Health Effects Support Document for Hexachlorobutadiene Printed on Recycled Paper Health Effects Support Document for Hexachlorobutadiene U. S. Environmental Protection Agency Office of Water ( 4304T) Health and Ecological Criteria Division Washington, DC 20460 www. epa. gov/ safewater/ ccl/ pdf/ hexachlorobutadiene. pdf EPA 822 R 03 002 February 2003 iii HCBD   February 2003 FOREWORD The Safe Drinking Water Act ( SDWA), as amended in 1996, requires the Administrator of the Environmental Protection Agency ( EPA) to establish a list of contaminants to aid the agency in regulatory priority setting for the drinking water program. In addition, SDWA requires EPA to make regulatory determinations for no fewer than five contaminants by August 2001. The criteria used to determine whether or not to regulate a chemical on the CCL are the following:

The contaminant may have an adverse effect on the health of persons.

The contaminant is 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.

In the sole judgment of the administrator, regulation of such contaminant presents a meaningful opportunity for health risk reduction for persons served by public water systems.

The Agency's findings for the three criteria are used in making a determination to regulate a contaminant. The Agency may determine that there is no need for regulation when a contaminant fails to meet one of the criteria.

This document provides the health effects basis for the preliminary regulatory determination for hexachlorobutadiene. In arriving at the preliminary regulatory determination, data on toxicokinetics, human exposure, acute and chronic toxicity to animals and humans, epidemiology, and mechanisms of toxicity were evaluated. In order to avoid duplication of effort, information from the following risk assessments by the EPA and other government agencies was used in development of this document.

U. S. EPA. 1991a. Drinking Water Health Advisory: Hexachlorobutadiene. In: Volatile Organic Compounds. United States Environmental Protection Agency, Office of Drinking Water. Lewis Publishers. Ann Arbor, Michigan.

ATSDR. 1994. Toxicological Profile for Hexachlorobutadiene. Agency for Toxic Substances and Disease Registry, Department of Health and Human Services.

U. S. EPA, 1998a. Draft Ambient Water Quality Criteria for the Protection of Human Health. Office of Water. EPA 822 R 98 004.

Information from the published risk assessments was supplemented with information from recent studies of hexachlorobutadiene identified by literature searches conducted in 1999 and 2000 and the primary references for key studies.

Generally a Reference Dose ( RfD) is provided as the assessment of long term toxic effects other than carcinogenicity. RfD determination assumes that thresholds exist for certain toxic effects such as cellular necrosis. It is expressed in terms of milligrams per kilogram per day ( mg/ kg day). In general, the RfD is an estimate ( with uncertainty spanning perhaps an order of magnitude) of a iv HCBD   February 2003 daily exposure to the human population ( including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.

The carcinogenicity assessment for hexachlorobutadiene includes a formal hazard identification as well as a quantitative dose response assessment of the risk from oral exposure. Hazard identification is a weight of evidence judgment of the likelihood that the agent is a human carcinogen via the oral route and the conditions under which the carcinogenic effects may be expressed.

Guidelines that were used in the development of this assessment may include the following: the Guidelines for Carcinogen Risk Assessment ( U. S. EPA, 1986a), Draft Guidelines for Carcinogen Risk Assessment ( USEPA, 1999c), Guidelines for the Health Risk Assessment of Chemical Mixtures ( U. S. EPA, 1986b), Guidelines for Mutagenicity Risk Assessment ( U. S. EPA, 1986c), Guidelines for Developmental Toxicity Risk Assessment ( U. S. EPA, 1991b), Proposed Guidelines for Carcinogen Risk Assessment ( 1996a), Guidelines for Reproductive Toxicity Risk Assessment ( U. S. EPA, 1996b), and Guidelines for Neurotoxicity Risk Assessment ( U. S. EPA, 1998b); Recommendations for and Documentation of Biological Values for Use in Risk Assessment ( U. S. EPA, 1988); Use of the Benchmark Dose Approach in Health Risk Assessment ( U. S. EPA, 1995); Science Policy Council Handbook: Peer Review ( U. S. EPA, 1998c); and Memorandum from EPA Administrator, Carol Browner, dated March 21, 1995.

The chapter on occurrence and exposure to hexachlorobutadiene through potable water was developed by the Office of Ground Water and Drinking Water. It is based primarily on unregulated contaminant monitoring ( UCM) data collected under SDWA. The UCM data are supplemented with ambient water data as well as information on production, use, and discharge. v HCBD   February 2003 ACKNOWLEDGMENTS This document was prepared under the U. S. EPA Contract No. 68 C 02 009, Work Assignment No. B 13 with ICF Consulting, Fairfax, VA. The Lead U. S. EPA Scientist is Diana Wong, Ph. D., DABT, Health and Ecological Criteria Division, Office of Science and Technology, Office of Water. vi HCBD   February 2003 TABLE OF CONTENTS FOREWORD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v LIST OF TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix LIST OF FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x 1.0 EXECUTIVE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2.0 IDENTITY: PHYSICAL AND CHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . 2 1 3.0 USES AND ENVIRONMENTAL FATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 3.1 Uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 1 3.2 Release to the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3 3.3 Fate in Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3 3.4 Fate in Water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3 3.5 Fate in Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4 4.0 EXPOSURE FROM DRINKING WATER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1 4.1 Ambient Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1 4.1.1 Data Sources and Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1 4.1.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2 4.2 Drinking Water Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2 4.2.1 Data Sources, Data Quality, and Analytical Methods . . . . . . . . . . . . . . . . . . . . 4 3 4.2.2 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 10 4.3 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 17 5.0 EXPOSURE FROM MEDIA OTHER THAN WATER . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 5.1 Exposure from Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 5.1.1 Concentrations in Non Fish Food Items . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 5.1.2 Concentrations in Fish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1 5.1.3 Intake of HCBD from Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 5.2 Exposure from Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 5.2.1 Concentration of HCBD in Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 4 5.2.2 Intake of HCBD from Air . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 5 5.3 Exposure from Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 5.3.1 Concentration of HCBD in Soil and Sediment . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 5.3.2 Intake of HCBD from Soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 5.4 Other Residential Exposures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 5.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6 6.0 TOXICOKINETICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1 vii HCBD   February 2003 6.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1 6.2 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2 6.3 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 3 6.4 Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 7 7.0 HAZARD IDENTIFICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 7.1 Human Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 7.1.1 Short Term Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 7.1.2 Long Term and Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1 7.2 Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2 7.2.1 Acute Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2 7.2.2 Short Term Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 6 7.2.3 Subchronic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 8 7.2.4 Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 10 7.2.5 Developmental/ Reproductive Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 11 7.2.6 Chronic Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 13 7.2.7 Carcinogenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 14 7.3 Other Key Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 15 7.3.1 Mutagenicity/ Genotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 15 7.3.2 Immunotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 22 7.3.3 Hormonal Disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 23 7.3.4 Physiological or Mechanistic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 23 7.3.5 Structure Activity Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 27 7.4 Hazard Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 28 7.4.1 Synthesis and Evaluation of Major Noncancer Effects . . . . . . . . . . . . . . . . . . 7 28 7.4.2 Synthesis and Evaluation of Carcinogenic Effects . . . . . . . . . . . . . . . . . . . . . 7 34 7.4.3 Mode of Action and Implications in Cancer Assessment . . . . . . . . . . . . . . . . 7 34 7.4.4 Weight of Evidence Evaluation for Carcinogenicity . . . . . . . . . . . . . . . . . . . . 7 36 7.4.5 Sensitive Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 37 8.0 DOSE RESPONSE ASSESSMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1 8.1 Dose Response for Noncancer Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1 8.1.1 RfD Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1 8.1.2. RfC Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5 8.2 Dose Response for Cancer Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5 8.2.1 Choice of Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 5 8.2.2 Dose Response Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 6 8.2.3 Extrapolation Model and Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 10 8.2.4 Cancer Potency and Unit Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 11 8.2.5 Discussion of Confidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 12 9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK FROM DRINKING WATER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1 9.1 Regulatory Determination for Chemicals on the CCL . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1 9.1.1 Criteria for Regulatory Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1 viii HCBD   February 2003 9.1.2 National Drinking Water Advisory Council Recommendations . . . . . . . . . . . . 9 2 9.2 Health Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2 9.2.1 Health Criterion Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 3 9.2.2 Hazard Characterization and Mode of Action Implications . . . . . . . . . . . . . . . 9 3 9.2.3 Dose Response Characterization and Implications in Risk Assessment . . . . . . 9 4 9.3 Occurrence in Public Water Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 8 9.3.1 Occurrence Criterion Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 8 9.3.2 Monitoring Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 8 9.3.3 Use and Fate Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 9 9.4 Risk Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 10 9.4.1 Risk Reduction Criterion Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 11 9.4.2 Exposed Population Estimates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 11 9.4.3 Relative Source Contribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 11 9.4.4 Sensitive Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 13 9.5 Regulatory Determination Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 13 10.0 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1 APPENDIX A: Abbreviations and Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A 1 APPENDIX B: Round 1 and Round 2 Occurrence Data Tables for Hexachlorobutadiene . . . B 1 ix HCBD   February 2003 LIST OF TABLES Table 2 1. Chemical and Physical Properties of Hexachlorobutadiene. . . . . . . . . . . . . . . . . . . 2 2 Table 3 1. Environmental Releases ( in pounds) for Hexachlorobutadiene in the United States, 1988   1998. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2 Table 4 1. Cross section States for Round 1 ( 24 States) and Round 2 ( 20 States). . . . . . . . . . 4 7 Table 4 2. Summary Occurrence Statistics for Hexachlorobutadiene. . . . . . . . . . . . . . . . . . . 4 12 Table 5 1. HCBD Tissue Concentration in Fish Collected Near Four Chemical Manufacturing Plants. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3 Table 5 2. Summary of Concentration Data and Exposure Estimates for Media Other Than Water. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 7 Table 7 1. Histopathological Findings in Adult Rats Fed Diets containing Hexachlorobutadiene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 9 Table 7 2. Mutagenicity of HCBD in Salmonella typhimurium Test Systems. . . . . . . . . . . . 7 17 Table 7 3. Mutagenicity of HCBD Metabolites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 19 Table 7 4. Genotoxicity of HCBD in Eukaryotic Assay Systems. . . . . . . . . . . . . . . . . . . . . . 7 21 Table 7 5. Summary of Principal HCBD Toxicity Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . 7 32 Table 8 1. Incidence of Renal Tubular Regenerative Response in Mice Treated with HCBD for 13 Weeks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 3 Table 8 2. Benchmark Dose Estimates from NTP ( 1991) Female Mouse Renal Tubular Regeneration Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4 Table 8 3. Incidence of Renal Tubular Neoplasms in Rats Treated with HCBD for 2 Years. . 8 6 Table 8 4. Dose Related Changes in the Rodent Kidney after Oral Exposure to HCBD, Chronic Study  Rat ( Kociba et al., 1977). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 7 Table 8 5. Summary of Cancer Risk Values for HCBD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 13 Table 9 1. Dose Response Information from Several Key Studies of HCBD Toxicity ( Oral Exposure). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 7 Table 9 2. National Population Estimates for HCBD Exposure via Drinking Water. . . . . . . 9 12 Table 9 3. Comparison of Average Daily Intakes from Drinking Water and Other Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 13 Table 9 4. Ratios a of Exposures from Various Media to Exposures from Drinking Water. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 13 x HCBD   February 2003 LIST OF FIGURES Figure 2 1. Chemical Structure of Hexachlorobutadiene. . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1 Figure 4 1. Geographic Distribution of Cross section States for Round 1 ( left) and Round 2 ( right). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 7 Figure 4 2. States with PWSs with Detections of Hexachlorobutadiene for all States with Data in URCIS ( Round 1) and SDWIS/ FED ( Round 2). . . . . . . . . . . . . . . . . . 4 15 Figure 4 3. States with PWSs with Detections of Hexachlorobutadiene ( any PWSs with results greater than the Minimum Reporting Level [ MRL]) for Round 1 ( above) and Round 2 ( below) Cross section States. . . . . . . . . . . . . . . . . . . . . 4 15 Figure 4 4. Cross section States ( Round 1 and Round 2 combined) with PWSs with Detections of Hexachlorobutadiene ( above) and concentrations greater than the Health Reference Level ( HRL; below). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 17 Figure 6 1. Proposed Pathways for Hexachlorobutadiene Metabolism. . . . . . . . . . . . . . . . . 6 4 Figure 8 1. Benchmark Dose Estimate Using Weibull Model. . . . . . . . . . . . . . . . . . . . . . . 8 2 Figure 8 2. Renal Tumor Dose Response Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 10 HCBD   February 2003 1 1 1.0 EXECUTIVE SUMMARY The U. S. Environmental Protection Agency ( EPA) has prepared this Health Effects Support Document for Hexachlorobutadiene ( HCBD) to assist in determining whether to regulate HCBD with a National Primary Drinking Water Regulation ( NPDWR). The available data on occurrence, exposure, and other risk considerations suggest that, because HCBD does not occur in public water systems at frequencies and levels of public health concern, regulating HCBD will not present a meaningful opportunity for health risk reduction for persons served by public water systems. EPA presents its determination and data analysis in the Federal Register Notice covering the Contaminant Candidate List ( CCL) regulatory determinations.

HCBD ( Chemical Abstracts Services Registry Number 87 68 3) is a colorless liquid at room temperature. It is poorly soluble in water, and has a high affinity for organic particulate matter. HCBD has never been specifically manufactured as a commercial product in the United States. However, significant quantities of hexachlorobutadiene are generated in the United States as waste by product from the chlorination of hydrocarbons. The chemical is used as an intermediate product in rubber manufacturing and chlorofluorocarbon and lubricant production, as well as for transformer and hydraulic fluids, fluid for gyroscopes, heat transfer liquid, solvents, laboratory reagents, and as a wash liquor for removing C 4 and higher hydrocarbons. Hexachlorobutadiene has also been used as a fumigant in some overseas countries. Some of the chemical properties for hexachlorobutadiene ( CAS# 87 68 3) include the following: water solubility = 2 2.55 mg/ L; vapor pressure ( 25 ° C) = 0.15 mmHg; Log K ow = 4.78; and Log K oc = 3.67.

Emissions into air is the major pathway of release. For hexachlorobutadiene, air emissions constitute most of the on site releases. Hexachlorobutadiene is listed as a toxic release inventory ( TRI) chemical. It is included in the Agency for Toxic Substances and Disease Registry's ( ATSDR) Hazardous Substance Release and Health Effects Database ( HazDat) and has been detected in site samples in fifteen States: AL, AZ, CA, CT, IA, LA, MI, MN, NJ, NY, OH, PA, RI, SC, WA ( ATSDR, 2000).

Ambient air concentration data are available from Shah and Heyerdahl ( 1988). The mean and median of all ambient concentrations were 0.42 µ g/ m3 and 0.04 µ g/ m3, respectively. Air intake for adults is estimated to be 1.2 × 10 4 mg/ kg day using the mean air concentration, and inhalation is the main pathway of exposure ( U. S. EPA, 1998a). Hexachlorobutadiene is not found in non fish dietary foods for the majority of regions in the US. It was detected in fish at 3% of 362 sites sampled. The mean fish concentration at all sites was 0.6 ng/ g ( Kuehl et al., 1994). An estimate of adult exposure via fish consumption is 1.54 × 10 7 mg/ kg day ( U. S. EPA, 1998a).

Cross sectional monitoring data from two rounds of sampling conducted under EPA's Unregulated Contaminant Monitoring ( UCM) program indicate that the frequency of detection of HCBD in public water systems ( PWSs) is low. Round 1, conducted from 1987 to 1992 in 24 States, detected HCBD at levels above the minimum reporting level ( MRL) of 0.5 µ g/ L for 0.35% of the PWSs, while Round 2, conducted from 1993 to 1997 in 20 States, detected HCBD at levels above the MRL for 0.18% of the PWSs. The health reference level ( HRL) of 0.9 : g/ L for HCBD is a preliminary health effect level used in the UCM analysis ( U. S. EPA, 2001c). It is the concentration HCBD   February 2003 1 2 corresponding to 10 6 incremental cancer risk, calculated from the slope factor using the linear method. In that analysis, 0.114% of the PWSs in Round 1 ( 74 systems) exceeded the HRL, while 0.018% ( 11 systems) in Round 2 exceeded the HRL. The United States Geological Survey's National Ambient Water Quality Assessment ( NAWQA) program did not detect HCBD in the ground water or well water samples surveyed. When average daily drinking water intakes for HCBD are compared with intakes from food, air and soil, drinking water accounts for a relatively small proportion of total HCBD intake. This drinking water intake, however, does not include other uses for potable water such as bathing and showering.

Hexachlorobutadiene ( HCBD) is readily absorbed following oral administration in rats. Following gastrointestinal uptake, HCBD and its metabolites distribute preferentially to the kidney, liver, adipose tissue and the brain ( Reichert et al., 1985). The primary pathway for HCBD metabolism is conjugation with glutathione, with subsequent conversion to a cysteine conjugate. Activation of the cysteine conjugate by $ lyase yields a highly reactive thioketene intermediate. Covalent binding of this thioketene to DNA, proteins and other macromolecules is considered to be the mechanism responsible for the observed cytotoxic and mutagenic effects of HCBD and its metabolites. Evidence exists for a male specific metabolic pathway in rats ( Birner et al., 1995). The primary routes for elimination of absorbed HCBD are urinary and fecal excretion; a small amount of absorbed HCBD is oxidized to carbon dioxide ( U. S. EPA, 1991; U. S. EPA, 1999; ATSDR, 1994).

There are no reliable dose response data for humans exposed to HCBD. There is no information available to determine the carcinogenic potential of HCBD exposure in humans. Studies in animals show a selective adverse effect of HCBD on the kidney, specifically the proximal tubule. Subchronic ( NTP, 1991) and chronic ( Kociba et al., 1977) studies in rodents present a clear picture of dose related renal damage at 2 mg/ kg day and above, with possible effects at 0.2 mg/ kg day. Progressive events over time include changes in kidney weight, renal tubular degeneration and regeneration, hyperplasia, focal adenomatous proliferation, and renal tumor formation. One subacute inhalation study also found enlarged adrenals and degeneration of adrenal cortex at 250 ppm ( Gage, 1970). Developmental effects were also associated with hexachlorobutadiene exposure in animals ( Harleman and Seinen, 1979). However, these effects were observed at higher doses than required to produce renal toxicity. Pups with lower birth weights and reduced body weight gain were reported at maternal dose of 8.1 15 mg/ kg day in rats ( Badaeva, 1983; Harleman and Seinen, 1979). In the presence of metabolic activation, HCBD and its reactive metabolites are mutagenic in some ( Simmon, 1977; Reichert et al., 1984; Reichert and Schutz, 1986; Wild et al., 1986) but not all studies. Only one study of lifetime oral exposure to hexachlorobutadiene was located ( Kociba et al., 1977). At 20 mg/ kg day, benign and malignant renal tumors were seen in approximately 23% ( 9/ 39) of the male rats, and 15% ( 6/ 40) of the female rats. This dose exceeded the maximum tolerated dose at which increased mortality, severe renal toxicity, and significant weight loss were also observed. There were no tumors in the second highest dose of 2 mg/ kg day in this study. The conclusion from the dose response analysis is that hexachlorobutadiene is carcinogenic only in the kidney following ingestion at cytotoxic doses in the rat.

The nephrotoxicity of HCBD in rodents is dependent on a multi step bioactivation mechanism involving both kidney and liver enzymes. The ultimate step in this pathway is a $ lyase mediated degradation of a HCBD metabolite that generates a highly reactive thioketene in proximal tubule cells. In vitro studies suggest that cortical mitochondria are the critical subcellular target for HCBD   February 2003 1 3 toxicity. Covalent binding of this reactive thioketene to cellular macromolecules ( e. g. proteins, mitochondrial DNA) and the resultant mitochondrial dysfunction is believed to underlie the development of renal cytotoxicity and renal tubular adenomas and carcinomas in rodents.

Limited in vitro studies suggest humans have the ability to metabolize HCBD. The activity of HCBD metabolizing enzymes, particularly renal $ lyase, may be many fold lower in humans than the corresponding enzymes in rats ( Lock, 1994; Lash et al., 1990; Anders and Dekant, 1998); although the activity of glutathione S transferase was not different between rodents and humans ( Dekant et al., 1998). Due to the fact that lower levels of reactive metabolites would be assumed to form, there would be less concern for toxicity in humans.

The primary target organ for HCBD is the kidney. Individuals with preexisting kidney damage may represent a potentially sensitive subpopulation for hexachlorobutadiene health effects. Studies in animals showed that the young rats and mice were more sensitive to the acute effects of oral HCBD than adults ( Hook et al., 1983; Lock et al., 1984). Those data may suggest that infants may potentially be more susceptible to hexachlorobutadiene toxicity.

Three key studies which have been used in determining points of departure for the reference dose ( RfD) are the Kociba et al. ( 1977) study and Schwetz et al. ( 1977) studies in rats and the NTP ( 1991) study in mice. In the Kociba ( 1977) study, male and female Sprague Dawley rats were fed diets that contained 0, 0.2, 2, or 20 mg/ kg day HCBD for 22 months ( males) or 24 months ( females). Non neoplastic effects, including increased coproporphyrin excretion and microscopic renal tubule epithelial hyperplasia, were seen at the two high doses, while renal tubule adenomas and carcinomas were found only at the highest dose. In the Schwetz et al. ( 1977) study, male and female Sprague Dawley rats were fed a diet containing 0.2, 2.0, or 20 mg/ kg day HCBD for evaluation of reproductive effects. HCBD was provided in the diet before and during mating, and throughout gestation and lactation, for a total study duration of 148 days. At necropsy, relative kidney weights were increased in high dose males and females. Relative liver weight was increased in high dose males, and relative brain weight was increased in high dose females. The kidneys of males at the two high doses were roughened and had a mottled cortex. Histopathological examination revealed dose related increases in tubular dilation and regeneration in animals at the two high doses. In the 13 week NTP ( 1991) study, B6C3F 1 mice were fed a diet containing 0, 0.1, 0.4, 1.5, 4.9 or 16.8 mg/ kg day for males and 0, 0.2, 0.5, 1.8, 4.5 or 19.2 mg/ kg day for females. Reduced body weight gain was reported in males at the two high doses and in females at the highest dose. Relative kidney weight was decreased in the three high dose groups for males, and in females in the highest dose group. High dose males also exhibited decreased relative heart weight. Necropsy revealed treatmentrelated increases in renal tubular cell regeneration in all dose groups in female mice and in the two high dose groups in male mice.

A previous RfD for hexachlorobutadiene was 2 x 10 4 mg/ kg day ( EPA, 1998a). It was derived from a NOAEL of 0.2 mg/ kg day for renal tubular epithelial cell degeneration and regeneration from the Kociba et al. ( 1977) study on rats and supported by the NTP ( 1991) study on mice. A composite uncertainty factor ( UF) of 1,000 was used in the derivation of the RfD.

The RfD for hexachlorobutadiene is 3 x 10 4 mg/ kg day. This is derived from the BMDL of 0.1 mg/ kg day calculated from a BMD analysis of renal tubular epithelial cell regeneration from the HCBD   February 2003 1 4 NTP ( 1991) study, with support from the Kociba ( 1977) and Schwetz ( 1977) studies in rats. A composite UF of 300 is now used in the derivation of the RfD. The composite uncertainty factor includes a factor of 10 to account for extrapolation from animals to humans; a factor of 10 for protection of sensitive subpopulation; and a factor of 3 for database deficiencies ( lack of a 2 generation reproductive study and developmental toxicity studies in only one species). In accordance with EPA's 1986 Guidelines for Carcinogen Risk Assessment ( U. S. EPA, 1986), HCBD is classified as a Group C ( possible human) carcinogen. Under EPA's 1999 draft Guidelines for Carcinogen Risk Assessment ( U. S. EPA, 1999c), HCBD is classified as likely to be carcinogenic to humans by the oral route of exposure. Its carcinogenic potential by the inhalation and dermal routes of exposure is classified as cannot be determined because there are inadequate data to perform an assessment. Two different approaches were used for dose response extrapolation to estimate excess human cancer risk for HCBD exposure from the rodent data. The default linearized multi stage model calculated a slope factor of 4 × 10 2 ( mg/ kg day) 1, and a unit risk of 1.1 × 10 6 per : g/ L. For the nonlinear approach, the RfD of 3 × 10 4 mg/ kg day is used for the protection of cancer effect. In consideration of the overall evidence, including the possible genotoxicity of HCBD metabolites, the linear approach is recommended by EPA. HCBD   February 2003 2 1 Hexachlorobutadiene 2.0 IDENTITY: PHYSICAL AND CHEMICAL PROPERTIES The chemical and physical properties of hexachlorobutadiene ( HCBD) are summarized in Table 2 1. Synonyms for this chemical include perchlorobutadiene; 1,1,2,3,4,4 hexachloro 1,3 butadiene; 1,3 hexachlorobutadiene; Dolen Pur; and GP 40 66: 120.

HCBD is a colorless liquid at room temperature with a mild turpentine like odor ( HSDB, 2000). HCBD is poorly soluble in water, but is miscible in ethanol and ether ( HSDB, 2000). HCBD has a relatively low vapor pressure of 0.15 mm Hg at 25 ° C ( U. S. EPA, 1991a). An odor threshold of 0.006 mg/ L has been reported for HCBD in water ( U. S. EPA, 1980), and an air odor threshold of 12 mg/ m3 ( Ruth, 1986). The Occupational Safety and Health Administration ( OSHA) Permissible Exposure Limit ( PEL) is 0.21 mg/ m3 ( OSHA, 1989), making odor a poor warning characteristic for HCBD. HCBD is characterized by high log K oc and log K ow values, 3.67 and 4.78, respectively ( ATSDR, 1994), reflecting properties which strongly influence its behavior and fate in environmental media. The chemical structure of HCBD is shown in Figure 2 1.

Figure 2 1. Chemical Structure of Hexachlorobutadiene. HCBD   February 2003 2 2 Table 2 1. Chemical and Physical Properties of Hexachlorobutadiene.

Property Information Chemical Formula C 4 Cl 6 Molecular Weight 260.76 Synonyms HCBD; Perchlorobutadiene; Hexachlorbutadiene; 1,1,2,3,4,4 Hexachloro 1,3 butadiene; 1,3 Hexachlorobutadiene; Dolen Pur; GP 40 66: 120NIOSH Registry of Toxic Effects of Chemical Substances ( RTECS) No. EJ0700000U. S. EPA Hazardous Waste No. U128Oil and Hazardous Materials/ Technical Assistance Data System ( OHM/ TADS) No. OHM 8100011Hazardous Substances Data Bank ( HSDB) No. 2870 Boiling Point ( at 760 mm Hg) 215oC Melting Point  21oC Vapor Pressure ( at 25oC) 0.15 mm Hg Density ( at 20oC) 1.55 g/ cm3 Water Solubility ( at 20oC) 2   2.55 mg/ L Organic Solvents Ethanol, Ether Partition Coefficients Log K ow 4.78 Log K oc 3.67 Odor Threshold ( air) Odor Threshold ( water) 12.00 mg/ m3 0.006 mg/ L Conversion Factor 1 ppm = 10.66 mg/ m3 1 mg/ m3 = 0.0938 ppm Sources: U. S. EPA ( 1980, 1991a); ChemIDplus ( 2000); HSDB ( 2000) HCBD   February 2003 3 1 3.0 USES AND ENVIRONMENTAL FATE 3.1 Uses HCBD has never been specifically manufactured as a commercial product in the United States. However, significant quantities of the chemical are generated in the U. S. as waste by product from the chlorination of hydrocarbons such as tri and tetrachloroethylene and carbon tetrachloride. Lesser quantities have been imported in past decades for commercial purposes, mostly from Germany. Until 1975 the most important commercial use of HCBD in the United States was for the recovery of chlorine containing gases in chlorine plants. Since then, HCBD has been used primarily as a chemical intermediate in the production of rubber, and also as a hydraulic fluid, a fluid for gyroscopes, a heat transfer liquid, a solvent, a laboratory reagent, a wash liquor for removing C 4 and higher hydrocarbons, and as a chemical intermediate in the production of chlorofluorocarbons and lubricants ( ATSDR, 1995; Howard, 1989). The chemical has also been used as a fumigant in Russia, France, Italy, Greece, Spain, and Argentina, although use in the European Community is reported to have ceased ( van de Plassche and Schwegler, 2002).

Eight million pounds of HCBD were generated as a waste by product in the U. S. in 1975, with 0.1 million pounds released into the environment. By 1982, the annual U. S. by product generation of the chemical had increased to 28 million pounds. In contrast, the annual import rate of HCBD dropped from 500,000 lbs/ yr imported annually in the late 1970s, to 145,000 lbs/ yr imported in 1981 ( ATSDR, 1994; Howard, 1989). Van de Plassche and Schwegler ( 2002) report that all commercial production in Europe has ceased, and estimate that worldwide commercial production has dropped from 10,000 tonnes in 1982 to virtually nil today.

3.2 Release to the Environment HCBD is listed as a toxic release inventory ( TRI) chemical. In 1986, the Emergency Planning and Community Right to Know Act ( EPCRA) established the Toxic Release Inventory ( TRI) of hazardous chemicals. Created under the Superfund Amendments and Reauthorization Act ( SARA) of 1986, EPCRA is also sometimes known as SARA Title III. The EPCRA mandates that larger facilities publicly report when TRI chemicals are released into the environment. This public reporting is required for facilities with more than 10 full time employees that annually manufacture or produce more than 25,000 pounds, or use more than 10,000 pounds, of TRI chemical ( U. S. EPA, 1996c, 2000a).

Under these conditions, facilities are required to report the pounds per year of HCBD released into the environment both on and off site. The on site quantity is subdivided into air emissions, surface water discharges, underground injections, and releases to land ( see Table 3 1). For HCBD, air emissions constitute most of the on site releases. Also, over the period for which data are available ( 1988   1998), surface water discharges generally increased, peaked in 1992   1993, and then decreased significantly through the late 1990s. The TRI data for HCBD were reported from eight States ( CA, IL, KS, LA, NJ, NY, TX, UT); however, HCBD contamination has often been found in remote areas far from apparent physical discharge sources ( U. S. EPA, 2000b; Howard, 1989). HCBD   February 2003 3 2 Table 3 1. Environmental Releases ( in pounds) for Hexachlorobutadiene in the United States, 1988   1998.

Year On Site Releases Off Site Releases Total On & Off site Releases Air Emissions Surface Water Discharges Underground Injection Releases to Land 1998 2,421 5 0 0 510 2,936 1997 1,415 9 299 0 200 1,923 1996 2,381 256 952 0 310 3,899 1995 3,310 661 434 0 252 4,657 1994 1,410 351 201 0 430 2,392 1993 1,747 1,200 520 0 12 3,479 1992 4,134 1,911 738 0 5 6,788 1991 3,410 681 200 2 4,263 8,556 1990 4,906 715 330 0 45 5,996 1989 4,628 622 330 1 26,343 31,924 1988 2,508 153 220 0 19,640 22,521 source: U. S. EPA ( 2000b)

Although the TRI data can be useful in giving a general idea of release trends, it is far from exhaustive and has significant limitations. For example, only industries which meet TRI criteria ( at least 10 full time employees and manufacture and processing of quantities exceeding 25,000 lbs/ yr, or use of more than 10,000 lbs/ yr) are required to report releases. These reporting criteria do not account for releases from smaller industries. Threshold manufacture and processing quantities also changed from 1988   1990 ( dropping from 75,000 lbs/ yr in 1988 to 50,000 lbs/ yr in 1989 to its current 25,000 lbs/ yr in 1990) creating possibly misleading data trends. Finally, the TRI data is meant to reflect releases and should not be used to estimate general exposure to a chemical ( U. S. EPA, 2000c, d).

While TRI releases were reported in only eight States, the use of HCBD is widespread. It is included in the Agency for Toxic Substances and Disease Registry's ( ATSDR) Hazardous Substance Release and Health Effects Database ( HazDat) and has been detected in site samples in fourteen States ( AL, AZ, CT, IA, LA, MI, MN, NJ, NY, OH, PA, RI, SC, WA; ATSDR, 2000). These States are distributed nationwide and include 11 States and two regions ( New England and the Pacific Northwest) not reporting TRI releases yet manifesting HCBD detections in the environment.

The National Priorities List ( NPL) of hazardous waste sites, created in 1980 by the Comprehensive Environmental Response, Compensation and Liability Act ( CERCLA), is a listing of some of the most health threatening waste sites in the United States. HCBD was detected in eleven NPL sites in 1999. These sites are located in eight States: AK, CO, IN, LA, NJ, OH, PA, WA. Again, note that there is little overlap between these States and the eight TRI reporting States ( U. S. EPA, 1999a).

In summary, although HCBD is not manufactured in the United States, both its use in industry and occurrence in the environment are widespread. Significant quantities of HCBD are generated in the United States as a waste by product, and smaller quantities are imported for industrial needs. HCBD is present in hazardous waste sites in at least 8 States ( at NPL sites), has HCBD   February 2003 3 3 been detected in site samples in at least 14 States ( listed in ATSDR's HazDat), and has been released into the environment directly in at least 8 States ( based on TRI data).

3.3 Fate in Air HCBD is released to air via chemical manufacturing and processing and by waste incineration ( HSDB, 2000). Modeling and monitoring data suggest that the atmospheric burden of HCBD in the northern hemisphere is approximately 3.2 million kg/ yr ( Class and Ballschmiter, 1987). Dispersion of HCBD in the atmosphere has been confirmed by detection of HCBD at locations distant from sources of release ( WHO, 1994). The high log organic carbon partition coefficient ( log K oc) of HCBD indicates that it will readily adsorb to airborne particulate matter with a high organic content. Thus, HCBD in air is found both as a vapor and in association with atmospheric particulates.

No specific information is available on the transformation and degradation of HCBD in air.

3.4 Fate in Water HCBD is released to surface and ground water via industrial effluents, by leaching from landfills or soil, or by urban runoff ( ATSDR, 1994). Sorption to sediments and suspended particulates is an important factor in the fate of HCBD in water ( U. S. EPA, 1991a). As a result of this affinity for particulates and sediments, HCBD contaminated areas will usually have higher sediment concentrations than water concentrations of the chemical. U. S. EPA ( 1976) found that HCBD concentrations in the Mississippi delta water were < 2 : g/ L, while concentrations in mud or soil were > 200 : g/ L. Leeuwangh et al. ( 1975) observed that equilibration of initially uncontaminated sediment with HCBD contaminated water resulted in sediment concentrations 100 fold greater than those observed in the water.

Volatilization of HCBD from water to air also occurs, although the low vapor pressure of HCBD ( 0.15 mmHg at 25 ° C) suggests that this process may occur relatively slowly ( U. S. EPA, 1991a). Limited data are available on the transformation and degradation of HCBD in water. Under aerobic conditions in batch culture, complete biodegradation has been observed to occur in sewageinoculated waters after seven days ( Tabak et al., 1981). These data suggest that HCBD may biodegrade in natural waters. In contrast, no degradation was observed under anaerobic conditions in a separate study ( Johnson and Young, 1983). No data were available on hydrolysis or photolysis of HCBD in water. Estimates of HCBD half life range from 3 to 30 days in rivers and 30 to 300 days in lakes and groundwater ( Zoeteman et al., 1980).

The high octanol water partition coefficient ( K ow) of HCBD suggests that this chemical can readily partition from water into biota. Laboratory and field investigations confirm that HCBD has bioaccumulation potential ( WHO, 1994). Field measured bioaccumulation factors range from 46 to 27,780 ( U. S. EPA, 1999b). No evidence for biomagnification has been observed in laboratory or field studies ( WHO, 1994). HCBD   February 2003 3 4 3.5 Fate in Soil HCBD can be released to soil by disposal of industrial waste in landfill operations ( ATSDR, 1994). Volatilization from soil surfaces is expected to be a primary process for loss of HCBD from soil ( Tabak et al., 1981). However, as HCBD readily adsorbs to soil organic particles, volatilization from highly organic soils is predicted to be low ( HSDB, 2000).

No data regarding transformation or degradation of HCBD in soil were located. Data from experiments conducted in water ( Tabak et al., 1981) suggest that biodegradation will occur if aerobic conditions are present ( HSDB, 2000). Results obtained in sludge incubated under anaerobic conditions ( Johnson and Young, 1983) suggest that biodegradation will not occur under anaerobic soil conditions. Soil organic matter content is likely to be an important factor in biodegradation time, since adsorption of HCBD to organic matter will significantly decrease its bioavailability to microorganisms. In the absence of significant biodegradation or other loss processes, persistence of HCBD in soil may allow migration of the compound into groundwater, particularly in sandy soils ( U. S. EPA, 1984). HCBD   February 2003 4 1 4.0 EXPOSURE FROM DRINKING WATER This section of the report examines the occurrence of HCBD in drinking water. While no complete national database exists of unregulated or regulated contaminants in drinking water from public water systems ( PWSs) collected under SDWA, this report aggregates and analyzes existing State data that have been screened for quality, completeness, and representativeness. Populations served by PWSs exposed to HCBD are estimated, and the occurrence data are examined for regional or other special trends. To augment the incomplete national drinking water data and aid in the evaluation of occurrence, information on ambient occurrence of HCBD is also reviewed.

4.1 Ambient Occurrence To understand the presence of a chemical in the environment, an examination of ambient occurrence is useful. In a drinking water context, ambient water is source water existing in surface waters and aquifers before treatment. The most comprehensive and nationally representative data describing ambient water quality in the United States are being produced through the United States Geological Survey's ( USGS) National Water Quality Assessment ( NAWQA) program. NAWQA, however, is a relatively young program and complete national data are not yet available from their entire array of sites across the nation.

4.1.1 Data Sources and Methods To examine water quality status and trends in the United States, the USGS instituted the NAWQA program in 1991. NAWQA is designed and implemented in such a manner to allow consistency and comparison between representative study basins located around the country, facilitating interpretation of natural and anthropogenic factors affecting water quality ( Leahy and Thompson, 1994).

The NAWQA program consists of 59 significant watersheds and aquifers referred to as " study units." The study units represent approximately two thirds of the overall water usage in the United States and a similar proportion of the population served by public water systems. Approximately one half of the Nation's land area is represented ( Leahy and Thompson, 1994).

To facilitate management and make the program cost effective, approximately one third of the study units at a time engage in intensive assessment for a period of 3 to 5 years. This is followed by a period of less intensive research and monitoring that lasts between 5 and 7 years. This way all 59 study units rotate through intensive assessment over a ten year period ( Leahy and Thompson, 1994). The first round of intensive monitoring ( 1991   1996) targeted 20 watersheds. This first group was more heavily slanted toward agricultural basins. A national synthesis of results from these study units and other research initiatives focusing on pesticides and nutrients is being compiled and analyzed ( Kolpin et al., 1998; Larson et al., 1999).

For volatile organic chemicals ( VOCs), the national synthesis will compile data from the first and second rounds of intensive assessments. Study units assessed in the second round represent conditions in more urbanized basins, but initial results are not yet available. However, VOCs were HCBD   February 2003 4 2 analyzed in the first round of intensive monitoring and data are available for these study units ( Squillace et al., 1999). The minimum reporting limit ( MRL) for most VOCs, including HCBD, was 0.2 µ g/ L ( Squillace et al., 1999). Additional information on analytical methods used in the NAWQA study units, including method detection limits, are described by Gilliom and others ( in press).

Furthermore, the NAWQA program has compiled, by study unit, data collected from local, State, and other Federal agencies to augment its own data. The data set provides an assessment of VOCs in untreated ambient groundwater of the conterminous United States for the period 1985   1995 ( Squillace et al., 1999). Data were included in the compilation if they met certain criteria for collection, analysis, well network design, and well construction ( Lapham et al., 1997). They represent both rural and urban areas, but should be viewed as a progress report as NAWQA data continue to be collected that may influence conclusions regarding occurrence and distribution of VOCs ( Squillace et al., 1999).

4.1.2 Results Initial results published for the 20 NAWQA study units undergoing intensive assessment from 1991   1996 indicate that HCBD was not detected in ground water ( Squillace et al., 1999). HCBD also was not detected in rural or urban wells of the local, State, and federal data set compiled by NAWQA. These data represent untreated ambient ground water of the conterminous United States for the years 1985   1995 ( Squillace et al., 1999).

Furthermore, a review of highway and urban runoff studies found no detections of HCBD ( Lopes and Dionne, 1998). This review was undertaken as part of the National Highway Runoff Data and Methodology Synthesis and examined 44 studies implemented since 1970.

4.2 Drinking Water Occurrence The Safe Drinking Water Act ( SDWA), as amended in 1986, required Public Water Systems ( PWSs) to monitor for specified " unregulated" contaminants, on a five year cycle, and to report the monitoring results to the States. Unregulated contaminants do not have an established or proposed National Primary Drinking Water Regulation ( NPDWR), but they are contaminants that were formally listed and required for monitoring under federal regulations. The intent was to gather scientific information on the occurrence of these contaminants to enable a decision as to whether or not regulations were needed. All non purchased community water systems ( CWSs) and nonpurchased non transient non community water systems ( NTNCWSs), with greater than 150 service connections, were required to conduct this unregulated contaminant monitoring. Smaller systems were not required to conduct this monitoring under federal regulations, but were required to be available to monitor if the State decided such monitoring was necessary. Many States collected data from smaller systems. Additional contaminants were added to the Unregulated Contaminant Monitoring ( UCM) program in 1991 ( U. S. EPA, 1991c) for required monitoring that began in 1993 [ 57 FR 31776] ( U. S. EPA, 1992c).

HCBD has been monitored under the SDWA UCM program since 1987 [ 52 FR 25720]. Monitoring for HCBD under UCM continued throughout the 1990s, but ceased for small public HCBD   February 2003 4 3 water systems ( PWSs) under a direct final rule published on January 8, 1999 ( 64 FR 1494). Monitoring ended for large PWSs with promulgation of the new Unregulated Contaminant Monitoring Regulation ( UCMR) issued September 17, 1999 ( 64 FR 50556) and effective January 1, 2001. At the time the UCMR lists were developed, the Agency concluded there were adequate monitoring data for a regulatory determination. This obviated the need for continued monitoring under the new UCMR list.

4.2.1 Data Sources, Data Quality, and Analytical Methods Currently, there is no complete national record of unregulated or regulated contaminants in drinking water from public water systems collected under SDWA. Many States have submitted their unregulated contaminant PWS monitoring data to EPA databases, but there are issues of data quality, completeness, and representativeness. Nonetheless, a significant amount of State data are available for UCM contaminants that can provide estimates of national occurrence.

The National Contaminant Occurrence Database ( NCOD) is an interface to the actual occurrence data stored in a database called the Safe Drinking Water Information System ( Federal version; SDWIS/ FED) and can be queried to provide a summary of the data in SDWIS/ FED for a particular contaminant. The data used in this report were derived from the data in SDWIS/ FED and another database called the Unregulated Contaminant Information System ( URCIS).

The data in this report have been reviewed, edited, and filtered to meet various data quality objectives for the purposes of this analysis. Hence, not all data from a particular source were used, only data meeting the quality objectives described below. The sources of these data, their quality and national aggregation, and the analytical methods used to estimate a given contaminant's national occurrence ( from these data) are discussed in this section ( for further details see U. S. EPA, 2001a, b).

UCM Rounds 1 and 2 The 1987 UCM contaminants include 34 volatile organic compounds ( VOCs), divided into two groups: one with 20 VOCs for mandatory monitoring, and the other with 14 VOCs for discretionary monitoring [ 52 FR 25720]. HCBD was among the 14 VOCs included for discretionary monitoring. The UCM ( 1987) contaminants were first monitored coincident with the Phase I regulated contaminants, during the 1988   1992 period. This period is often referred to as " Round 1" monitoring. The monitoring data collected by the PWSs were reported to the States ( as primacy agents), but there was no protocol in place to report these data to EPA. These data from Round 1 were collected by EPA from many States over time.

The Round 1 data were collected in the URCIS. Most of the Phase 1 regulated contaminants were also VOCs. Both unregulated and regulated VOCs are analyzed using the same sample and the same laboratory methods. Hence, the URCIS database includes data on all of these 62 contaminants: the 34 UCM ( 1987) VOCs; the 21 regulated Phase 1 VOCs; 2 regulated synthetic organic contaminants ( SOCs); and 5 miscellaneous contaminants that were voluntarily reported by some States ( e. g., isomers of other organic contaminants). HCBD   February 2003 4 4 The 1993 UCM contaminants include 13 SOCs and 1 inorganic contaminant ( IOC) [ 56 FR 3526]. Monitoring for the UCM ( 1993) contaminants began coincident with the Phase II/ V regulated contaminants in 1993 through 1998. This is often referred to as " Round 2" monitoring. The UCM ( 1987) contaminants were also included in the Round 2 monitoring. As with other monitoring data, PWSs reported these results to the States. EPA, during the past several years, requested that the States submit these historic data to EPA.

The details of the actual individual monitoring periods are complex. The timing of required monitoring was staggered related to different size classes of PWSs, and the program was implemented somewhat differently by different States. Round 1 includes the period from 1988   1992, it also includes results from samples analyzed prior to 1988 ( for further details see U. S. EPA, 2001a, b).

Developing a Nationally Representative Perspective The URCIS and SDWIS/ FED databases contain contaminant occurrence data from a total of 40 and 35 primacy entities ( largely States), respectively. However, data from some States are incomplete and biased. Furthermore, the national representativeness of the data is questionable because the data were not collected in a systematic or random statistical framework. These State data could be heavily skewed to low occurrence or high occurrence settings. Hence, the data were evaluated based on pollution potential indicators and the spatial/ hydrologic diversity of the nation. This evaluation enabled the construction of a cross section from the available State data sets that provides a reasonable representation of national occurrence.

A national cross section from State SDWA contaminant databases was established using the approach developed for the EPA report A Review of Contaminant Occurrence in Public Water Systems ( U. S. EPA, 1999c). This approach was developed to support occurrence analyses for EPA's Chemical Monitoring Reform ( CMR) evaluation. It was supported by peer reviewers and stakeholders because it is clear, repeatable, and understandable. The approach cannot provide a " statistically representative" sample because the original monitoring data were not collected or reported in an appropriate fashion. However, the resultant " national cross section" of States should provide a clear indication of the central tendency of the national data. The remainder of this section provides a summary description of how the national cross sections for the URCIS ( Round 1) and SDWIS/ FED ( Round 2) databases were developed. The details of the approach are presented in U. S. EPA ( 2001a, b).

Cross Section Development As a first step in developing the cross section, the State data contained in the URCIS database ( which contains Round 1 monitoring results) and SDWIS/ FED database ( which contains Round 2 monitoring results) were evaluated for completeness and quality. For both the URCIS ( Round 1) and SDWIS/ FED ( Round 2) databases, some State data were unusable for a variety of reasons. Some States reported only detections, or their data had incorrect units. Datasets only including detections are obviously biased. Other problems included incomplete data sets without all PWSs reporting. Also, data from Washington, D. C. and the Virgin Islands were excluded from this HCBD   February 2003 4 5 analysis because it was difficult to evaluate them for the current purposes in relation to complete State data ( U. S. EPA, 2001a, Sections II and III).

The balance of the States remaining after the data quality screening were then examined to establish a national cross section. This step was based on evaluating the States' pollution potential and geographic coverage in relation to all States. Pollution potential is considered to ensure a selection of States that represent the range of likely contaminant occurrence and a balance with regard to likely high and low occurrence. Geographic consideration is included so that the wide range of climatic and hydrogeologic conditions across the United States are represented, again balancing the varied conditions that affect transport and fate of contaminants ( U. S. EPA, 2001b, Sections III. A. and III. B.).

The cross section States were selected to represent a variety of pollution potential conditions. Two primary pollution potential indicators were used. The first factor selected indicates pollution potential from manufacturing/ population density and serves as an indicator of the potential for VOC contamination within a State. Agriculture was selected as the second pollution potential indicator because the majority of SOCs of concern are pesticides ( U. S. EPA, 2001b, Section III. A.). The 50 individual States were ranked from highest to lowest based on the pollution potential indicator data. For example, the State with the highest ranking for pollution potential from manufacturing received a ranking of 1 for this factor and the State with the lowest value was ranked as number 50. States were ranked for their agricultural chemical use status in a similar fashion.

The States' pollution potential rankings for each factor were subdivided into four quartiles ( from highest to lowest pollution potential). The cross section States were chosen from all quartiles for both pollution potential factors to ensure representation, as follows: States with high agrochemical pollution potential rankings and high manufacturing pollution potential rankings; States with high agrochemical pollution potential rankings and low manufacturing pollution potential rankings; States with low agrochemical pollution potential rankings and high manufacturing pollution potential rankings; and States with low agrochemical pollution potential rankings and low manufacturing pollution potential rankings ( U. S. EPA, 2001b, Section III. B.). In addition, some secondary pollution potential indicators were considered to further ensure that the cross section States included the spectrum of pollution potential conditions ( high to low).

The data quality screening, pollution potential rankings, and geographic coverage analysis established national cross sections of 24 Round 1 ( URCIS) States and 20 Round 2 ( SDWIS/ FED) States. In each cross section, the States provide good representation of the Nation's varied climatic and hydrogeologic regimes and the breadth of pollution potential for the contaminant groups ( Table 4 1 and Figure 4 1).

Cross Section Evaluation To evaluate and validate the method for creating the national cross sections, the method was used to create smaller State subsets from the 24 State, Round 1 cross section and aggregations. Again, States were chosen to achieve a balance from the quartiles describing pollution potential, and a balanced geographic distribution, to incrementally build HCBD   February 2003 4 6 Table 4 1. Cross section States for Round 1 ( 24 States) and Round 2 ( 20 States).

Round 1 ( URCIS) Round 2 ( SDWIS/ FED)

Alabama Alaska* Arizona California Florida Georgia Hawaii Illinois Indiana Iowa Kentucky* Maryland* Minnesota* Montana New Jersey New Mexico* North Carolina* Ohio* South Dakota Tennessee Utah Washington* West Virginia Wyoming Alaska* Arkansas Colorado Kentucky* Maine Maryland* Massachusetts Michigan Minnesota* Missouri New Hampshire New Mexico* North Carolina* North Dakota Ohio* Oklahoma Oregon Rhode Island Texas Washington*

* cross section State in both Round 1 and Round 2 Figure 4 1. Geographic Distribution of Cross section States for Round 1 ( left) and Round 2 ( right).

subset cross sections of various sizes. For example, the Round 1 cross section was tested with subsets of 4, 8 ( the first 4 State subset plus 4 more States), and 13 ( 8 State subset plus 5) States. Two additional cross sections were included in the analysis for comparison: a cross section composed of the 16 biased States eliminated from the 24 State cross section for data quality reasons and a crosssection composed of all 40 Round 1 States ( U. S. EPA, 2001, Section III. B. 1). HCBD   February 2003 4 7 These Round 1 incremental cross sections were then used to evaluate occurrence for an array of both high and low occurrence contaminants. The comparative results illustrate several points. The results are quite stable and consistent for the 8, 13 and 24 State cross sections. They are much less so for the 4 State, 16 State ( biased), and 40 State ( all Round 1 States) cross sections. The 4 State cross section is apparently too small to provide balance both geographically and with pollution potential, a finding that concurs with past work ( U. S. EPA, 1999c). The CMR analysis suggested that a minimum of 6   7 States was needed to provide balance both geographically and with pollution potential, and the CMR report used 8 States out of the available data for its nationally representative cross section. The 16 State and 40 State cross sections, both including the biased States, provided occurrence results that were unstable and inconsistent for a variety of reasons associated with their data quality problems ( U. S. EPA, 2001, Section III. B. 1).

The 8, 13, and 24 State cross sections provide very comparable results, are consistent, and are usable as national cross sections to provide estimates of contaminant occurrence. Including greater data from more States improves the national representation and the confidence in the results, as long as the States are balanced related to pollution potential and spatial coverage. The 24 and 20 State cross sections provide the best, nationally representative cross sections for the Round 1 and Round 2 data.

Data Management and Analysis The cross section analyses focused on occurrence at the water system level; i. e., the summary data presented discuss the percentage of public water systems with detections, not the percentage of samples with detections. By normalizing the analytical data to the system level, skewness inherent in the sample data, particularly over the multi year period covered in the URCIS data, is avoided. System level analysis was used since a PWS with a known contaminant problem usually has to sample more frequently than a PWS that has never detected the contaminant. Obviously, the results of a simple computation of the percentage of samples with detections ( or other statistics) can be skewed by the more frequent sampling results reported by the contaminated site. This level of analysis is conservative. For example, a system need only have a single sample with an analytical result greater than the MRL, i. e., a detection, to be counted as a system with a result " greater than the MRL."

Also, the data used in the analyses were limited to only those data with confirmed water source and sampling type information. Only standard SDWA compliance samples were used; " special" samples, or " investigation" samples ( investigating a contaminant problem that would bias results), or samples of unknown type were not used in the analyses. Various quality control and review checks were made of the results, including follow up questions to the States providing the data. Many of the most intractable data quality problems encountered occurred with older data. These problematic data were, in some cases, simply eliminated from the analysis. For example, when the number of data with problems were insignificant relative to the total number of observations, they were dropped from the analysis ( For further details, see Cadmus, 2000). HCBD   February 2003 4 8 Occurrence Analysis To evaluate national contaminant occurrence, a two stage analytical approach has been developed. The first stage of analysis provides a straight forward, conservative, broad evaluation of occurrence of the Contaminant Candidate List ( CCL) preliminary regulatory determination priority contaminants as described above. These descriptive statistics are summarized here. Based on the findings of the Stage 1 Analysis, EPA will determine whether more intensive statistical evaluations, the Stage 2 Analysis, may be warranted to generate national probability estimates of contaminant occurrence and exposure for priority contaminants ( for details on this two stage analytical approach see Cadmus, 2000)

The summary descriptive statistics presented in Table 4 2 for HCBD are a result of the Stage 1 analysis and include data from both Round 1 ( URCIS, 1987   1992) and Round 2 ( SDWIS/ FED, 1993   1997) cross section States. Included are the total number of samples, the percent samples with detections, the 99th percentile concentration of all samples, the 99th percentile concentration of samples with detections, and the median concentration of samples with detections. The percentages of PWSs and population served indicate the proportion of PWSs whose analytical results showed a detection( s) of the contaminant ( simple detection, > MRL) at any time during the monitoring period; or a detection( s) greater than half the Health Reference Level ( HRL); or a detection( s) greater than the Health Reference Level. The Health Reference Level, 0.9 µ g/ L, is a preliminary estimated health effect level used for this analysis. The HRL was derived using the 10 6 cancer risk as calculated by the linear method using a body weight to the three quarter power ( section 8.8.2; slope factor 4 x 10 2 ( mg/ kg/ day) 1.

When monitoring results were compared to a value of one half of the HRL, 0.16% of Round 1 ( 106 systems) and 0.08% of Round 2 ( 51 systems) water supplies exceeded this benchmark at least once during the reporting period. The percentages of water supplies that exceeded the HRL at least once in Round 1 and Round 2 monitoring were 0.11% ( 74 systems) and 0.02% ( 11 systems), respectively.

The 99th percentile concentration is used here as a summary statistic to indicate the upper bound of occurrence values because maximum values can be extreme values ( outliers) that sometimes result from sampling or reporting error. The 99th percentile concentration is presented for both the samples with only detections and all of the samples because the value for the 99th percentile concentration of all samples is below the MRL ( denoted by "<" in Table 4 2). For the same reason, summary statistics such as the 95th percentile concentration of all samples or the median ( or mean) concentration of all samples are omitted because these also are all "<" values. This is the case because only 0.1 to 0.05% of all samples recorded detections of HCBD in Round 1 and Round 2.

As a convention, a value of half the MRL is often used as an estimate of the concentration of a contaminant in samples/ systems whose results are less than the MRL. With a contaminant with relatively low occurrence such as HCBD in drinking water occurrence databases, the median or mean value of occurrence using this assumption would be half the MRL ( 0.5 × MRL). However, for these occurrence data this is not straightforward. For Round 1 and Round 2, States have reported a wide HCBD   February 2003 4 9 range of values for the MRLs. This is in part related to State data management differences as well as real differences in analytical methods, laboratories, and other factors.

The situation can cause confusion when examining descriptive statistics for occurrence. For example, the modal MRL value for the Round 1 samples is 0.50 µ g/ L   a value twice as large as the median concentration of detections for Round 1 ( 0.25 µ g/ L) ( This occurs because some States and/ or systems reporting detections were using a lower MRL and had positive results lower than the MRL used by other States or systems). For Round 2, most States reported non detections as zeros resulting in a modal MRL value of zero. By definition the MRL cannot be zero. This is an artifact of State data management systems. Because a simple meaningful summary statistic is not available to describe the various reported MRLs, and to avoid confusion, MRLs are not reported in the summary table, but rather are designated as " variable" ( Table 4 2).

In Table 4 2, national occurrence is estimated by extrapolating the summary statistics for the 24 and 20 State cross sections to national numbers for systems, and population served by systems, from the Water Industry Baseline Handbook, Second Edition ( U. S. EPA, 2000e). From the handbook, the total number of community water systems ( CWSs) plus non transient, non community water systems ( NTNCWSs) is 65,030, and the total population served by CWSs plus NTNCWSs is 213,008,182 persons ( see Table 4 2). To arrive at the national occurrence estimate for a particular cross section, the national estimate for PWSs ( or population served by PWSs) is simply multiplied by the percentage for the given summary statistic. [ i. e., for Round 1, the national estimate for the total number of PWSs with detections ( 228) is the product of the percentage of Round 1 PWSs with detections ( 0.35%) and the national estimate for the total number of PWSs ( 65,030)].

Because the State data used for the cross section are not a strict statistical sample, national extrapolations of these Stage 1 analytical results can be problematic, especially for contaminants with very low occurrence like hexachlorobutadiene and other CCL regulatory determination priority contaminants. For this reason, the nationally extrapolated estimates of occurrence based on Stage 1 results are not presented in the CCL Federal Register Notice. The presentation in the Federal Register Notice of only the actual results of the cross section analysis maintains a straight forward presentation, and the integrity of the data, for stakeholder review. The nationally extrapolated Stage 1 occurrence values are presented here, however, to provide additional perspective. A more rigorous statistical modeling effort, the Stage 2 analysis, could be conducted on the cross section data ( Cadmus, 2001). The Stage 2 results would be more statistically robust and more suitable to national extrapolation. This approach would provide a probability estimate and would also allow for better quantification of estimation error.

Round 1( 1987   1992) and Round 2 ( 1993   1997) data were not merged because they represent different time periods, different States ( only eight States are represented in both rounds), and each round has different data management and data quality problems. The two rounds are only merged for the simple spatial analysis overview presented in Section 4.2 and Figures 4 2 and 4 4. HCBD   February 2003 4 10 4.2.2 Results Occurrence Estimates While States with detections of HCBD are widespread ( Figure 4 2), the percentages of PWSs by State with detections are low ( Table 4 2). In aggregate, the cross sections show only 0.2   0.4 % of PWSs in both rounds experienced detections (> MRL), affecting 0.9   2.4% of the population served ( approximately 2   5 million people). Percentages of PWSs with detections greater than half the Health Reference Level (> ½ HRL) are slightly lower: 0.1   0.2%. The percentage of PWSs exceeding the Health Reference Level (> HRL) for both rounds is very small ( see also Figure 4 4). The percentage of PWSs that experienced detections > HRL in Rounds 1 and 2 are 0.1% and 0.02%, respectively; affecting a population of approximately 780,000 and 10,000, respectively.

There are some qualifying notes for both rounds of data that warrant discussion. The Round 1 estimates of PWSs affected by HCBD are influenced by the State of Florida ( Table 4 2; Figures 4 3 and 4 4). This State reports that 5.4% of its PWSs experienced detections greater than the HRL during Round 1, a value considerably greater than the next highest State ( 1.5%). This suggests that Florida's data for HCBD is incomplete and may be biased. Out of 855 Florida PWSs reporting contaminant data for Round 1 monitoring, only 112 provided data for HCBD ( U. S. EPA, 2001a). Also, the 5.4% of systems reporting detections all reported concentrations greater than the Health Reference Level. These figures suggest that perhaps only systems experiencing problems submitted data for HCBD, biasing Florida's results for occurrence measures examined in this report.

The large values for the Round 2 national estimates of population served with detections greater than the MRL and greater than half the HRL are influenced by the inclusion of one PWS serving a very large population ( 1.5 million people). While the percentage of systems with detections of HCBD are similar ( both rounds show low values, 0.2   0.4% PWSs > MRL), the difference in population served results in a larger difference in the population extrapolations.

Note that for the Round 1 cross section, the total number of PWSs ( and the total population served by the PWSs) is not the sum of the number of ground water and surface water systems ( or the populations served by those systems). Because some public water systems are seasonally classified as either surface or ground water, some systems may be counted in both categories. The population numbers for the Round 1 cross section are also incomplete. Not all of the PWSs for which occurrence data was submitted reported the population they served. However, the population numbers presented in Table 4 2 for the Round 1 cross section are reported from 94% of the systems.

The national estimates extrapolated from Round 1 and Round 2 PWS, numbers and populations are not additive. In addition to the Round 1 classification and reporting issues outlined above, the proportions of surface water and ground water PWSs, and populations served by them, are different between the Round 1 and 2 cross sections and the national estimates. For example, approximately 48% of the population served by PWSs in the Round 1 cross section States are served by surface water PWSs ( Table 4 2). Nationally, however, that proportion changes to 60%. HCBD   February 2003 4 11 Table 4 2. Summary Occurrence Statistics for Hexachlorobutadiene.

Frequency Factors 24 State Cross Section1 ( Round 1) 20 State Cross Section2 ( Round 2) National System & Population Numbers3 Total Number of Samples 42,839 93,585

Percent of Samples with Detections 0.13% 0.05%

99th Percentile Concentration ( all samples) < ( Non detect) < ( Non detect)

Health Reference Level 0.9 : g/ L 0.9 : g/ L

Minimum Reporting Level ( MRL) Variable* Variable*

99th Percentile Concentration of Detections 10 : g/ L 1.5 : g/ L

Median Concentration of Detections 0.25 : g/ L 0.30 : g/ L

Total Number of PWSs 12,284 22,736 65,030 Number of GW PWSs 10,980 20,380 59,440 Number of SW PWSs 1,385 2,356 5,590 Total Population 71,582,571 67,075,493 213,008,182 Population of GW PWSs 40,399,177 24,960,222 85,681,696 Population of SW PWSs 34,418,834 42,115,271 127,326,486 National Extrapolation4 Occurrence by System Round 1 Round 2 PWSs with detections (> MRL) 0.350% 0.180% 228 117 Range of Cross Section States 0   5.36% 0   3.36% N/ A N/ A GW PWSs with detections 0.301% 0.132% 179 79 SW PWSs with detections 0.722% 0.594% 40 33 PWSs > ½ Health Reference Level ( HRL) 0.163% 0.079% 106 51 Range of Cross Section States 0   5.36% 0   0.51% N/ A N/ A GW PWSs > ½ Health Reference Level 0.118% 0.064% 70 38 SW PWSs > ½ Health Reference Level 0.505% 0.212% 28 12 PWSs > Health Reference Level 0.114% 0.018% 74 11 Range of Cross Section States 0   5.36% 0   0.24% N/ A N/ A GW PWSs > Health Reference Level 0.064% 0.005% 38 3 SW PWSs > Health Reference Level 0.505% 0.127% 28 7 Occurrence by Population Served Round 1 Round 2 PWS Population Served with detections 0.896% 2.360% 1,909,000 5,027,000 Table 4 2 ( continued)

Frequency Factors 24 State Cross Section1 ( Round 1) 20 State Cross Section2 ( Round 2) National System & Population Numbers3 HCBD   February 2003 4 12 Range of Cross Section States 0   11.38% 0   29.93% N/ A N/ A GW PWS Population with detections 1.458% 0.186% 1,249,000 159,000 SW PWS Population with detections 0.153% 3.649% 194,000 4,646,000 PWS Population Served > ½ Health Ref Level 0.569% 2.331% 1,213,000 4,965,000 Range of Cross Section States 0   11.38% 0   29.92% N/ A N/ A GW PWS Population > ½ Health Ref Level 0.978% 0.177% 838,000 152,000 SW PWS Population > ½ Health Ref Level 0.036% 3.607% 46,000 4,593,000 PWS Population Served > Health Ref Level 0.367% 0.005% 781,000 10,000 Range of Cross Section States 0   9.66% 0   0.02% N/ A N/ A GW PWS Population > Health Ref Level 0.619% 0.011% 531,000 9,000 SW PWS Population > Health Ref Level 0.036% 0.001% 46,000 1,000 1. Summary Results based on data from 24 State Cross Section, from URCIS, UCM ( 1987) Round 1. 2. Summary Results based on data from 20 State Cross Section, from SDWIS/ FED, UCM ( 1993) Round 2. 3. Total PWS and population numbers are from EPA March 2000 Water Industry Baseline Handbook. 4. National extrapolations are from the 24 State data and 20 State data using the Baseline Handbook system and population numbers. * see text for discussion  PWS = Public Water Systems; GW = Ground Water; SW = Surface Water; MRL = Minimum Reporting Level ( for laboratory analyses);  Health Reference Level = Health Reference Level, an estimated health effect level used for preliminary assessment for this review; N/ A = Not Applicable  The Health Reference Level used for hexachlorobutadiene is 0.9 : g/ L. This is a draft value for working review only.  Total Number of Samples = the total number of analytical records for hexachlorobutadiene.  99th Percentile Concentration = the concentration value of the 99th percentile of either all analytical results or just the samples with detections ( in : g/ L).  Median Concentration of Detections = the median analytical value of all the detections ( analytical results greater than the MRL) ( in : g/ L).  Total Number of PWSs = the total number of public water systems with records for hexachlorobutadiene.  Total Population Served = the total population served by public water systems with records for hexachlorobutadiene.  % PWS with detections, % PWS > ½ Health Reference Level, % PWS > Health Reference Level = percent of the total number of public water systems with at least one analytical result that exceeded the MRL, ½ Health Reference Level, Health Reference Level, respectively.  % PWS Population Served with detections, % PWS Population Served > ½ Health Reference Level, % PWS Population Served > Health Reference Level = percent of the total population served by PWSs with at least one analytical result exceeding the MRL, ½ Health Reference Level, or the Health Reference Level, respectively.

Both Round 1 and Round 2 national cross sections show a proportionate balance in source waters. Nationally, 91% of PWSs use ground water ( and 9% surface waters): Round 1 shows 89%, and Round 2 shows 90% of systems using ground water. The relative populations served are not as closely comparable. Nationally, about 40% of the population is served by PWSs using groundwater ( and 60% by surface water). Round 2 data is most representative with 37% of the cross section population served by ground water; Round 1 shows about 55%.

There are differences in the occurrence results between Round 1 and Round 2, as should be expected. The differences are not great, however, particularly when comparing the proportions of HCBD   February 2003 4 13 systems affected. The results range from 0.2   0.4% of PWSs with detections of HCBD and range from 0.02   0.1% of PWSs with detections greater than the Health Reference Level of 0.9 µ g/ L. These are not substantively different, given the data sources.

The differences in the population extrapolations appear greater, but still constitute relatively small proportions of the population. The most pronounced difference is in the estimate of the population served by PWSs with detections greater than the Health Reference Level, ranging from 10,000 to 780,000. In both cases, this is less than 0.5% of the population. The difference in this category is largely driven by the Florida data in Round 1, as discussed above.

The Round 2 cross section provides a better proportional balance related to the national population of PWSs and may have fewer reporting problems than Round 1 ( i. e., incomplete population numbers, Florida). The larger estimate of the national population served by PWSs with detections greater than the Health Reference Level using Round 1 data can also provide an upper bound estimate in considering the data.

Regional Patterns Occurrence results are displayed graphically by State in Figures 4 2, 4 3, and 4 4 to assess whether any distinct regional patterns of occurrence are present. Combining Round 1 and Round 2 data ( Figure 4 2), there are 47 States reporting. Six of those States have no data for HCBD, while another 21 have no detections of the chemical. The remaining 20 States have detected HCBD in drinking water and are well distributed throughout the United States.

The simple spatial analysis presented in Figures 4 2, 4 3, and 4 4 suggests that special regional analyses are not warranted. Florida's possible bias is notable, however. While no clear geographical patterns of occurrence are apparent, comparisons with environmental use and release information are useful ( see also Section 2.2). Five of the eight Toxic Release Inventory States that reported releases of HCBD into the environment between 1988 and 1998 have also detected the chemical in PWS sampling. Of the remaining three ( Kansas, Louisiana, and California), Kansas hasn't reported any data for either Round 1 or 2. Also, of the eight States with detections of HCBD at CERCLA National Priorities List ( NPL) hazardous waste sites, five have detected the chemical in drinking water. Finally, six of the States detecting HCBD in PWS samples have also detected it in site samples reported to the ATSDR's HazDat database. It is interesting to note that neither Alabama nor Florida, the two States with the highest percentage of PWSs with detections greater than the Health Reference level, are Toxic Release Inventory ( TRI) States for HCBD, nor do they have CERCLA NPL sites with detections of the chemical ( Figure 4 4). HCBD   February 2003 4 14 All States Hexachlorobutadiene Detections in Round 1 and Round 2 States not in Round 1 or Round 2 No data for Hexachlorobutadiene States with No Detections ( No PWSs > MRL) States with Detections ( Any PWSs > MRL) Figure 4 2. States with PWSs with Detections of Hexachlorobutadiene for all States with Data in URCIS ( Round 1) and SDWIS/ FED ( Round 2). HCBD   February 2003 4 15 * State of Florida is an outlier with 5.36% PWS > MRL Hexachlorobutadiene Occurrence in Round 1 States not in Cross Section No data for Hexachlorbutadiene 0.00% PWSs > MRL 0.01  1.00% PWSs > MRL 1.00  3.50% PWSs > MRL*

Hexachlorobutadiene Occurrence in Round 2 States not in Cross Section No data for Hexachlorbutadiene 0.00% PWSs > MRL 0.01  1.00% PWSs > MRL 1.00  3.50% PWSs > MRL Figure 4 3. States with PWSs with Detections of Hexachlorobutadiene ( any PWSs with results greater than the Minimum Reporting Level [ MRL]) for Round 1 ( above) and Round 2 ( below) Cross section States. HCBD   February 2003 4 16 * State of Florida is an outlier with 5.36% PWS > MRL Hexachlorobutadiene Occurrence in Round 1 and Round 2 States not in Cross Section No data for Hexachlorbutadiene 0.00% PWSs > MRL 0.01  1.00% PWSs > MRL 1.00  3.50% PWSs > MRL*

Hexachlorobutadiene Occurrence in Round 1 and Round 2 States not in Cross Section No data for Hexachlorobutadiene 0.00% PWSs > HRL 0.01  1.00% PWSs > HRL 1.00  3.50% PWSs > HRL* * State of Florida is an outlier with 5.36% PWS > HRL Figure 4 4. Cross section States ( Round 1 and Round 2 combined) with PWSs with Detections of Hexachlorobutadiene ( above) and concentrations greater than the Health Reference Level ( HRL; below). HCBD   February 2003 4 17 4.3 Conclusions While there have not been detections of the chemical in ambient water reported in USGS NAWQA studies to date, hexachlorobutadiene has been detected at a very low percentage of ATSDR HazDat sites and CERCLA NPL sites. Furthermore, releases have been reported through the TRI.

Hexachlorobutadiene has also been detected in PWS samples collected under SDWA. Occurrence estimates are low for Round 1 and Round 2 monitoring with only 0.13 % and 0.05% of all samples showing detections, respectively. Significantly, the values for the 99th percentile and median concentrations of all samples are less than the Minimum Reporting Level. For Round 1 samples with detections, the median concentration is 0.25 µ g/ L and the 99th percentile concentration is 10 µ g/ L. Median and 99th percentile concentrations for Round 2 detections are 0.30 µ g/ L and 1.5 µ g/ L, respectively. Systems with detections only constitute 0.4% of Round 1 systems and 0.2% for Round 2. National estimates for the population served by PWSs with detections are also low, especially for detections greater than the Health Reference Level. For both rounds, these estimates are less than 0.5% of the national population ( Round 1: 781,076; Round 2: 9,721). HCBD   February 2003 5 1 5.0 EXPOSURE FROM MEDIA OTHER THAN WATER This section describes studies which measured concentrations of HCBD in food, air, and soil. Exposure of adults and children is estimated by combining the reported concentrations with the estimated intake of each medium. These calculations enable a comparison of exposure to HCBD from air, food, and soil with that anticipated from ingestion of drinking water ( see Chapter 9.0). Estimates of human exposure to HCBD via food and air have previously been calculated by U. S. EPA ( 1998a).

5.1 Exposure from Food Food may be contaminated with HCBD via environmental sources or by contact with contaminated water during food processing activity ( DiNovi, 1997). According to the Food and Drug Administration ( FDA), there are no approved uses of HCBD either directly or indirectly in foods, including food processing equipment ( DiNovi, 1997). HCBD is not regulated in plastics.

5.1.1 Concentrations in Non Fish Food Items Two reports provide data for the concentration of HCBD in food items. Yip ( 1976) measured HCBD in food items within a 25 mile radius of tetrachloroethylene and trichloroethylene manufacturing plants that emit HCBD as a waste product. No HCBD was detected in 15 egg samples and 20 vegetable samples. One of 20 milk samples contained 1.32 mg/ kg HCBD. Resampling in the same area revealed no further detections in milk, raising the possibility that the concentration of 1.32 mg/ kg measured in the original data set was an artifact. This study reported two detection limits for HCBD: 0.005 mg/ kg for nonfatty foods and 0.04 mg/ kg for fatty foods. Based on information supplied by Kusznesof ( 1997), U. S. EPA ( 1998a) concluded that more than 30% of foods may be considered fatty foods for the purpose of estimating exposure from food ( see Section 5.1.3).

IARC ( 1979) reported concentrations of HCBD in foods sampled in the United Kingdom. HCBD was found at concentrations of 0.00008 mg/ kg in fresh milk, 0.002 mg/ kg in butter, 0.0002 mg/ kg in cooking oil, 0.0002 mg/ kg in light ale, 0.0008 mg/ kg in tomatoes, and 0.0037 mg/ kg in black grapes ( IARC, 1979).

5.1.2 Concentrations in Fish Concentrations of HCBD in fish have been reported in multiple studies. Tchounwou et al. ( 1998) demonstrated that aquatic organisms, particularly fish, may be a significant source of HCBD transmission from contaminated wetlands to humans. Tissue concentrations of HCBD were 226.33 ± 778.40 ng/ g in fish collected from a contaminated study site in Louisiana and 6.84 ± 10.41 ng/ g in fish collected from the corresponding control site.

In other studies, fish samples from the Mississippi River were reported to contain HCBD levels ranging from 100 to 4,700 ng/ g ( Laska et al., 1976; Yip, 1976; Yurawecz et al, 1976). Levels of HCBD generally were not detected in fish from the Great Lakes ( Camanzo et al., 1987; DeVault, 1985), with the exception of trout from Lake Ontario, which were reported to contain 60 to 300 ng/ g HCBD   February 2003 5 2 ( Oliver and Nimi, 1983). HCBD was not detected in 51 biota samples catalogued in the STORET database ( Staples et al., 1985).

The National Study of Chemical Residues in Fish ( NSCRF), conducted by EPA's Office of Water, was undertaken to determine the occurrence of selected pollutants in fish from various locations across the United States. Pollutants were measured in bottom feeding and game fish at nearly 400 sites between 1986 and 1989 ( Kuehl et al., 1994). A complete presentation of the study plan and results is contained in a joint Office of Water and Office of Research and Development report ( U. S. EPA, 1992a). To obtain nationwide coverage, samples were collected at sites near potential point and nonpoint pollution sources, at background sites in areas generally without pollution sources, and at a few sites from the U. S. Geological Survey's National Stream Quality Accounting Network ( NASQAN). Targeted sites were chosen near areas of significant industrial, urban, or agricultural activities, including more than 100 sites near pulp and paper mills.

Fish species chosen for sampling were those routinely consumed by humans and/ or those expected to bioaccumulate organic contaminants. At most locations, the NSCRF analyzed one composite sample of bottom feeding fish, usually composed of whole body samples. Some bottomfeeding fish composite samples were composed of fillets. In areas where whole body concentrations were high, composite samples of game fish were usually composed of fillets. Each composite sample contained approximately three to five adult fish of similar size from the site. Pollutant concentrations were measured in units of wet weight ( U. S. EPA, 1992a).

HCBD was detected in fish at 3% of the 362 sites sampled. Fillet samples were taken from 106 sites. The mean and standard deviation of HCBD fish concentrations at all sites were 0.6 ng/ g and 8.7 ng/ g, respectively ( Kuehl et al., 1994). These statistics represent the overall mean from all samples, not just from the positive samples. Concentrations were above 2.5 ng/ g at only four sites, which were all near organic chemical manufacturing plants ( U. S. EPA, 1992a). The concentrations observed at these four sites are provided in Table 5 1.

The methods for determining the mean and standard deviation for HCBD concentration and for evaluating samples below the analytical detection limit were not specifically stated by U. S. EPA ( 1992a). The value of the detection limit for HCBD was not given in U. S. EPA ( 1992a) or Kuehl et al. ( 1994). However, in the Kuehl et al. ( 1994) study, the mean concentration was calculated using one half of the detection limit concentration when the analyte was not detected. The raw data for HCBD were not presented.

Hendricks et al. ( 1998) evaluated HCBD levels in zebra mussel ( Dreissena polymorpha) and eel ( Anguilla anguilla) from approximately 30 locations in the Rhine Meuse river basin. In zebra mussel, HCBD levels were 240 ng/ kg at a background location and ranged from 950 to 14,000 ng/ kg wet weight within the study area. In eel, HCBD levels were found to range from 5,000 to 55,000 ng/ kg wet weight within the study area. HCBD   February 2003 5 3 Table 5 1. HCBD Tissue Concentration in Fish Collected Near Four Chemical Manufacturing Plants.

CONCENTRATION ( ng/ g wet weight) TYPE OF SAMPLE LOCATION 164.0 Sea Catfish  Whole Body Louisiana 23.0 Sea Catfish  Whole Body Texas 10.50 Catfish  Fillet Illinois 2.54 Catfish  Whole Body Louisiana source: U. S. EPA ( 1992a)

5.1.3 Intake of HCBD from Food Non fish Dietary Intake As noted above, HCBD has been found in a variety of foods in the United Kingdom. In addition, HCBD may have been incorrectly measured in one milk sample in the study by Yip ( 1976). It is also possible that HCBD could be found in measurable quantities in the United States. However, because HCBD was generally undetected in samples taken from areas within 25 miles of emission sources, U. S. EPA ( 1998a) concluded that it is appropriate to assume that, on average, HCBD will not be found in food at detectable levels. Given this observation, along with the fact that HCBD has no approved uses in food, it is anticipated that there would typically be no chronic exposure to HCBD via non fish dietary foods ( U. S. EPA, 1998a). Therefore, the average estimate of HCBD intake from non fish foods is assumed to be zero ( U. S. EPA, 1998a).

A high end estimate of HCBD exposure may be made by assuming a concentration of onehalf the detection limit ( U. S. EPA, 1999b). Because the percentages of fatty or non fatty foods in the diet are not known with certainty, a conservative estimate is made using one half the detection limit of 0.04 mg/ kg noted for fatty foods in Yip ( 1976). The resulting concentration of 0.02 mg/ kg is multiplied by an estimate of total daily food intake of 2.6 kg/ day and divided by 70 kg to obtain a total daily intake of HCBD from food of 7.4 × 10 4 mg/ kg day in adults. For children, the resulting concentration of 0.02 mg/ kg was multiplied by an estimate of total daily food intake of 0.84 kg/ day ( U. S. EPA, 1988) and divided by a body weight of 10 kg to obtain a total daily intake of HCBD from food of 1.68 × 10 3 mg/ kg day. For the majority of regions of the United States in which HCBD is not found, using one half the detection limit will overestimate the amount of HCBD in food ( U. S. EPA, 1999b).

Because the data on concentrations in food are limited, and because the implications of assuming that HCBD occurs at one half the detection limit for fatty foods are large, further research may be required to refine this estimate. HCBD   February 2003 5 4 Fish Dietary Intake U. S. EPA ( 1998a) estimated HCBD intake from fish using the tissue concentration data from Kuehl et al. ( 1994). Because these data were taken from many monitoring stations throughout the United States, the estimate may be reasonably indicative of the magnitude of intake from fish consumption when HCBD is present in fish tissue. An average estimate of adult exposure was obtained by multiplying the mean concentration of 0.6 ng/ g from the Kuehl et al. ( 1994) data by a fish intake of 18 g/ day for the general population and dividing by a body weight of 70 kg. The resulting estimate is 1.54 × 10 7 mg/ kg day. The maximum concentration detected in fish by Kuehl et al. ( 1994) can also be used to estimate the high end intake. Following the same procedure above, but substituting a concentration of 164 ng/ g, one obtains a high end intake of 4.22 × 10 5 mg/ kg day.

An average estimate of HCBD exposure in children was determined by multiplying the mean concentration of 0.6 ng/ g from the Kuehl et al. ( 1994) data by a fish intake of 4 g/ day for the general population and dividing by a body weight of 10 kg. The resulting estimate is 2.4 × 10 7 mg/ kgday The maximum concentration detected in fish by Kuehl et al. can also be used to calculate a high end estimate of intake in children. Following the same procedure above, but substituting a concentration of 164 ng/ g, results in an intake of 4.37 × 10 5 mg/ kg day.

5.2 Exposure from Air 5.2.1 Concentration of HCBD in Air Concentration data for HCBD in air have previously been summarized by U. S. EPA ( 1998a). The largest compilation of data on ambient air concentrations is available from Shah and Heyerdahl ( 1988). Shah and Heyerdahl compiled ambient air monitoring data for volatile organic compounds for the period from 1970 to 1987. A total of 72 observations from six studies were reported for HCBD. In cases where more than one sample was taken per day, the concentrations were averaged and weighted by sampling time when the sampling time varied throughout the day. When more than one sample was included in the average, values less than the minimum quantifiable limit ( MQL) were included as one half the MQL when the MQL was given. When the MQL was not indicated in the Shah and Heyerdahl study, values less than the MQL were included as zeros in the average. If the resulting average was less than the MQL, a zero was included. If the average was greater than the MQL, the calculated average was used.

As reported in U. S. EPA ( 1998a), the average and median of all ambient HCBD air concentrations measured by Shah and Heyerdahl ( 1988) were 0.036 parts per billion ( ppb) ( 0.42 : g/ m3) and 0.003 ppb ( 0.04 : g/ m3), respectively. The 25th and 75th percentiles were 0.001 ppb ( 0.01 : g/ m3) and 0.006 ppb ( 0.07 : g/ m3). Only median values were reported for urban areas and sourcedominated areas. Of 56 samples taken from urban areas, the median was 0.003 ppb ( 0.04 : g/ m3). Of 16 samples taken from source dominated areas, the median was 0.002 ppb ( 0.02 : g/ m3). No indoor concentrations were reported ( Shah and Heyerdahl, 1988).

Shah and Heyerdahl's compilation included the results from Pellizzari et al. ( 1979), who surveyed the occurrence of halogenated hydrocarbons in various environmental media of five HCBD   February 2003 5 5 metropolitan areas. As part of this study, HCBD concentrations in the vapor phase of ambient air of four sites were compiled from other research programs, as well as from monitoring conducted specifically for this project. In the Niagara Falls and Buffalo, New York area, concentrations were found to range from trace levels to 389 ng/ m3, with six of 15 determinations ( 40%) containing detectable levels. In the Baton Rouge, Louisiana area, two of 11 determinations ( 18%) were 18 and 37 ng/ m3. Sampling in Houston, Texas, and surrounding areas showed a range of trace levels to 2,066 ng/ m3, with seven positive values from a total of 17 determinations ( 41%).

Class and Ballschmiter ( 1987) reported that the troposphere of the Northern Hemisphere contained an average concentration of 0.17 parts per trillion ( ppt) ( 2 : g/ m3) HCBD at 18 locations sampled from 1982 to 1986. The detection limits in this survey were between 0.01 and 0.1 ppt.

HCBD concentrations in ambient air were measured in two studies included in a compilation of ambient monitoring data for the Urban Area Source Program ( U. S. EPA, 1994). In the first survey, concentrations of HCBD were reported at a minimum detection level of 540 : g/ m3 when measured at six monitoring stations in Columbus, Ohio, in 1989. The second survey was conducted in Cincinnati, Ohio, from 1989 to 1991, and detected HCBD at one monitoring site at a concentration of 1,000 : g/ m3.

A number of cities had HCBD levels ranging from 2 to 11 ppt ( 0.02 to 0.12 : g/ m3) ( Pellizzari, 1978; Singh et al., 1980, 1982). Niagara Falls had higher HCBD levels, with concentrations up to 37 ppt ( 0.39 : g/ m3) found in ambient air levels and up to 38 ppt ( 0.41 : g/ m3) found in the basement air of homes near industrial and chemical waste disposal sites ( Pellizzari, 1982).

However, a study of air contaminants in Porto Alegre, Brazil ( Grosjean and Rassmussen, 1999) did not find detectable levels of HCBD ( detection limit = 100 ppt) at any of 46 sampling locations. A monitoring study at 6 sampling locations in Columbus, Ohio also failed to detect HCBD in the air ( Spicer et al., 1996).

5.2.2 Intake of HCBD from Air The air concentrations reported in Shah and Heyerdahl ( 1988) were utilized by U. S. EPA ( 1998a) to calculate an estimate of exposure because this data set included a reasonable number of observations ( n= 72). For adults, the mean concentration of 0.42 : g/ m3 was multiplied by an average air intake of 20 m3/ day ( U. S. EPA, 1988). The resulting value was divided by a body weight of 70 kg, and the units were converted from : g to mg, resulting in an average intake of 1.2 × 10 4 mg/ kgday For children, the mean concentration of 0.42 : g/ m3 was multiplied by an average air intake of 15 m3/ day ( U. S. EPA, 1988). The resulting value was divided by a body weight of 10 kg and the units were converted from : g to mg, resulting in an intake of 6.3 × 10 4 mg/ kg day. As noted in U. S. EPA ( 1998a), these estimates may be indicative of the magnitude of HCBD intake from air in urban and source dominated areas where the chemical is present. It should be noted, however, that these concentration data are older than data from the Urban Area Source Program ( U. S. EPA, 1994) and Class and Ballschmiter ( 1987). In addition, the number of geographic areas sampled throughout the United States by Shah and Heyerdahl was not indicated. HCBD   February 2003 5 6 5.3 Exposure from Soil 5.3.1 Concentration of HCBD in Soil and Sediment Limited data on the concentrations of HCBD in soil was identified in a RCRA corrective measures study, and ranged from 0.043  0.35 mg/ kg ( USDOE, 2001) . Sediments adsorb HCBD from contaminated water. As reported in U. S. EPA ( 1999b), HCBD was not detectable in any of the 196 sediment samples reported in the STORET database, based on a detection limit of 500 : g/ kg for the analyses ( Staples et al., 1985). Sediments from the Niagara River contained 2.9 to 11 : g/ kg HCBD ( Oliver and Bourbonniere, 1985). Sediments from the Great Lakes contain HCBD typically ranging from 0.08 to 120 : g/ kg ( McConnell et al., 1975). Suspended solids collected from the Rhine Meuse river basin indicate HCBD levels ranging from < 3.4 to 19 : g/ kg ( Hendriks et al., 1998); which is comparable to the previously mentioned data for sediments collected in the United States.

Several studies have investigated HCBD levels in sediments from sites in Louisiana. HCBD levels in sediment samples from a Louisiana swamp environment ranged from less than 0.05 : g/ kg to 0.40 : g/ kg ( Abdelghani et al,. 1995). These concentrations were well below the action levels of 4,000 : g/ kg for sediment ( U. S. EPA, 1991a). At a Federal Superfund site near Baton Rouge, Louisiana, preliminary data from a sampling of sediments showed HCBD levels from 2 to 3,770 mg/ kg ( U. S. EPA, 1992b). The HCBD level in a sediment sample from Lake Charles, Louisiana was found to be 3,500 : g/ kg ( Chen et al., 1999). A sediment sample collected from the intersection of an industrial canal and Bayou d'Inde ( a tributary of the Calcasieu River near Lake Charles) and analyzed via Soxhlet extraction was found to contain HCBD at a level of 17,200 ± 1,000 : g/ kg ( Prytula and Pavlostathis, 1996). Another reported sediment sample collected from this industrial canal area had an HCBD level of 36,000 ± 6,900 : g/ kg ( Gess and Pavlostathis, 1997). A third study of sediments from Bayou d'Inde found levels of HCBD ranging from 1,550 to 8,220,000 : g/ kg of organic carbon. Assuming an organic carbon content in the sediment of 1%, this level is equivalent to sediment concentrations of 15 to 82,200 : g/ kg.

5.3.2 Intake of HCBD from Soil Because no data were available on the concentration of HCBD in soil or dust, intake from soil was not estimated.

5.4 Other Residential Exposures HCBD was not detected in sewage influents ( Levins et al., 1979) or in sewage samples ( U. S. EPA, 1990). No other information on exposure via other potentially complete residential pathways was identified.

5.5 Summary Estimated mean concentration and average intake values for HCBD in media other than water are summarized in Table 5 2. Assuming that there is no chronic exposure of the general population HCBD   February 2003 5 7 Table 5 2. Summary of Concentration Data and Exposure Estimates for Media Other Than Water.

PARAMETER MEDIUM Food Air Mean Concentration in medium Non fish ( NF): nondetect Fish ( F): 0.6 ng/ g 0.42 : g/ m3 Estimated average daily intake ( mg/ kg day) Adult Child Adult Child NF: 0 F: 1.5 × 10 7 NF: 0 F: 2.4 × 10 7 1.2 × 10 4 6.3 × 10 4 to HCBD from non fish dietary sources, inspection of the data indicates that most intake of HCBD by the general population occurs via inhalation. However, it should be cautioned that this preliminary conclusion is subject to a number of uncertainties: 1) the database for the occurrence of HCBD in media other than water is limited; 2) many of these data are more than 20 years old; 3) in some cases, information on the geographic location of sample collection or analytical details are lacking; and 4) data for HCBD in soil and dust were not available to estimate via this pathway. HCBD   February 2003 6 1 6.0 TOXICOKINETICS This section describes the absorption, distribution, metabolism, and excretion of hexachlorobutadiene. The information in this section focuses on findings in animals exposed primarily via the oral route. No studies were identified that evaluated the toxicokinetic behavior of HCBD in humans. The development of a physiologically based pharmacokinetic ( PBPK) model would be desirable for summarizing and extrapolating the toxicokinetic behavior of HCBD between high dose animal studies and low dose human exposure. In order to develop such a model, blood or plasma time course data for HCBD and, if possible, its metabolites, would be required. However, no pharmacokinetic parameters ( half life, partition coefficients, etc.) for HCBD or its metabolites have been published in the peer reviewed literature, and no blood or plasma time course for HCBD or its metabolites has been published for any species. This remains as an important gap in the database for this chemical.

6.1 Absorption HCBD is readily absorbed following oral administration to experimental animals. Although no studies have quantitatively determined the rate of absorption of HCBD following oral dosing, useful information has been obtained from studies that evaluated the distribution and excretion of this compound. Reichert et al. ( 1985) administered 1 mg/ kg of 14C HCBD to female Wistar rats via gavage. The compound was administered in a tricaprylin suspension to accommodate its low water solubility. Approximately 76% of the radioactivity was excreted as metabolites in the urine, feces, or expired air within 72 hours after administration, suggesting that most of the dose was absorbed. When a higher dose of 50 mg/ kg 14C HCBD was administered in the same study, 69% of the radioactivity was found in the feces and was predominantly associated with unchanged HCBD. Just 11% of the administered radioactivity was excreted in the urine for the high dose group, compared to 31% for the low dose animals. The study authors concluded that absorption of HCBD was saturated in animals in the higher dose group ( Reichert et al. 1985; U. S. EPA, 1991a).

Nash et al. ( 1984) administered 200 mg/ kg 14C HCBD via oral gavage in corn oil to male Wistar derived rats. Animals were sacrificed 2, 4, 8, or 16 hours after dosing, and the fate of the administered radioactivity was evaluated using whole body autoradiographs. The investigators reported that absorption was virtually complete within 16 hours after dosing.

Payan et al. ( 1991) administered 1 mg/ kg and 100 mg/ kg 14C HCBD to male Sprague Dawley rats, using an aqueous polyethylene glycol vehicle, and found that 18.5 and 8.9% of the administered radioactivity, respectively, was excreted over 72 hours in the urine. Since urinary excretion at a dose of 1 mg/ kg in the Reichert et al. ( 1985) study was 31%, these data suggest that gastrointestinal absorption of HCBD was greater when administered in a lipophilic vehicle ( tricaprylin) than with an aqueous vehicle ( aqueous polyethylene glycol), although it could also be due to differences in animal sex and strain ( female Wistar rats vs. male Sprague Dawley rats). As noted for other unsaturated chlorinated compounds, HCBD absorption presumably occurs by passive diffusion across the lipid portion of the intestinal matrix rather than by active or protein facilitated transport ( ATSDR, 1994). HCBD   February 2003 6 2 Little information is available regarding HCBD absorption following exposure by other routes. Although no studies were located that described absorption in humans or animals after inhalation exposure to this compound, the occurrence of systemic effects following exposure indicates that absorption occurs by this route ( ATSDR, 1994). With regard to dermal exposure, Duprat and Gradiski ( 1978) applied doses of 419 to 1,675 mg/ kg HCBD to the skin of rabbits under occluded conditions, and reported that the compound was completely absorbed within 8 hours.

6.2 Distribution HCBD has been detected in the adipose tissue of human cadavers at concentrations of 0.003 ± 0.001 : g/ g ( Mes et al., 1985), but not whole blood in any of 36 residents of Love Canal, New York or in any of 12 laboratory volunteers ( Bristol et al., 1982). Olea et al. ( 1999) detected HCBD in the adipose tissue of 13 of 50 children living in an agricultural region of southern Spain. The mean concentration in the 13 children was 0.70 : g HCBD/ g of fat ( range: 0.23 to 2.43 : g HCBD/ g of fat). No data were available concerning the route of exposure.

Following oral administration, HCBD related radioactivity preferentially distributed to the kidney, liver, adipose tissue and brain of experimental animals ( Reichert, 1983; Reichert et al., 1985; Dekant et al., 1988a). Covalent binding of HCBD related radioactivity to tissue proteins in female Wistar rats was highest during the first six hours after dosing, and was higher in the kidney than in the liver. This effect was independent of dose ( Reichert et al., 1985). In female Wistar rats administered 1 mg/ kg 14C HCBD, covalent binding of the radioactivity to protein in the kidney was about twice that in the liver 72 hours after dosing ( Reichert et al., 1985). Nash et al. ( 1984) reported a specific localization of administered radioactivity in male Wistar derived rats in the outer medulla of the kidney, as revealed by autoradiographic analysis following an oral dose of 200 mg/ kg 14CHCBD Payan et al. ( 1991) conducted a study in male Sprague Dawley rats in which the bile ducts of one group of animals administered an oral dose of 100 mg/ kg 14C HCBD were cannulated so that bile secretions from these animals could be infused directly into the duodenum of another group of animals. In both groups, the kidneys contained about twice as much radiolabel as the liver.

No studies were located regarding the distribution of HCBD in humans or animals after inhalation or dermal exposure. Davis et al. ( 1980) administered 0.1 mg/ kg radiolabeled 14C HCBD as a tracer dose to a control group of male Sprague Dawley rats ( 5 animals/ group) via intraperitoneal injection. Another group received the same amount of labeled HCBD plus a nephrotoxic dose of 300 mg/ kg non labeled HCBD. The highest concentrations of radiolabel were found in the liver, kidney, and adipose tissue 48 hours after administration. Approximately 2.6 and 2.3% of the administered 14C radiolabel were retained in the livers of low and high dose animals, respectively. The fraction of the tracer retained in kidney varied from 2.5% at the low dose to 0.5% at the high dose. The fraction of the dose found in adipose tissue was not determined. Very low levels of the radiolabel ( less than 0.2%) were found in the brain, lung, heart, and muscle. HCBD   February 2003 6 3 6.3 Metabolism No available studies have characterized the metabolism of HCBD in animals following inhalation or dermal exposure. The metabolism of HCBD in animals has been studied in isolated hepatocytes from male Sprague Dawley rats ( Jones et al., 1985) and by characterization of metabolites identified in urine, bile, and feces following oral exposure to the compound ( Figure 6 1). Following ingestion and absorption from the gastrointestinal tract of mice and rats, HCBD is initially transported to the liver, where it is conjugated with glutathione to form S( 1,1,2,3,4  pentachlorobutadienyl) glutathione in a reaction mediated by glutathione S transferase ( Wolf et al., 1984; Garle and Fry, 1989; Dekant et al., 1988b; Koob and Dekant, 1992). No studies have found non enzymatic glutathione conjugation of HCBD, and none have investigated GST subtype specificity for HCBD. In male Sprague Dawley rats, a di substituted glutathione conjugate, 1,4 bis( 1,2,3,4 tetrachlorobutadienyl) glutathione, is also formed in the liver ( Jones et al., 1985), whereas in mice, only the mono substituted conjugate is produced ( Dekant et al., 1988a). The glutathione conjugate is then excreted in bile and transported back into the gastrointestinal tract ( Koob and Dekant, 1992). Nash et al. ( 1984), for example, collected bile excretions from cannulated male Wistar derived rats that had been orally administered 200 mg/ kg 14C HCBD and determined that 40% of the bile radioactivity was associated with the glutathione conjugate. Studies conducted by Lock et al. ( 1984) demonstrate that induction or inhibition of cytochrome P450 metabolism does not alter the nephrotoxicity of HCBD in male or female mice administered 24, 48, 96, or 144 mol/ kg HCBD by gavage. Glutathione and N acetylcysteine conjugates of HCBD exhibit more potent nephrotoxicity in male and female mice ( Lock et al., 1984; Ishmael and Lock, 1986) and male Sprague Dawley rats ( Nash et al., 1984) than unconjugated HCBD. This suggests that conjugated metabolites, unlike oxidative metabolites, may play a large role in HCBD nephrotoxicity.

The glutathione conjugate of HCBD can be reabsorbed intact from the gastrointestinal tract of male rats ( Koob and Dekant, 1992; Gietl et al., 1991). Alternatively, a portion of it can be catabolized by ( glutamyltranspeptidase and dipeptidases in the rat gastrointestinal tract to the cysteine conjugate, S( 1,1,2,3,4 pentachlorobutadienyl) L cysteine ( Jones et al., 1985; Gietl et al., 1991; Koob and Dekant, 1992). In the rat, both the glutathione and cysteine conjugates are subject to several alternative fates. These conjugates may be reabsorbed from the gut and be translocated to the kidney ( Koob and Dekant, 1992), undergo enterohepatic circulation ( Nash et al., 1984; Gietl et al., 1991; Gietl and Anders, 1991), or be excreted with the feces ( Dekant et al. 1988a). However, the majority of the glutathione conjugate is delivered to the kidney by systemic circulation in the rat ( Koob and Dekant, 1992). Working with isolated perfused rat livers, Koob and Dekant ( 1992) determined that a maximum of 39% of the glutathione conjugate was recirculated to the liver of rats, whereas up to 79% of the cysteine conjugate was recirculated. Nash et al. ( 1984) reported that the cysteine and glutathione conjugates represented 12% and 40%, respectively, of the radioactivity excreted in the bile of cannulated rats orally administered 200 mg/ kg HCBD. When the cysteine conjugate is recirculated to the rat liver, a minor fraction of this metabolite is converted by Nacetyltransferase to an acetylated cysteine conjugate, N acetyl S( 1,1,2,3,4 pentachlorobutadienyl) Lcysteine ( N AcPCBC) ( Koob and Dekant, 1992). HCBD   February 2003 6 4 NHCOCH 3 NHCOCH3 O Cl Cl Cl C C C C Cl Cl Cl Cl Cl Cl C C C C Cl Cl Cl Cl Cl C C C C Cl Cl Cl Cl C C C C Cl SG Cl Cl Cl Cl C C C C Cl SOH Cl SG S Cys Gly GS Cl Cl C C C C Cl Cl Cl Cl C C C C Cl Cl Cl Cl Cl C C C S CH2 CH Cl Cl Cl Cl Cl C C C C S CH2 COOH Cl Cl Cl Cl Cl C C C C SH Cl Cl Cl Cl Cl C C C C Cl S CH2 CH COOH COOH S Hexachloro 1,3 butadiene Glutathione Transferase GSH Liver S( 1,1,2,3,4 pentachloro butadienyl) glutathione ( PCBG)

1,4 bis( 1,2,3,4 tetrachloro butadienyl) glutathione ( b)  glutamic acid 1,1,2,3,4 pentachloro butadienyl sulfenic acid N acetyl transferase N acetyl S( 1,1,2,3,4

pentachlorobutadienyl L cysteine ( N AcPCBC)  lyase deamination decarboxylation S methylation 1,1,2,3,4 pentachlorobutadienyl methylthioether Thioketene S( 1,1,2,3,4 pentachlorobutadienyl)

L cysteine ( PCBC) 1,1,2,3,4 pentachloro butadienylthiol HCl 1,1,2,3,4 pentachlorobutadienyl carboxymethylthioether  glycine Glutathione Transferase GSH Liver dipeptidase Notes:

( a) Di substituted compounds are formed in rats, but not in mice ( b) Metabolism parallels that for the monosubstituted compound * Adapted from: Dekant et al., 1991; Jaffe et al., 1983; Nash et al., 1984; Wolf et al., 1984; Jones et al., 1985; Reichert et al., 1985;

Reichert and Schutz, 1986; Wild et al., 1986; Birner et al., 1998; ATSDR, 1994. deacetylase Cyt. P450 3A Male specific Sulfoxidation pathway    glutamyl transpeptidase N acetyl S( 1,1,2,3,4 pentachlorobutadienyl)

 L cysteine sulfoxide ( N AcPCBC SO)

covalent binding Cl Cl C C C C Cl Cl S CH2 CH Cl toxicity ( a)

( a) S CH 3 COOH C Cl Cl NH2 decarboxylation   GSH = glutathione gly = glycine cys = cysteine Figure 6 1. Proposed Pathways for Hexachlorobutadiene Metabolism. HCBD   February 2003 6 5 Further processing of both the cysteine and glutathione conjugates occurs in the kidney, which possesses high ( glutamyltranspeptidase activities in the brush border membrane of the proximal tubular cells ( Dekant and Vamvakas, 1993; Dekant et al., 1990). Renal deacetylase, ( glutamyltranspeptidase, and dipeptidase enzymes convert the acetylated cysteine conjugate and the glutathione conjugate to the cysteine conjugate, which accumulates in the kidney ( Dekant et al., 1990). The cysteine conjugate is subsequently activated to a reactive and electrophilic thioketene intermediate ( Dekant et al., 1990; Green and Odum 1985). This conversion is catalyzed by the enzyme cysteine conjugate $ lyase, which is localized in the cytosol and mitochondria of the epithelial cells of the proximal tubule ( Lash et al., 1986; Stevens, 1985; Stevens et al. 1986; Jones et al., 1988; MacFarlane et al., 1989; Kim et al., 1997).

Another pathway for metabolic disposition of the cysteine conjugate of HCBD in the kidney is the conversion of the cysteine conjugate to a mercapturic acid, N acetyl S( 1,1,2,3,4 pentachlorobutadienyl) L cysteine, by the renal enzyme N acetyltransferase ( Birner et al., 1997). This metabolite is excreted in the urine, accounting for 10% of urinary radioactivity in rats orally administered 100 mg/ kg 14C HCBD ( Reichert and Schutz, 1986). Other pathways that result in the excretion of the cysteine conjugate involve the deamination and subsequent decarboxylation of the cysteine conjugate, resulting in the formation of methylthiolated metabolites such as 1,1,2,3,4 pentachlorobutadiene methylthioether and 1,1,2,3,4 pentachlorobutadiene carboxymethylthioether ( Reichert et al., 1985). 1 to 8% of the administered radioactivity is recovered as carbon dioxide in exhaled air from rats ( Reichert et al., 1985; Payan et al., 1991), probably from decarboxylation of the cysteine conjugate.

Evidence for a male specific HCBD metabolic pathway in rats has been reported by Birner and colleagues ( Birner et al., 1995, 1998; Werner et al. 1995a). The metabolite N acetyl S( 1,1,2,3,4 pentachlorobutadienyl) L cysteine sulfoxide ( N AcPCBC SO) is detected in the urine of male, but not female, rats following oral administration of HCBD. Formation of this metabolite is mediated by cytochrome P450 3A monooxygenases, which are expressed only in male rats ( Birner et al., 1995; Werner et al., 1995a). This metabolite has been found to be cytotoxic to proximal tubular cells in vitro without activation by $ lyase ( Birner et al., 1995). When given intravenously, N AcPCBC SO produced necroses of the kidney tubules in male rats ( Birner et al., 1998).

The N AcPCBC SO formed in male rats occurs as two diastereomers present in equimolar amounts: ( R) N AcPCBC SO and ( S) N AcPCBC SO ( Werner et al., 1995b). These compounds are structurally analogous to unsaturated carbonyl compounds and thus may be candidates for detoxification via glutathione conjugation ( Rosner et al., 1998). Experimental evidence obtained in vitro suggests that glutathione conjugation of the two diastereomers is catalyzed by different glutathione S transferases, resulting in the formation of different products ( Rosner et al., 1998). Incubation of the ( R) sulfoxide diastereomer with rat liver cytosol resulted in formation of ( R) Nacetyl S( 4 glutathion S yl 1,2,3,4 tetrachlorobutadienyl) L cysteine sulfoxide. Incubation of the ( S) sulfoxide produced two glutathione conjugates identified as ( S) N acetyl S( 4 glutathion S yl 1,2,3,4 tetrachlorobutadienyl) L cysteine sulfoxide and ( S) N acetyl S( 2 glutathion S yl 1,3,4,4 tetrachlorobutadienyl) L cysteine sulfoxide. In the presence of rat kidney cytosol, only the ( S) Nacetyl S( 2 glutathion S yl 1,3,4,4 tetrachlorobutadienyl) L cysteine sulfoxide conjugate was formed. Glutathione conjugation of the ( R) sulfoxide was not observed. The observed pattern of HCBD   February 2003 6 6 product formation was attributed to catalysis by different glutathione S transferases in liver (" and : class) and kidney (" class). This hypothesis was confirmed by product analysis following incubation of N AcPCBC SO with purified rat " and : class glutathione S transferases.

Very little information is available on the toxicokinetic behavior of HCBD in humans. However, the key steps in the metabolism of HCBD have been examined in vitro using human tissues. The human liver microsomal glutathione transferase responsible for HCBD conjugation has been isolated and purified ( McLellan et al., 1989), and the microsomal enzyme activity is 40 fold higher than the activity detected in the cytosol ( Oesch and Wolf, 1989). The rate of enzymatic formation of S( 1,2,3,4,4 pentachlorobutadienyl) glutathione ( PCBG) from HCBD in human liver cytosol is in the same order of magnitude as the rates observed in rat and mouse cytosol ( Dekant et al., 1998).

The enzyme ( glutamyl transpeptidase, which catalyzes the conversion of glutathione Sconjugates to the corresponding cysteine conjugates, has been detected in human tissues ( Shaw et al., 1978). The kidney to liver activity ratio for ( glutamyl transpeptidase in human tissues is approximately 22, which is comparable to the ratios observed in pig and guinea pig. However, this ratio is much lower than in rat, where a kidney to liver ratio of 875 has been observed ( Hinchman and Ballatori, 1990).