney tumor data in male Osborne-Mendel 



rats reported by Jorgenson et al. (1985) was used to estimate the 



carcinogenic risk. An MCLG of zero was proposed. Because the mode of 



carcinogenic action was not understood at that time, EPA used the 



linearized multistage model and derived an upper bound carcinogenicity 



potency factor for chloroform of 6  x  10<SUP>-3</SUP> mg/kg/d. The 



lifetime cancer risk levels of 10<SUP>-6</SUP>, 10<SUP>-5</SUP>,



and 



10<SUP>-4</SUP> were determined to be associated with concentrations of 



chloroform in drinking water of 6, 60, and 600 <greek-m>g/L.



    Since the 1994 rule, several new studies have provided insight into 



the mode of carcinogenic action for chloroform. EPA has reassessed the 



cancer risk associated with chloroform exposure (USEPA, 1998c) by 



considering the new information, as well as the 1997 ILSI panel report. 



This reassessment used the principles of the 1996 EPA Proposed 



Guidelines for Carcinogen Risk Assessment (USEPA, 1996b), which are 



considered scientifically consistent with the Agency's 1986 guidelines 



(USEPA, 1986). Based on the current evidence for the mode of action by 



which chloroform may cause tumorgenesis, EPA has concluded that a 



nonlinear approach is more appropriate for extrapolating low dose 



cancer risk rather than the low dose linear approach used in the 1994 



proposed rule. Because tissue toxicity is key to chloroform's mode of 



action, EPA has also considered noncancer toxicities in determining the 



basis for the MCLG. After evaluating both cancer risk and noncancer 



toxicities as the basis for the MCLG, EPA concluded that the RfD for 



hepatoxicity should be used. Hepatotoxicity, thus, serves as the basis 



for the MCLG given that this is the primary effect of chloroform and 



the more sensitive endpoint. Therefore, EPA is considering changing the 



proposed MCLG for chloroform from zero to 0.3 mg/L based on the RfD for 



hepatoxicity. The basis for these conclusions are discussed below.



    a. Weight of the Evidence and Understanding of Mode of Carcinogenic 



Action. EPA has fully considered the 1997 ILSI report and the new 



science that has emerged on chloroform since the 1994 proposed rule. 



Based on this new information, EPA considers chloroform to be a likely 



human carcinogen by all routes of exposure (USEPA, 1998c). Chloroform's 



carcinogenic potential is indicated by animal tumor evidence (liver 



tumors in mice and renal tumors in both mice and rats) from inhalation 



and oral exposures, as well as metabolism, toxicity, mutagenicity and 



cellular proliferation data that contribute to an understanding of mode 



of carcinogenic action. Although the precise mechanism of chloroform 



carcinogenicity is not established, EPA agrees with the ILSI panel that 



a DNA reactive mutagenic mechanism is not likely to be the predominant 



influence of chloroform on the carcinogenic process. EPA believes that 



there is a reasonable scientific basis to support a mode of 



carcinogenic action involving cytotoxicity produced by the oxidative 



generation of highly reactive metabolites, phosgene and HCl, followed 



by regenerative cell proliferation as the predominant influence of 



chloroform on the carcinogenic process (USEPA, 1998c). EPA, therefore, 



agrees with the ILSI report that the chloroform dose-response should be 



considered nonlinear.



    A recent article by Melnick et al. (1998) was published after the 



1997 ISLI panel report and concludes that cytotoxicity and regenerative 



hyperplasia alone are not sufficient to explain the liver 



carcinogenesis in female B6C3F1 mice exposed to trihalomethanes, 



including chloroform. Although this article raises some interesting 



issues, EPA views the results for chloroform supportive of the role 



that toxicity and compensatory proliferation may play in chloroform 



carcinogenicity because statistically significant increases (p<0.05) in 



hepatoxicity and cell proliferation are found for chloroform in this 



study.



    b. Dose-Response Assessment. EPA has used several different 



approaches for estimating the MCLG for chloroform: the LED<INF>10</INF> 



for tumor response; the ED<INF>10</INF> for tumor response; and the RfD 



for hepatoxicity. Each of these approaches are described below. EPA 



believes the RfD based on hepatotoxicity serves as the most appropriate 



basis for the MCLG for the reasons discussed below.



    EPA has presented the linear and nonlinear default approaches to 



estimating the cancer risk associated with drinking water exposure to 



chloroform (USEPA, 1998c). EPA considered the linear default approach 



because of remaining uncertainties associated with the understanding of 



chloroform's mode of carcinogenic action: for example, lack of data on







[[Page 15686]]







cytotoxicity and cell proliferation responses in Osborne-Mendel rats, 



lack of mutagenicity data on chloroform metabolites, and the lack of 



comparative metabolic data between humans and rodents. Although these 



data deficiencies raise some uncertainty about how chloroform may 



influence tumor development at low doses, EPA views the linear dose-



response extrapolation approach as overly conservative in estimating 



low-dose risk.



    EPA concludes that the nonlinear default or margin of exposure 



approach is the preferred approach to quantifying the cancer risk 



associated with chloroform exposure because the evidence is stronger 



for a nonlinear mode of carcinogenic action. The tumor kidney response 



data in Osborne-Mendel rats from Jorgenson et al. (1985) are used as 



the basis for the point of departure (i.e., LED<INF>10</INF> and 



ED<INF>10</INF>) because a relevant route of human exposure (i.e., 



drinking water) and multiple doses of chloroform (i.e., 5 doses 



including zero) were used in this study (USEPA, 1998c). The animal data 



were adjusted to equivalent human doses using body weight raised to the 



\3/4\ power as the interspecies scaling factor, as proposed in the 1996 



EPA Proposed Guidelines for Carcinogen Risk Assessment. The 



ED<INF>10</INF> and LED<INF>10</INF> were estimated to be 37



and 23 mg/



kg/d, respectively.



    As part of the margin of exposure analysis, a 100 fold factor was 



applied to account for the variability and uncertainty associated with 



intra- and interspecies differences in the absence of data specific to 



chloroform. An additional factor of 10 was applied to account for the 



remaining uncertainties associated with the mode of carcinogenic action 



understanding and the nature of the tumor dose response relationship 



being relatively shallow. EPA believes 1000 fold represents an adequate 



margin of exposure that addresses inter- and intra-species differences 



and uncertainties in the database. Other factors considered in 



determining the adequacy of the margin of exposure include the size of 



the human population exposed, duration and magnitude of human exposure, 



and persistence in the environment. Taking these factors into 



consideration, a MoE of 1000 is still regarded as adequate. Although a 



large population is chronically exposed to chlorinated drinking water, 



chloroform is not biopersistent and humans are exposed to relatively 



low levels of chloroform in the drinking water (generally under 100 



<greek-m>g/L), which are below exposures needed to induce a cytotoxic 



response. Furthermore, EPA believes that a MoE of 1000 is protective of 



susceptible groups, including children. The mode of action 



understanding for chloroform's cytotoxic and carcinogenic effects 



involves a generalized mechanism of toxicity that is seen consistently 



across different species. Furthermore, the activity of the enzyme 



(i.e., CYP2E1) involved in generating metabolites key to chloroform's 



mode of action is not greater in children than in adults, and probably 



less (USEPA, 1998c). Therefore, the ED<INF>10</INF> of 37 mg/kg-d and 



the LED<INF>10</INF> of 23 mg/kg-d is divided by a MoE of 1000 giving 



dose estimates of 0.037 and 0.023 mg/kg/d for carcinogenicity, 



respectively. These estimates would translate into MCLGs of 1.0 mg/L 



and 0.6 mg/L, respectively.



    The underlying basis for chloroform's carcinogenic effects involve 



oxidative generation of reactive and toxic metabolites (phosgene and 



HCl) and thus are related to its noncancer toxicities (e.g., liver or 



kidney toxicities). It is important, therefore, to consider noncancer 



outcomes in the risk assessment (USEPA, 1998c). The electrophilic 



metabolite phosgene would react with macromolecules such as 



phosphotidyl inositols or tyrosine kinases which in turn could 



potentially lead to interference with signal transduction pathways 



(i.e., chemical messages controlling cell division), thus, leading to 



carcinogenesis. Likewise, it is also plausible that phosgene reacts 



with cellular phospholipids, peptides, and proteins resulting in 



generalized tissue injury. Glutathione, free cysteine, histidine, 



methionine, and tyrosine are all potential reactants for electrophilic 



agents. Hepatoxicity is the primary effect observed following 



chloroform exposure, and among tissues studied for chloroform-oxidative 



metabolism, the liver was found to be the most active (ILSI, 1997). In 



the 1994 proposed rule, data from a chronic oral study in dogs (Heywood 



et al., 1979) were used to derive the RfD of 0.01 mg/kg/d (USEPA, 



1994a). This RfD is based on a LOAEL for hepatotoxicity and application 



of an uncertainty factor of 1000 (100 was used to account for inter-and 



intra-species differences and a factor of 10 for use of a LOAEL). The 



MCLG is calculated to be 0.3 mg/L by assuming an adult tap water 



consumption of 2 L of tap water per day for a 70 kg adult, and by 



applying a relative source contribution of 80% (EPA assumes most 



exposure is likely to come from drinking water):



[GRAPHIC] [TIFF OMITTED] TP31MR98.026







    Therefore, 0.3 mg/L based on hepatoxicity in dogs (USEPA, 1994a) is 



being considered as the MCLG because liver toxicity is a more sensitive 



effect of chloroform than the induction of tumors. Even if low dose 



linearity is assumed, as it was in the 1994 proposed rule, a MCLG of 



0.3 mg/L would be equivalent to a 5 x 10<SUP>-5</SUP> cancer risk 



level. EPA concludes that an MCLG based on protection against liver 



toxicity should be protective against carcinogenicity given that the 



putative mode of action understanding for chloroform involves 



cytotoxicity as a key event preceding tumor development. Therefore, the 



recommended MCLG for chloroform is 0.3 mg/L. The assessment that forms 



the basis for this conclusion can be found in the docket for this 



Notice (USEPA, 1998c).



3. External Peer Review of EPA's Reassessment



    Three external experts reviewed the EPA reassessment of chloroform 



(USEPA, 1998c). The peer review generally indicated that the nonlinear 



approach used for estimating the carcinogenic risk associated with 



exposure to chloroform was reasonable and appropriate and that the role 



of a direct DNA reactive mechanism unlikely. Other comments concerning 



improved clarity and completeness of the assessment were considered by 



EPA in revising the chloroform assessment document.



4. Summary of Key Observations



    Based on the available evidence, EPA concludes that a nonlinear 



approach should be considered for estimating the carcinogenic risk 



associated with lifetime exposure to chloroform via drinking water. It 



should be noted that the margin of exposure approach taken for 



chloroform carcinogenicity is consistent with conclusions reached in a 



recent report by the World Health







[[Page 15687]]







Organization for Chloroform (WHO, 1997). The 1994 proposed MCLG was 



zero for chloroform. EPA believes it should now be 0.3 mg/L given that 



hepatic injury is the primary effect following chloroform exposure, 



which is consistent with the mode of action understanding for 



chloroform. Thus, the RfD based on hepatoxicity is considered a 



reasonable basis for the chloroform MCLG. EPA believes that the RfD 



used for chloroform is protective of sensitive groups, including 



children. Current methods for developing RfDs are designed to be 



protective for sensitive populations. In the case of chloroform a 



factor of 10 was used to account for variability between the average 



human response and the response of more sensitive individuals. 



Furthermore, the mode of action understanding for chloroform does not 



indicate a uniquely sensitive subgroup or an increased sensitivity in 



children.



    EPA continues to conclude that exposure to chloroform may have an 



adverse effect on the public health. EPA also continues to believe the 



MCL of 0.080 mg/L for TTHMs is appropriate despite the increase in the 



MCLG for chloroform. EPA believes that the benefits of the 1994 



proposed MCL of 0.080 mg/L for TTHMs will result in reduced exposure to 



chlorinated DBPs in general, not solely THMs. EPA considers this a 



reasonable assumption at this time given the uncertainties existing in 



the current health and exposure databases for DBPs in general. 



Moreover, the MCLGs for BDCM and bromoform remain at zero and thus, a 



TTHM MCL of 0.080 mg/L is appropriate to assure that levels of these 



two THMs are kept as low as possible. In addition, the MCL for TTHMs is 



used as an indicator for the potential occurrence of other DBPs in high 



pH waters. The MCL of 0.080 mg/L for TTHMs to control DBPs in high pH 



waters (in conjunction with the MCL of 0.060 mg/L for HAA5 to control 



DBPs in lower pH waters) and enhanced coagulation treatment technique 



remains a reasonable approach at this time for controlling chlorinated 



DBPs in general and protecting the public health. There is ongoing 



research being sponsored by the EPA, NTP, and the American Water Works 



Research Foundation to better characterize the health risks associated 



with DBPs.



5. Requests for Comments



    Based on the information presented above, EPA is considering 



revising the MCLG for chloroform from zero to 0.30 mg/L. EPA requests 



comments on this possible change in the MCLG and on EPA's cancer 



assessment for chloroform based on the results from the ILSI report 



(1997) and new data.







C. Haloacetic Acids







    The 1994 proposed rule included an MCL of 0.060 mg/L for the 



haloacetic acids (five HAAs-monobromoacetic acid, dibromoacetic acid, 



monochloroacetic acid, dichloroacetic acid, and trichloroacetic acid). 



An MCLG of zero was proposed for dichloroacetic acid (DCA) based on 



sufficient evidence of carcinogenicity in animals, and an MCLG of 0.3 



mg/L for trichloroacetic acid (TCA) was based on developmental toxicity 



and possible carcinogenicity. As pointed out in the 1997 NODA, several 



toxicological studies have been identified for the haloacetic acids 



since the 1994 proposal (also see USEPA, 1997b).



    Since the 1997 NODA, the EPA has evaluated the significance of the 



1997 ILSI panel report on the cancer assessment for DCA. EPA has 



conducted a reassessment of DCA (USEPA, 1998e) using the principles of 



the EPA 1996 Guidelines for Carcinogen Risk Assessment (USEPA, 1996b), 



which are considered scientifically consistent with the Agency's 1986 



guidelines (USEPA, 1986). This reassessment has been peer reviewed 



(USEPA, 1998e). Based on the scope of the ILSI report, EPA's own 



assessment and comments from peer reviewers, the Agency believes that 



the MCLG for DCA should remain as proposed at zero. This conclusion is 



discussed in more detail below.



1. 1997 International Life Sciences Institute Expert Panel Conclusions 



for Dichloroacetic Acid (DCA)



    ILSI convened an expert panel in 1996 (ILSI, 1997) to explore the 



application of the USEPA's 1996 Proposed Guidelines for Carcinogen Risk 



Assessment (USEPA, 1996a) to the available data on the potential 



carcinogenicity of chloroform and dichloroacetic acid (as described 



under the chloroform section). The panel considered data on DCA which 



included chronic rodent bioassay data and information on mutagenicity, 



tissue toxicity, toxicokinetics, and other mode of action information.



    The ILSI panel concluded that the tumor dose-response (liver tumors 



only) observed in rats and mice was nonlinear (ILSI, 1997). The panel 



noted that the liver was the only tissue consistently examined for 



histopathology. It further concluded that all the experimental doses 



that produced tumors in mice also produce hepatoxicity (i.e., most 



doses used exceeded the maximally tolerated dose). Although the mode of 



carcinogenic action for DCA was unclear, the ISLI panel concluded that 



DCA does not directly interact with DNA. It speculated that the 



hepatocarcinogenicity was related to hepatotoxicity, cell 



proliferation, and inhibition of program cell death (apoptosis). The 



panel concluded that the potential human carcinogenicity of DCA 



``cannot be determined'' given the lack of adequate rodent bioassay 



data, as well as human data. This conclusion is in contrast to the 1994 



EPA proposal in which it was concluded that DCA was a Group 



B<INF>2</INF> probable human carcinogen. In its current reevaluation of 



DCA carcinogenicity, EPA disagrees with the panel's conclusion that the 



human carcinogenic potential of DCA can not be determined. EPA's more 



recent assessment of DCA data includes published information not 



available at the time of the ILSI panel assessment. Based on the 



current weight of the evidence EPA concludes that DCA is a likely human 



carcinogen as it did in the 1994 proposed rule for the reasons 



discussed below.



2. MCLG for DCA: EPA's Reassessment of the Cancer Hazard



    In the 1994 proposed rule, DCA was classified as a Group B2, 



probable human carcinogen in accordance with the 1986 EPA Guidelines 



for Carcinogen Risk Assessment (USEPA, 1986). The DCA categorization 



was based primarily on findings of liver tumors in rats and mice, which 



was regarded as ``sufficient'' evidence in animals. No lifetime risk 



calculation was conducted at that time; EPA proposed an MCLG of zero 



(USEPA, 1994a).



    EPA has prepared a new hazard characterization regarding the 



potential carcinogenicity of DCA in humans (USEPA, 1998e). The 



objective of this report was to develop a weight-of-evidence 



characterization using the principles of the EPA's 1996 Proposed 



Guidelines for Carcinogen Risk Assessment (USEPA, 1996), as well as to 



consider the issues raised by the 1997 ILSI panel report. The EPA 



hazard characterization relies on information available in existing 



peer-reviewed source documents. Moreover, this hazard characterization 



considers published information not available to the ILSI panel (e.g., 



mutagenicity studies). This new characterization addresses issues 



important to interpretation of rodent cancer bioassay data, in 



particular, mechanistic information pertinent to the etiology of DCA-



induced rodent liver tumors and their relevance to humans.



    Based on the hepatocarcinogenic effects of DCA in both rats and 



mice in multiple studies, and mode of action







[[Page 15688]]







related effects (e.g., mutational spectra in oncogenes, elevated serum 



glucocorticoid levels, alterations in cell replication and death), EPA 



concludes that DCA should be considered as a ``likely'' cancer hazard 



to humans (USEPA, 1998e). This is similar to the 1994 view of a B2, 



probable human carcinogen, in the proposed rule.



    DCA concentrations as low as 0.5 g/L have been observed to cause a 



tumor incidence in mice of about 80% and in rats of about 20% in a 



lifetime bioassays, as well as inducing multiple tumors per animal 



(USEPA, 1998e). Higher doses of DCA are associated with up to 100% 



tumor incidence and as many as four tumors per animal in a number of 



studies. Time-to-tumor development in mice is relatively short and 



decreases with increased dose. The ILSI panel concluded that doses of 1 



g/L or greater in mice produced severe hepatotoxicity, and thus 



exceeded the MTD. They further indicated that there was marked 



hepatoxicity at 0.5 g/L of DCA, (albeit not as severe as the higher 



doses). EPA agrees that there was hepatoxicity at all the doses wherein 



there was a tumor response in mice. It should be noted that the MTD 



selected for the DeAngelo et al. (1991) mouse study was a dose that 



results in a 10% inhibition of body weight gain when compared to 



controls. This is within the limits designated in EPA guidelines 



(USEPA, 1998e). Furthermore, no hepatoxicity was seen in the rat 



studies, where DCA induced liver tumors of approximately 20% at the 



lowest dose, 0.5g/L (USEPA, 1998e). It appears that the ILSI report did 



not give full consideration to the rat tumor results as part of the 



overall weight-of-the-evidence for potential human carcinogenicity. EPA 



agrees with the ILSI panel, that the rodent assay data are not complete 



for DCA; for example, full histopathology is lacking for both sexes in 



two rodent species. This deficiency results in uncertainty concerning 



the potential of DCA to be tumorgenic at lower doses and at tissue 



sites other than liver. Nevertheless, the finding of increased tumor 



incidences as well as multiplicity at DCA exposure levels (0.5 g/L) in 



both rats and mice where minimal hepatotoxicity and no compensatory 



replication was seen supports the belief that observed tumors are 



related to chemical treatment.



    Although DCA has been found to be mutagenic and clastogenic, 



responses generally occur at relatively high exposure levels (USEPA, 



1998e). EPA acknowledges that a mutagenic mechanism may not be as 



important influence of DCA on the carcinogenic process at lower 



exposure levels as it might be at higher exposures. Evidence is still 



accumulating that suggests a mode of carcinogenic action for DCA 



through modification of cell signaling systems, with down-regulation of 



control mechanisms in normal cells giving a growth advantage to altered 



or initiated cells (USEPA, 1998e). The tumor findings in rodents and 



the mode of action information contributes to the weight-of-evidence 



concern for DCA (USEPA, 1998e; ILSI, 1997). EPA considers that a 



contribution of cytotoxicity and compensatory proliferation at high 



doses cannot be ruled out at this time; however, these effects were 



inconsistently observed in mice at lower exposure levels, and not at 



all in mice at 0.5 g/L, or in rats, at all exposure doses. Although the 



shape of the tumor dose responses are nonlinear, there is, however, an 



insufficient basis for understanding the possible mechanisms that might 



contribute to DCA tumorigenesis at low doses, as well as the shape of 



the dose response below the observable range of tumor responses.



    In summary, EPA considers the mode of action through which DCA 



induces liver tumors in both rats and mice to be unclear. As discussed 



above, EPA considers the overall weight of the evidence to support 



placing DCA in the ``likely'' group for human carcinogenicity 



potential. This hazard potential is indicated by tumor findings in mice 



and rats, and other mode of action data using the 1996 guideline 



weight-of-evidence process. The remaining uncertainties in the data 



base include incomplete bioassay studies for full histopathology and 



information on an understanding of DCA's mode of carcinogenic action. 



The likelihood of human hazard associated with low levels of DCA 



usually encountered in the environment or in drinking water is not 



understood. Although DCA tumor effects are associated with high doses 



used in the rodent bioassays, reasonable doubt exists that the mode of 



tumorgenesis is solely through mechanisms that are operative only at 



high doses. Therefore, as in the 1994 proposed rule, EPA believes that 



the MCLG for DCA should remain as zero to assure public health 



protection. NTP is implementing a new two year rodent bioassay that 



will include full histopathology at lower doses than those previously 



studied. Additionally, studies on the mode of carcinogenic action are 



being done by various investigators including the EPA health research 



laboratory.



3. External Peer Review of EPA's Reassessment



    Three external experts reviewed the EPA reassessment of DCA (USEPA, 



1998e). The review comments were generally favorable. There was a range 



of opinion on the issue of whether DCA should be considered a likely 



human cancer hazard. One reviewer agreed that the current data 



supported a human cancer concern for DCA, while another reviewer 



believed that it was premature to judge the human hazard potential. The 



third reviewer did not specifically agree or disagree with EPA's 



conclusion of ``likely'' human hazard. Other issues raised by the peer 



review concerned the dose response for DCA carcinogenicity. The peer 



review generally concluded on the one hand that the mode of action was 



incomplete to support a nonlinear approach, but on the other hand, the 



mutagenicity data did not support low dose linearity. One reviewer 



believed that the possibility of a low dose risk could not be 



dismissed. Other comments concerning improved clarity and completeness 



of the assessment were considered by EPA in revising the DCA assessment 



document.



4. Summary of Key Observations



    EPA continues to believe that exposure to DCA may have an adverse 



effect on the public health. Based on the above discussion, EPA 



considers DCA to be a ``likely'' cancer hazard to humans. This 



conclusion is similar to the conclusion reached in the 1994 proposed 



rule that DCA was a probable human carcinogen (i.e., Group 



B<INF>2</INF> Carcinogen). EPA considers the DCA data inadequate for 



dose-response assessment, which was the view in the 1994 proposed rule. 



EPA, therefore, believes at this time that the MCLG should remain at 



zero to assure public health protection. The assessment that this 



conclusion is based on can be found in the docket for this Notice 



(USEPA, 1998e).



5. Requests for Comments



    Based on the information presented above, EPA is considering 



maintaining the MCLG of zero for DCA. EPA requests comments on 



maintaining the zero MCLG for DCA and on EPA's cancer assessment for 



DCA in light of conclusions from the ILSI report (1997) and new data.







D. Bromate







    The 1994 proposed rule included an MCL of 0.010 mg/L and an MCLG of 



zero for bromate. Since the 1994 proposed rule, EPA has completed and 



analyzed a new chronic cancer study in male rats and mice for bromate







[[Page 15689]]







(DeAngelo et al., 1998). EPA has reassessed the cancer risk associated 



with bromate exposure and had this reassessment peer reviewed (USEPA, 



1998d). Based on this reassessment, EPA believes that the MCLG for 



bromate should remain as zero.



1. 1998 EPA Rodent Cancer Bioassay



    In the cancer bioassay by DeAngelo et al. (1998), 78 male F344 rats 



were administered 0, 20, 100, 200, 400 mg/L potassium bromate 



(KBrO<INF>3</INF>) in the drinking water, and 78 male B6C3F1 mice were 



administered 0, 80, 400, 800 mg/L KBrO<INF>3</INF>. Exposure was 



continued through week 100. Although a slight increase in kidney tumors 



was observed in mice, there was not a dose-response trend. In rats, 



dose-dependent increases in tumors were found at several sites (kidney, 



testicular mesothelioma, and thyroid). This study confirms the findings 



of Kurokawa et al. (1986a and b) in which potassium bromate was found 



to be a multi-site carcinogen in rats.



2. MCLG for Bromate: EPA's Reassessment of the Cancer Risk



    In the 1994 proposal, EPA concluded that bromate was a probable 



human carcinogen (Group B2) under the 1986 EPA Guidelines for 



Carcinogen Risk Assessment weight of evidence classification approach. 



Combining the incidence of rat kidney tumors reported in two rodent 



studies by Kurokawa et al. (1986a), lifetime risks of 10<SUP>-4</SUP> 



10<SUP>-5</SUP>, and 10<SUP>-6</SUP> were determined to be



associated 



with bromate concentrations in water at 5, 0.5, and 0.05 ug/L, 



respectively.



    The new rodent cancer study by DeAngelo et al. (1998) contributes 



to the weight of the evidence for the potential human carcinogenicity 



of KBrO<INF>3</INF> and confirms the study by Kurokawa et al. (1986a, 



b). Under the principles of the 1996 EPA Proposed Guidelines for 



Carcinogen Risk Assessment weight of evidence approach, bromate is 



considered to be a likely human carcinogen. This weight of evidence 



conclusion is based on sufficient experimental findings that include 



the following: Tumors at multiple sites in rats; tumor responses in 



both sexes; and evidence for mutagenicity including point mutations and 



chromosomal aberrations in vitro. It has been suggested that bromate 



causes DNA damage indirectly via lipid peroxidation, which generates 



oxygen radicals which in turn induce DNA damage. There is insufficient 



evidence, however, to establish lipid peroxidation and free radical 



production as key events responsible for the induction of the multiple 



tumor responses seen in the bromate rodent bioassays. The assumption of 



low dose linearity is considered to be a reasonable public health 



protective approach for extrapolating the potential risk for bromate 



because of limited data on its mode of action.



    Cancer risk estimates were derived from the DeAngelo et al. (1998) 



study by applying the one stage Weibull model for the low dose linear 



extrapolation (EPA, 1998d). The Weibull model, which is a time-to-tumor 



model, was considered to be the preferred approach to account for the 



reduction in animals at risk that may be due to the decreased survival 



observed in the high dose group toward the end of the study. However, 



mortality did not compromise the results of this study (USEPA, 1998d). 



The animal doses were adjusted to equivalent human doses using body 



weight raised to the \3/4\ power as the interspecies scaling factor as 



proposed in the 1996 EPA cancer guidelines (USEPA, 1996b). The 



incidence of kidney, thyroid, and mesotheliomas in rats were modeled 



separately and then the risk estimates were combined to represent the 



total potential risk to tumor induction. The upper bound cancer potency 



(q \1\*) for bromate ion is estimated to be 0.7 per mg/kg/d (USEPA, 



1998d). Assuming a daily water consumption of 2 liters for a 70 kg 



adult, lifetime risks of 10<SUP>-4</SUP>, 10<SUP>-5</SUP> and 



10<SUP>-6</SUP> are associated with bromate concentrations in water of 



5, 0.5 and 0.05 ug/L, respectively. This estimate of cancer risk from 



the DeAngelo et al. study is similar with the risk estimate derived 



from the Kurokawa et al. (1986a) study presented in the 1994 proposed 



rule. The cancer risk estimation presented for bromate is considered to 



be protective of susceptible groups, including exposures during 



childhood given that the low dose linear default approach was used as a 



public health conservative approach.



3. External Peer Review of the EPA's Reassessment



    Three external expert reviewers commented on the EPA assessment 



report for bromate (USEPA, 1998d). The reviewers generally agreed with 



the key conclusions in the document. The peer review indicated that it 



is a reasonable default to use the rat tumor data to estimate the 



potential human cancer risk. The peer review also indicated that the 



mode of carcinogenic action for bromate is not understood at this time, 



and thus it is reasonable to use a low dose linear extrapolation as a 



default. One reviewer indicated that it was not appropriate to combine 



tumor data from different sites unless it is shown that similar 



mechanisms are involved. EPA modeled the three tumor sites separately 



to derive the cancer potencies, and thus did not assume a similar mode 



of action. The slope factors from the different tumor response were 



combined in order to express the total potential tumor risk of bromate. 



Other comments raised by the peer reviewers concerning improved clarity 



and completeness of the assessment were considered by EPA in revising 



this document.



4. Summary of Key Observations



    EPA continues to believe that exposure to bromate may have an 



adverse effect on the public health. The DeAngelo et al. (1998) study 



confirms the tumor findings reported in the study by Kurokawa et al. 



(1986a) and contributes to the weight of the carcinogenicity evidence 



for bromate. EPA believes that the an MCL of 0.010 mg/L and an MCLG of 



zero should remain for bromate as proposed in 1994. The assessment that 



this conclusion is based on can be found in the docket for this Notice 



(USEPA, 1998d).



    5. Requests for Comments



    Based on the recent two-year cancer bioassay on bromate by DeAngelo 



et al. (1998), EPA is considering maintaining the MCLG of zero for 



bromate. EPA requests comments on maintaining the zero MCLG for bromate 



and on EPA's cancer assessment for bromate.







IV. Simultaneous Compliance Considerations: D/DBP Stage 1 Enhanced 



Coagulation Requirements and the Lead and Copper Rule







    EPA received comment on the November 3, 1997 Federal Register Stage 



1 D/DBP Notice of Data Availability that expressed concern regarding 



utilities' ability to comply with the Stage 1 D/DBP enhanced 



coagulation requirements and Lead and Copper Rule (LCR) requirements 



simultaneously. Commentors stated that enhanced coagulation will lower 



the pH and alkalinity of the water during treatment. They indicated 



concern that the lower pH and alkalinity levels may place utilities in 



noncompliance with the LCR by causing violations of optimal water 



quality control parameters and/or an exceedence of the lead or copper 



action levels. EPA is not aware of data that suggests that low pH and 



alkalinity levels cannot be adjusted upward following enhanced 



coagulation to meet LCR compliance requirements. However, as discussed 



below, the Agency solicits further comment and data on this issue.



    The LCR separates public water systems into three categories: large







[[Page 15690]]







(>50,000), medium (<ls-thn-eq>50,000 but >3,300) and small (<3,300). 



Small and medium systems that do not exceed the lead and copper action 



levels (90th percentile levels of 0.015 mg/L and 1.3 mg/L, 



respectively) during the required monitoring are deemed to have 



optimized corrosion control. These systems do not have to operate under 



optimal water quality control parameters. Optimal water quality control 



parameters consist of pH, alkalinity, calcium concentration, and 



phosphate and silicate corrosion inhibitors. They are designated by the 



State. Small and medium systems exceeding the action limits must 



operate under State specified optimal water quality parameters. Large 



systems must operate under optimal water quality parameters specified 



by the State unless the difference in lead levels between the source 



and tap water samples is less than the Practical Quantification Limit 



(PQL) of the prescribed method (0.005 mg/L).



    Maintenance of each optimal water quality control parameter 



mentioned above (except for calcium concentration) is directly related 



to meeting specified pH and alkalinity levels at the entry point to the 



distribution system and in tap samples to establish LCR compliance. In 



treatment trains that EPA is aware of, utilities have the technological 



capability to raise the pH (by adding caustic--NaOH, 



Ca(OH)<INF>2</INF>) and alkalinity (by adding Na<INF>2</INF>CO3



or 



NaHCO<INF>3</INF>) of the water following enhanced coagulation and 



before it enters the distribution system. Although certain utilities 



may need to add chemical feed points to provide chemical adjustment, pH 



and alkalinity can be maintained at the values used prior to the 



implementation of enhanced coagulation. Systems that operate with pH 



and alkalinity optimal water quality control parameters should be able 



to meet the State-prescribed values by providing pH and alkalinity 



adjustment prior to entry to the distribution system. Systems that 



operate without pH and alkalinity optimal water quality control 



parameters can raise the pH and alkalinity to the levels they were at 



before enhanced coagulation by providing chemical adjustment prior to 



distribution system entry.



    The goal of calcium carbonate stabilization is to precipitate a 



layer of CaCO<INF>3</INF> scale on the pipe wall to protect it from 



corrosion. As the pH of a water decreases, the concentration of 



bicarbonate increases and the concentration of carbonate, which 



combines with calcium to form the desired CaCO<INF>3</INF>, decreases. 



At the lower pH used during enhanced coagulation, it will generally be 



more difficult to form calcium carbonate. However, post--coagulation pH 



adjustment will increase the pH and hence the concentration of 



carbonate available to form calcium carbonate scale. Systems that must 



meet a specific calcium concentration to remain in compliance with 



optimal water quality control parameters should not experience an 



increase in LCR violations due to the practice of enhanced coagulation 



provided the pH is adjusted prior to distribution system entry and the 



calcium level in the water prior to and after implementation of 



enhanced coagulation remains the same.



    EPA recognizes that the inorganic composition of the water may 



change slightly due to enhanced coagulation. For example, small amounts 



of anions and compounds that can affect corrosion rates (Cl-, 



SO<INF>4</INF><SUP>-2</SUP>) may be removed or added to the



water. The 



effect of these constituents is difficult to predict, but EPA believes 



they should be minimal for the great majority of systems due to the 



generally modest changes in the water's inorganic composition and 



because alkalinity and pH levels have a greater influence on corrosion 



rates. Increases in sulfate concentration due to increased alum 



addition during enhanced coagulation can actually lower the corrosion 



rates of lead pipe. EPA requests comment on whether changes in the 



inorganic matrix can be quantified to allow States to easily assess 



potential impacts to corrosion control.



    EPA requests comment on how lowering the pH and alkalinity during 



enhanced coagulation may cause LCR compliance problems, given that both 



pH and alkalinity levels can be adjusted to meet optimal water quality 



parameters prior to entry to the distribution system. EPA also requests 



comment on whether decreasing the pH and alkalinity during enhanced 



coagulation, and then increasing it prior to distribution system entry, 



may increase exceedences of lead and copper action levels.



    EPA is currently developing a simultaneous compliance guidance 



document working with stakeholders. The document will provide guidance 



to States and systems on maintaining compliance with other regulatory 



requirements (including the LCR) during and after the implementation of 



the Stage 1 D/DBP rule and the Interim Enhanced Surface Water Treatment 



Rule. EPA requests comment on what issues should be addressed in the 



guidance to mitigate concerns about simultaneous compliance with 



enhanced coagulation and LCR requirements. Further, the Agency requests 



comment on whether the proposed enhanced coagulation requirements and 



the existing LCR provisions that allow adjustment of corrosion control 



plans are flexible enough to address simultaneous compliance issues. Is 



additional regulatory language necessary to address this issue, or is 



guidance sufficient to mitigate potential compliance problems?







V. Compliance With Current Regulations







    EPA reaffirms its commitment to the current Safe Drinking Water Act 



regulations, including those related to microbial pathogen control and 



disinfection. Each public water system must continue to comply with the 



current regulations while new microbial and D/DBP rules are being 



developed.







VI. Conclusions







    This Notice summarizes new health information received and analyzed 



for DBPs since the November 3, 1997 NODA and requests comments on 



several issues related to the simultaneous compliance with the Stage 1 



D/DBP Rule and the Lead and Copper Rule. Based on this new information, 



EPA has developed several new documents. EPA is requesting comments on 



this new information and EPA's evaluation of the information included 



in the new documents. Based on an assessment of the new toxicology 



information, EPA believes the MCLs and MRDLs in the 1994 proposal, and 



confirmed in the 1997 FACA process, will not change. Based on the new 



information, EPA is considering increasing the proposed MCLG of zero 



for chloroform to 0.30 mg/L and the proposed MCLG for chlorite from 



0.080 mg/L to 0.80 mg/L. EPA is also considering increasing the MRDLG 



for chlorine dioxide from 0.3 mg/L to 0.8 mg/L.







VII. References







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source and bladder cancer: a case-control study. In Jolley RL, Bull RJ, 



Davis WP, et al. (eds), Water chlorination: chemistry, environmental 



impact and health effects, vol. 5. Lewis Publishers, Inc., Chelsea, MI 



pp 145-152



    3. Cantor KP, Hoover R, Hartge P. et al. 1987. Bladder cancer, 



drinking water







[[Page 15691]]







source and tap water consumption: a case control study. JNCI; 79:1269-



79.



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M, Craun GF. 1998. Drinking water source and chlorination byproducts. 



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Quintiles Report Ref. CMA/17/96.



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disinfection byproducts. In: Proceedings: Safety of Water Disinfection: 



Balancing Chemical and Microbial Risk. pp. 277-303, International Life 



Sciences Institute Press, Washington, D.C.



    7. Deangelo, A.B., Daniel, F.B, Stober, J.A., and Olson, G.R. 1991. 



The Carcinogenicity of Dichloroacetic Acid in the Male B6C3F1 mouse. 



Fundam. Appli. Toxicol. 16:337-347.



    8. DeAngelo AB, George MH, Kilburn SR, Moore TM, Wolf DC. 1998. 



Carcinogenicity of Potassium Bromate Administered in the Drinking Water 



to Make B6C3F1 Mice and F344/N Rats, Toxicologic Pathology vol. 26, No. 



4 (in press).



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Folsom AR. 1997. The association of drinking water source and 



chlorination by-products with cancer incidence among postmenopausal 



women in Iowa: a prospective cohort study. American Journal of Public 



Health. 87:7.



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chemical and microbial risks of disinfection. In: Proceedings: Safety 



of Water Disinfection: Balancing Chemical and Microbial Risk. pp. 3-10, 



International Life Sciences Institute Press, Washington, D.C.



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Wang SS. 1997. Bladder cancer and drinking water: a population-based 



case-control study in Washington County, Maryland (United States). 



Cancer Causes and Control. 8, pp 738-744.



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Containing Chloroform. III. Long-Term Study in Beagle Dogs. J. Environ. 



Pathol. Toxicolo. 2:835-851.



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Alavanja M, and Craun GF. 1998. Drinking water source and chlorination 



byproducts: Risk of colon and rectal cancers. Epidemiology. 9:1, pp: 



29-35.



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Drinking Water: A Population-Based Case-Control Study in Washington 



County, Maryland. Am. J. Epidemiol. 136:836-842.



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Carcinogen Risk Assessment Using Chloroform and Dichloroacetate as Case 



Studies: Report of an Expert Panel. International Life Sciences 



Institute, Health and Environmental Sciences Institute November, 1997.



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Robinson. 1985. Carcinogenicity of chloroform in drinking water to male 



Osborne-Mendal rats and female B6C3F1 mice. Fundam. Appl. Toxicol. 



5:760-769.



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Disinfection and Somatic Parameters at Birth. Environ. Health 



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    18. King, W. D. and L. D. Marrett. 1996. Case-Control Study of 



Water Source and Bladder Cancer. Cancer Causes and Control, 7:596-604.



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Tube Defects and Drinking Water Contaminants. New Jersey Department of 



Health and Senior Services. Sponsored by Agency for Toxic Substances 



and Disease Registry. January 1998.



    20. Kurokawa et al. 1986a Long-term in vivo carcinogenicity tests 



of potassium bromate, sodium hypochlorite, and sodium chlorite 



conducted in Japan. Environ Health Perspect 69:221-235.



    21. Kurokawa et al. 1986b. Dose response studies on the 



carcinogenicity of potassium bromate in F344 rats after long-term oral 



administration. J Natl Cancer Inst 77:977-982.



    22. Melnick, R., M. Kohn, J.K. Dunnick, and J.R. Leininger. 1998. 



Regenerative Hyperplasia Is Not Required for Liver Tumor Induction in 



Female B6C3F1 Mice Exposed to Trihalomethanes. Tox. And Applied Pharm. 



148: 137-147.



    23. McGeehin, M. A. et al. 1993. Case-Control Study of Bladder 



Cancer and Water Disinfection Methods in Colorado. Am. J. Epidemiology, 



138:492-501.



    24. Mobley, S.A, D.H. Taylor, R.D. Laurie, and R.J. Pfohl. 1990. 



Chlorine dioxide depresses T3 uptake and delays development of 



locomotor activity in young rats. In: Water Chlorination: Chemistry, 



Environmental Impact and Health Effects. Vol 6. Lolley, Condie, 



Johnson, Katz, Mattice and Jacobs, ed. Lewis Publ., Inc. Chelsea MI., 



pp. 347-360.



    25. Morris, R.D. et al. 1992. Chlorination, Chlorination By-



products, and Cancer: A Meta-Analyis. American Journal of Public 



Health, 82(7): 955-963.



    26. Morris, RD. 1997. Letter from Dr. RD Morris to Patricia Murphy 



on response to Poole Critique. December 11, 1997.



    27. Murphy, PA. 1993. Quantifying chemical risk form 



epidemiological studies: application to the disinfectant byproduct 



issues. In: Proceedings: Safety of Water Disinfection: Balancing 



Chemical and Microbial Risk. pp. 373-389, International Life Sciences 



Institute Press, Washington, D.C.



    28. NCI. 1998. Cancer Facts, National Cancer Institute, National 



Institutes of Health. http://www.meb.uni-bonn.de/cancer net/600314.html



    29. Orme, J. D.H. Taylor, R.D. Laurie, and R.J. Bull. 1985. Effects 



of Chlorine Dioxide on Thyroid Function in Neonatal Rats. J. Tox. and 



Environ. Health. 15:315-322.



    30. Poole, C. 1997. Analytical Meta-Analysis of Epidemiological 



Studies of Chlorinated Drinking Water and Cancer: Quantitative Review 



and Reanalysis of the Work Published by Morris et al., Am J Public 



Health 1992:82:955-963. National Center for Environmental Assessment, 



Office of Research and Development, September 30, 1997.



    31. Reif, J. S. et al. 1996. Reproductive and Developmental Effects 



of Disinfection By-products in Drinking Water. Environmental Health 



Prospectives. 104(10):1056-1061.



    32. Rockhill, B, B. Newman, and C. Weinberg. 1998. Use and Misuse 



of Population Attributable Fraction. Am. J. Public Health. 88(1):15-19.



    33. Savitz, D. A., Andrews, K. W. and L. M. Pastore. 1995. Drinking 



Water and Preganancy Outcome in Central North Carolina: Source, Amount, 



and Trihalomethane levels. Environ. Health Perspectives. 103(6), 592-



596.



    34. Swan SH, Waller K, Hopkins B, Windham G, Fenster L, Schaefer C, 



Neutra R., 1998. A prospective study of spontaneous abortion: Relation 



to amount and source of drinking water consumed in early pregnancy, 



Epidemiology 9(2):126-133.



    35. U.S. EPA. 1979. National Interim Primary Drinking Water 



Regulations; Control of Trihalomethanes in Drinking Water. Vol. 44, No. 



231. November 29, 1979. Pp. 68624-68707.



    36. U.S. EPA. 1986. Guidelines for carcinogen risk assessment, FR 



51(185):33992-34003.



    37. U.S. EPA. 1991. Guidelines for developmental toxicity risk 



assessment (Notice), FR 56(234):63798-63826.



    38. U.S. EPA. 1992. Guidelines for reproductive testing. CFR 



798.4700. July 1, 1992.







[[Page 15692]]







    39. U.S. EPA/ILSI. 1993. A Review of Evidence on Reproductive and 



Developmental Effects of Disinfection By-Products in Drinking Water. 



Washington: U.S. Environmental Protection Agency and International Life 



Sciences Institute.



    40. U.S. EPA. 1994a. National Primary Drinking Water Regulations; 



Disinfectants and Disinfection Byproducts; Proposed Rule. FR, 



59:145:38668. (July 29, 1994).



    41. U.S. EPA. 1994b. Workshop Report and Recommendations for 



Conducting Epidemiologic Research on Cancer and Exposure to Chlorinated 



Drinking Water. U.S. EPA, July 19-21, 1994.



    42. U.S. EPA. 1994c. U.S. Environmental Protection Agency. 



Regulatory Impact Analysis of Proposed Disinfectant/Disinfection By-



Products Regulations. Washington, D.C.



    43. U.S. EPA. 1996a. Reproductive toxicity risk assessment 



guidelines, FR 61(212):56274-56322.



    44. U.S. EPA. 1996b. Proposed guidelines for carcinogen risk 



assessment, FR 61(79):17960-18011.



    45. U.S. EPA. 1997a. National Primary Drinking Water Regulations; 



Disinfectants and Disinfection Byproducts; Notice of Data Availability; 



Proposed Rule. Fed. Reg., 62 (No. 212):59388-59484. (November 3, 1997).



    46. U.S. EPA. 1997b. Summaries of New Health Effects Data. Office 



of Science and Technology, Office of Water. October 1997.



    47. U.S. EPA. 1997c. External Peer Review of CMA Study -2- 



Generation, EPA Contract No. 68-C7-0002, Work Assignment B-14, The 



Cadmus Group, Inc., October 9, 1997.



    48. U.S. EPA. 1998a. Quantification of Cancer Risk from Exposure to 



Chlorinated Water. Office of Science and Technology, Office of Water. 



March 13, 1998.



    49. U.S. EPA. 1998b. Health Risk Assessment/Characterization of the 



Drinking Water Disinfection Byproduct Chlorine Dioxide and the 



Degradation Byproduct Chlorite. Office of Science and Technology, 



Office of Water. March 13, 1998.



    50. U.S. EPA. 1998c. Health Risk Assessment/Characterization of the 



Drinking Water Disinfection Byproduct Chloroform. Office of Science and 



Technology, Office of Water. March 13, 1998.



    51. U.S. EPA. 1998d. Health Risk Assessment/Characterization of the 



Drinking Water Disinfection Byproduct Bromate. Office of Science and 



Technology, Office of Water. March 13, 1998.



    52. U.S. EPA. 1998e. Dichloroacetic acid: Carcinogenicity 



Identification Characterization Summary. National Center for 



Environmental Assessment--Washington Office. Office of Research and 



Development. March 1998.



    53. U.S. EPA. 1998f. NCEA Position Paper Regarding Risk Assessment 



Use of the Results from the Published Study: Morris et al. Am J Public 



Health 1992;82:955-963. National Center for Environmental Assessment, 



Office of Research and Development, October 7, 1997.



    54. U.S. EPA. 1998g. Synthesis of the Peer-Review of Meta-analysis 



of Epidemiologic Data on Risks of Cancer from Chlorinated Drinking 



Water. National Center for Environmental Assessment, Office of Research 



and Development, February 16, 1998.



    55. U.S. EPA. 1998h. EPA Panel Report and Recommendation for 



Conducting Epidemiological Research on Possible Reproductive and 



Developmental Effects of Exposure to Disinfected Drinking Water. Office 



of Research and Development.



    56. U.S. EPA. 1998i. Final guidelines for neurotoxicity risk 



assessment.



    57. Vena JE, Graham S, Freudenheim JO, Marshall J, Sielezny M, 



Swanson M, Sufrin G. 1993. Drinking water, fluid intake, and bladder 



cancer in western New York. Archives of Environmental Health. 48:(3)



    58. Waller K, Swan SH, DeLorenze G, Hopkins B., 1998. 



Trihalomethanes in drinking water and spontaneous abortion. 



Epidemiology. 9(2):134-140.



    59. WHO. 1997. Rolling Revision of WHO Guidelines for Drinking-



Water Quality; Report of Working Group Meeting on Chemical Substances 



for the Updating of WHO Guidelines for Drinking-Water Quality. Geneva, 



Switzerland, 22-26 April 1997.



    National Primary Drinking Water Regulations: Disinfectants and 



Disinfection Byproducts Notice of Data Availability page 86 of 86.







    Dated: March 24, 1998.



Robert Perciasepe,



Assistant Administrator for Office of Water.



[FR Doc. 98-8215 Filed 3-30-98; 8:45 am]



BILLING CODE 6560-50-U











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