Document MMOL6Ema0xJqM19bMj61r0r4M

t> CM f>tM!CAL MAMlJRACTijRbRS ASSOCIATION September 4, 1990 TO: Vinylidene Chloride Panel RE: ATSDR Tox Profile on Vinylidene Chloride I have enclosed a copy of the final ATSDR profile on Vinylidene Chloride (1,1-Dichloroethene). The profile does not have an ATSDR cover because I received the report directly from the prime contractor, Clement Associates. Also enclosed is a letter about the profile from Bruce Dickson, the Panel's legal counsel. Of particular interest to the Panel may be the profile sections on cancer (pp. 32-35, 46-49, 57-58) and data needs (pp. 73-78, 84, 93, 99), I will be in touch with each of you about whether or not the Panel wants to take any actions, particularly in response to the data need for additional information on chronic toxicity and carcinogenicity. I look forward to working with each of you. If you have any questions, I can be reached at 202/887-1189. My staff assistant, Amy Kosko, can be reached at 202/887-1345. Sincerely, Jonathon T, Busch Manager, Vinylidene Chloride 02 -v'TT"00 T=ie< 0O617 CMA SL 064440 Ti COVxlI. wCt O **UL oc`r * vcon*ro a c-*rlcs w W*UHC* lOS anGClCS office 555 SOUTH FlOWCR STREET ,,OS ANGfc-uES, CAJFOBNIA 00071 TELEPHONE (2i3i 683'SOOO ORANGE COUNTv OFFICE 695 TOWN CENTS" 0'VE COSTA MESA, CauiFORNIA 92929 TClCPhQnC *7i*i 641-nOO WEST LOS ANGELES OFFICE <200 OCEAN AVENUE SANTA MQNiCA, CALIFORNIA 00*0' TClEPmOnC (213) 45MZOO LAW OFFICES Or Paul. Hastings. Janofsky & Walker a *ATh,C*-l* INClUO'NG PROFESSIONAL CORPORATIONS twelfth floor 1050 CONNECTICUT AVENUE, N, W. WASHINGTON, D, C 20036 TELEPHONE (202) 223-0000 TWX 7iO- 822-9002 TELECOPIER (202) *52-61*9 August 31, 1990 202-457-9423 MEMORANDUM TO THE CMA VINYLIDENE CHLORIDE PANEL Re: ATSDR Tox Profile ATLANTA OFFICE GCORGia-paCific center 133 PEACHTREE STREET, n E ATLANTA, GEORGIA 30303 TELEPHONE 1*0*) 398-9900 CONNECTICUT OFFICE ONE CANTERBUPV GREEN STAMFORO. CONNECTICUT Q6BO1 TELEPHONE (2031 3S7-OIOC NEW YORK OFFICE 9 WEST ST*" STREET NEW YORK. NEW YORK 10019 TELEPHONE (2<2) 032-91OO TOKYO OFFICE TORanOmOn Ohtori ouilDinG A-3, tqranOmOn i-ChOme MINATO-KU, TOKYO IOS TElCRhOnC (03) 307-0730 ATSDR has issued the final version of its Toxicological Profit for 1,1-Dichloroethene (vinylidene chloride). The Tox Profile contains the following evaluation of data needs: "Chronic Exposure and Carcinogeni city. Data from animal studies on the chronic toxicity and carcinogenicity of DCE are sparse, and limited in their usefulness because of experimental design flaws. The data presented do not sufficiently characterize the carcino genic or chronic toxic effects of DCE. However, the available information does suggest that DCE is carcinogenic in animals. Additional information on the chronic toxicity and carcinogenicity of DCE from well-conducted animal bioassays and human epidemiological studies using various routes of exposure would be useful in predicting the likelihood that such effects occur in humans." You will recall that at a meeting with the Panel on May 19, 1989, Richard Troast stated that EPA was awaiting the Tox Profile before deciding whether to withdraw the test SL 064441 MEMORANDUM TO THE CMA VINYLIDENE CHLORIDE PANEL August 31, 1990 Page 2 rule. We have discussed this development with Jon Busch, who agrees that a conference call or meeting of the Panel should be held in the near future to discuss whether any further action should be taken by the Panel. R. Br-ce Dickson Enclosure cc: Zeb Bell, Ph.D., Chairman James Barter, Ph.D. Stanley Dombrowksi William Haye^" Jon Busch i/ Marilyn Browning, Esq. TOXICOLOGICAL PROFILE FOR 1,1-DICHLOROETHENE Prepared by: Clement Associates Under Contract No. 205-88-0608 Prepared for: Agency for Toxic Substances and Disease Registry U.S. Public Health Service In collaboration with: U.S. Environmental Protection Agency December 1989 Lt ii DISCLAIMER Mention of company name or product does not constitute endorsement by the Agency for Toxic 'ubstances and Disease Registry. SL 064444 ri iii FOREWORD The Superfund Amendments and Reauthorization Act of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law (also known as SARA) directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCXA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The list of the 100 most significant hazardous substances was published in the Federal Register on April 17, 1987. Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. Each profile must include the following content: "(A) An examination, summary and interpretation of available toxicological information and epidemiological evaluations on the hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects, (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute, subacute, or chronic health effects, and (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans." This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary, but no less often than every three years, as required by SARA. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature that describes a hazardous substance's toxicological properties. Other literature is presented but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. Each toxicological profile begins with a public health statement, which describes in nontechnical language a substance's relevant toxicological properties. Following the statement is material that presents levels of significant human exposure and, where known, significant health effects. The SL 064445 L1 iv adequacy of information to determine a substance's health effects is described in a health effects summary. Research gaps that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program of the Public Health Service, and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the front of the document. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. We plan to revise these documents in response to public comments and ^ additional data become available; therefore, we encourage comment that wil ike the toxicological profile series of the greatest use. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, EPA, the Centers for Disease Control, and the National Toxicology Program. It has also been reviewed by a panel of nongovernment peer reviewers and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Walter R. Dowdle, Ph.D. Acting Administrator Agency for Toxic Substances and Disease Registry SL 064446 J V CONTENTS FOREWARD............................................................................................................................................. iii LIST OF FIGURES.......................................................................................................................... ix LIST OF TABLES.............................................................................................................................. xi 1. PUBLIC HEALTH STATEMENT ............................................................................................... 1.1 WHAT IS DCE?............................................................................................................ 1.2 HOW MIGHT I BE EXPOSED TO DCE?..................................................................... 1.3 HOW CAN DCE ENTER AND LEAVE MYBODY?.......................................................... 1.4 HOW CAN DCE AFFECT MY HEALTH? ..................................................................... 1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO DCE?................................................................................................... 1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?................................................................................................... ... . . . 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO* PROTECT HUMAN HEALTH? ...................................................................................... 1.8 WHERE CAN I GET MORE INFORMATION?........................................................... 1 1 I 2 3 3 3 4 9 2. HEALTH EFFECTS................................................................................................................. 2.1 INTRODUCTION............................................................................................................ 2.2 DISCUSSION OF HEALTH EFFECTS BYROUTE OF EXPOSURE ......................... 2.2.1 Inhalation Exposure ............................................................................. 2.2.1.1 Death ...................................................................................... 2.2.1.2 Systemic Effects ............................................................... 2.2.1.3 Immunological Effects ................................................. 2.2.1.4 Neurological Effects ...................................................... 2.2.1.5 Developmental Effects .................................................. 2.2.1.6 Reproductive Effects ...................................................... 2.2.1.7 Genetic Effects ............................................................... 2.2.1.8 Cancer..................................................................................... 2.2.2 Oral Exposure.......................................................................................... 2.2.2.1 Death ..................................................................................... 2.2.2.2 Systemic Effects ............................................................... 2.2.2.3 Immunological Effects ................................................. 2.2.2.4 Neurological Effects ...................................................... 2.2.2.5 Developmental Effects ................................................. 2.2.2.6 Reproductive Effects ..................................................... 2.2.2.7 Genetic Effects .............................................................. 2.2.2.8 Cancer..................................................................................... 2.2.3 Dermal Exposure...................................................................................... 2.2.3.1 Death ..................................................................................... 2.2.3.2 Systemic Effects............................................................... 2.2.3.3 Immunological Effects ................................................. 2.2.3.4 Neurological Effects ...................................................... 2.2.3.5 Developmental Effects .................................................. 2.2.3.6 Reproductive Effects ...................................................... 11 11 11 12 12 23 29 29 30 31 32 32 35 35 42 45 45 45 46 46 46 47 47 48 48 48 48 48 SL 064447 I! vi 2.2.3.7 Genetic Effects ................................................................ 2.2.3.8 Cancer....................................................................................... 2.3 RELEVANCE TO PUBLIC HEALTH .............................................................................. 2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS ......................................................................................................... 2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES..................................................................................................... 2.6 TOXICOKINETICS......................................................................................................... 2.6.1 Absorption................................................................................................ 2.6.1.1 Inhalation Exposure ....................................................... 2.6.1.2 Oral Exposure ..................................................................... 2.6.1.3 Dermal Exposure ................................................................ 2.6.2 Distribution........................................................................................... 2.6.2.1 Inhalation Exposure ....................................................... 2.6.2.2 Oral Exposure ..................................................................... 2.6.2.3 Dermal Exposure ................................................................ 2.6.2.4 Other ....................................................................................... 2.6.3 Metabolism................................................................................................ 2.6.4 Excretion..................................................................................................... 2.6.4.1 Inhalation Exposure ....................................................... 2.6.4.2 Oral Exposure ..................................................................... 2.6.4.3 Dermal Exposure ................................................................ 2.6.4.4 Other Routes of Exposure .............................................. 2.7 INTERACTIONS WITH OTHER CHEMICALS............................................................ 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE.......................................... 2.9 ADEQUACY OF THE DATABASE.................................................................................. 2.9.1 Existing Information on Health Effects of DCE................... 2.9.2 Data Needs ................................................................................................ 2.9.3 On-going Studies .................................................................................. 3. CHEMICAL AND PHYSICAL INFORMATION......................................................................... 3.1 CHEMICAL IDENTITY................................................................................................ 3.2 PHYSICAL AND CHEMICAL PROPERTIES................................................................ 4. PRODUCTION, IMPORT, USE, AND DISPOSAL................................................................ 4.1 PRODUCTION.................................................................................................................. 4.2 IMPORT........................................................................................................................... 4.3 USE................................................................................................................................ 4.4 DISPOSAL....................................................................................................................... 4.5 ADEQUACY OF DATABASE........................................................................................... 4.5.1 Data Needs ................................................................................................ 5. POTENTIAL FOR HUMAN EXPOSURE.................................................................................. 5.1 OVERVIEW....................................................................................................................... 5.2 RELEASES TO THE ENVIRONMENT......................................................................... 5.2.1 Air.................................................................................................................. 5.2.2 Water.............................................................................................................. 5.2.3 Soil.............................................................................................................. 5.3 ENVIRONMENTAL FATE................................................................................................ 5.3.1 Transport and Partitioning ............................................................ 5.3.2 Transformation and Degradation.................................................. 48 48 49 58 58 59 59 59 61 61 61 62 62 62 62 63 68 68 69 70 70 70 71 73 73 73 78 79 79 79 83 83 83 83 84 84 84 85 85 85 85 86 86 87 87 88 064448 SL vii 5.3.2.1 Air .......................................................................................... 5.3.2.2 Water ...................................................................................... 5.3.2.3 Soil.......................................................................................... 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT........................... 5.4.1 Air................................................................................................................. 5.4.2 Water............................................................................................................ 5.4.3 Soil ............................................................................................................ 5.4.4 Other Media............................................................................................... 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE.................................... 5.6 POPULATIONS WITH UNUSUALLY HIGH EXPOSURES ......................................... 5.7 ADEQUACY OF THE DATABASE................................................................................. 5.7.1 Data Needs............................................................................................... 5.7.2 On-going Studies ................................................................................. 88 88 89 89 89 90 90 91 91 92 93 93 93 6. ANALYTICAL METHODS ........................................................................................................ 6.1 BIOLOGICAL MATERIALS .......................................................................................... 6.2 ENVIRONMENTAL SAMPLES...................................................................................... 6.3 ADEQUACY OF THE DATABASE................................................................................. 6.3.1 Data Needs ............................................................................................... 6.3.2 On-going Studies ................................................................................. 95 95 98 98 99 99 7. REGULATIONS AND ADVISORIES ...................................................................................... 101 8. REFERENCES............................................................................................................................... 105 9. GLOSSARY....................................................................................................................................127 APPENDIX....................................................................................................................................... 131 SL 064449 ix LIST OF FIGURES 2-1 Levels of Significant Exposure for DCE-- InhalationExposure . . 2-2 Levels of Significant Exposure for DCE-- Oral Exposure................... 2-3 Percentage of Systemic Uptake of DCE During Inhalation Exposures ................................................................................. 2-4 Metabolic Pathway of DCE in Animals .............................................................. 2-5 Physiologically-Based Pharmacokinetic Model for DCE ......................... 2-6 General Proposed Scheme for Oxidative and Conjugative Metabolism of Vinylidene Chloride Not Metabolized Via Epoxide Intermediate ..................................................................................................................... 2-7 Existing Information on Health Effects of DCE.......................................... 13 36 60 64 65 66 74 SL 064450 I1 xi LIST OF TABLES 1*1 Human Health Effects from Breathing DCE ......................................................... 5 1-2 Animal Health Effects from Breathing DCE ....................................................... 6 1-3 Human Health Effects from Eating/DrinkingDCE .......................................... 7 1- 4 Animal Health Effects from Eating/DrinkingDCE .......................................... 8 2- 1 Levels of Significant Exposure for DCE -Inhalation.......................................................................................................................... 15 2-2 Levels of Significant Exposure for DCE -Oral....................................................................................................................................... 38 2-3 Genotoxicity of DCE in Vitro................................................................................ 55 2- 4 Genotoxicity of DCE in Vivo................................................................................ 56 3- 1 Chemical Identity of DCE......................................................................................... 80 3-2 Physical and Chemical Properties of DCE..................................................... 81 6-1 Analytical Methods for the Detection of DCE in Biological Samples.............................................................................................................................. 96 6- 2 Analytical Methods for the Detection of DCE in Environmental Samples.............................................................................................................................. 97 7- 1 Regulations and Guidelines Applicable toDCE .............................................. 102 064451 I 1 1. PUBLIC HEALTH STATEMENT 1.1 WHAT IS 1,1-DICHLOROETHENE (DCE)? 1,1-Dichloroethylene (DCE) also known as vinylidene chloride is a chemical used Co make certain plastics such as packaging materials (flexible films [SARAN"1 wrap]) and flame-retardant fabrics. DCE is also used to make other chemicals. It is a clear, colorless liquid that evaporates quickly at room temperature and has a mild, sweet smell like chloroform. DCE also burns. DCE is a man-made chemical that is not found naturally in the environment. It is released into the environment mostly in the air and water coming from factories where it is made, at hazardous waste sites where it has been disposed, and from accidental spills. DCE can also be found as a breakdown product of other chemicals in the environment. Although high amounts of DCE in soil and water will quickly escape to the air, small amounts will stay and be broken down. We do not known how long DCE will stay in soil and water. DCE quickly breaks down in the air. DCE released into the atmosphere is estimated to last for only about 2 days. The physical and chemical properties of DCE are explained in Chapter 3, production and use information can be found in Chapter 4, and more information on environmental fate is given in Chapter 5. 1.2 HOW MIGHT I BE EXPOSED TO DCE? Besides the high exposures in plants where DCE is made, low-level exposures to DCE may occur In the environment. DCE is found at very low amounts in indoor and outdoor air (estimated as less than one part per trillion). Therefore, the potential for exposure in the environment is extremely low. Somewhat highef amounts are found in the air near some factories that make or use DCE (as in the making of plastic food-packaging films, adhesives, flame-retardant coatings for fiber and carpet backing, in piping, and in coating for steel pipes), hazardous waste sites, and areas near accidental spills. The amount of DCE in the air near these factories is not known exactly. In air around waste sites DCE amounts range from 0.39 to 36.4 parts DCE in one billion parts of air (ppb). The levels of DCE in air around waste sites are usually much lower than those that affect the health of laboratory animals. The plants that make DCE are located in Texas and Louisiana. DCE is now estimated to be in the air around 97 factories throughout the United States. Air levels inside manufacturing plants have recently been measured to range from less than 5 parts DCE in 1 million parts of air (ppm) to 25 ppm. The Occupational Health and Safety Administration (OSHA) has recently established a limit for air contaminants of 1 ppm for an 8-hour work day which should significantly reduce worker exposure in the future. DCE was found at approximately 16% of all hazardous waste sites tested through the U.S. Environmental Protection Agency (EPA) Contract Laboratory Program and is found at 175 of the 1177 National Priorities List (NPL) SL 064452 2 1. PUBLIC HEALTH STATEMENT 4J hazardous waste sites. DCE has been found in the soil at a small number of these hazardous waste sites, but the amounts were not reported. A small percentage (3%) of the drinking water sources in the United States has been found to contain low amounts of DCE (0.2-0.5 ppb with an estimated average of 0.3 ppb). Again, the amounts are very low when compared with levels that are expected to affect human health. Levels in groundwater samples taken from hazardous waste sites where DCE was found average 1.38 ppm. Finally, because DCE is used in making some consumer products, exposure might occur during the making and use of these products. For example, DCE has been estimated at less than 1.26 ppm in plastic food-packaging films, and DCE measured in foodstuffs wrapped in these films is less than 0.01 ppm. These numbers represent the levels found only in food samples chat had DCE in them as not every food sample tested was found to contain DCE. However, the Food and Drug Administration (FDA) regulates the use of plastic packaging films, and the low levels of DCE found in foods wrapped in these films are considered by the FDA to present no health risk to the consumer. More information on human exposure can be found in Chapter 5. 1.3 HOW CAN DCE ENTER AND LEAVE MY BODY? DCE can easily enter the body through the lungs as an air pollutant or through the digestive tract as a contaminant of food or water. DCE can probably also enter the body through the skin. This assumption is based on the physical and chemical properties of DCE, the fact that chemicals similar to DCE are known to be absorbed through the skin, and the occurrence of t xic effects in animals after DCE was applied to their skin. The most common means of exposure in. the workplace, in the general population, and in areas around hazardous waste sites is breathing contaminated air. However, some DCE can be taken in by drinking contaminated ground water, particularly around hazardous waste sices. Research using animals has led to the following information. Within hours of exposure, DCE begins to leave the body through the lungs. Remaining DCE in the body is broken down into other substances and removed through the kidneys within 1 to 2 days. The way DCE and its breakdown products leave th body depends on the level of exposure to DCE. Low or moderate levels breathed in (25-200 ppm) or taken by mouth (up to 50 mg DCE/kg body weight), leave the body mainly as breakdown products in the urine. As the levels of exposure increase, more and more DCE leaves the body in the exhaled breath. DCE breathed in and taken by mouth both leave the body about the same way, DCE is not stored very much in the body after exposure to moderate (up to 300 ppm) levels. More information is given in Chapter 2. SL 064453 i* 3 1. PUBLIC HEALTH STATEMENT 1.4 HOW CAN DCE AFFECT MY HEALTH? The health effects of DCE in humans are not known. High amounts of DCE in animal studies have caused liver, kidney, heart, and lung damage and have also caused nervous system disorders and death after short exposures. Liver damage has also been seen when exposure was long (weeks to years). The amount of damage depends on the level of exposure and the length of time exposed. Exposure by breathing DCE appears to be more harmful in animals than exposure through food or water. After short exposures to high levels of DCE, the same kinds of effects can be expected to occur in humans. An increased risk for cancer has been shown in one study in which animals were exposed to DCE. Although most studies have shown that DCE does not cause cancer in animals, it is wise to consider the possibility that DCE may cause cancer in humans because of this one suggestive study. Harmful effects on the developing fetus have been seen in the offspring of pregnant animals inhaling this chemical. Sickness of the mothers was also seen. The health effects of DCE in both humans and animals are explained in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO DCE? DCE can be measured in the breath, blood, urine, and body of exposed individuals. However, only relatively high levels of DCE can be detected in body tissues and fluids using currently available analytical techniques. Because breath samples are easily collected, tests of exhaled air are now the most common way to tell whether a person has been exposed to high levels of DCE. Other medical tests can measure breakdown products of the chemical in the blood and urine. None of these tests is regularly available at a doctor's office, because they need special equipment for sampling and measuring the compound. Although these tests can prove that a person has been exposed to DCE, they can not yet tell how severe any health effects might be. Because DCE leaves the body fairly quickly, these methods are best for finding exposures that have occurred within the last several days. Levels of DCE measured in the body with these types of medical tests may not reflect exposure to DCE alone, because exposure to DCE at hazardous waste sites is likely to include exposure to other organic compounds at the same time that result in similar breakdown products as DCE. Other methods of measuring the effects associated with exposure to DCE (such as reduced enzyme levels) are not sufficiently specific to detect effects caused by exposure to DCE alone. Information on tests to find DCE in the body is given in Chapter 6. 1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS? Except for loss of breath, fainting, and nervous system disorders like drunkenness that result from exposure to high amounts of DCE in a closed space, there are few medical reports to prove that human exposure to DCE affects health. However, human exposure has not been studied very much. The available information on DCE exposure in humans is not very useful for telling how DCE affects human health and at what levels and kinds of exposure. The SL 064454 4 1. PUBLIC HEALTH STATEMENT information is mainly reports about small numbers of people, without the level and time of exposure to DCE given, and with the possibility of exposure to other harmful chemicals. So, levels of exposure that may affect human health must be estimated from animal studies. Studies In animals indicate that the normal actions of the liver, kidney, lungs, heart, and blood can be affected by exposure to DCE. These effects began to occur at air amounts of IS ppm after 5 days of exposure. Animals exposed to DCE at 98 ppm DCE in the air for 7 days have died. Exposure of animals to 24 ppm DCE in air for 6 hours a day, 5 days a week, for months to years, can cause liver damage. Vhen animals had 200 milligrams of DCE per kilogram of body weight per day (mg/kg/day) (4,000 ppm) placed in their stomachs experimentally, they developed liver disease, and some even died. Animals fed amounts of 7 mg DCE/kg/day (50 ppm) in their drinking water over a period of months to years also developed liver disease. Tables 1-1 through 1-4 show the relationship between exposure to DCE and known health effects. Minimal Risk Levels (MRLs) are also included in Tables 1-1 and 1-3. These MRLs were derived from animal data for both sh rtterm or longer-term exposure, as described in Chapter 2 and in Tables 2-1 and 2-2. The MRLs provide a basis for hazard in humans, based upon all known experimental data on the chemical. Should a person be exposed to DCE at an amount below the MRL, it is not expected that harmful (noncancer) health effects will occur. Since these levels are based on information that is currently available from animal studies; there is always some uncertainty associated with them. Also, since the method for deriving MRLs does not use any information about cancer, a MRL does not imply anything about the presence, absence, or level of risk to cancer. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The Federal Government has developed regulatory guidelines and standards to protect individuals from the possible health effects of DCE. EFA has ruled that the highest level of DCE in drinking water be less than 7 #*g/L and any release of more than 5,000 lb to the environment be reported. However, EPA has recently suggested that this level should be no more than 100 lb. For short-term exposures EPA has decided that drinking water levels should not be more than 2 mg/L (2 ppm) for one day or 1 mg/L (1 ppm) for 10 days. The National Institute for Occupational Safety and Health (NIOSH) has decided that the highest level of DCE in workplace air should not be more than 4 mg/m3 (1 ppm). 0SHA recently established a limit for air contaminants of SL 064455 J 5 1. PUBLIC HEALTH STATEMENT TABLE 1-1. Human Health Effects from Breathing DCE* Short-term Exposure (less than or equal to 14 days) Levels in air (onm) 0.9 500 4,000 Duration of Exnosure < 1 day Deserintion of Effects*** Estimated minimal risk level (based on animal studies, see section 1.6 for discussion) Odor threshold Temporary nervous system disorders Levels in Air (oom) Long-term Exposure (greater than 14 days) Duration of Exnosure Deserintion of Effects** 0.02 Estimated minimal risk level (based on animal studies, see section 1.6 for discussion) * See Section 1.2 for a discussion of exposures encountered in daily life. ** These effects are listed at the level at which they were first observed. They may also be seen at higher levels. SL 064456 1. PUBLIC HEALTH STATEMENT TABLE 1-2. Animal Health Effects from Breathing DCE Short-term Exposure (less than or equal to 14 days) Levels in air (Dorn) 10 15 15 40 50 60 Duration of Exposure 4 hr. 8 days 11 days 4 hr. 6 hr. 5 days Deae: nzion of Effects** Kidnt disease in fasted mice Changes in the appearance of the liver in mice Toxicity to developing fetus in mice Death in fasted male mice More severe kidney disease in fasted male mice Severe liver disease in male mice. Long-term Exposure (greater than 14 days) Levels in air (tram) 4 4 25 48 Duration of Exoosure 6 months 18 months 1 year 3 months Descriotlon of Effects** Changes in the appearance of the liver in rats Liver disease in rats Kidney disease in mice Changes in Che appearance of the lungs and kidneys in rats ** These effects are listed at the level at which they were first observed. They may also be seen at higher levels. SL 064457 7 1. PUBLIC HEALTH STATEMENT TABLE 1-3. Human Health Effects from Eating or Drinking DCE* Short-term Exposure (less than or equal to 14 days) Levels in food (ppm^ Duration of Exposure Levels in water (ppm) Description of Effects*** The health effects of short term human exposure resulting from DCE in food containing specific levels of DCE are not known The health effects of short term human exposure resulting from DCE in water containing specific levels of DCE are not known Long-term Exposure (greater than 14 days) Levels in food (ppm) 0.32 gyration Of Expomo Levels in water (ppm) Description of Effects** Estimated minimal risk level (based on animal studies, see section 1.6 for discussion) The health effects of long term human exposure resulting from DCE in water containing specific levels of DCE are not known * See Section 1.2 for a discussion of exposures encountered In daily life. ** These effects are listed at the level at which they were first observed They may also be seen at higher levels. SL 064458 8 1. PUBLIC HEALTH STATEMENT J TABLE 1-4. Animal Health Effects from Eating or Drinking DCE Short-term Exposure (less than or equal to 14 days) Levels in food (oom) 500 1,000 1,540 4,000 Duration of Exposure 1 day 1 day 1 day 1 day 4,000 Levels in water (nom) 1 day Descrlotion of Effects** Changes in the appearance of liver in rats Death in rats Changes in the appearance of of the lung in mice Changes in the appearance of the kidney and stomach in fasted rats Liver disease in fasted rats The health effects resulting from short-term animal exposure to DCE in water containing specific levels of DCE are not known Long-term Exposure (greater than 14 days) Levels in food (ppm) Duration of Exposure Levela-inl.ttatgg-XjpB) 50 Of EffgCtg** The health effects resulting from long-term animal exposure to DCE in food containing specific levels of DCE are not known. Changes in the appearance of the liver in rats ** These effects are listed at the level at which they were first observed. They may also be seen at higher levels. SL 064459 9 1. PUBLIC HEALTH STATEMENT 1 ppm. Employers must be in compliance with this standard by September 1, 1989. This new Permissible Exposure Limit (PEL) should significantly reduce future workplace exposure to DCE. EPA estimates that for an average-weight adult, an exposure of 0.63 mg of DCE or less per day will probably not cause harmful health effects (not including cancer).Work is now being done by EPA to measure the levels of DCE found at abandoned waste sites. 1.8 WHERE CAN I GET MORE INFORMATION? If you have further questions or concerns, please contact your state health or environmental department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton road, E-29 Atlanta, Georgia 30333 SL 064460 10 1. PUBLIC HEALTH STATEMENT I SL 064461 11 2. HEALTH EFFECTS 2.1 INTRODUCTION This chapter contains descriptions and evaluations of studies and interpretation of data on the health effects associated with exposure to DCE. Its purpose is to present levels of significant exposure for DCE based on toxicological studies, epidemiological investigations, and environmental exposure data. This information is presented to provide public health officials, physicians, toxicologists, and other interested individuals and groups with (1) an overall perspective of the toxicology of DCE and (2) a depiction of significant exposure levels associated with various adverse health effects. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the data in this section are organized first by route of exposure -- inhalation, oral and dermal -- and then by health effect -- death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods -- acute, intermediate, and chronic. Levels of significant exposure for each exposure route and duration (for which data exist) are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear, determine whether or not the intensity of the effects varies with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown on the tables and graphs may differ depending on the user's perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons or with the identification of persons with the potential to develop such disease may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with response actions at Superfund sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (minimal risk levels, MRLs) are of interest to health professionals and citizens alike. For certain chemicals, levels of exposure associated with carcinogenic effects may be indicated in the figures. These levels reflect the actual doses associated with the tumor incidences reported in the studies cited. Because cancer effects could occur at lower exposure levels, the figures also SL 064462 12 2. HEALTH EFFECTS i show estimated excess risks, ranging from a risk of one in 10,000 to one in 10,000,000 (10'* to 10'7), as developed by EPA. Estimates of exposure posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer endpoint for each exposure duration. MRLs include adjustments to reflect human variability and, where appropriate, the uncertainty of extrapolating from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et al. 1987; EPA 1980c), uncertainties are associated with the techniques. 2.2.1 Inhalation Exposure Figure 2-1 and Table 2-1 describe the health effects observed in laboratory animals associated with exposure level and exposure duration. minimal risk levels to humans for adverse effects other than cancer are presented in Figure 2-1 for the inhalation route of exposure. The 2.2.1.1 Death No studies were found regarding death in humans following inhalation exposure to DCE. However, studies in rats, mice, and hamsters provide evidence that inhalation exposure to DCE can be lethal. The lethality of DCE in animals following inhalation exposure has been found to vary considerably and is influenced by such factors as species, strain, sex, and nutritional status. Differences between strains could account for the range of reported 4-hour LCsos in fed rats (approximately 6,000-8,000 pr~ in males, and a value of 10,000 ppm has been reported in females) (Hen .ler 1979; Siegel et al. 1971; Zeller et al. 1979a,b). High r 4-hour LCJ0s (10,000-15,000 ppm) have been reported for fed rats (sex not specified) but the animals were observed only for 24 hours (Jaeger et al. 1973b). The LC30s reported for 16-hour fasted rats are generally orders of magnitude lower than those reported for fed rats. For instance, a 4-hour LCS0 of 400 ppm was reported for fasted male rats (Zeller et al. 1979b). Female rats appear to be more resistant to the detrimental effects of starvation; a 4-hour LCS0 of 6,545 ppm was reported by the same author for fasted female rats. Finally, Jaeger et al. (1974) compared the effects of nutritional status on lethality in male rats exposed to DCE for 24 hours and found that the LCJ0 for fasted animals was almost 30 times lower than that for fed animals. The proposed mechanism by which fasting increases the toxicity of DCE will be discussed in Sections 2.3 and 2.6. SL 064463 ACUTE (5.14 Pay) / // Otlr 9i fa to 01 0.01 HEALTH EFFECTS 0.0001 FIGURE 2-1. Levels of Significant Exposure To DCE - Inhalation SL 064464 INTERMEDIATE (15-364 Pays) CHRONIC (>365 Days) 10,000 |-- 1.000 100 10 // / / (I Mr QM MS0T.4M.Mh lltk ll Sk )l1k o o 3 m* 33m. I /// 3i ,03i 3: o33S' O <03 41k Q 0< 0 3i^ (I4** ro HEALTH EFFECTS 0.1 001 0.001 00001 000001 0000001 Estimated UpperBound Human Canes. Risk 0.0000001 FIGURE 2-1. Levels of Significant Exposure To DCE - Inhalation (Continued) SL 064465 TABLE 2-1. Laval* of Significant Expoaura to 1,1-Dlcbloroathana - Inhalation Graph Kay Epaclaa Expoaura Duration/ Fraquancy Effact LMS.fStfasU ROAEL Laaa Sarioua Sarioua <W> Rafaranca ACUTE EXPOSURE 1 rat 4 hr 1x 2,010 (LC50-HSF1** Zallar at al. 415 (LC50 - HI** 1979b (aa cltad 6,543 (LC30 - FI** in Flaldar at al. 19631 2 rat 4 hr 1x 3 rat 4 hr 1x 4 rat 4 hr 1x 10.000 -(LC50) 15.000 Jaagar at al. 1973b 0,600 (LCSO-HAF) 7,100 (LCS0 - H) 10,300 (LCS0 - F) Banachlar 1979 (aa cltad in Flaldar at al. 19051 500- (LC501** 2,500 Jaagar at al. 1973a 5 anuaa 4 hr 1x 6 noun a 4 hr 1x 7 sous* 1d 23 hr/d SL 064466 40 (LCSO - M)** Banschlar 1979 115 (LCSO - F)** (aa citad in Flaldar at al. 19651 115 (LCSO - H) 205 (LCSO - F) Banschlar 1979 (aa cltad in Flaldar at al. 1903] 90 (LC50 - Ml Short at al. 105 (LCSO - FI 1977c HEALTH EFFECTS SI Graph Kay Species TABLE 2-1 (Continued) Exposure Duration/ Frequency Elfaet LOAEL (Effect! Lass Sarlous Serious <PS") Reference HEALTH EFFECTS hamster hamster 10 11 Systemic 12 rat 1 hr 1x 6 hr 1x 7d 2223hr/d 1-8 d (hr/d 10 1,6(0 {LC50 - H) 2,90 (LCSO - F) Klimisch and Fralsbierg 1979s (as cited In Flalder at al. 1985) 150 (LCSO - H)** Klimtsch and 655 (LCSO - F)** Frelebier* 1979a (as cited In FleLdar at al. 1985) 60 (H-70I mort) Short et al. 1977c 50 (H-69I mort) Oeach at al. 1983 6 hr 1x Hepatic 250 250** (>sense SDH, orn car tr) Jaeger 1977 13 rat ( hr 1x Hepatic Renal 200 200 200** (necrosis) McKenna et al. 200** (haaoglob) 1978a (deg tub ep) 16 rat l-3d Renal 23br/d Hepatic (0 (0 (degen lean) Short et al. 1977 15 rat 6 hr 1x Reap 5,000 (hlsto) SL 064467 Henschler 1979 (as cited in Fielder et al. 1985) HEALTH EFFECTS o *h4iI*I4 Graph Kay Spaclaa TABLE 2-1 (Continued) Exposure Duration/ Frequency Effect _______ LQAH. (Effect 1 NQAEL Leas Serious Serious (> Reference 16 rt 6 hr 1x Renal 230" (swelling) 300i" (nscroala) Jackson and Conolly 1983 17 rat ia MOUIt 19 MUBI 20 aousi MeuroLogical 21 rat 22 rat 6 hr 1X Hepatic 10 d 5d/wk 6hr/d Hepatic Renal 2,000 (>ser Ad, no histo) 130" <>aar AKT) Jaegsr et al. 1974 100 (F-hlsto) 33 (F-blsto) 200 (F-hlsto) 200 (M-renal failure) Bench at al. 1979 Sd 23hr/d 13 (degen) 13 (tub neph) 60 (degen) Short at el. 1977 6 hr Hepatic 10 30 (histo) 1 i Renal 10 (histo) Reits et al. 30 (necrosis) I960 6 hr 1X 3,000 (CS) Henachlar 1979 (as cited In Fielder at al. 1903) 10 nln 1X 23,600 (cardiac erryttaias) Slletchnik and Carlaon 1974 Save lopisntal 23 rat 11 d 26-16 23hr/d SL 064468 13* (fetL aiuxa) Short at el. 1977a ro Graph Ear Spaclaa TABU 2-1 (Continued) Expoaura Duration/ Praquancy Effact _______ LOAEL (Effact) NOMEL Laaa Sarloua Sarloua (ppa) Rafaranca 21 rat 10 d t-13 7b/d 20 00 (akal alt) Hurray at al. 1979 23 26 27 20 rabbit Raproductlva 29 'rat 11 d |-li 23hr/d Id 012-13 23hr/d 0d *0-13 nbr/d a- 1# 7h/d 11 afe Sd/ufc 6hx/d 00 S3 15 (akal anon) Short at al. 1977a 31 (raaorb) Short at al. 1977a 11 (akal anon) Short at al. 1977a 160 (akal alt) Murray at al. 1979 Short at al. 1977b 30 aouaa 3d 6hr/d MTEBHEDIATE EXPOSURE Daath 31 aonfcay 90 d oont. 30 13 Andaraon at al. 1977 Prandar*aat at al. 1967 SL 064469 HEALTH EFFECTS N> Griph Kay Spaciaa TABLE 2-1 (Continued) Expoiura Duration/ Frequency Effect I1MKI. (Effect) HQAEL Lass Sarioua Sarioua <PI) Raferenc a Systanlc 32 rat 33 rt 36 rit 35 rat 6 no 5d/wk thr/d Raap Bans to Bapatie Dene/Oc 66 66 21b(fatty) 66 90 d coot. Bapatie Banal Rasp 3 ** 5d/uk thr/d Hapatlc Rasp Othar 25 68 (fatty) 68 (Hue Hyp lu Ep) 13 68 (inftanatn) 500 (Dag LivCel) 200 (lrcitation) 500 (< tm) 5 * Sd/uk 6hr/d Bapatie Ranal Othar 100 (> art) 100 (bisto,> wt) 100 (biochan) Quaat at al 1986 Frandargaat at al. 1967 Gaga 1970 KUalich at al. 1979 (am cltad In Pialdar at al. 19J 36 rat 30 d Sd/wk 6tar/d Hapatlc 123 (histo) 200 (hiato) Quaat 1976 37 rat 90 d 5d/uk thr/d Bapatie 200 (htsto) Balnar at ai. 1976 38 *n pit 90 d Bapatie 68 coat. Ranal 68 Frandargaat at al. 1967 Sl* 0644 70 HEALTH EFFECTS ho Graph Key Species TABU 2-1 (Continued) Exposure Duration/ Frequency Effect _______ LQAEL (Effect) HOAEL Less Serious Serloue __ Reference HEALTH EFFECTS 3* s pis 40 rabbit 41 rabbit 42 do* 43 dog 44 aonkey 45 aonkey CHROMIC EXPOSURE Syatanlc 46 rat 47 nous* 6 uk Sd/uk Shr/d Rssp Hsaeto 100 100 6 ek 5d/k 6hr/d Other . 100 (< bu) 90 d coot. Other 23 (< bu) 90 d cant. Reap Hepatic Other 25 25 40 (fatty) 25 40 (adenema) 6 uk 5d/wk 8br/d 6 wk 3d/wk Shr/d Reap Basteto Reap Other 100 100 too 100 {< be) 90 d cont. Reap Hepatic Other 23 23 4B (hlato) 5 13 (< bu) IB no 5d/uk 6hr/d Reap Baneto Bapatlc Renal Other 1 yr Sd/uk Heisato Hapatic 72 72 24(<ut, fatty) 72 72 53 35 (necrosis) Prendergaat at el. 1967 Prendergaat et al. 1967 Prendergaat et el. 1967 Prsndargaat et el. 1967 Prendergaat et al. 1967 Prendergaat et al. 1967 Prendergaat et al. 1967 Quaat et al. 1986 Lee et el. 1977 Graph Kay Species TABLE 2-1 (Continued) Exposure Duration/ Frequency Effect LOAEL (Effect) BQAEL Lees Serious Serious <PI> Reference Censor 40 nous* 32 k 5d/wk 4hx/d 10 (CEL) Halton1 at el. 1903 *Uaed to derive acute lnheletlon MIL; divided by an uncertainty factor of 1,000 (10 for uaa of a LOAEL, 10 for extrapolation from animals to biaeana and 10 for hiaaan variability) resulting in an HRL of 0.9 ppe. This MU. is preeented in Table 1-1. ^Uisd to darlve an intamediate inhalation MU.; adjusted for intamittant axpoaura and hunan breathing rata and divided by an uncertainty factor of 1,000 (10 for uaa of a LOAEL, 10 for extrapolation (ion aniaals to humane, and 10 fox human variability) resulting in an MU. of 0.02 ppm. This MU. la presented in Table 1-1.. cUaad to darlve a chronic Inhalation) MIL; adjusted for intamittant axpoaura and hiaaan breathing rate divided by an uncertainty factor of 1,000 <10 for uaa of a LOAEL, 10 for extrapolation from animals to humane and 10 for homan variability) resulting in an MU. of 0.03 ppm. to health effects `Pasted prior to exposure SL 064472 TABLE 2-1 (continued) Legaod tut Unit of Significant Exposure Tdilta for toxicity tttdiM for 1,1-DithluMthaa HOAEL LOAEL 1 kg no-oba arvad-advera a-affact-lava L Iowa at-oba arvad*advaraa-fact-lava1 milligram kilogram cm2 cubic eater cantlawtar aquarad Duratloo/Fxequancy of tipiwifl lx on* tlaa hr hour bu month wt week ft gaatatioq d day gan generation min mlnutaa ft yaar PS poat-gaatat1on Koute (C) capaula (G) gavaga <P) faad <H) watar o/Sex/Group r US female not apaclfiad H mala Spcia Bn pig guinea pig Effact Cardlo Dara/Oc Gaatro Results cardiovaacular da naal/ocular gaatrointaatlnal Baawto baautologleal Huac/Skal muaculoskeletal Hasp raapiratory > < adan adranalactmy bll aac biocham CEL dagan Dag LlvCal dag tub ap davalopmt dlapoa ana act fatl anoa GSH hamoglob hiato implnt loa lnflt inflamatn incraaaad dacraaaad adanoma adranalactomy biliary accretion biochemical cancar affect level degeneration degraded liver ealla degraded tubular epithelium development dlapoaItion anryma activity fetal anaaaliea glutathione tranaferaee hemoglobin hit topathology implantation loaa infiltration inflaBaation lean aidron neo mort Rue Hyp Tu Ep nx om ear tr path chg reaorp SD a ana aer MCI ear ereat akel anom ekel alt tub napb TWA vacuolatn art leaIona mid-aenal necroaia anrtallty nuclear hypertrophy ol l^^Iu apitheliia next ornithine carbamoyl tranaferaae pathological change reaorpticn aorbitol debydroganaae aenaltivity aero ACT aerua eraatInina ekeletal anamallea akeletal aIteratIona tubular napbroala tlaa weighted average vaeuolatioa weight SL 064473 HEALTH EFFECTS K> 23 2. HEALTH EFFECTS These same trends are seen in mice and hamsters, i.e,, nutritional status and sex influence the lethality of DCE following inhalation exposure. However, mice are considerably more susceptible to the lethal effects of DCE than rats. Reported 4-hour LC50s in fed mice range from 100 (males) to 200 ppm (females) (Henschler 1979), and in fasted mice from 40 (males) to 115 ppm (females) (Henschler 1979). The concentration of 40 ppm in air (Henschler 1979) is presented in Table 1-2. Similarly, fasted male Chinese hamsters are more susceptible to the lethal effects of inhaled DCE than fasted females (Henschler 1979; Klimisch and Freisberg 1979a,b). The highest NOAEL values and all reliable LOAEL values for death in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.2 Systemic Effects Limited information is available on the systemic effects of inhaled DCE in humans. This information comes primarily from case reports and/or insufficiently detailed mortality studies wherein the concentration and duration of exposure to DCE has not been quantified. Concurrent exposure to other toxic substances cannot be ruled out in most of these cases. Given these limitations, the information available indicates that inhaled DCE can induce neurotoxicity after short-term exposure (Henschler et al. 1970; Tierney et al. 1979) and that DCE is possibly associated with hepato- and nephrotoxicity after repeated, low-level exposure in humans (e.g., Tierney et al. 1979). Considerable information is also available on the systemic effects of DCE following both short- and long-term exposure in laboratory animals. The target organs or systems of DCE toxicity are reported to be the central nervous system, liver, kidney, and lungs, with adverse effects occasionally being noted in the heart. No studies were located regarding gastrointestinal or musculoskeletal effects in laboratory animals following inhalation exposure to DCE. One trend that is observed in these studies is that animals are much less tolerant to continuous exposure to DCE than to intermittent exposure. This is because continuous exposure does not allow the animal time to clear the chemical from the body; this will be discussed in detail in the sections on hepatic and renal effects. Another trend observed is that fasting tends to exacerbate the acute toxic effects of DCE in male animals to a greater extent than in female rats. The level of glutathione (GSH) present in the liver appears to modulate the toxic effects of DCE in animals. GSH is believed to be actively involved in the biotransformation and detoxification of DCE (Andersen et al. 1980; Liebler et al. 1985, 1988--see Section 2.3). Furthermore, the level of binding of reactive intermediate(s) to cellular macromolecules may be reduced SL 064474 24 2. HEALTH EFFECTS by elevated levels of GSH (Andersen et al. 1978, 1980; Moslen and Reynolds 1985; Okine et al. 1985; Reynolds et al. 1984), which has been proposed to chemically inactivate the reactive intermediate and thereby decrease the toxicity of the chemical. Also, acute inhalation exposure to DCE results in a decrease in hepatic GSH concentration in rats with concomitant manifestation of toxic effects (Jaeger et al. 1974), The role of GSH in DCEinduced toxicity will be explored further in the discussion of hepatic and renal toxicity and in Section 2.3. Respiratory Effects. Aside from some reports of upper airway irritation in acutely exposed humans (ITII 1982), no studies were located regarding respiratory effects in humans following inhalation exposure to DCE. Irritation of the mucous membranes and pulmonary edema/congestion and hyperemia are consistently seen at necropsy in rodents acutely exposed to high levels of DCE (500-15,000 ppm) via inhalation (Henschler 1979; Klimisch and Freisberg 1979a; Rylova 1953 and Zeller et al. 1979b). The severity of these effects is increased in fasted rats (Zeller et al. 1979b) Chronic inhalation exposure to DCE is also associated with adverse respiratory effects as evidenced by irritation of the upper respiratory tract. For example, nasal irritation was observed in rats exposed to 200 ppm for 4 weeks (Gage 1970). Quest et al. (1986) reported inflammation of the trachea in rats exposed to 72 ppm of DCE for 6 months. Other pulmonary effects seen in rats, guinea pigs, and dogs exposed to similar concentrations (189 mg/m3 or 48 ppm) of DCE for 90 days include discoloration and morphologic changes In the lungs (Prendergast et al. 1967). The concentration of 48 ppm in air (Prendergast et al. 1967) is presented in Table 1-2. These effects appear to be rather nonspecific and are due -;o DCE's local irritating properties. Therefore, these data suggest that any possible respiratory effects associat d with inhalation exposure to DCE (particularly acute) in humans are likely to be just a consequence of local, nonspecific irritation. The highest NOAEL values and all reliable LOAEL values for respiratory effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following inhalation exposure to DCE. Few studies are available that describe adverse cardiovascular effects of DCE following inhalation exposure in laboratory animals. In one experiment conducted in rats, acute administration of extreme concentrations (25,600 ppm for 10 minutes) produced arrhythmias mediated by the sympathetic nervous system (Siletchnik and Carlson 1974). These authors also found that DCE at 26,500 ppm increased the sensitivity of the myocardium to epinephrine, thereby providing a mechanism for the electrocardiographic changes. Cardiac effects such as contraction of the main vessels, dilation of the right side (most likely secondary to pulmonary congestion) and hyperemia are SL 064475 # 25 2. HEALTH EFFECTS seen following acute, high-level exposure (500-15,000 ppm) to DCE in rodents (Klimisch and Freisberg 1979a,b; Zeller et al. 1979b), Cardiovascular toxicity is generally not seen following more prolonged lower-level exposure, and is, therefore, most likely not a concern for prolonged low-level exposure in humans. The highest N0AEL values and all reliable LOAEL values for cardiovascular effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Hematological Effects. In several inhalation studies using animals where hematological parameters have been monitored, no statistically significant effects were seen in rats (72 ppm/18 months) (Quast et al. 1986) or mice (55 ppm/1 year) (Lee et al. 1977) as compared to controls. No studies were located regarding hematological effects in humans following inhalation exposure to DCE. However, given the lack of effect noted in animals in two species in well-conducted long-term studies, it is unlikely that DCE adversely affects hematological parameters in humans. The highest NOAEL values for hematological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Hepatic Effects. Hepatotoxicity has been observed in humans following repeated exposure to DCE, presumably by the inhalation route. Preliminary clinical findings on workers exposed to DCE for up to 6 years in a DCE polymerization plant revealed a high incidence of hepstotoxicity. Liver scans and measurements of liver enzymes revealed marked dysfunction in 27 (59%) of the 47 exposed workers (EPA 1985a; Tierney et al. 1979). These data were presented briefly with little detail, and no follow-up study has been reported. Therefore, these findings must be considered only to be qualitative in nature. The liver is a major target organ of DCE toxicity following both acute and longer-term inhalation in laboratory animals. Hepstotoxicity is evident by the appearance of both biochemical changes (alterations in serum enzyme levels, indicative of liver dysfunction and induction of hepatic enzymes) and marked histological changes (e.g., midzonal and centrilobular swelling, degeneration, and necrosis). These effects appear to follow a dose-response relationship that may also be influenced by duration of exposure. Mice inhaling 50 ppm DCE for 6 hours exhibited only slight centrilobular swelling (Reitz et al. 1980; Watanabe et al. 1980), whereas continuous inhalation exposure of mice to 15 ppm DCE for 23 hours/day for 5 days resulted in an increase in serum enzymes indicative of liver dysfunction, and hepatic degeneration was seen at 60 ppm under the same exposure regimen (Short et al. 1977c). The concentrations of 15 and 60 ppm in air (Short et al. 1977c) are presented in Table 1-2. Similar results were obtained in four strains of mice that were exposed to DCE by inhalation at concentrations of 55, 150 and 200 ppm 6 hours/day, 5 days/week for 10 days. Hepatotoxic effects (characterized by hepatocellular degeneration and necrosis with centrilobular SL 64476 26 2. HEALTH EFFECTS hepatocellular swelling and pleomorphism at 100 and 200 ppm) were observed in all strains, with the effects being more severe in the females (Henck et al. 1979). Severe effects are seen at higher doses in rats at even shorter duration exposures. Four-hour inhalation exposure to 200-250 ppm of DCE resulted in increased liver weight, induction of certain liver enzymes (Jackson and Conolly 1985; Jaeger 1977) and massive histologic injury (Reynolds et al. 1980). The degree of DCE-induced hepatotoxicity is influenced by the nutritional status of the organism, with more severe effects displayed by animals fasted overnight prior to exposure. This suggests that a relationship exists between chemical toxicity and depletion of GSH (Reynolds et al. 1980). For exampl , results from acute studies in both fed and fasted male rats demonstrate that inhalation exposures to low levels (60 to 200 ppm) of DCE for periods ranging from 75 minutes to 23 hours induced increases in serum enzyme levels indicative of liver dysfunction--aspartate aminotransferase (AST) and alanine aminotransferase (ALT)--in fasted animals, but not In fed animals (Andersen et al. 1979; Jaeger et al. 1974; Jaeger et al. 1975b). Only a slight increase in these serum enzymes was seen in fed rats exposed to DCE at levels of 2,000 ppm or above (Jaeger et al. 1974). Gross, histological and biochemical evidence of hepatotoxicity is seen earlier and is more extensive in fasted rats following short-term inhalation exposure to DCE. Inhalation of 200 ppm of DCE by fasted rats for up to 4 hours resulted in aberrations in hepatic sodium, potassium, calcium, and GSH levels which preceded and/or accompanied major histologic changes (Jaeger et al. 1975b; McKenna et al. 1978a; Reynolds et al. 1980). As mentioned above, the increased hepatotoxic effects of DCE following inhalation exposure seen in fasted vs. fed animals may be related to depletion of hepatic GSH levels in the fasted animals. GSH is known to be involved in the metabolism of DCE (see Section 2.3). Jaeger et al. (1973a) reported that GSH levels in rats fed ad libitum exhibited a marked diurnal rhythm with levels being minimal at 1900-2200 hr and maximal at 0700-1300 hr. This increase was prevented in fasted rats, with maximal levels reduced by 50X. They further demonstrated that DCE-induced hepatotoxicity coincided with the reduction in liver GSH levels. Fed rats exposed to DCE via inhalation during the period 1000-1400 hours exhibited no signs of hepatotoxicity whereas 401 mortality and a marked increase in serum enzyme markers was seen in fed rats exposed to similar levels of DCE during the period of minimal GSH levels. The hepatotoxic effects of DCE following intermediate or chronic exposure in animals resemble those described above for acute exposure (e.g., Gage 1970; Lee et al. 1977; Quast et al. 1986). Many of the studies that describe the longer-term effects of DCE in animals are limited in that there is often a lack of experimental detail reported or only one or two doses are studied. This often prevents a full assessment of the quality of the results. Male and female rats exposed 6 hours/day, 5 days/week over a 30-day period to 125 or 200 ppm DCE exhibited liver changes. These changes were more severe in females, and were characterized by a minimal degree of centrilobular fatty degeneration or hepatocellular necrosis (Quast 1976). Mild dose-related SL 064477 27 2. HEALTH EFFECTS hepatotoxic effects consisting of cytoplasmic vacuolation were observed in male and female rats exposed to 25 or 75 ppm DCE 6 hours/day, 5 days/week for either 30 or 90 days (fialmer et al. 1976). The authors considered these changes to be reversible. Quast et al. (1986) reported that ratsexposed to 25 ppm DCE 6 hours/day, 5 days/week for six months exhibited fatty infiltration of the liver. Based on this value, an intermediate inhalation MRL of 0.02 ppm was calculated, as described in the footnote in Table 2-1. This MRL has been adjusted for intermittent exposure and human breathing rate and is presented in Table 1-1. The concentration of 4 ppm (Quast et al. (1986) in air is presented in Table 1-2. Animals appear to be much less tolerant to continuous exposure (2324 hours per day) than to intermittent exposure to DCE. There was no evidence of toxicity in beagles exposed to 100 ppm of DCE for 8 hours/day, 5 days/week for 43 days, but continuous exposure to 48 ppm of DCE for 90 days resulted in marked liver damage (Prendergast et al. 1967).Similarly, marked evidence f liver damage was exhibited by squirrel monkeys continuously exposed to 48 ppm f DCE for 90 days, whereas no liver toxicity was apparent following 42 days of intermittent exposure to 100 ppm DCE (Prendergast et al. 1967). It would appear that when animals are exposed to DCE on an intermittent basis, they are better able to compensate for the toxic effects induced by this chemical. This observation supports the involvement of depletable stores of liver GSH as a possible mediator of DCE-induced hepatotoxicity. Hepatotoxic effects similar to those discussed above are seen following chronic inhalation exposure to DCE in laboratory animals (e.g., Lee et al. 1977, Quast et al. 1986). Quast et al. (1986) observed that rats exposed to DCE via inhalation at a time-weighted average concentration of 24 ppm 6 hours/day, 5 days/week for 18 months exhibited fatty changes in the liver. Based on this value, a chronic Inhalation MRL of 0.03 ppm was calculated, as described in the footnote in Table 2-1. This MRL has been adjusted for intermittent exposure, and human breathing rate and this value is presented in Table 1-1. The concentration of 4 ppm (Quast et al. 1986) in air is presented in Table 1-2. The information available on chronic inhalation exposure to DCE in animals is generally limited, and the quality of reporting is generally poor. In conclusion, hepatotoxic effects have been observed in experimental animals following inhalation exposure to DCE. The reversibility of the hepatotoxic effects of DCE has not been studied. The limited information available on human exposure indicate that DCE is hepatotoxic. Thus, one may assume, based on the studies in several species of animals, that humans are at risk for DCE-induced liver toxicity following inhalation exposure to this chemical at high levels and/or for prolonged periods. The highest HOAEL values and all reliable L0AEL values for hepatic effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. SL 064478 28 2. HEALTH EFFECTS < Renal Effects. No studies were found regarding renal effects in humans following inhalation exposure to DCE. However, adverse effects have been observed in the kidneys of laboratory animals following acute, intermediate, and chronic inhalation exposure to DCE. These effects are manifested as enzyme changes (decreases in kidney monooxygenase and epoxide hydrolase levels) (Oesch et al. 1983), functional changes (hemoglobinuria) (McKenna et al. 1978a), gross changes (increase in organ weight) (Henck et al. 1979; Quast et al. 1986), and histological changes (tubular swelling, degeneration and necrosis) (Henck et al. 1979; Jackson and Conolly 1985; Lee et al. 1977; McKenna et al. 1978a; Prendergast et al. 1967; Reitz et al. 1980; Short et al. 1977c; and tfatanabe et al. 1980). Following acute exposure, the range of DCE concentrations that produced the aforementioned effects in rats is 50-300 ppm, with the severity of the kidney lesions increasing with increasing dose and duration of exposure. Male mice appear to be more susceptible to the acute nephrotoxic effects of inhaled DCE than female mice or rats of both sexes. Severe histological lesions of the kidney are often seen in mice following acute inhalation exposure to 10-50 ppm of DCE (Reitz et al. 1980; Short et al. 1977c; Watanabe et al. 1980). The concentrations of 10 ppm and 50 ppm (Reitz et al. 1980; Short et al. 1977c; Watanabe et al. 1980) in air and the renal histological changes resulting from the exposure in mice are presented in Table 1-2. Similar results were obtained in four strains of mice that were exposed to DCE by inhalation at concentrations of 55, 150 and 200 ppm 6 hours/day, 5 days/week for 10 days. Adverse renal effects (characterized by moderate to severe nephrosis) were observed in all strains, with the effects observed predominantly in the males. (Henck et al. 1979). There is evidence that the kidney damage produced by acutely inhaled DCE in animals is reversible, though this may depend on the dose level and duration of exposure. Reitz et al. (1980) reported that tubular regeneration was evident in mice 48 hours after a single 6-hour exposure to 50 ppm DCE. However, reversibility of kidney damage at higher concentrations of exposure has not been demonstrated. As was seen with hepatotoxicity, the nutritional status of the animal appears to be an important determinant of DCE-induced nephrotoxicity. McKenna et al. (1978a) observed that fasted male rats exposed once to 200 ppm DCE for 6 hours exhibited delayed hemoglobinuria and marked tubular degeneration, while fed male rats similarly exposed displayed no treatment-related toxic effects. GSH depletion may play an indirect role in the exacerbation of DCEinduced nephrotoxicity. Though the bulk of the information on DCE-induced nephrotoxicity in animals comes from acute experiments, there is limited evidence that nephrotoxicity is also seen following intermediate exposure. Prendergast et al. (1967) reported that continuous inhalation exposure of rats to 189 mg/m3 (48 ppm) of DCE for 90 days resulted in nuclear hypertrophy of the renal tubular epithelium in all rats exami d, Maltoni et al. (1985) reported that severe nephrotoxicity occurred in ma^a mice exposed to 25 ppm DCE 4 hours/day, 4-5 days/wk for one year. The concentrations of 25 and 48 ppm in air (Maltoni et al. 1985; Prendergast et al. 1967) are presented in Table 1-2. The SL 064479 29 2. HEALTH EFFECTS reversibility of this effect was not determined. No treatment-related effects were noted in the kidneys of rats chronically exposed to DCE at a timeweighted average concentration of 24 or 72 ppm for 6 hours/day, 5 days/week for 18 months (Quast et al. 1986). Though data on kidney toxicity following inhalation exposure to DCE in humans are lacking, evidence from animal studies in two species suggest that DCE may also exhibit a toxic effect on the kidney of humans, particularly following acute DCE exposure. The limited animal data on the kidney effects of inhaled DCE following more prolonged exposure at lower concentrations coupled with the observation that the nephrotoxic effects are reversible after acute exposure is terminated suggest that repair mechanisms may be operating. DCE-induced nephrotoxicity may be transient and reversible; the effects in humans exposed to low levels over a long period of time are not known. The highest NOAEL values and all reliable LOAEL values for renal effects in each species and duration category are recorded in Table 2*1 and plotted in Figure 2-1. Dermal/Ocular Effects. Limited information was found regarding the dermal/ocular effects of inhaled DCE in humans or animals. No eye irritation was observed in rats exposed to a time-weighted-average (TWA) concentration of 72 ppm DCE for 18 months (Quast et al. 1986). This LOAEL is recorded in Table 2*1 and plotted in Figure 2-1. 2.2.1.3 Immunological Effects No studies were found regarding immunological effects in humans or animals following inhalation exposure to DCE. 2.2.1.4 Neurological Effects Central nervous system depression with accompanying symptoms of inebriation, which may progress to convulsions, spasms, and unconsciousness have been observed in humans acutely exposed to high concentrations (approximately 4,000 ppm) of inhaled DCE (Tierney et al. 1979). Complete recovery occurs if exposure is not prolonged. In addition, two cases of persistent cranial nerve disorders were observed involving primarily the trigeminal nerve and, to a lesser extent, the hypoglossal, occipital, auricular, and cervical cutaneous nerves, as well as the innervation of muscles of mastication, and the eye muscles (Henschler et al. 1970). These two patients were involved in the manual cleaning of tanks used in the transport of an aqueous dispersion of DCE copolymers. The effects were most likely a result of dichloroacetylene formation from DCE as a result of heat and the presence of alkali from the soaps used. Chloroacetylenes are highly neurotoxic (Fielder et al. 1985). Although this does not provide direct evidence that DCE can produce adverse neurological effects, it is possible that similar conditions may occur (i.e. heat and an alkali environment) which generate chloroacetylenes at hazardous waste sites where DCE is present. SL 6448Q 30 2. HEALTH EFFECTS 1I Signs of central nervous system toxicity are the predominant effect observed in animals acutely exposed to high concentrations of DCE via the inhalation route. The toxic signs are similar across species and consist primarily of central nervous system depression, lacrimation, dyspnea, tremor, convulsions, uncoordinated motor response, and narcosis, finally resulting in death (e.g., Henschler 1979; Klimisch and Freisberg 1979a,b; Zeller et al. 1979a,b). These symptoms can also be accompanied by lethargy, stark coats and a hunched appearance (Zeller et al. 1979b). No studies were found regarding neurolo cal effects in humans or animals following intermediate or chronic exposure. All reliable LOAEL values for neurological effects in each species and duration category are recorded in Table 2-1 and Figure 2-1. 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans following acute inhalation exposure to DCE. Based upon studies by Short et al. (1977a), DCE has weak teratogenic effects in laboratory animals. Prenatal exposure resulted in soft tissue anomalies in rats and skeletal defects in rats, mice, and rabbits. Maternal toxicity, as evidenced by decreased body weight and death, was also observed at developmentally toxic doses. Doses of DCE used in these studies ranged from 15 ppm to 449 ppm. Increased mortality was observed in both pregnant and nonpregnant mice at exposure concentrations of 144 ppm and above and in pregnant rats at 57 ppm and above. Skeletal anomalies were seen at 15 ppm in mice. In the interest of public health, an acute inhalatior RL of 0.9 ppm was calculated based on this v?lue, as described l" the footnote in Table 2-1. This value, adjusted for humai jreath ig rate i:; asented in Table 1-1 (Short et al. 1977a). Though it is not optimal to base an MRL on a serious effect, developmental effects appear to be the most sensitive endpoint of DCE-induced toxicity for this duration of exposure. Thus, an MRL calculated from this value would be most protective of human health. The concentration of 15 ppm (Short et al. 1977a) In air is presented in Table 1-2. Because a high incidence of resorption was observed in these initial experiments, Short et al. (1977a) conducted additional studies in mice. Pregnant animals were exposed via Inhalation to various concentrations of DCE ranging from 41 to 112 ppm. These experiments were carried out over different exposure durations that covered various phases of fetal development. The statistical analysis by two sample rank tests demonstrated that the treatment-induced increases in resorption frequency were significantly reduced at the shorter exposure periods, although the treatment-related weight loss was still evident in the dams. The viable pups demonstrated a variety of soft tissue anomalies, such as hydrocephalus, microphthalmia, cleft palate, and hydronephrosis. Skeletal anomalies were also present. SL 064481 31 2. HEALTH EFFECTS Murray et al. (1979) reported a statistically significant increase in the incidence of skeletal anomalies following inhalation of DCE in rats at 80 and 160 ppm and in rabbits at 160 ppm. Developmental toxicity was evidenced by wavy ribs and delayed ossification in rat fetuses, and by increased resorption and skeletal alterations in rabbit fetuses. A statistically significant decrease in maternal body weight gain was also noted at these concentrations. In this study, no statistically significant adverse effects were noted in rats at 20 ppm or in rabbits at 80 ppm. Thus, among all these developmental studies discussed above, the most sensitive indicators of hazard were maternal and developmental toxicity. The L0AEL in rats for these end points was 15 ppm (Short et al. 1977a). A NOAEL for developmental toxicity following continuous inhalation exposure was not identified. Based upon these studies in laboratory animals, it would be prudent to consider that potential adverse maternal and developmental effects from exposure to DCE could occur in humans. The highest NOAEL values and all reliable LOAEL values for developmental effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Reproductive Effects No studies were located regarding reproductive effects in humans following acute inhalation exposure to DCE. Studies by Short et al. (1977a) demonstrated that inhalation exposure of pregnant dams to DCE produced-a statistically significant increase in the incidence of early embryo resorptions in rats at 57 and 449 ppm (49% and 64% resorptions, respectively) and in mice exposed at 57 ppm (100% resorption), but a dose-response was not observed. In another study by Short et al. (1977b), pre-mating exposure of male rats to DCE at 55 ppm did not affect their fertility. This was evidenced by the lack of pre- and post-implantation losses in untreated pregnant females resulting from the matings with treated males. Anderson et al. (1977) found that inhalation exposure of male mice to 10 and 30 ppm of DCE 6 hours/day for 5 days had no adverse effect on fertility. Decreased fertility was observed at inhalation concentrations of 50 ppm, but the authors attributed this to infertility in males that ordinarily might not have been used, but had to be included in the study in order to establish a group of sufficient size. The biological significance of these findings in animals with regard to potential reproductive effects in humans is not known. The highest NOAEL values for reproductive effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. SL 064482 32 2. HEALTH EFFECTS 2.2.1.7 Genetic Effects No studies were located regarding genotoxic effects in humans following inhalation exposure to DCE. Inhalation of DCE vapors in animals has not been shown to result in dominant lethal gene mutations (Anderson et al. 1977; Short et al. 1977b), but it has been observed to produce DNA damage as indicated by slightly increased DNA repair rates in cells of mouse kidney (in which normal replicative DNA synthesis had been inhibited) (Reitz et al. 1980). Inhalation of DCE has been associated with minimal rates of DNA alkylation in mouse and rat kidney and liver cells (Reitz et al. 1980). These data suggest that inhalation exposure to DCE does not lead to significant levels of unrepaired DNA damage in the germ cells of the testes at the doses tested (as shown by the lack of a dominant lethal effect). However, these same doses are capable of inducing low levels of DNA damage in kidney cells of mice and minimal alkylation in liver and kidney. 2.2.1.8 Cancer No relationship between the occurrence of cancer in humans and occupational exposure (primarily chronic inhalation exposure) to DCE has been demonstrated. However, only three studies are currently available for analysis. Chronic occupational exposure to DCE was not associated with the occurrence of angiosarcoma in rubber-plant workers (Waxweiler 1981). Similarly, no association was found between morbidity and mortality and occupational exposure to DCE in DCE production and polymerization plant workers (Ott et al. 1976). Thiess et al. (1979) also studied workers in a DCE production and polymerization plant and found no association between exposure and cancer mortality. Both the Ott et al. (1976) and Thiess et al. (1979) studies are limited in their usefulness in assessing the cancer risk to humans exposed to DCE. In both studies the cohort size was limited, the observation period was too short, and there was a small number of deaths from specific causes. No allowance was made for a latency period, thus resulting in an overestimation of risk. Despite these limitations, the results of the Ott et al. (1976) study are of some value. These authors intended to conduct only a mortality study and not a carcinogenicity study and they recognized the need to do additional research before any definitive conclusions could be drawn. The carcinogenicity of DCE in laboratory animals following inhalation exposure has been evaluated in intermediate and chronic studies with rats, mice, and Chinese hamsters (Hong et al. 1981; Lee et al. 1977, 1978; Maltoni et al. 1982, 1985; Quast et al. 1986; Rampy et al. 1977; Viola and Caputo 1977). Exposure concentrations of DCE in these studies ranged from 10 ppm to 150 ppm. Of the long-term inhalation bioassays conducted in laboratory animals to date, only the results of a study by Maltoni et al. (1985) in mice have provided some suggestive evidence of a carcinogenic effect associated with DCE exposure. SL 064483 33 2. HEALTH EFFECTS In a study reported by Maltoni et al. (1985), male and female Swiss mice were exposed by inhalation to DCE for 4 hours/day, 4-5 days/week at concentrations of 0, 10, or 25 ppm for 1 year, and then observed until spontaneous death occurred. Increases in both malignant and nonmalignant tumors were observed. In female mice of both treatment groups (10 and 25 ppm), carcinomas of the mammary gland were increased. Lung tumors (most of which were benign pulmonary adenomas) were increased in males at 10 ppm, and in both males and females at 25 ppm. Although the authors stated that these increases were statistically significant, no statistical analyses were presented. The authors concluded that no dose-response relationship could be established for either increased tumor incidence. Of the 150 high-dose males in the 25 ppm groups examined, 28 had renal adenocarcinomas, but no such tumors were found in either the 30 males in the low-dose (10 ppm) group nor in the 186 control males. Renal adenocarcinomas are rare tumors in the Swiss mouse. The kidney tumors were accompanied by severe nephrotoxic effects including nephrosis. Indeed, an increased incidence of renal tumors in the male mice was only observed at doses that induced toxicity and were near the acutely lethal concentration. Only one female developed kidney tumors, whereas there appeared to be no difference between the sexes with regard to the incidence of regressive changes in the kidney. Thus, it is difficult t assess whether the occurrence of nephrosis predisposes the animal to the development of kidney tumors. However, this study can only be used to provide suggestive evidence of DCE-induced carcinogenicity in animals because.the maximum tolerated dose (MTD) appeared to have been exceeded. Maltoni et al. (1985) reported an increased incidence of malignant mammary tumors and leukemias in rats exposed to 100 ppm of DCE by inhalation 7 hours/day, 5 days/week. Inhalation exposure commenced on pregnant females on gestation day 12, and continued in mothers and approximately half of the offspring of both sexes (in 12-day and older embryos via transplacental exposure followed by inhalation exposure for all exposed animals in this group) for 104 weeks. The other half were exposed for 15 weeks only. The highest tumorigenic response was seen in offspring treated for 104 weeks. The authors concluded that under conditions of exposure to high doses during embryonal development and later, DCE is carcinogenic in rats. However, there are several flaws that limit the usefulness of this study; no statistical analyses were presented, and ambiguous terminology (i.e., "total malignant tumors") was employed to present the results. Results of other inhalation studies with laboratory animals have provided negative results with respect to the carcinogenicity of DCE (e.g., Hong et al. 1981; Lee et al. 1977, 1978; Maltoni et al. 1982, 1985; Quast et al. 1986; Rampy et al. 1977; Viola and Caputo 1977). In studies by Lee et al. (1977, 1978), mice and rats were exposed by inhalation to DCE at concentrations of 0 or 55 ppm for 1 year. Few hepatic hemangiosarcomas, hepatomas, bronchloalveolar adenomas, and skin keratoacanthomas were observed in experimentally treated mice, whereas some of the rats exposed to 55 ppm DCE had hemangiosarcoma of the mesenteric lymph nodes and of the subcutaneous tissue. These incidences were not statistically significant. Carcinogenicity SL 064484 34 2. HEALTH EFFECTS was examined in rats and mice during a 12-month period subsequent to the exposures described in Lee et al. (1977, 1978) in a follow-up study conducted by Hong et al. (1981). Except for mammary tumors in female mice, no significant increase in cumulative tumor incidence was observed in either species at 55 ppm DCE, regardless of duration of exposure. Though the increased tumor incidences observed in the Lee et al. (1977, 1978) and Hong et al. (1981) studies were not statistically significant, these studies provide evidence of the differences in species and strain sensitivity to the effects of DCE exposure. Quast et al. (1986) administered DCE by inhalation to male and female rats at concentrations of 0, 25, or 75 ppm for 18 months. A statistically significant increase (p<0.05) in adenocarcinomas of the mammary gland was noted in the low-dose females (25 ppm). This increase was not considered by the authors to be related to inhalation of DCE because the incidences of mammary gland adenocarcinomas were within the range of historical control data and were not dose-related. Maltoni et al. (1985) exposed female and male rats to DCE at concentrations of 0, 10, 25, 50, 100, or 150 ppm for 1 year. An increase in the incidence of total mammary tumors (fibroadenomas, carcinomas, sarcomas, carcinosarcomas) was observed in females of the 10 and 100 ppm exposure groups. However, evidence for a carcinogenic effect from inhalation exposure of DCE in this study was inconclusive because (a) there was no clear doserelated increase in total mammary tumor incidence, (b) the latency time for mammary tumor incidence was similar in all treated and control groups, (c) there was a high (62%) incidence of spontaneous mammary tumors in controls, and (d) the incidence of mammary gland carcinomas in treated groups was lower than that of controls (Maltoni et al. 1985). The effects of chronic inhalation exposure of CD-I mice and CD rats to 55 ppm DCE for 12 months was studied by Lee et al. (1978, 1979). There was no statistically significant increase in tumors at any of the sites examined compared to the respective control animals. However, two treated male rats and three mice exhibited hemangiosarcomas, an uncommon tumor type, while n ne were found in the controls. The authors claimed that rats were more resistant to the carcinogenic effects of DCE, but the data do not support this since there was no significant increase in the incidence of tumors in either species, and the incidence of hemangiosarcomas was practically the same across the two species. The short duration of this study may have precluded observing tumors that have a long latency period. In a follow-up study, CD-I mice and CD rats were exposed to 55 ppm DCE by inhalation for 1, 3, or 6 months (mice) or 1, 3, 6, or 10 months (rats) followed by a 12 month observation period (Hong et al. 1981). There was a high incidence of mortality; in the groups that were exposed the longest, 18% and 21% of the control mice, 50% and 42% of the treated mice, 38% and 44% of the control rats, and 79% and 56% of the treated rats died before terminal sacrifice. There was no statistically significant increase in the incidence SL 064485 35 2. HEALTH EFFECTS of tumors in any of the treated animals, though tumors were observed in some treated and control animals. The small number of animals in each group weakens the ability of this study to detect a tumorigenic response, and the exposure durations were considerably less than lifetime. The negative findings of various inhalation studies may be partially explained by inadequate test conditions (EPA 1985a), Study limitations for many of these investigations included less than lifetime exposure, use of concentrations below or above the maximum tolerated dose, use of single exposure concentrations, small numbers of animals, and/or limited gross or microscopic examinations (Hong et al. 1981; Lee et al. 1977, 1978; Maltoni et al. 1982, 1985; Quast et al. 1986; Rampy et al. 1977; Viola and Caputo 1977). Such limitations reduce the sensitivity of a test to detect a carcinogenic response. EPA has derived a qx* of 1.2 (mg/kg/day)-1 for cancer risk associated with inhalation exposure to DCE based on the study by Maltoni et al. (1985) in mice. This value is plotted in Figure 2-1. 2.2.2 Oral Exposure Figure 2-2 and Table 2-2 describe the health effects observed in laboratory animals associated with oral exposure level at varying time and exposure durations. The MRL to humans for adverse effects (ocher than cancer effects) is also presented for the oral route of exposure. 2.2.2.1 Death No studies were located regarding lethality in humans following oral exposure to DCE. Death has been observed in laboratory animals following the ingestion of DCE. The database on the lethality of ingested DCE in animals consists primarily of gavage studies in fasted rats. Few data were found on lethality in mice or other species. Reported oral LDsos in rats are approximately 1,500 mg DCE/kg body weight (Jenkins et al. 1972; Jones and Hathway 1978a). The threshold for mortality 10 percent mortality in male rats is 50 DCE mg/kg in com oil (Andersen and Jenkins 1977). No short-term studies of DCE administered in food were located; therefore, the dose level of 50 mg/kg/day, which was administered by gavage in com oil, was converted to an equivalent concentration of 1,000 ppm in food for presentation in Table 1-4. The limited data available for mice indicate that this species is considerably more sensitive than rats to the lethal effects of ingested DCE. Reported LDS0 values in mice are approximately 200 mg DCE/kg body weight (Jones and Hathway 1978a). Since all available data are from fasted animals, it is difficult to assess if the nutritional status of the animal influences the lethality of ingested DCE, as was the case for inhalation exposure. Jenkins et al. (1972) demonstrated that adrenalectomy exacerbates the lethal effects of ingested DCE SL 064486 10.000 r1,000 100 10 ACUTE (<14 Days) / // / // 111.* 8 8iomO o* o* o o* 7,. i a, I" >2> On* HEALTH EFFECTS 0.1 0.01 0.001 0.0001 r Rat m Mouaa Knr UMO LOAB. fa aarioua altacta (anlaiala) UMELbftaaa aarioua aOacta (ariaiala) O NOAEL(antawlt) Tha maribar naxl to aadt poM comaponda to antrtaa In *ia accompanying tabla. FIGURE 2-2. Levels of Significant Exposure To DCE - Oral SL 064487 (mo*gUm/} INTERMEDIATE (15*364 Days) / / CHRONIC (a;365 Days) / / // ro HEALTH EFFECTS SL 064488 HEALTH EFFECTS TABLE 2-2. Lavala of Significant Expoaura to 1,1-Dichloroathan# - Oral Graph Kay Expoaura Duration/ Spaciaa Routa Fraquancy Effact ~` ' ACUTE EKNSURE LQAEL (Effect) HQAEL Laaa Sarioua Sarioua (ng/kg/day) Rafaranca Daatb 1 2 rat HS rat S) 1 d 1X 1,500 **(LD50) Jankina at al. SO * *(LD50 - 1972 adranalact) 50 **<K) Andaraan and Jankina 1977 3 rat (G) 1 d 1X 1,550 (laiOU) Jonaa and Bathway 1978a 4 aou (G) 1 d 1X SyitMic 5 rat (G) 1 d 1X 19* (LD50 - F) 217 (LDS0 - M) Jonaa and Bathway 1970a Ranal 200** *00** (blato, > aar. craat.) Jankina and Andaraan 1978 t rat (G) 1 d Sapatic 200 *00 (fatty) 1X Jaagar at al. 1973b 7 rat <G> 1 d Rapatlc 1X a rat (G) 1 d Gaatro 1 X Rapatic Ranal 200 (< bil aac) Moalan at al. 1985 200 (blato) 200 (blato) 200 (blato) 200 (hiato) a* Chiaco at al. 1901 SL 064489 Graph Key Expoaura Duration/ Spaclaa Route Frequency Effect TABU 2-2 (Continued) 10ABL (Effect) HQAEL Leaa Serloua Sarloua (mg/kg/day > Reference HEALTH EFFECTS 9 rat <G) 1 d Reap 200 1 X Cardlo 200 Gaatro 200 Hepatic 200 (hlato)** 10 (G) 1 d Reap 200 (hlato) 1x Developaental 11 rat (M) 10 d (0-13 ad 11b INTERMEDIATE EXPOSURE Death 12 rat (W) 90 d 7d/k 40 60 13 dog Systealc 14 dog Neurological 13 dog CHRONIC EXPOSURE Systemic 16 ret (C) 97 d lx/d 23 (C> 97 d lx/d Hepatic Baaato Renal 23" 23 23 (C) 97 d lx/d 23 (H) 2 yr Hepatic ad 11b Haasto 10 19.3 (hleto - M) 19.3 Chi*co at al 1981 Forkert at el. 1903 Hurray at el. 1979 ro Moore 1900 (>iast at al. 1903 (h>aat at al. 1903 Quest at el. 1903 Rempy et el. 1977 SL 064490 Graph Kay Expoiur* Duration/ Spaclaa Routt Fraquancy Effact TABLE 2-2 (Continued) (Kact) RQAEL Laaa Sarloua Sarloua (g/kg/day) Rafaranca 17 rat (W) 3 gan Bapatlc coat. 7 (fatty Inflit) Mltacbka at al. 1903 10 rat (H) 2 yr Bapatlc 10 20 (hiato - H) ad lib Baawto 20 19 rat (W) 2 yr Baawto 30 ad lib Bapatlc 9b (availing aildxon fatty changaa-P) 20 rat Raproductlva 21 rat (H) 2 yr ad lib Baawto Bapatlc Ranal 25.6 10.0 19.3 (>vacuolatn) 23.6 (H) 3 gan ad lib 20 Quaat at al. 1903 Quaat at al. 1903 Raapy at al. 1977 Hltacbka at al. 1903 *11aad to darlva an lntaxawdlata oral HU.; dlvldad by an unoartalnty factor of 100 (10 for extrapolation from anlaala to buaana and 10 for biaaan variability) raaulting In an MSI t 0.25 ag/kg/day. ^Uaad to darlva a chronic oral MRL; dlvldad by an uncartalnby factor ol i ,000 (10 for uaa of a LOAEL, 10 tor axtrapolatlon fro* anlawla to buawna and 10 tor huwan variability) raaultlng In an MRL of 0.009 ag/kg/day. Tbla MU. has baan coovartad to an equivalent concantratlon In food (0.32) for praaantatlon in Tabla 1-3. *`Parted prior to axpoaura HEALTH EFFECTS st 0644gj TABLE 2-2 (Continued) Lagand for Unit of Significant (quoin Tabloo for ladoltr Itadaa for 1.l-DiahlnweHiia no-obaarvad-adverse-affect-level loweat-obeerved-adveree-effect-leval ol111tree * kllogran car cubic aMter cantinator squared lx ooa tine br hour no nooth wk weak gestation d day gan generation aln nlootaa yt yaar pg poet-geatatIon (C) capsule <6) lavage (ft feed <H) water F fanala US not specified Spaclea gn pig guinea pig Effect Cardlo Dem/Oc Gaatro cardiovascular daraa1/ocular gaa trointea tInal Baneto haautologlcal Huac/Skal nuaeuloakalatal Keep faspirstory > < adan edranalecta? bll aao blochan CEL dag an Dag LlvCal dag tub ap davelopnt dlspos ana act fatl anon GSB hanoglob blato laiplnt los Inf It lnflanatn loereased decreased idwf edrcoalectaagr biliary saoretlon blocbaaslaal cancer affect Level degeneration degraded liver calla degraded tubular epltballi devalopwcot disposition ansyna activity fatal ancnallas hanoglobIn bistopathology lnplantatlon loss Infiltration lnflaanatlon Lean wort he Byp Tu Ip oca car tr path ohg aar in aar ereat kel anon akal alt tub nepfa rm. aacuolato wt laalona nld-aonal naoroals Mortality nuclear bypertrophy of tubular apltballun ornithine carbaooyl tranafaraaa pathological change raaorptlon aorbltol dabydroganaaa aaoaltlvlty aarwn tfl aarun craatlnlne akalatal aweIlea akalata1 altaratlona tubular naphroala tlaa weighted average vaouolatlon weight SL 064492 HEALTH EFFECTS to 42 2. HEALTH EFFECTS in rats. They reported that the oral LDj0 for DCE in adrenalectomized animals is 80 mg DCE/kg body weight. The mechanism and significance of this effect is unclear, but may involve a compromise in the animal's response to stress. Oral administration of a single dose of DCE to fasted rats revealed that young male rats (100-200 g) appeared to be more susceptible to the lethal effects of this chemical (Andersen and Jenkins 1977). This age-dependent differential toxicity was not seen in females, although male rats exhibited enhanced toxicity upon fasting prior to inhalation exposure. In summary, inge ~ed DCE is moderately toxic in at least two species of laboratory animals. ong animals and those with compromised stress responses appear to be most sut ptible to these effects. Therefore, orally-ingested DCE at high doses is likely to cause death in humans, and younger members (particularly males) of the population may be at higher risk. The highest NOAEL values and all reliable LOAEL values for death in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects No studies were located regarding systemic effects in humans following oral exposure to DCE. However, DCE has been shown to adversely affect several organ systems in laboratory animals. The major target organs of DCE toxicity following oral administration to laboratory animals are the liver and kidney. In addition, some evidence exists for DCE-induced adverse effects on the respiratory system (lungs), digestive tract (rat forestomach) and kidney following oral administration. No reports were identified that discussed adverse cardiovascular, hematological, dermal, or ocular consequences of acute, intermediate, or chronic oral treatment with DCE. Respiratory Effects. No studies were located regarding respiratory effects in humans following oral exposure to DCE. Pulmonary injury has been reported in mice following the oral administration of a single dose of 200 mg DCE/kg body weight (Forkert et al. 1985). Histopathological changes were observed in Clara cells within 24 hours, and these were accompanied by pulmonary edema, hemorrhage, and focal lung collapse. This damage appeared to be reversible as cellular regeneration was evident within 5 days of treatment. No short-term studies of DCE administered in food were located; therefore, the dose level of 200 mg DCE/kg body weight/day (Forkert et al. 1985), which was administered by gavage in com oil, was converted to an equivalent concentration of 4,000 ppm in food for presentation in Table 1-4. The relevance of these findings to human exposure is not understood. No studies were located regarding respiratory effects in animals following intermediate or chronic exposure to DCE. SL 064493 43 2. HEALTH EFFECTS The highest NOAEL values and all reliable LOAEL values in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following oral exposure to DCE. Minor effects on the gastrointestinal system have been reported in laboratory animals following a single oral administration of 200 mg DCE/kg body weight to fasted rats. Chieco et al. (1981) observed forestomach edema in these animals. However, this alteration was not associated with any discernible degenerative changes, and its relevance to human exposure is therefore unknown. No short-term studies of DCE administered in food were located; therefore, .the dose level of 200 mg DCE/kg body weight/day, (Chieco et al. 1981) which was administered by gavage in corn oil, was converted to an equivalent concentration of 4,000 ppm in food for presentation in Table 1-4. No studies were located regarding gastrointestinal effects in animals following intermediate or chronic oral exposure to DCE. The highest NOAEL values and all reliable LOAEL values in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure to DCE. This chemical is hepatotoxic in laboratory animals, particularly after ingestion of an acute dose. A. whole spectrum of effects indicative of liver toxicity has been observed in animals following acute oral administration of DCE, and their incidence and severity tend to follow a dose-response relationship. Significant increases in serum enzyme markers of liver dysfunction (AlT and AsT) have been noted in fasted rats after the ingestion of a single dose of 50 mg DCE/kg body weight or higher (Andersen et al. 1980; Andersen and Jenkins 1977; Jenkins and Andersen 1978). Increases in liver weight have been observed in acutely exposed rats at doses of 50 mg DCE/kg body weight and above (Chieco et al. 1981), and severe histological evidence of liver damage (i.e., necrosis, hemorrhage) was noted following the oral administration of 200 mg DCE/kg body weight to rats (Chieco et al. 1981). No short-term studies of DCE administered in food were located; therefore, the dose level of 200 mg DCE/kg body weight/day (Chieco et al. 1981), which was administered by gavage in corn oil, was converted to an equivalent concentration of 4,000 ppm in food for presentation in Table 1-4. Ultrastruetural changes in hepatocellular organelles have also been noted in rats after a single dose of 25 mg DCE/kg body weight (Kanz and Reynolds 1986). No short-term studies of DCE administered in food were located; therefore, the dose level of 25 mg DCE/kg body weight/day (Kanz and Reynolds 1986), which was administered by gavage in oil was converted to an equivalent concentration of 500 ppm in food for presentation in Table 1-4. The hepatotoxicity of orally administered DCE in animals has been shown to be influenced by the nutritional status of animals, and also on the dosing vehicle. Fasting exacerbates DCE-induced hepatotoxicity; fed animals exhibit only mild effects at comparable doses (i.e., increases in organ weight) (Andersen and Jenkins 1977; Andersen et al. 1980; Chieco et al. 1981; Jenkins SL 064494 2. HEALTH EFFECTS and Andersen 1978). The hepatotoxic effects of DCE in rats tend to be more severe when administered in mineral or com oil than when Tween 80 is used as the vehicle (Chieco et al. 1981). These authors have suggested that an aqueous solution of Tween 80 facilitates the clearance of DCE from the body. This observation has important implications with regard to humans, since oral exposure to DCE, particularly in individuals in close proximity to Superfund sites, will most likely be via groundwater. Little information was obtained relevant to effects of intermediate treatment regimens with DCE. However, a subchronic study in beagles (97 days) given up to 25 mg DCE/kg body weight/day in the drinking water revealed no exposure-related gross or histopathological changes in the liver (Quast et al. 1983). An intermediate oral MRL of 0.25 mg DCE/kg body weight/day (Quast et al. 1983) was calculated for DCE as described in the footnote in Table 2-2. Chronic studies have been performed in rats ingesting low levels (10-20 mg DCE/kg body weight/day) of DCE for 2 years. The results indicated few treatment-related changes. After 1 year of treatment, only a minimal increas in cytoplasmic vacuolation of hepatocytes was noted (Rampy et al. 1977). After 2 years, only a minimal amount of hepatocellular swelling with midzonal fatty change was reported (Quast et al. 1983). Nitschke et al. (1983) observed slight hepatocellular changes in rats exposed to DCE in the drinking water at levels equivalent to 7 mg DCE/kg body weight/day in utero. during lactation, and through weaning into adulthood. The dose level of 9 mg DCE/kg body weight/day (Quast et al. 1983) was calculated from the administered concentration of 50 ppm in water. This concentration in water is presented in Table 1-4. A chronic oral MRL of 0.009 mg DCE/kg body weight (Quast et al. 1983) was calculated for DCE as described in the footnote in Table 2-2. This MRL has been converted to an equivalent concentration in food (0.32 ppm) for presentation in Table 1-3. The highest NOAEL values and all reliable LOAEL values for hepatic effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Renal Effects. No studies were located regarding renal effects in humans following oral exposure to DCE. Evidence for DCE-induced 'kidney dysfunction has been observed in laboratory animals following acute oral exposure. Jenkins and Andersen (1978) found that fasted rats given single gavage doses of 200 mg DCE/kg body weight and above exhibited increased plasma urea levels and creatinine levels (at 400 mg DCE/kg body weight). Histopathological changes (vacuolization, pigmentation, tubular dilation, and necrosis) were observed at 400 mg DCE/kg body weight. These changes were more severe in females though some recovery was evident in females 96 hours post-exposure. Chieco et al. (1981) noted histological changes in the kidneys of rats administered single doses of 200 mg DCE/kg body weight by gavage. No short term studies of DCE administered in food were located; therefore the dose level of 200 mg DCE/kg body weight/day (Chieco et al. 1981), which was administered by gavage in corn oil, was converted to an equivalent SL 064495 45 2. HEALTH EFFECTS concentration of 4,000 ppm in food for presentation in Table 1-4. As has been noted previously for hepatic effects, DCE-induced nephrotoxicity is exacerbated in fasted animals; no renal effects were observed in fed animals administered single doses of 400 mg DCE/kg body weight in the study described above. No renal effects were noted in animals following intermediate or chronic oral exposure to DCE at doses of 25-200 mg DCE/kg body weight/day. An intermediate MRL of 0.25 mg DCE/kg body weight (Quast et al. 1983) was calculated as described in the footnote in Table 2-2. This MRL has been converted to an equivalent concentration in food (10 ppm) for presentation in Table 1-3. Given the relative scarcity of data on DCE-induced renal effects in animals, particularly following prolonged exposures, and the possibility that the effects that have been observed are reversible, the-potential for nephrotoxic effects in humans via ingestion of DCE cannot be evaluated. The highest NOAEL values and all reliable L0AEL values for renal effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans or animals following oral exposure to DCE. 2.2.2.4 Neurological Effects No studies were located regarding neurological effects in humans following oral exposure to DCE. No adverse effects on neurological parameters were identified subsequent to oral administration of DCE under any duration of exposure in animals. No effects were seen on either appearance or demeanor of the test animals in either an intermediate feeding study in dogs (25 mg DCE/kg body weight/day for 97 days) or a chronic study in rats (up to 30 mg DCE/kg b dy weight/day for 2 years) (Quast et al. 1983). These NOAELs for neurological effects in each species are listed in Table 2-2 and plotted in Figure 2-2. 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans following oral exposure to DCE. Murray et al. (1979) reported that ingestion by pregnant rats of 40 mg DCE/kg body weight/day in drinking water resulted in an increased mean fetal crown-rump length in the pups. No skeletal alterations occurred. There was no evidence of toxicity to the dams. SL 064496 46 2. HEALTH EFFECTS The highest NOAELs for developmental effects in each duration categoryare listed in Table 2-2 and plotted in Figure 2*2, 2.2.2.6 Reproductive Effects No studies were located regarding reproductive effects in humans following oral exposure to DCE. DCE (99.5X purity) was administered in the drinking water of rats at dosages up to 28 mg DCE/kg body weight/day for three generations. Histopathological examinaiion of treated adult r* revealed mild dose-related hepatotoxic effects. No dose-related changes we ;een in reproduction or neonatal development (Nitschke et al. 1983). Th. JOAEL for reproductive effects is listed in Table 2-2 and plotted in Fig-je 2-2. 2.2.2.7 Genetic Effects No studies were located regarding genetic effects in humans or animals following oral exposure to DCE. 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans following oral exposure to DCE. The carcinogenicity of DCE by the oral route has been evaluated in a number of chronic studies in rats and mice (Maltoni et al. 1982, 1985; Ponomarkov and Tomatis 1980; Quast et al. 1983; Rampy et al. 1977). Dosages of DCE in these studies ranged from 0.5 mg DCE/kg body weight/day to 30 mg DCE/kg body weight/day. Administration was by gavage with the exception of two studies in which DCE was administered daily in the drinking water (Quast et al. 1983; Rampy et al. 1977). Major organs and tissues of treated and control animals in these investigations were subjected to both gross and microscopic examination. Under conditions of the oral bioassays performed to date, DCE has not demonstrated carcinogenic activity. No statistically significant changes in tumor incidence in treated animals have been noted when DCE is administered orally. However, a trend toward increased incidence of malignant and nonmalignant tumors in DCE-treated animals has been reported in several studies (Ponomarkov and Tomatis 1980; Quast et al. 1983). However, relative to controls, the incidence of these and other tumors were not statistically significant. Ponomarkov and Tomatis (1980) reported an increased incidence of meningiomas and liver cell carcinomas and adenomas in rats given weekly gavage doses of 50 mg DCE/kg body weight from weaning until 120 weeks of age. The mothers of these animals received a single oral dose of 150 mg DCEAg body weight by gavage in corn oil SL 064497 *> 47 2. HEALTH EFFECTS on day 17 of gestation. The incidence of the hepatocellular tumors were statistically significant (p-0,04). Increases in hyperplastic nodules of the liver were seen in these animals. These hepatic lesions were not observed in controls. Statistically significant increases in certain types of tumors and cancers have been reported in bioassays in which rats and beagles were orally exposed to DCE (Quast et al. 1983); however, these results have been discounted by the investigators. In a 2-year study by Quast et al. (1983), DCE doses of 7, 10, and 20 mg DCE/kg body weight/day and 9, 14, and 30 mg DCE/kg body weight/day were administered in the drinking water of male and female rats, respectively. A statistically significant increase (p<0.05) in the incidence of combined mammary gland fibroadenomas and adenofibromas was noted in low-dose females, because the incidence of these types of tumors were within the normal range of historical control data and because these tumors were not observed in higher-dose females or in treated males, these increases were not considered by the authors to be related to ingestion of DCE, and thus are of questionable biological significance. Clinical signs of toxicity were not generally observed in the various oral carcinogenicity studies on DCE; consequently, maximum tolerated doses may not have been achieved (Ponomarkov and Tomatis 1980; Quast et al. 1983; Rampy et al. 1977). Long-term animal studies at or near the maximum tolerated dose are necessary to ensure an adequate power for the detection of carcinogenic activity (EPA 1986). Two of the oral carcinogenicity studies also used exposure periods that were less than lifetime (52-59 weeks) (Maltoni et al. 1982, 1985). However, the animals were observed for 136 or 147 weeks in the studies conducted by Maltpni et al. (1982, 1985), thus allowing an adequate latency period for the development of late-appearing tumors. 2.2.3 Dermal Exposure With the exception of reports describing local irritant effects following dermal contact with DCE in both humans and animals and positive tumorinitiating effects in animals (Van Duuren et al. 1979), no studies were located regarding health effects in humans or animals following dermal exposure to DCE. 2.2.3.1 Death No studies were located regarding lethal effects in humans or animals following dermal exposure to DCE. SL 06449g 48 2. HEALTH EFFECTS 2.2.3.2 Systemic Effects With the exception of reports describing dermal/ocular irritation following local contact in humans and animals, no studies were located regarding systemic effects in humans or animals following dermal exposure to DCE. Dermal/Ocular Effects. Liquid DCE is irritating when applied to the skin of humans (Tierney et al. 1979) and animals (Irish 1963), after exposures lasting only a few minutes. Details concerning these studies are lacking, but it has been suggested that these irritant effects may be due to the inhibitor, p-hydroxyanisole (HEHQ), that is present in these formulations. MEHQ is an antioxidant which on contact results in skin depigmentation in concentrations as low as 0.25Z (Busch 1985). Similarly, DCE is an ocular irritant in humans (Tierney et al. 1979), and this effect has also been ascribed to HEHQ. 2.2.3.3 Immunological Effects No studies were located regarding immunological effects in humans or animals following dermal exposure to DCE. 2.2.3.4 Neurological Effects No studies were located regarding neurological effects in humans or animals following dermal exposure to DCE. 2.2.3.5 Developmental Effects No studies were ocated regarding developmental effects in humans or animals following de' .al exposure to DCE. 2.2.3.6 Reproductive Effects No studies were located regarding reproductive effects in humans or animals following dermal exposure to DCE. 2.2.3.7 Genetic Effects No studies were located regarding genetic effects in humans or animals following dermal exposure to DCE. 2.2.3.8 Cancer No studies were located regarding carcinogenic effects in humans following dermal exposure to DCE. The carcinogenicity of DCE following dermal exposure has been evaluated by Van Duuren et al. (1979). In this study, DCE at doses of 40 mg or 121 mg (1,143 mg DCE/kg body weight or 3,457 mg DCE/kg body weight, respectively) in SL 064499 49 2. HEALTH EFFECTS acetone was applied three times weekly for periods up to 595 days to the skin of Swiss mice. No skin tumors were noted in treated animals. Increased incidences of pulmonary papillomas and squamous-cell carcinomas of the forestomach were observed in treated mice; however, the incidences of these tumors were not statistically different from controls. These results suggest DCE is inactive as a complete carcinogen when applied repeatedly to the mouse skin.1 Van Duuren et al. (1979) also evaluated the ability of DCE to act as a tumor initiator in the skin of Swiss mice. DCE (121 mg or 3,457 mg DCE/kg body weight) in acetone was applied to the skin once, followed 2 weeks later by dermal application of the tumor promoter, phorbol myristate acetate (TPA) three times a week for periods up to 576 days.2 Untreated, vehicle-treated, and TPA-only-treated animals served as negative and positive controls. A statistically significant (p<0.005) increase in the incidence of skin papillomas was recorded in mice treated with DCE relative to controls. These results indicate that DCE is a tumor-initiating agent. 2.3 RELEVANCE TO PUBLIC HEALTH Evidence was found in the scientific literature that DCE is toxic to both humans and laboratory animals. Disregarding tobacco smoking, human exposure to DCE occurs primarily in the industrial work environment, in communities surrounding these sites of DCE synthesis and use, and at areas in and around hazardous waste sites. Exposure of the general population distant from these particular emission sources of DCE tends to be low. The available information on adverse health effects associated with DCE exposure in humans comes primarily from reports of accidental exposure to high concentrations for a short period of time. Since these are cases of emergency, the information concerning exposure is limited. It can be ascertained from this limited information that acute inhalation exposure to DCE induces adverse health effects in humans, with central nervous system toxicity and irritation of mucous membranes being the primary manifestations of these toxic effects. There is also some limited evidence to suggest that repeated exposure to DCE is associated with liver damage in humans.* *A complete carcinogen is an agent, which if applied in sufficient concentrations, can induce tumors by itself. zIn two-stage tumorigenesis, a tumor initiator is applied in a subthreshold dose. An initiator does not generally produce tumors at .this dose but causes "dormant" cell changes so that later repeated applications of a promoter (an agent that by itself will not produce tumors) will induce benign and malignant tumors at the site of application. SL 064500 50 2. HEALTH EFFECTS There is convincing evidence from animal studies to indicate that DCE toxicity is mediated by metabolism to a reactive intermediate that acts at the cellular level to ultimately compromise the viability of the target tissues. While the metabolic pathways for DCE are similar in the rat and mouse, the rate of metabolism is greater in the mouse resulting in a greater concentration of toxic metabolites. Thus, the severity of DCE-induced toxicity in humans may be dependent on the extent to which DCE is metabolized, and which intermediates are formed. Furthermore, it may be possible to identify sensitive subpopulations based on the status of their liver function. The toxicity of DCE to laboratory animals is fairly well characterized, particularly for acute and intermediate inhalation exposure. As can be seen in Figures 2-1 and 2-2, the major target organs of DCE ;oxicity in animals appear to be the liver, the kidney, and the lungs with jwer level prolonged exposure. In short-term duration, high-concentration posure, the central nervous system is also affected. Data from animal studies will be discussed here with regard to their implications on human toxicity. Death. Though no deaths have been reported in humans following DCE exposure, DCE was lethal to animals following acute exposures to high levels via the inhalation or oral routes (see Figures 2-1 and 2-2). DCE-induced lethality appeared to be influenced by the nutritional status of the animal regardless of exposure route, with LD30s for fasted animals generally significantly lower than those reported for fed animals (e.g., Chieeo et al. 1981; Jaeger et al. 1973c; Jenkins and Andersen 1978; Moslen et al. 1987; Siegel et al. 1971). Hales appeared to be affected to a greater extent by fasting than females. Experimental evidence suggests that this enhanced toxicity in fasted animals resulted from increased levels of the reactive intermediate of DCE available for binding to macromolecules in target tissues after fasting (McKenna et al. 1978a). Carlson d Fuller (1972) reported that fed rats exposed to 20,000 or 32,000 ppm of DCE - inhalation for 1 hour survived for at least 24 hours. However, when s mals were pretreated with the microsomal enzyme inducers phenobarbital or .^echylcholanthrene, these exposure levels were lethal to nearly all of the animals within 2 hours, suggesting that lethality was due to an increase in the formation of toxic metabolites. Similar results (i.e., potentiation of DCE-induced lethality by phenobarbltone) were obtained by Harris and Anders (1980) in rats administered DCE by intraperitoneal injection. However, Carlson and Fuller (1972) found that pretreatment of rats with two different inhibitors of microsomal metabolism which presumably would reduce the formation of reactive intermediates (SKF 525A and Lilly 18947) prior to inhalation exposure to DCE also reduced the survival time following exposure to DCE. Masuda and Nakayama (1983) found that other inhibitors of microsomal metabolism (carbon disulfide and diethyldithiocarbamate) protected mice against all DCE-induced toxic effects at low doses following intraperitoneal injection. These results indicate that biotransformation plays an important role in the expression of DCE-induced effects. Increased susceptibility of fasted animals to the lethal effects of DCE may occur because fasting depleted GSH in the target tissues, SL 064501 ) 51 2. HEALTH EFFECTS resulting in less GSH available to bind to the active intermediate (Jaeger et al. 1973a). Mice have been observed to be more sensitive than rats to the lethal effects of inhaled DCE (see Figure 2-1) (Jaeger et al. 1974). This differential sensitivity also has been observed by the oral exposure route (see Figure 2-2) (Jenkins et al. 1972; Jones and Hathway 1978a). Pharmacokinetic studies suggest that, relative to rats, the rate of metabolism is higher in mice resulting in a greater degree of damage from electrophilic species capable of reacting with intracellular macromolecules (McKenna et al. 1977; Reitz et al. 1980). Though animal studies indicate that nutritional status affects DCEinduced lethality, how nutritional status affects the susceptibility of humans to the toxic effects of OCE is not known. Human subpopulations most likely exist with differing biochemical capacities for DCE metabolism and thereby are more or less able to form reactive intermediates. It is not known if these differing biochemical capacities will affect an individual's susceptibility to DCE-induced lethality. Respiratory Effects. Irritation of the mucous membranes of the upper respiratory tract and pulmonary congestion, hyperemia, and morphological changes were seen at necropsy in rats and mice acutely exposed to high levels of DCE via inhalation (Henschler 1979; Kllmisch and Freisberg 1979a; Rylova 1953; Zeller et al. 1979b). Longer-term inhalation exposure to DCE was associated with similar adverse respiratory effects (Gage 1970; Prendergast et al. 1967; Quest et al. 1986). These effects appeared to be rather nonspecific and most likely resulted from DCE's irritating properties. Therefore, these data suggest that any possible non-genotoxic respiratory effects associated with inhalation exposure to DCE (particularly acute) in humans may be a consequence of local, nonspecific irritation. However, a local nonspecific irritant effect cannot explain the pulmonary injury observed in mice following the oral administration of a single-dose of DCE. The effects seen included histopathological changes in Clara cells, pulmonary edema, hemorrhage, and focal atelectasis. These effects were reversible since cellular regeneration was evident within 5 days of treatment (Forkert et al. 1985). Clara cell degeneration was also seen in mice following acute intraperitoneal administration of DCE (Forkert et al. 1985; Krijgsheld et al. 1984b). The relevance of these findings to prolonged human exposure is not known since (a) the findings in the one oral study are not substantiated by other studies, and (b) intraperitoneal administration is not a relevant route of administration in humans. Hepatic Effects. Results from animal studies indicate that the liver is a primary target organ for DCE-induced toxicity. Hepatotoxicity following both inhalation and oral exposure to DCE was manifested by biochemical changes (i.e., increases in serum enzyme markers of liver dysfunction and induction of hepatic enzymes), and mild to marked histological changes (e.g., midzonal SL 064502 52 2. HEALTH EFFECTS K and/or centrilobular vacuolization, swelling, degeneration and necrosis). More severe hepatotoxic effects were seen in fasted animals (particularly males) as compared to fed animals (Andersen et al. 1979; Andersen et al. 1980; Andersen and Jenkins 1977; Chieco et al. 1981; Jaeger et al. 1974; Jaeger et al. 1975b; Jenkins and Andersen 1978; McKenna et al. 1978; Reynolds 1980). The increased susceptibility to DCE-induced hepatotoxicity seen in fasted rats may be related to the depletion of GSH levels. Indirect evidence of the role of GSH in DCE*induced hepatotoxicity is provided by Jaeger et al. (1974) who demonstrated that diethyl maleate, a substance that depletes liver GSH levels, potentiates liver toxicity in fed rats exposed to DCE via inhalation. In addition, thyroidectomy, a surgical procedure that results in increased liver GSH levels, has been shown to protect against DCE-induced hepatotoxicity and lethality whereas thyroxine replacement restored or even potentiated the susceptibility of thyroidectomized animals to DCE-induced hepatotoxicity (Jaeger et al. 1977b, Szabo et al. 1977). Results from in vivo studies in animals suggest that DCE-induced hepatic injury may result from the formation of a reactive epoxide or other intermediate in vivo (Andersen et al. 1978, 1980; Jaeger et al. 1977a; Jones and Hathway 1978b), which in turn binds to macromolecules in the target tissues. These intermediates are believed to be generated via the cytochrome F450 mixed function oxidase system (Forkert et al. 1986). Other subcellular mechanisms of DCE-induced toxicity have been proposed. For example, it has been suggested that DCE-induced inhibition of calciumdependent ATPase may be the initial biochemical insult that triggers a sequence of events that may culminate in cell death (Luthra et al. 1984). Results of in vitro studies in liver perfusates have suggested that metabolism of DCE reduces viability of liver cells (Reichert et al. 1978). Histochemical and biochemical evidence support the concept that plasma membranes and mitochondrial membranes may be the primary foci of acute hepatocellular injury in fasted rats (Jaeger 1977; Reynolds et al. 1980). In conclusion, DCE induces hepatotoxicity in animals following both inhalation and oral acute and repeated exposures. The limited information available in humans also suggests that DCE is hepatotoxic. Thus, it may b assumed that humans, particularly those exposed to high levels of DCE in occupational settings or in areas surrounding hazardous waste sites via inhalation and those with compromised hepatic function are at risk for DCEinduced liver toxicity. Renal Effects. Renal toxicity (e.g., enzyme changes, hemoglobinuria, increases in organ weight, and tubular swelling, degeneration and necrosis) has been observed following both inhalation and oral exposure to DCE in animals (see Figures 2-1 and 2-2) (e.g., Jackson and Conolly 1985; Lee et al. 1977; McKenna et al. 1978; Oesch et al. 1983; Short et al. 1977c). Fasted animals (particularly males) were again more susceptible to these effects than 064503 SL 53 2. HEALTH EFFECTS fed animals (e.g., Chieco et al. 1981; McKenna et al. 1978a), and mice were more susceptible than rats, as was seen for DCE-induced hepatotoxicity (Reitz et al, 1980; Short et al. 1977c; Watanabe et al. 1980). There is some evidence that the kidney damage induced by acutely inhaled or ingested DCE may be reversible (Jenkins and Andersen 1979; Reitz et al. 1980), but this may be concentration or duration dependent. Though data on kidney toxicity in humans following exposure to DCE do not currently exist, evidence from animal studies in two species suggest that nephrotoxicity may also occur in humans, particularly following acute exposure to DCE. The fact that adverse renal effects were rarely seen following more prolonged exposure to DCE (except in male mice), coupled with the observation that the acute nephrotoxic effects were reversible suggest that repair mechanisms may be operating. The renal effects of long-term exposure to DCE in humans are not known. Neurological Effects. Central nervous system toxicity has been observed in humans acutely exposed to high concentrations (approximately 4,000 ppm) of inhaled DCE (Tierney et al. 1979). Complete recovery occurred if exposure was n t prolonged. In addition, signs of central nervous system toxicity was the predominant effect observed in animals acutely exposed to high concentrations of DCE via the inhalation route of exposure (see Figure 2-1). Effects on the central nervous system have not been observed following oral or repeated inhalation exposures to DCE in animals (see Figure 2-2). However, these studies were not designed to detect subtle neurological effects. Developmental Effects. Based on studies by Short et al. (1977a), DCE has weak teratogenic effects in laboratory animals. Developmental toxicity was enhanced following inhalation exposure to DCE as compared to oral exposure. Developmental toxicity was often observed at doses of DCE that also induce maternal toxicity in animals (see Figures 2-1 and 2-2). Studies by Murray et al. (1979) demonstrated that the sensitivity of pregnant rats to DCE was greater by inhalation than by ingestion. After inhalation exposure at 80 and 160 ppm for 7 hours/day on gestation days 6-18, DCE produced maternal toxicity and increased resorption and skeletal alterations. Except for the increased mean fetal crown-rump length in the offspring, no adverse effects were noted in rats receiving 40 mg DCE/kg body weight/day in drinking water. The author hypothesized a possible mechanism to explain the route-dependent differences in DCE-induced toxicity. Since detoxication of DCE was reported to occur via conjugation of its active metabolites with GSH (McKenna et al. 1977) and GSH levels undergo diurnal variations (Jaeger et al. 1973a; Watanabe et al. 1976), Murray et al. (1979) speculated that sufficient GSH levels were available to detoxify 40 mg DCE/kg body weight administered in drinking water over a 24-hour period but not when the animals were exposed via inhalation between 8:30 am and 3:30 pm. When DCE doses are converted into equivalent units, animals exposed by inhalation received approximately 76.6 and 153 mg DCE/kg body weight/day (assuming all DCE was absorbed by the lungs) compared to 40 mg DCE/kg body weight/day in drinking water. Thus, a difference in total dose may also explain the greater toxicity seen following inhalation exposure. SL 064504 54 2. HEALTH EFFECTS Genocoxiclcy. The available data suggest that DCE produces genotoxic effects in a number of test systems. The results of in vitro and in vivo studies indicate that DCE exhibited mutagenic properties upon metabolic activation (i.e., requiring the presence of an exogenous mammalian metabolic system) in bacteria and yeast and that it induced gene conversion in yeast. It was also shown to be mutagenic in green plants without activation by mammalian metabolic systems. DCE induced chromosome aberrations and sister chromatid exchanges in cultured mammalian cells in vitro and DNA damage in mice in vivo. DCE has been shown to be genotoxic in several in vitro test systems. However, a metabolic activation system was required for activity. Results of in vitro genotoxicity studies are shown in Table 2-3. Gene mutations were observed in bacteria, yeast and green plant cells (Bartsch et al. 1975, 1979; Bronzetti 1981; Greim et al. 1975; Jones and Hathway 1978; Oesch et al. 1983; Van't Hof 1982), and it induced gene conversion in yeast (Bronzetti 1981). Both base-pair substitution and frameshift mutations were reported in Salmonella tvphimurium after continuous exposure to DCE vapors (Bartsch et al. 1975, 1979; Jones and Hathway 1978; Oesch et al. 1983). Another study reported negative results from tests in Salmonella (Mortelmans et al. 1986). However, the Mortelmans et al. (1986) study incorporated single doses of DCE into the wanned incubation medium instead of exposing the bacteria continuously to vapor. Given that DCE is very volatile and would be expected to escape from the culture, continuous exposure to vapor is considered a more reliable method. DCE was mutagenic in Salmonella after metabolic activation with an exogenous activation system derived from human liver samples (Jones and Hathway 1978b), thus supporting the concept that the human liver is capable of activating DCE into mutagenic metabolites. In cultured mammalian cells, DCE was reported negative in a point mutation assay in 8-azaguanine and ouabain resistant V79 Chinese hamster lung cells (Drevon and Kuroki 1979), but it produced chromosomal aberrations and sister chromatid exchanges in a Chinese hamster lung fibroblast cell line in the presence of a metabolic activation system (Sawada et al, 1987). DCE also been tested in several in vivo studies in animals. Results of in vivo genotoxicity studies are shown in Table 2-4. Negative results were reported in assays for dominant lethal mutations in mice (Anderson et al. 1977) and rats (Short et al. 1977b) and in a micronucleus test in mice using both the bone marrow assay system following gavage administration and the transplacental assay system following intraperitoneal administration to pregnant mothers (Sawada et al. 1987). Inhalation of DCE was associated with low rates of DNA alkylation in the livers and kidneys of mice and rats as compared to dimethyInitrosamine-treated control. Furthermore, DNA repair mechanisms were induced in the kidneys of mice in cells in which normal replicative DNA synthesis had been inhibited. A significant increase in DNA repair rates was not observed in mouse liver nor in the kidneys or liver of rats (Reitz et al. 1980). In a mouse host-mediated assay system, DCE was mutagenic and induced gene conversion in yeast (Bronzetti et al. 1981). SL 064505 55 2. HEALTH EFFECTS TABLE 2-3. Genotoxicity of DCE In Vitro Endpoint Species/Test System Result Reference With Without Activation Activation PROKARYOTIC ORGANISMS Gene mutation Salmonella tvnhlmurlun/ desiccator test for exposure to gases exposure S^-t-Vphlmurium/gas exposure + + + preincubation test E. coli WF2 E- coll K12 + + EUKARYOTIC ORGANISMS FUNGI Gena mutation Gene conversion Saccharomvcea cerevislae 07 S. cerevlslae 07 + + PUNT Gena mutation Tradescantla clone 4430 NT MAMMALIAN CELLS Gena mutation Chromosomal Sister chroma tid exchange Chinese hamster V79 cells Chinese hamster CHL cells Chinese hamster Don-6 cells Chinese hamster CHL cells " + NT (+) NT Bartsch et *1. 1979 Oesch et al. 1983 - Bartsch et al. 1975 NT Jones and Hathvay 1978b - Morteloans et al. 1986 - Oesch et al. 1983 Grelm et al. 1975 - Bronzetti et al. 1981 * Bronzetti et al. 1981 <+) Van't Hof and Schairer 1982 NT Drevon and Kuroki 1979 - Sawada et al. 1987 - Savada et al. 1980 - Sawada et al. 1987 NT - Noe Tested; - - negative result; + - positive results; (+) - weakly positive or marginal result. SL 064506 56 2. HEALTH EFFECTS TABLE 2-4 Genotoxicity of DCE In Vivo Endpoint Species/Test System Result Reference MAMMALIAN SYSTEMS Dominant Lethals Mouse Rat Micronuclai DNA damage Mouse bone marrow Mouse fetal liver and blood Mouse kidney/DNA repair HOST-MEDIATED ASSAYS Gene mutation Gene conversion Saccharomvces cercvisiac/ mouse host-mediated assay Saccharomvces cerevisiae/ mouse host-mediated assay Negative Negative Anderson et al. 1977 Short et al. 1977b Negative Negative Sawada et al. 1987 Sawada et al. 1987 tfeak positive Reitz et al. 1980 Positive Positive Bronzetti et al. 1981 Bronzetti et al. 1981 SL 064507 57 2. HEALTH EFFECTS Carcinogenicity. The carcinogenicity of DCE following inhalation, oral, dermal, and subcutaneous exposure has been evaluated in mice (Hong et al. 1981; Lee et al. 1978; Maltoni et al. 1985; Van Duuren et al. 1979), rats (Hong et al. 1981; Maltoni et al. 1982, 1985; Ponomarkov and Tomatis 1980; Quast et al. 1983, 1986; Rampy et al. 1977; Viola and Caputo 1977), and Chinese hamsters (Maltoni et al. 1985). Of the carcinogenicity bioassays conducted to date, only the results of a single inhalation study in mice by Maltoni et al. (1985) provide possible evidence of a positive carcinogenic effect from DCE exposure. In this study, increases in renal adenocarcinomas were noted in male Swiss mice exposed by inhalation to 25 ppm DCE. Mammary gland carcinomas and lung tumors, most of which were benign pulmonary adenomas, were also observed in this study. Results of all other carcinogenicity studies with laboratory animals have been negative. Nonsignificant increases in a variety of malignant and nonmalignant tumors were reported in studies involving inhalation and oral exposure; however, these increases either were not statistically significant or were not considered by the respective authors to be exposure related (Lee et al. 1977, 1978; Maltoni et al. 1985; Ponomarkov and Tomatis 1980; Quast et al. 1983, 1986). Study limitations for several of the investigations included less than lifetime exposure, use of doses below the maximum tolerated dose, small numbers of animals, and limited gross and microscopic examinations. Such limitations reduce the sensitivity of a bioassay system to detect a carcinogenic response. Van Duuren et al. (1979) evaluated the carcinogenicity of DCE in mice treated by dermal application.and by subcutaneous injection. DCE was inactive as a complete carcinogen when applied repeatedly for lifetime to the mouse skin, and did not induce local sarcomas when administered chronically to mice by subcutaneous injection. However, a dermal initiation-promotion study with Swiss mice has shown that DCE was active as a tumor-initiating agent. A statistically significant increase in the incidence of skin papillomas was noted in Swiss mice treated dermally with both DCE and the tumor-promoting agent phorbol myristate acetate (Van Duuren et al. 1979). On the basis of the suggestive inhalation study by Maltoni et al. (1985), DCE should be regarded as a possible animal carcinogen and therefore as a possible human carcinogen. Results of studies with laboratory animals indicating nonsignificant or non-dose-related increases in various malignant and nonmalignant tumors following oral or inhalation exposure provide limited but suggestive support that DCE may be a weak carcinogen (Lee et al. 1978, 1977; Maltoni et al. 1985; Ponomarkov and Tomatis 1980; Quast et al. 1986, 1983). The positive initiation-promotion study by Van Duuren et al. (1979) also suggests that DCE in concert with tumor-promoting agents can induce cancer. This is particularly relevant to humans in and around hazardous waste sites who are often exposed to more than one potentially carcinogenic and/or tumor promoting substance at a time (e.g., tobacco smoke). SL 064508 58 2. HEALTH EFFECTS EPA has classified DCE as a Group C agent (Possible Human Carcinogen). This category applies to chemical agents for which there is limited evidence of carcinogenicity in animals. Based on the inhalation study by Maltoni et al. (1985) in which a statistically significant increase in the incidence of renal adenocarcinomas was observed in treated male Swiss mice, EPA (1988) has calculated an inhalation cancer slope factor (or qx*) for DCE of 1.2 (mg DCE/kg body weight/day)'1. In experimental studies with mice, it has been observed that doses of DCE that induce renal tumors also induce renal tissue damage (degeneration and necrosis) (Maltoni et al. 1985; Reitz et al. 1980; Watanabe et al. 1980). These tumorigenic doses, however, are associated in mice with only minimal DNA alkylation and DNA repair (Reitz et al. 1980). These findings suggest that kidney toxicity may play a contributing role in the induction of renal tumors (Watanabe et al. 1980), and that tumors observed in mice exposed to DCE may be the result of the chemical's toxic effect upon nongenetic components of the cell (Reitz et al. 1980). However, DCE is mutagenic in lower organisms and has been shown to be a probable initiator in mouse skin (Van Duuren et al. 1979). It has been suggested that the toxic and carcinogenic effects of DCE may depend on species, strain, and sex of the tested animals (Maltoni 1977; Maltoni et al. 1985). Results of studies suggest that male Swiss mice are more susceptible to the toxic effects of DCE than female Swiss mice, rats, or hamsters (EPA 1985; Oesch et al. 1983). Pharmacokinetic studies also suggest that compared to rats, mice have a greater rate of DCE activation to electrophilic species capable of reacting with intracellular macromolecules (McKenna et al. 1977; Reitz et al. 1980). 2.4 Levels in Human Tissues and Fluids Associated with Effects Exposure to DCE is primarily determined by the appearance of the compound in expired air. A number of studies were conducted to examine exposure to DCE as measured in expired air (Conkle et al. 1975; Wallace et al. 1984, 1986); small amounts of DCE were found in the breath of study populations in New Jersey and North Carolina, but no health effects were reported. The available data are insufficient to determine the body levels of DCE in human tissues, fluids and expired air associated with health effects. 2.5 Levels in the Environment Associated with Levels in Human Tissue and/or Health Effects Data from available studies have been insufficient to correlate levels of DCE in the environment with levels in breath. In an investigation on the trace organic compounds in human breath, a 60-minute sampling period yielded 13.0 ng of DCE in the breath (volume unspecified) of one individual (Conkle et al. 1975). This value was corrected for the amount of DCE in the air supplied to the individual during the sampling period. The authors attributed the amount of DCE in the individual's breath to previous exposure; however, no SL 064509 59 2. HEALTH EFFECTS levels of previous exposure to DCE were reported for the test subject. The breath of 1 out of 12 individuals tested by Wallace et al. (1984) contained DCE (levels not specified). No environmental levels of DCE were reported for this study. Twelve percent of the breath samples from 350 residents of New Jersey contained measurable amounts of DCE, ranging from approximately 0.2 to 2 Mg/3 of expired air (Wallace et al. 1986). The levels of DCE in drinking water samples from homes of the test subjects had an arithmetic mean value of 0.2 jig/m3 and a maximum value of 2.4 fig/m3 which corresponds to values of 2.0xl0'7 ppm and 2.4xl0'6 ppm, respectively (Wallace et al. 1987). Occupational exposure studies have investigated health effects associated with exposure to DCE. Because of the small cohort size and concurrent exposure to other compounds, the information from these studies is not sufficient to correlate levels of DCE in the environment with health effects (Apfeldorf and Infante 1981). A study of 138 workers exposed to DCE (TWA concentrations ranging from less than 5 to 70 ppm) and copolymers other than DCE reported no statistically-related changes attributable to DCE in long-term mortality or health-inventory findings (Ott et al. 1976). Waxweiler (1981) found no association between occupational exposure to DCE (with concurrent exposure to other chemicals) and cases of angiosarcomas of the liver. 2.6 TOXICOKINETICS 2.6.1 Absorption 2.6.1.1 Inhalation Exposure No studies were located regarding the absorption of DCE in humans following inhalation exposure. Studies in laboratory animals have demonstrated that DCE was rapidly absorbed following inhalation exposure (Dallas et al. 1983; McKenna et al. 1978a), Substantial levels of the parent compound were found in the venous blood of rats within 2 minutes after inhalation exposure (Dallas et al. 1983). Absorption of DCE was duration- and d se-dependent, as shown in Figure 2-3. The percentage of systemic uptake was found to decrease with time from the onset of exposure until an equilibrium was reached within an hour. Once equilibrium was reached, percentage uptake varied inversely with dose. The cumulative uptake of DCE following inhalation exposure was linear for levels up to 150 ppm. However, at higher levels of DCE exposure, steady-state was never achieved. This finding indicates that DCE absorption following inhalation exposure was saturable at high levels, and the kinetics at these levels are best described by a cubic curve (Dallas et al. 1983). No studies were located that described transport mechanisms for DCE absorption, but since DCE is a small organic molecule with chemical and physical properties similar to lipid soluble anesthetics, it is expected to easily penetrate pulmonary membranes and rapidly enter the blood stream in humans following inhalation exposure. SL 064510 FIGURE 2-3. Percentage Systemic Uptake of DCE During Inhalation Exposur s 1.1-DCE PERCENT UPTAKE 100 AO 90 " A % 26 ppm O 75 ppm A 150 ppm 300 ppm 80 " 70 60 ? O 0OOO OQOO a*aaaaaaaaaaa o to HEALTH EFFECTS 50 ------------ 1----------------1----------------1--------------- 1---------------- 1----------------1 30 60 90 120 150 160 TIME (min) Rails were exposed to 25,75.150, or 300 ppm DCE tor 3 hours. Percentage uptake was determined at 8-minute intervals. Each point represents the mean percentage uptake in tour animals per group. Standard deviation brackets are otraled tor the sake ol clarity Reproduced from Dalas et al. 1983. SL 064511 61 2. HEALTH EFFECTS 2.6.1.2 Oral Exposure No studies were located regarding absorption in humans following oral exposure to DCE. Studies in animals clearly indicated that doses of DCE ranging from 10 to 100 mg DCE/kg body weight were rapidly and almost completely absorbed from the gastrointestinal tract of rats and mice following oral administration in corn oil (Jones and Hathway 1978a; McKenna et al. 1978b; Putcha et al. 1986). Rapid absorption has also been demonstrated to occur following the oral administration of 200 mg DCE/kg body weight in an aqueous emulsion, as evidenced by the observation that the largest percentage of the dose was exhaled during the initial 15-minute period (Chieco et al. 1981). Peak blood levels were achieved in rats within 2*8 minutes after oral administration (Putcha et al. 1986). When 0.5-50 mg radiolabeled DCE/kg body weight was given to female rats by the oral route, approximately 102 of the parent compound was recovered in the expired air by 1 hour post-exposure, indicating that oral absorption was rapid (Reichert et al. 1979). Furthermore, almost complete absorption of orally administered DCE by rats was demonstrated by the fact that 81-99.82 of the administered radioactivity was recovered within 72 hours (i.e., 21X was recovered in the expired air, 53.92 in urine, 14.52 in feces, 2.82 in the carcass and 7.52 in the cage rinse following oral administration of 5 mg [l4C]-DCE/kg body weight) (Reichert et al. 1979). Based on these results is likely that DCE is rapidly and c mpletely absorbed in humans following oral exposure (e.g., via ingestion of contaminated groundwater). 2.6.1.3 Dermal Exposure No studies were located regarding absorption in humans or laboratory animals following dermal exposure to DCE. However, the physical/chemical properties of DCE indicate that absorption of the liquid form of DCE via this route is possible. DCE is a small organic molecule with properties similar to the lipid-soluble anesthetics. Thus, liquid DCE is expected to readily penetrate the skin, which is a lipid-rich tissue. 2.6.2 Distribution No studies were located regarding distribution in humans following dermal exposure to DCE. Results from animal studies indicated that DCE was rapidly distributed throughout the bodies of both rats and mice following exposure via several routes. DCE appeared to accumulate preferentially in the kidney, liver, and lung. Fasted animals displayed higher levels of DCE and/or its metabolites in these target tissues than fed animals. These findings provide some basis for the observation that the liver, kidney, and lung are target tissues for DCE-induced toxicity, and explain why fasted animals are more susceptible to these toxic effects. SL 064512 62 2. HEALTH EFFECTS 2.6.2.1 Inhalation Exposure McKenna et al. (1978a) reported that, after inhalation exposure of rats to 10 or 200 ppm of [ 14C]-labeled DCE, the highest level of radioactivity was found in the liver and kidneys after 72 hours, with only very small amounts present in other tissues. These authors found that tissue burden/gram of tissue (microgram equivalents of [UC]-DCE per gram of tissue/total milligram equivalents recovered per rat) in the liver, kidneys, and lungs of fasted rats were significantly greater than in fed rats at both exposure levels, even though the total accumulation of [14C] in fasted rats was less than in fed rats. The results of this study suggest that fasted rats retain [14C] from administered DCE to a greater extent in specific target tissues. A preferential accumulation of radioactivity in the kidney and liver of rats, with fasted rats showing higher levels than fed rats in these tissues, was also observed by Jaeger et al. (1977) 30 minutes after a 2-hour inhalation exposure to 2,000 ppm radiolabeled DCE. Examination of tl4C]-activity at the subcellular level in these two tissues revealed that significantly more watersoluble [X*C]-activity was present in the cytosolic fractions of fasted rats than in fed rats (Jaeger et al. 1977), suggesting that distribution pathways for metabolism differ according to the nutritional status of the animals. 2.6.2.2 Oral Exposure Jones and Hathway (1978c) demonstrated that DCE is rapidly distributed throughout the body tissues in rats following a single oral administration.of the [14C]-labeled compound. They found that the highest amount of radioactivity occurred in the liver and kidneys within 30 minutes of administration. More general redistribution throughout the body followed. Quantitative distribution analyses revealed that the level of radiolabel in tissues decreased rapidly, with less than 3X of the administered dose present in the body 72 hours post-exposure. At that time, the highest levels were found in liver and kidney, with very little remaining in other tissues, Including fat (Jones and Hathway 1978c). 2.6.2.3 Dermal Exposure No studies were located regarding distribution in humans or animals following dermal exposure to DCE. 2.6.2.4 Other In a study by Okine et al. (1985) in which mice were administered a single intraperitoneal injection of 125 mg [14C]*DCE/kg body weight, radioactivity was distributed to all tissues examined, with peak levels seen 6 hours post-administration. The highest levels of radioactivity were found in the kidney, liver, and lung with lesser amounts in the skeletal muscle, heart, spleen, and gut. SL 064513 63 2. HEALTH EFFECTS 2.6.3 Metabolism No studies were located regarding metabolism in humans following exposure to DCE. The metabolism of DCE following oral administration in rats has been extensively studied in rats (e.g., Jones and Hathway 1978a; Jones and Hathway 1978c; McKenna et al. 1978b; Reichert et al. 1979). These studies demonstrate that DCE undergoes biotransformation processes and several metabolites have been identified. An overall summary of the metabolic profile of DCE in animals is presented in Figure 2-4. D'Souza and Anderson (1988) developed a physiologically-based pharmacokinetic model for DCE based on its oxidative metabolism and subsequent conjugation with GSH, a principal pathway (see Figure 2-5). Their model demonstrates that because of DCE's low blood:air partition coefficient and saturable metabolism, the metabolism of DCE is sensitive to the rate of absorption. Furthermore, DCE's metabolic profile (i.e. the percentage of DCE exhaled, metabolized and conjugated with GSH) is different for different routes of exposure and dose levels. This model, which the authors verified experimentally, is useful in predicting the kinetics, and thus the potential toxicity of DCE under various exposure conditions. An initial step in the metabolism of DCE is possibly the formation of the epoxide (oxirane) intermediate, 1,1-dichloroethylene oxide, but this reactive compound has never been Isolated upon administration of DCE to laboratory animals (e.g., Jones and Hathway 1978c; Reichert et al. 1979; McKenna et al. 1977). An alternate metabolic scheme that does not go through the epoxide intermediate was proposed based on studies in isolated hepatocytes by Liebler et al. (1985, 1988) and is presented in Figure 2-6. The main biotransformation pathways for DCE in the rat are suggested to involve conjugation with GSH, either with the epoxide or following rearrangement of the epoxide to chloroacetylchloride, with subsequent hydrolysis to monochloroacetic acid. This is consistent with the observation that exposure to DCE causes depletion of GSH levels in the liver (Jaeger et al. 1974; Reichert et al. 1979; Reynolds et al. 1980). For example, Reynolds et al. (1980) reported that there was a linear relationship in rats between intraperitoneally administered DCE and GSH depletion over the range of 20-100 mg DCE/kg body weight; above this level GSH depletion plateaued. The maximum reduction seen (70%) occurred 4 hours post-dose with a subsequent gradual recovery to normal levels within 24 hours. These findings have led several investigators to suggest that DCE-induced hepatotoxicity is related to the depletion of hepatic GSH levels, thereby permitting the reactive intermediate to bind to and alkylate hepatic macromolecules instead of being SL 064514 Cl H cc Cl H -- -- ~ HO Cl\ /\ / H 1 II C --C a -- c -- c -- ci a^ h1 tm |_ H _J HO I II Cl -- C C OH I H is> HEALTH EFFECTS : ft - HVDfKWEIHVL) - N - ACEmCVBTEWE P<m,so%* HOOC-CH. t-GHf CHOOOH 1 MIOOCH, H - ACETYL 80 - CMBOXVMEIHVL) CVSTEME (0*4*1 HOOC - CH , S - CM t OOOH THCOGLYOOUJC AC (22%; 9%) I l-Monu* HS-CHrCOOH TMOGLYCOLUC ACC 0*0*) Not*: PoGtaoavduM0hranlnldwl*mfl(<toHdiMM(WunM(t^, mow) lol-lns naw8 M< 10 m^As b> tw ral m. Mwlpa MtalMriltaa ariif an rfuM IWprwiiwd home flitdm 1 a. IMS V 8 CHjCOOH 8 CH,COOH OITHOGLYCOU.IC ACC (6*23%) FIGURE 2-4. Metabolic Pathway of DCE In Animals SL 064515 HEALTH EFFECTS Ji 8 1J I 1 OSH Kb. Ki te*. GUaMomconcanMlM. RreHadw ra conttanl tof tom--tan at MAT. FkBHMtar ran amuml tor tamatan at OCM. FtaMtenm K. K*r K, FMadifM K,- Rapioduoad bom PSouzi and Andaman (1bM| PmMonooaMck UMrttood RkMypaffcmctttood frtnedy pertaerttitoort 8to"FabMood v. (mghr ) K.<ma>Mr,| Kp.Oitf'hr') Kt. (hr') K*. (hr*) mKoo, <**'') h*o i.i OA IB.4 sa 2.6 0.25 0.33 50 9000 1.02x10-* 55 FIGURE 2-5. Physiologically-Based Pharmacokinetic Model for DCE SL 064516 66 2. HEALTH EFFECTS Cl h2c C Cl 0 Cl OH JI:-Ah-ci os - c - CHCI2 (A) H1-C --c / Cl \ OFe Cl P4S0 /a I H,C -- cC----Cl H+ 1 H 0 S - (2,2-dichloro-1-hydroxy) ethylglutathione /-A.. Cl GSH Cl i 0Fe*~ \ | GSH (I CI*CH2*C-a------- GS-CH-SG (B) S - (2-glutathfonyl) acetylglutathione iHjO | Ha ________ GSH f CI-CHpOOH----------GSCH2COOH + GSH (C) 2 - (S-glutatMonyt) acetal* Reproduced from Llebler et al. 1985. Figure 2-6. General proposed scheme for oxidative and conjugative metabolism of 1,1-dichloroethene not metabolized via the epoxide intermediate. SL 064517 67 2. HEALTH EFFECTS detoxified, ultimately leading to cell death (Jaeger et al. 1974; McKenna et al, 1977; Reynolds et al. 1980), Conjugation with monochloroacetic acid following by 0-thionase activity appeared to be the major metabolic route on a quantitative basis in rats, since thiodiglycollic acid was the predominant urinary metabolite (Jones and Hathway 1978a). Other metabolites identified in this pathway include monochloroacetic acid itself, thioglycollic acid, and dithioglycollic acid. However, direct GSH detoxication of the epoxide also apparently occurred to a significant degree as demonstrated by the formation of glutathionyl acetyl chloride with subsequent breakdown to an N-acetyl cysteine derivative (Jones and Hathway 1978a). Evidence exists to suggest that enzymatic hydration of the epoxide by epoxide hydrolase is a minor pathway in the metabolism of DCE in rats. This contention is supported by the observation that exacerbation of DCE-induced toxicity in rats by diethyl maleate and various epoxide inhibitors following inhalation exposure was directly related to their ability to decrease GSH levels and not with their ability to competitively inhibit epoxide hydrolase (Andersen et al. 1980). Reichert et al. (1979) proposed an alternative metabolic pathway (i.e., one not involving GSH conjugation) to account for the presence of the metabolite, methylthioacetylamino ethanol. They suggested that chloroacetylchloride, instead of being hydrolyzed to monochloroacetic acid, reacts with membrane phosphatidyl ethanolamine which is enzymatically cleaved to yield the ethanolamine derivative of chloroacetic acid. The methylthio group is then probably transferred from methionine as a result of direct nucleophilic attack. The pathways of DCE metabolism in the mouse were similar to those seen in the rat except that the rate of metabolism was greater in the mouse (i.e., a greater proportion of administered DCE was metabolized per given dose level by the mouse than the rat) (Jones and Hathway 1978a). The predominant urinary metabolite found in mice was the N-acetylcysteine derivative produced by GSH conjugation to detoxify the epoxide intermediate. In mice there were quantitatively greater amounts of water-soluble urinary metabolites present in the urine (and consequently less parent compound in the expired air) attesting to a greater metabolic capacity. Furthermore, 0-thionase activity was more pronounced since more dithioglycollic acid was found than thioglycollic acid (Jones and Hathway 1978a). In addition, Oesch et al. (1983) pointed out that DCE may have different effects on cytosolic GSH transferase activity and that this difference may have contributed to the species differences observed. Radiolabeled material has been shown by several investigators to covalently bind to liver and kidney tissues following the administration of [14C]-DCE, which may provide a basis for the toxic effects seen in these SL 064518 68 2. HEALTH EFFECTS V organs (Jaeger et al. 1977; McKenna et al. 1977). McKenna et al. (1977) reported a linear increase in the amount of covalently bound radioactivity in the liver of rats exposed to 5-200 ppm [14C]-DCE by inhalation for 6 hours. However, GSH depletion (and therefore metabolism) plateaued at about 200 ppm. Therefore, the actual amount of reactive metabolite formed and available for binding was probably determined by a combination of both activation and detoxication pathways. The increased severity of hepatotoxic and nephrotoxic effects induced by DCE in the mouse as compared to the rat may be partially explained by the observation that greater amounts of covalently bound reactive material were found in these two tissues in the mouse than the rat following exposure to the same dose of DCE (McKenna et al. 1977). The mouse exhibited greater DCEinduced nephrotoxic effects relative to the rat, and McKenna et al. (1977) reported that levels of covalently bound material were six times higher in the mouse kidney as compared to the rat kidney. Short et al. (1977d) reported similar results when a single dose of [l4C]-DCE was injected intraperitoneally to rats and mice. The highest level of covalently bound radioactivity was seen in the mouse kidney. The authors found that pretreatment with disulfiram also reduced the amount of covalent binding in both species. The authors speculated that disulfiram may reduce the activation of DCE and increase the extent of its detoxification. Thus, with respect to genotoxicity, conjugation of reactive intermediates of DCE with GSH is a major detoxification mechanism in laboratory animals by reducing the amount of reactive material available to covalently bind to cellular macromolecules. DCE can also potentially form adducts with hemoglobin, similar to what has been observed with ethylene oxide (Tornqvist et al. 1986). Electrophilic intermediates, such as the epoxide formed in DCE metabolism, can likely bind to proteins in hemoglobin as they have been demonstrated to do in liver and kidney. 2.6.4 Excretion 2.6.4.1 Inhalation Exposure No studies were located regarding excretion in humans following exposure to DCE. However, elimination of DCE following inhalation exposure in rats is rapid, with the bulk of absorbed material being eliminated as metabolites in the urine, and very little (IX of the administered dose) of the parent compound eliminated unchanged in the expired air at low levels of exposure (McKenna et al. 1978a). Steady-state levels of DCE in the expired air are achieved within 30-45 minutes after exposure to low (25-150 ppm) levels of DCE, indicating that elimination is first-order at these levels of exposure (Dallas et al. 1983). However, metabolic processes are saturated when exposure levels approach 200-300 ppm as evidenced by the fact that steadystate levels of DCE in expired air are never reached. Since DCE is volatile and relatively insoluble in blood, increased amounts can easily be eliminated unchanged via the lung once metabolic processes become saturated. Upon SL 064519 69 2. HEALTH EFFECTS cessation of exposure, concentrations of DCE in both blood and breath fell rapidly (Dallas et al. 1983). Similar results were obtained by McKenna et al. (1978a). DCE exhibited a biphasic elimination profile following inhalation exposure in rats (McKenna et al. 1978a). The first phase had a half-life of about 20 minutes for the elimination of unchanged DCE in breath and 3 hours for the elimination of water-soluble metabolites in urine. The second phase had a half-life of about 4 hours in breath and 20 hours in urine. The bulk of the material was eliminated in both the breath and the urine during the rapid phase. Nutritional status did not appear to affect the elimination kinetics of DCE following inhalation exposure in rats (McKenna et al. 1978a). Limited information is available on elimination following inhalation exposure to DCE in the mouse. However, McKenna et al. (1977) reported that at low levels of exposure (10 ppm for 6 hours), somewhat lower levels of unchanged DCE were eliminated in the expired air and higher levels of watersoluble metabolites were found in the urine as compared to the rat. This finding supports the observation that the mouse metabolizes DCE to a greater extent than the rat. 2.6.4.2 Oral Exposure No studies were located regarding the excretion in humans following oral exposure to DCE. Elimination of DCE and its metabolites following oral administration in rats has been demonstrated to be very similar to that seen following Inhalation exposure. Following oral administration of 1 mg [14C]DCE/kg body weight in com oil, less than 12 of the administered dose was excreted unchanged in the expired air, with 5-14% of the administered dose recovered as [1AC]-C02. The bulk of the administered [1AC]-DCE (44-80% of the administered dose) was eliminated in the urine within 3 days, most within th first 24 hours. Smaller amounts of water-soluble metabolites (8-16% of the administered dose) were found in the feces (Jones and Hathway 1978c; McKenna et al. 1978b; Reichert et al. 1979). Following the oral administration of higher doses to rats (50 mg [1AC] -DCE/kg body weight), a higher proportion of unchanged parent compound (16-30% of the administered dose) was excreted in the breath with a concomitant reduction in the amount of expired C02 (3-6% of the administered dose) and urine metabolites (35-42% of the administered dose) (Jones and Hathway 1978c; McKenna et al. 1978b; Reichert et al. 1979). Similar but more marked trends were observed at even higher doses (Chieco et al. 1981; Jones and Hathway 1978c). Thus, metabolic processes were shown to become saturated at these dose levels. Putcha et al. (1986) reported that the elimination of orally-administered DCE is triphasic, whereas McKenna et al. (1978a) and Reichert et al. (1979) reported that elimination is biphasic. The first phase identified by Putcha et al. (1986) occurred almost immediately, within the first few minutes after exposure, and the second two phases corresponded to those observed by the other investigators. Half-lives for these 2 phases of elimination in the SL 064520 70 2. HEALTH EFFECTS i breath after inhalation exposure were 20 minutes and 1 hour, and 6 hours and 17 hours in the urine. Nutritional status of the animal has been found to slightly modify the elimination of DCE by rats following oral administration. McKenna et al. (1978b) demonstrated that 19X of a 50 mg DCE/kg body weight dose was excreted unchanged by the lungs of fed rats, whereas 29% was excreted by fasted rats. This finding provides evidence that fasted rats eliminate unchanged DCE to a greater extent than fed rats. However, elimination of nor.' olatile metabolites was slightly greater in fed animals than in fasted an .s, indicating a reduced capacity for metabolism in fasted rats. ce have been shown to eliminate more DCE as water-soluble metabolites in r. - urine than do rats at comparable doses (Jones and Hathway 1978a). These results may indicate that mice also metabolize orally administered DCE to a greater extent than rats. 2.6.4.3 Dermal Exposure No studies were located regarding the excretion of DCE in humans or animals following dermal exposure. 2.6.4.4 Other Routes of Exposure Using the physiologically-based pharmacokinetic model developed for DCE discussed in Section 2.6.3, D'Souza and Anderson (1988) demonstrated that the half-life of DCE in blood is not representative of metabolism rates, but rather more closely corresponds to reequilibration of DCE from fat. Consequently, rats with higher fat content were verified to have longer DCE blood half-lives following intravenous administration. This could have important implications for obese individuals exposed to high levels of DCE. 2.7 INTERACTIONS WITH OTHER CHEMICALS As discussed in previous sections, it is apparent that the toxicity of DCE is largely due to the formation of toxic intermediates during metabolism in vivo. The production and biotransformation of toxic metabolic intermediates of DCE can be greatly influenced by various metabolic inhibitors and inducers, and by the availability of precursors of compounds involved in detoxication, such as GSH. Microsomal mixed-function oxidases (MFOs) are a group of enzymes involved in the biotransformation and detoxication of xenobiotics such as DCE. Inhibitors of some microsomal MFOs include the compound SKF-525-A, disulfiram, and other dithiocarbamates, such as thiram and diethyldithiocarbamate. These compounds reduce the toxic effects of DCE in the liver, probably by inhibiting the enzymes responsible for the formation of reactive, toxic intermediates (Masuda and Nakayama 1983; Short et al. 1977c,d). Inhibitors of metabolic enzymes responsible for the breakdown of these reactive intermediates may also SL 064521 71 2. HEALTH EFFECTS enhance che toxicity of DCE. For example, 1,1,1-trichloropropane and other inhibitors of epoxide hydrolase can potentiate the toxicity of DCE (Jaeger et al. 1977). Other chemicals that reduce the activity of metabolic enzymes and show some protective effects against the toxicity of DCE include pyrazole, 3-aminotriazol, and carbon tetrachloride (Andersen et al. 1978). Enzyme inducers (enhancers) may either protect against or exacerbate the toxicity of DCE. Induction of enzymes involved in the formation of toxic intermediates results in potentiation of DCE-induced toxicity following DCE exposure; conversely, induction of enzymes responsible for the biodegradation of the toxic intermediate(s) will decrease toxicity. Examples of compounds that induce MFOs and cause an increased toxic effect upon exposure to DCE include ethanol and acetone (Hewitt and Flaa 1983; Sato et al. 1983). Many inducers of MFO enzymes do not cause increased hepatotoxicity of DCE, perhaps because they stimulate a pathway not involved in the metabolism of DCE. An example of this type of compound is 3-methylcholanthrene (Carls n and Fuller 1972). The induction of metabolic enzymes by phenobarbital, even though protective against liver damage, has resulted in an increase in the cardiotoxicity of inhaled DCE at very high exposure levels. Thyroidectomy protected rats from the hepatotoxic effects of DCE (Szabo et al. 1977). Thyroxine replacement in thyroidectomized rats exacerbated the liver damage seen upon subsequent exposure to DCE (Szabo et al. 1977). Pretreatment of animals with compounds that deplete GSH levels (such, as diethyl maleate) increase the amount of liver damage caused by DCE exposure (Reichert et al. 1978). Conversely, pretreatment of animals with supplements containing high concentrations of the amino acids cysteine and/or methionine, both of which are metabolic contributors of the sulfhydryl group required for GSH biosynthesis, has been demonstrated to have a protective effect against the toxicity of DCE (Short et al. 1977d). 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE Specific information regarding human subpopulations that are unusually susceptible to the toxic effects of DCE were not located. However, animal studies have suggested that there are factors that may predispose some groups to be at increased risk for the toxic effects of DCE than the general population. These factors are discussed below. The influence that nutritional status and dietary intake can have upon the metabolism and detoxification of xenobiotics has been well documented. Nutritional status is known to modify the metabolism and toxicity of a variety of halogenated alkenes (Andersen et al. 1978; Nakajima et al. 1982). As discussed in previous sections, fasted animals or animals kept on a low carbohydrate diet exhibited a greater toxic effect when exposed to DCE when compared with similarly exposed control (carbohydrate-fed) animals (Nakajima et al. 1982). Reynolds and Moslen (1977) and Jaeger et al. (1974) note that SL 064522 72 2. HEALTH EFFECTS starvation prior to DCE exposure resulted in both an earlier appearance of hepatic lesions and a more extensive distribution of lesions compared to control (fed) rats. Sex differences in the toxic response to DCE have been observed in animals. For example, in a chronic inhalation exposure study in rats, hepatotoxic effects occurred at lower DCE concentrations in female rats than in male rats (24 ppm and 75 ppm, respectively) (Quast et al. 1986). Fasted male animals, particularly, young males, appear to be more susceptible to the toxic effects of DCE than fasted females, as evidenced by their enhanced responses at lower doses of DCE. Individuals taking certain drugs or who have pre-existing liver, ki ey, thyroid, or cardiac disease may be at greater risk for DCE-induced toxic-_y. Phenobarbital. even though somewhat protective against DCE-generated liver damage (Carlson and Fuller 1972), has been shown to sensitize the heart to DCE-induced arrhythmias (Siletchnik and Carlson 1974). Since phenobarbital is sometimes used as a soporific, and by those with various forms of epilepsy or seizure disorders, people who are taking this medication or those with pre existing arrhythmic heart conditions should not be exposed to high levels of DCE. Ethanol increases the amount of DCE-induced hepatotoxicity observed in rats, which suggests that alcohol ingestion could exacerbate DCE-induced toxicity in exposed individuals. Therefore, individuals taking alcoholcontaining medication or drinking alcoholic beverages may be more susceptible to the toxic effects of DCE. Thyroidectomy, either chemical or surgical, can protect against the hepatotoxicity associated with inhalation of DCE. Conversely, thyroxine treatment to replace or supplement normal thyroid function results in an increased amount of liver damage upon subsequent exposure to DCE in animals (Szabo et al. 1977). Individuals with liver or kidney disease or those with an acute hypersensitivity to DCE should avoid exposure to DCE. Specific data concerning teratogenicity in humans exposed to DCE were not found in the reviewed literature. DCE has been described as a possible teratogen responsible for soft-tissue anomalies in rats and skeletal defects in mice, rats, and rabbits, often at levels that produced clear evidence of toxicity in the dam. Therefore, pregnant women should also avoid exposure to DCE. To conclude, groups of people who should be specifically cautioned against exposure to DCE include the very young; the pregnant; those who ingest alcohol; people using phenobarbital (or possibly other hepatic enzyme-inducing drugs); those receiving thyroid replacement therapy or those who are hyperthyroid; people who, for whatever reason, are fasting and those with cardiac, hepatic, renal, and certain central nervous system dvsfunctions. SL 064523 73 2. HEALTH EFFECTS 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of DCE is available. Where adequate information is not available, ATSDR, in cooperation with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine these health effects (and techniques for developing methods to determine such health effects). The following discussion highlights the availability, or absence, of exposure and toxicity information applicable to human health assessment. A statement of the relevance of identified data needs is also included. In a separate effort, ATSDR, in collaboration with NTP and EPA, will prioritize data needs across chemicals that have been profiled. 2.9.1 Existing Information on Health Effects of DCE Figure 2-7 graphically depicts the existing health effects information n DCE for a specific route and duration of exposure. There is little information available concerning the long-term health effects of DCE in humans following inhalation exposure. Most of the information concerning health effects in humans is reported in occupational studies that are difficult to interpret due to limitations in study design (e.g., exposure levels and duration cannot be quantified and concurrent exposure to other toxic substances cannot be ruled out). No information concerning oral or dermal exposure to DCE in humans was found in the reviewed literature. The systemic effects of DCE in animals following inhalation and oral exposure have been studied in a variety of species following acute, intermediate, and chronic exposure durations. Information was not found concerning immunological effects following oral exposure. One oral exposure study reported observations of the "appearance" and "demeanor" of test animals, but this was not considered a good analysis of possible neurological effects. Genetic effect end points were examined following inhalation exposure only. Carcinogenicity studies in animals following exposure by oral, inhalation, and dermal exposure are available. 2.9.2 Data Needs Single-Dose Exposure. We are reasonably confident that the information available on the systemic toxicity of DCE following single-dose inhalation and oral exposure in animals will allow for extrapolation to effects that might be expected in humans following such exposures. Data on single-dose dermal exposure are lacking. Accidental contact with aqueous solutions of DCE is possible primarily in and around hazardous waste sites, so more information on the adverse systemic health effects in animals of dermal exposure to DCE in animals would be useful. SL 064524 74 2. HEALTH EFFECTS t. HUMAN # Existing Studies ANIMAL FIGURE 2-7. Existing Information on H iffects of DCE SL 064525 75 2. HEALTH EFFECTS Repeated-Dose Exposure. Information is available on the systemic toxicity of DCE following repeated-dose inhalation and oral exposure in animals, though these effects are not as well characterized as acute exposures. We are reasonably confident that the existing data will allow for extrapolation to systemic effects that might be expected in humans following such exposures. Data on repeated dose dermal exposure are lacking. However, as discussed above, this is not expected to be a major route of exposure for DCE. Most information available in the recent literature concerning the toxicity of DCE following both single- and repeated-dose exposure is derived from studies using fasted animals, since they are more susceptible to DCEinduced toxicity. Studies which clearly delineate between fasted and nonfasted experimental conditions would assist in the understanding of DCE toxicity in the human population. These studies need to focus on comparisons of biochemical functioning in laboratory animals and human nutritional status in the general population. For example, how do GSH levels in rodents compare to levels normally seen in human subpopulations, which might determine specific groaps at risk? Furthermore, many animal studies have mentioned the occurrence of increased serum enzyme markers of hepatic dysfunction following DCE exposure. Studies that attempt to correlate the presence of these enzymes in blood with functional and histopathological changes in the liver would greatly improve the utility of the data base. Specific differences with regard to susceptibility to the toxic effects of DCE are evident in animal studies; mice generally respond to lower doses of DCE than rats, and DCE-induced toxicity in male animals is exacerbated by fasting but not in female animals. However, developmental effects in rats are observed at lower doses than in mice in inhalation studies. Though the reasons for the differences are not known, it can be speculated that underlying biochemical differences, such as the ability to form reactive intermediates, may be involved. It is possible that human subpopulations may also differ in their ability to form reactive intermediates of DCE. Thus, further studies investigating the underlying mechanisms of species and sex variation to the toxicity of DCE may help identify sensitive human subpopulations. Chronic Exposure and Carcinogenicity. Data from animal studies on the chronic toxicity and carcinogenicity of DCE are sparse, and limited in their usefulness because of experimental design flaws. The data presented do not sufficiently characterize the carcinogenic or chronic toxic effects of DCE. However, the available information does suggest that DCE is carcinogenic in animals. Additional information on the chronic toxicity and carcinogenicity of DCE from well-conducted animal bioassays and human epidemiological studies using various routes of exposure would be useful in predicting the likelihood that such effects occur in humans. Genotoxicity. Information is available from short-term bacterial, yeast, plant and mammalian cell culture and in vivo tests. Though DCE is genotoxic SL 064526 76 2. HEALTH EFFECTS lf in in vitro systems, it has generally tested negative in in vivo mammalian systems. More information on the genotoxicity of DCE, particularly in mammals, may clarify these conflicting results. Reproductive Toxicity. One study has been conducted on the potential reproductive toxicity of DCE in animals (Nitschke et al. 1983). This study was conducted by the oral route in rats, and the results were negative. Studies by Short et al. (1977a) demonstrated that inhalation exposure of pregnant dams to DCE produced a statistically significant increase in the incidence of early embryo resorptions. Inhalation has been shown to be more harmful than oral exposure for several other end points; a standard reproductive toxicity study has not been done by the inhalation route and would be useful. Developmental Toxicity. Numerous studies on the potential developmental toxicity of DCE have been conducted in animals. Ve are reasonably confident that the available information is enough to conclude that adverse developmental effects may occur in humans at exposure levels that might cause toxic effects in the mother. However, a NOAEL in mice for continuous in utero inhalation exposure has not been established. A lower dose study to determine a safe level for developmental effects would add further confidence in the database. Monitoring and epidemiological studies in areas surrounding hazardous waste sites would be useful to more fully assess the developmental hazard of DCE in humans. Xmnrunotoxlcity. No information is available on the immunotoxicity of DCE. Studies investigating the potential for this effect would be useful,since compromised immunocompetence can be devastating to human health. Neurotoxicity. Information is available on the neurotoxic effects of acute inhalation exposures to DCE in both humans and animals. However, no information is available on the potential neurotoxic effects of long*term exposure to DCE. More information would be useful in assessing the neurotoxic effects of prolonged exposure to DCE, such as may occur in the vicinity of hazardous waste sites. Epidemiological and Human Dosimetry Studies. Most of the available information on the adverse effects of DCE in humans comes from cases of acute poisoning occurring primarily In the workplace. Limitations inherent In these studies include unquantified exposures, concentrations and durations, as well as concomitant exposure to other toxic substances. The few available industrial surveys and epidemiological studies are limited in their usefulness because of small sample size, short follow-up periods and/or brief exposure periods. Despite their inadequacies, studies in humans indicate that DCE can cause central nervous system toxicity and irritation of the mucous membranes. There is also some evidence to suggest that repeated exposure to DCE is associated with liver damage in humans. Well-controlled epidemiological studies of people living in close proximity to areas where DCE has been detected in surface and groundwater, in the vicinity of industries releasing DCE, near hazardous waste sites, and of people occupationally exposed could SL 064527 77 2. HEALTH EFFECTS add to and clarify the existing database on DCE-induced human health effects. However, occupational studies would probably be difficult to conduct since the majority of exposed workers are carpenters, warehousemen, and machine operators for whom exposure information and health follow-up is difficult to obtain, and the exposed population is either dropping or difficult to define. Biomarkers of Disease. Adequate methods exist for the analysis of DCE in expired air. However, no good quantitative correlation can be drawn between body levels of DCE and adverse health effects based on the available data. If epidemiological studies are conducted that correlate DCE exposure with specific adverse health effects, it may be possible to correlate these effects quantitatively with changes in tissue and/or body levels of DCE. Disease Registries. At present, the only known health effects of DCE in humans are central nervous system toxicity, upper respiratory tract irritation, and, possibly, liver damage. If epidemiological studies identify particular diseases produced by DCE, it may be possible to determine thenumber of people affected and the factors associated with identifying the disease in certain populations, such as exposure to high levels near hazardous waste sites. Bioavailability from Environmental Media. The monitoring data available indicate that DCE is present in the air, water, soil, and foodstuffs. DCE and metabolites can be measured in the breath, blood, urine, and adipose tissue of humans. Thus, it can be concluded that DCE is bloavailable from the environment. What is lacking is good quantitative data that correlate varying levels in the environment with levels in the body and health effects and the extent to which DCE can be absorbed from various media (i.e., soil). This may be difficult to obtain, since environmental levels can fluctuate widely because of the high volatility and rapid degradation of DCE. Food Chain Bioaccumulation. More data on levels of DCE in various parts of the food chain and how these levels impact on levels found in humans would be useful. Absorption. We are reasonably confident that the available animal data sufficiently characterize the absorption of DCE by the inhalation and oral routes of exposure. More data on absorption of DCE following dermal exposur would be useful since humans can be exposed via this route as well. Distribution. The distribution of DCE following inhalation and oral exposure has been sufficiently characterized in animals. More data on the distribution of DCE following dermal exposure would be useful, since humans can be exposed via this route as well. Metabolism. The metabolism of DCE to reactive intermediates is thought to be an important factor in the manifestation of DCE's toxic effects. The available data do not unequivocally identify the epoxide as the only reactive intermediate nor establish epoxide formation as the only route of metabolism. SL 064528 78 2. HEALTH EFFECTS ( Studies designed to clarify the intermediate metabolism of DCE and relate this metabolism to the manifestation of toxic effects would be useful, Excretion. Ve are reasonably confident that the available animal data sufficiently characterize the excretion of DCE following inhalation and oral exposure. More data on the excretion of DCE following dermal exposure would be useful, since humans can be exposed via this route as well. 2.9.3 On-going Studies A cohort mortality study (1940-1980) among grain millers exposed to several chemicals including DCE is being conducted by Dr. Alavanja at the National Cancer Institute. Data are being supplied by the American Federation of Grain Millers. Studies are currently being conducted by Dr. Kanz's research group at the University of Texas Medical Branch at Galveston to evaluate the modulation of DCE-induced hepatic injury by hypo- and hyperthyroidism. No other on-going studies on the health effects of DCE were identified. No on-going studies concerning the association between body tissue and fluid levels of DCE and health effects were located. No on-going studies concerning the environmental levels of DCE associated with body levels or health effects were identified. Studies at the University of Texas Medical Branch Department of Pathol gy conducted by Dr. Moslen's research group are trying to establish whether alterations in nutritional state or DCE metabolism cause changes in hepatobiliary clearance functions. Studies by Dr. Foyer's research group at the Oklahoma Medical Research Foundation are observing the extent to which DCE forms free radicals when metabolized by the mixed function oxidase system. Studies being conducted by Dr. Glende's research group at Case Western Reserve University are aimed at determining whether phospholipase A2 activation of DCE plays a role in the hepatotoxic action of this chemical. Dr. Shaikh's research group at the University of Arkansas is Investigating the kinetics and mechanisms of the interaction of superoxide with DCE to form active free radicals, which cause toxicity through lipid peroxidation. The overall aim is to determine which biotransformation products are truly responsible for DCE's toxic effects. SL 064529 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY The chemical formula, structure, synonyms, and identification numbers for DCE are listed in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Important physical and chemical properties of DCE are listed in Table 3-2. SL 064530 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of DCE Property Value Reference Chemical Name Synonyms DCE 1.1-Dichloroethylene; 1,1-DCE; 1.1-Dichloroethene asym- dichloroethylene; chlorure de vinylidene (French); ethene; 1,1,-dichloro; ethylene; 1,1,-dichloro; VDC; vinylidene chloride (inhibited); vinylidene chloride (II); vinylidene dichloride; vinylidine chloride HSDB Chemical formula C2-H2.-C12 Merck (1983) Structure Cl - C - C - H 11 11 Cl H Merck (1983) Identification Numbers: CAS Registry NIOSH RTECS EPA Hazardous Waste OHM/TADS DOT/UN/NA/IMCO Shipping HSDB NCI 75-35-4 KV9275000 U078 7216949 UN 1303;IMCO 3.1 1995 C54262 HSDB HSDB HSDB HSDB HSDB HSDB HSDB HSDB CAS - Chemical Abstracts Services NIOSH * National Institute for Occupational Safety and Health RTECS - Registry of Toxic Effects of Chemical Substances OHM/TADS - Oil and Hazardous Materials/Technical Assistance Data System DOT/UN/NA/IMCO - Department of Transportation/United Nation/International Maritime Dangerous Goods Code HSDB - Hazardous Substance Data Bank NCI - National Cancer Institute 81 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2.. Physical and Chemical Properties of DCE Property Value Reference Molecular weight Color Physical state Melting point, *C Boiling point, *C Density Odor Odor threshold: Water Air 96.95 Colorless Liquid -122.5 31.7 at 760 mm Hg 1.2129 g/cm3 (20*C) Mild sweet odor resembling that of chloroform 500 ppm S lubility: Water Organic solvents 0.25% by weight in water at 25* C Practically insoluble in water Soluble in organic solvents. Partition coefficients log octanol/water, kov log sediment coefficient, koc Vapor pressure Henry's law constant 2.13 1.81 500 mm Hg at 20* C 591 mm Hg at 25* C 720 mm Hg at 30* C 0.19 atm m3/mol Autoignition Temperature *C Flash point Flammability limits Conversion factors 517.8-555.0 3F (tag open-cup) -2F (tag closed-cup) 7.3%-16% 1 ppm x 3.97 - 1 mg/m3 1 mg/m3 x 0.25 - 1 ppm Merck (1983) Grayson (1985) Merck (1983) Merck (1983) Merck (1983) Merck (1983) Merck (1983) Clayton and Clayton (1981) Clayton and Clayton (1981) Merck (1983) Merck (1983) Mabey et al. 1982 Mabey et al. 1982 Verschueren (1983) Pankow and Rosen (1988) Weiss (1980) EPA 1985a Weiss 1986 SL 064532 82 3. CHEMICAL AND PHYSICAL INFORMATION SL 064533 83 4. PRODUCTION, IMPORT,*USE AND DISPOSAL 4.1 PRODUCTION DCE does not occur naturally (EPA 1985a). It is produced commercially by the dehydrochlorination of 1,1,2-trichloroethane with excess lime or caustic. Two hundred ppm p-hydroxyanisole is added as an inhibitor of the polymerization reaction, which is later removed by distillation or washing (Grayson 1985). Typically, a commercial grade contains 99.8X DCE (EPA 1985a). DCE polymerizes after the addition of an initiator by either an ionic or a free radial reaction. DCE can polymerize spontaneously at room temperature by the addition of peroxides (Grayson 1985). DCE is manufactured in chemical plants located in Texas and Louisiana. Currently, there are two major producers, Dow Chemicals and PPG Industries (Burke 1987, EPA 1977). Production capacity in 1985 was 178 million pounds per year (EPA 1985a). This has been decreased from 1977, when production capacity was estimated at 270 million pounds (EPA 1977). In 1988, plant capacity at PPG (Pittsburgh Paint and Glass) Industries was estimated at 64 million pounds per year (PPG Industries, personal communication, August 1, 1988). Estimated 1989 production is 230 million pounds (CMA 1989). 4.2 IMPORT In 1984, 40,000 pounds of DCE was imported into the U.S. (SRI 1987). No data are available on the export levels. 4.3 USE Monomeric DCE is used as an intermediate for captive organic chemical synthesis, and in the production of polyvinylidene chloride copolymers. These polymers which have been commercially important since their introduction in the early 1940s, are used extensively in many types of flexible packing materials (including barrier, multilayer, and monolayer), as flame retardant coatings for fiber and carpet backing, and in piping, coating for steel pipes, and adhesive applications (EPA 1977). The major application of polyvinylidene chloride copolymers is the production of flexible films for food packaging (SARAN* and VELON* wraps). DCE is found in many food and other packaging materials. Due to the instability of the pure polymer, DCE is used as a copolymer with acrylonitrile (Grayson 1985). In the late 1960's and early 1970's DCE monomer was used as an intermediate in the production of 1,1,1-trichloroethane; however, the compound is not believed to be currently used in that application (SRI 1987). SL 064534 84 4. PRODUCTION, IMPORT, USE AND DISPOSAL 4.4 DISPOSAL As a hazardous waste, DOE is classified as a flammable liquid (Weiss 1986). As such, the EPA (1987a) requires compliance with the regulations of the Resource Conservation and Recovery Act when producing, treating, transporting, storing, or disposing of this substance. Current disposal regulation of DCE requires dissolving it in combustible solvents and scatter spraying the solvent into a furnace with an afterburner and alkaline scrubber. However, significant revision of the criteria for land treatment and burial is occurring presently (HSDB 1988). The waste mother liquor probably contains higher concent: -ions (greater than 200 ppm) of the inhibitor, MEHQ. According to the NPL technical database, DCE has been designated as a chemical of concern at 175 of the 1177 total NPL sites (VIEW 1989). DCE has been detected at 16X of the 2,738 hazardous waste sites that have had samples of all media analyzed by EPA's Contract Laboratory Program statistical database (EPA 1988b). 4.5 ADEQUACY OP THE DATA BASE Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of DCE is available. Where adequate information is not available, ATSDR, ir cooperation with the National Toxicology Program (NTP), is required to assur ie initiation of a program of research designed to determine these health e,, cts (and techniques for developing methods to determine such health effects). The following discussion highlights the availability, or absence, of exposure and toxicity Information applicable to human health assessment. A statement of the relevance of identified data needs is also included. In a separate effort, ATSDR, in collaboration with NTP and EPA, will prioritize data needs across chemicals that have been profiled. 4.5.1 Data Needs Production, use. release, disposal. We are reasonably confident that enough information is available on the production, use, and release of DCE. More information on how much DCE has been disposed of at hazardous waste sites and how much has been abandoned would be useful, though it is unlikely to be obtained. According to the Emergency Planning and Community Right to Know Act of 1986 (EPCRTKA), (313). (Pub.L. 99-499, Title III, 313), industries are required to submit release information to the EPA. The Toxic Release Inventory (TRI), which contains release information for 1987, became available in May of 1989. This database will be updated yearly and should provide a more reliable estimate of industrial production and emission. 064535 SL 85 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW The primary sources of DCE in the environment are related to the synthesis, fabrication, and transport of DCE and its polymer products. Due to the volatile nature of the chemical, releases to the atmosphere are the greatest source of ambient DCE. Smaller amounts of the chemical are released to surface water and soil, primarily as a result of waste disposal. DCE in waste water should partition to the atmosphere as a result of volatilization during treatment processes. Most of the DCE released to the environment partitions to air or water, DCE is rapidly transformed in the troposphere where oxidation by hydroxyl radicals and photolysis are the dominant transformation processes. Biotransformation is believed to be the dominant transformation process for DCE in water, although this process is probably not important in aerobic surface waters due to the volatility of the compound. Biotransformation in soil has not been studied extensively, but methanogenesis has been shown to occur. Biotransformation will be an important process mainly in subsurface soils, since DCE in surface soils will volatilize to th atmosphere. DCE has been detected in air, surface water, groundwater, and soil, with the frequency of detection and the concentrations greatest near source areas (e.g., industrial areas, hazardous wastes sites). 5.2 RELEASES TO THE ENVIRONMENT DCE is a man-made chemical and there is no evidence that natural processes produce this compound except by degradation of synthetic chloroorganics. The primary anthropogenic sources of DCE in the environment are related to the synthesis, fabrication, and transport of DCE and 1,1,1-trichloroethane, which upon dehydrochlorination, yields DCE. 5.2.1 Air Air releases are the largest source of DCE in the environment, and emissions from polymer synthesis and fabrication industries contribute most to overall atmospheric loading. Singh et al. (1981) have estimated that air emissions of DCE from polymer synthesis in the U.S. range between 2-5X of the annual production. EPA (1985a) estimated total annual air emissions of DCE of about 650 tons/year, which was 0.8X of the production volume for that year. Ov r one-half of that total (355 tons) was from the polymer production/fabrication industries. The remaining emissions were from monomer synthesis (223 tons/year; 34X) and monomer storage, handling, and ~ransportation (73 tons/year; 11X). Small amounts of DCE (not quantified) were estimated to be released during the incineration (disposal) of polymer products containing the DCE monomer and 1,1,1-trichloroethane used as a metal cleaning solvent. However, more recent data indicate that both the number of emission point sources and the total amount of DCE released to the atmosphere are much less than EPA's earlier estimates. This decrease is the result of shifts away from the use of the compound by processors and improvements in control technology. For example, survey data submitted by the Chemical SI O64536 86 5. POTENTIAL FOR HUMAN EXPOSURE K Manufacturers Association to EPA indicate that approximately 103.4 tons of DCE per year are released from manufacturing and processing facilities (CMA 1989). Emissions of the compound to the atmosphere in 1987 were estimated to be 836,371 pounds in the SARA Section 313 Toxic Release Inventory (EPA 1989). Hazardous waste sites where DCE has been improperly disposed are additional potential sources of release of the chemical to the atmosphere due to volatilization (see Section 5.4.1). 5.2.2 Veter Industrial releases of DCE to surface water contribute to the overall environmental loading of the chemical, buc to a much lesser extent than atmospheric emissions. Liquid effluent pi luced during polymerization operations are estimated to contribute ar roximately 2 tons of waste DCE each year (Neufeld et al. 1977). Other potential industrial sources of waste DCE in surface water are metal finishing and nonferrous metals manufacturing industries, soap and detergent manufacturers, coil coating and battery manufacturers, coal mines, laundries, and industries involving paint and ink formulation. DCE has been measured in raw wastewater from these industries at mean concentrations of 3-760 ftg/L (EPA 1981). The total quantity of annual releases from these industries has not been estimated. Hazardous waste sites where DCE has been improperly disposed are additional potential sources of the chemical. According to EPA's Contract Laboratory Program (CLP) statistical database (EPA 1988b), DCE has been detected in approximately 2% of the surface water and 10X of the groundwater samples of the 2,783 hazardous waste sites that have had samples analyzed by the CLP. Concentration data for the surface water samples were not reported; however, the geometric mean concentration of the compound in the positive groundwater samples was 1.38 mg DCE/L. In addition, surface water or groundwater contaminated with 1,1,1-trichloroethane can be an additional source of DCE through abiotic dehydrochlorination (McCarty et al. 1986). Total releases of DCE from these sources have not been quantified or estimated. 5.2.3 Soli Limited information is available on the releases of DCE to soil. Neufeld et al. (1977) have estimated that a total of 180 lbs/yr of DCE are disposed of in municipal landfills as residual monomer in some consumer products on a national basis. Hazardous waste sites are additional sources of DCE in soil. DCE has been detected in the soil at an estimated 4.7X of the 2,783 hazardous wastes sites that have had samples analyzed by the CLP; concentration data were not reported (EPA 1988b). SL 064537 87 5. potential for human exposure 5.3 ENVIRONMENTAL FATE The behavior of DCE in the environment is influenced to a large degree by its high volatility. As a result, the majority of DCE released to the environment partitions to the atmosphere. DCE is water soluble (0.25X by weight at 25C), however, and some DCE released to the environment will dissolve and remain in solution, resulting in surface water or groundwater contamination and transport. DCE has a low propensity for binding to organic or particulate matter, and therefore its movement within and between media is not inhibited by adsorption processes. Once released to the environment, transformations of DCE can occur due to the reaction with radical species in the atmosphere and biodegradation in soil or water environments. 5.3.1 Transport and Partitioning The tendency of a chemical to partition between soil, water, sediment, air and biota can be inferred from its physical/chemical properties. Id a global sense, most of the DCE released into the environment will ultimately partition into the atmospheric environment as shown by the vapor partitioning model of Mackay and Paterson (1981). In localized situations, intervening processes such as biotransformation, may alter this outcome and become more important factors to consider. As the magnitude of the Henry's Law Constant for DCE presented in Section 3 indicates, DCE is a highly volatile chemical and is likely to partition readily into the atmosphere from water. Because of this, DCE is generally not persistent in surface water in high concentrations. Studies on chemical removal processes indicate that once in the atmosphere, DCE is unlikely to partition to water (e.g., rain) or to adsorb to atmospheric particulates (Cupitt 1980). DCE spilled onto surface soil will also tend to partition into the atmosphere, while some of the chemical will percolate into the subsurface soil. Once in the subsurface soil, DCE will partition between soil and water. DCE has high water solubility and a small soil organic carbon sorption coefficient (K,,e) value (see Section 3.0), indicating that small amounts of DCE will readily dissolve in water and migrate through soil without significant retardation by adsorption to organic carbon. Similarly, DCE will solubilize and migrate relatively freely within groundwater. DCE in surface water is unlikely to partition significantly into aquatic organisms. Although measured bioconcentration factors were not located in the available literature, partitioning of DCE from water into aquatic organisms can be predicted in part by the magnitude of the octanol/water partition coefficient (K^) value. Veith et al. (1985) have suggested that chemicals with a log less than 4.0 are unlikely to bioaccumulate to hazardous levels in human food chains. The log K^, presented in Section 3 Is 2.13, and based upon this calculation, bioaccumulation in the human food chain is not expected to be significant for this compound. 064538 88 5. POTENTIAL FOR HUMAN EXPOSURE \ 5.3.2 Transformation and Degradation Transformations of DCE can occur due to the reaction with radical species in the atmosphere, photolysis, biodegradation in soil or water environments, and abiotic transformations in water. 5.3.2.1 Air DCE reacts rapidly with hydroxyl radicals. EPA (1983a) investigated the hydroxyl-radical initiated gas-phase oxidation of DCE with oxides of nitrogen. DCE reacted with OH and NO radicals in air to produce chloroacetyl chloride, phosgene, formaldehyde, carbon mon ie and nitri acid. The atmospheric lifetime of DCE, assuming an OH co: ntration of 0s molecules cm*3, is reported as 16.1 hours. This compares favorably with the atmospheric lifetime of 2 days predicted by Cupitt (1980). Photolysis of DCE in the presence of nitrogen oxides is also rapid. Gay et al. (1976) studied the photoreaction of 4.85 ppm DCE in the presence of 2.26 ppm NO* and UV radiation. Under the conditions of the study, 83% of the DCE decomposed within 140 minutes. The identified reaction products were formaldehyde, hydrochloric acid, carbon monoxide, formic acid, ozone, phosgene, chloroacetyl chloride, formyl chloride and nitric acid. Dilling et al. (1976) also found rapid photodecomposition of DCE in the presence of NOx, and artificial lighting conditions. Although this relatively short lifetime indicates that DCE will not accumulate in the troposphere, EPA (1983a) indicated that fairly high concentrations of DCE will be found on urban and regional scales. 5.3.2.2 Hater Biotransformation is believed to be the dominant transformation process for DCE in water. However, the importance of this process under aerobic conditions, such as those normally found in ambient surface water, has not been determined. Conflicting results have been obtained for the aerobic degradation of DCE. Several investigations (McCarty et al. 1986, Bouwer et al. 1981, Pearson and McConnel 1975) have found no evidence for biotransformation of chlorinated ethenes such as DCE under aerobic conditions. In contrast, Tabak et al. (1981) reported transformation of 54% of 5 mg/L and 30X of 10 mg/L test concentrations of DCE under aerobic conditions within one week after incubation with a domestic wastewater seed; these removal figures were adjusted to account for volatilization losses from control flasks of 24Z for the 5 mg/L and 15Z for the 10 mg/L test concentrations. Under anaerobic conditions (such as those that occur in groundwater), the importance of biotransformation is more defined. McCarty et al. (1986) found that DCE was nearly quantitatively reduced to vinyl chloride under anaerobic methanogenic conditions after 108 days. In another study, vinyl chloride was produced from the reductive dechlorination of DCE by microorganisms in anoxic SL 064539 89 5. POTENTIAL FOR HUMAN EXPOSURE microcosms after 1-2 weeks of incubation (Barrio-Lage et al. 1986). Wilson et al. (1986) studied the behavior of DCE in authentic aquifer material known to support methanogenesis. The disappearance of this compound was observed with an initial long lag time, and vinyl chloride, a daughter product of degradation, was found in trace amounts. Vinyl chloride has been classified as a human carcinogen by the EPA (EPA 1985a). ATSDR has made available a Toxicological Profile on this compound. Photolysis and hydrolysis of DCE in natural aquatic media are probably not significant processes (Mabey et al. 1982). Similarly, oxidation is not a significant transformation mechanism for DCE in aqueous environments. Degradation rates due to reactions with singlet oxygen and the peroxy radical have been estimated to be environmentally insignificant in aquatic systems (Mill and Mabey 1980). 5.3.2.3 Soil A methane-utilizing culture isolated from lake sediment was found to degrade DCE to non-chlorinated end products under aerobic conditions (Fogel et al. 1986). These authors found that biodegradation of chlorinated aliphatic compounds carried out by methanotrophs occurred in the order of days, and did not require acclimation as do methanogenic dechlorinations. Information on soil degradation processes under aerobic conditions is lacking. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air The National Ambient Volatile Organic Compound (VOC) Database, updated in 1988 to include ambient and indoor VOC concentrations in urban, rural, remote, source-dominated and indoor environments, reports an ambient daily average concentration for DCE of 4.621 parts per billion (ppb) and an indoor daily average concentration of 19.665 ppb (Shah and Heyerdahl 1988). The ambient average concentration represents contributions from rural, suburban, urban, and source-dominated sites. The median concentration was reported as less than 1 part per trillion (ppt); this concentration was considered by the authors to be more representative of the database than the mean since it does not give undue weight to the higher values found at the source-dominated sites. The indoor average represents input from personal monitoring, and a median value of less than 1 ppt was also reported. The results of an on-site field data collection program based on short term studies conducted in seven U.S. cities indicated that DCE was present in air at an average concentration range of 0.005-0.03 ppb in various U.S. cities (Singh et al. 1981, 1982). DCE has been measured in air in the vicinity of hazardous waste sites as well as a sanitary landfill in New Jersey, with arithmetic mean concentrations ranging from 0.39 to 36.4 ppb measured at waste sites, and an arithmetic mean SL 064540 90 5. POTENTIAL FOR HUMAN EXPOSURE <' concentration of 2.6 ppb measured at the sanitary landfill (LaRegina et al. 1986). Although quantitative information on the air concentrations of DCE at hazardous waste sites on the National Priorities List (NPL) is not available, DCE is probably present in air at those NPL sites where it has been measured in either the soil, surface water or groundwater. 5.4.2 Water DCE concentrations greater than 5 mg/liter have been measured in raw wastewater from the metal finishing and nonferrous metals manufacturing industries (EPA 1981). Lower concentrations (less than 1 mg/L) have been measured in raw wastewater from industries involving paint and ink formulation, soap and detergent manufacturing, coil coating, battery manufacturing, coal mining and laundries (EPA 1981). Treated wastewaters from all these industries ranged from less than 1 to 4 mg/L (EPA 1981). DCE has been detected in surface waters sampled near industrial sites at concentrations ranging from less than 1 to 550 pg/L (Going and Spigarelli 1977). However, no DCE was detected in raw surface water during a 105-city survey of U.S. cities (Coniglio and Miller 1980). DCE has been detected infrequently at low concentrations in urban runoff which will contribute to surface water concentrations. The Nationwide Urban Runoff Program (NURP), initiated to evaluate the significance of priority pollutants in urban st rm water runoff, report a detection frequency of only 3X, with a range of concentrations of 1.5-4 pg/L (Cole et al. 1984). About 3X of the drinking water supplies in the U.S. have been found to contain DCE at 0.2-0.5 pg/L (estimated mean 0.3 pg/L) concentration in a survey conducted by EPA (EPA 1985a). DCE was also detected (quantification limit of 0.2 ppb) in 2.3X of the 945 samples of finished drinking water taken from groundwater sources in a nationwide survey by Westrick et al. (1984). The maximum concentration of DCE detected in the positive samples was 6.3 ppb (subset median values were 0.28-1.2 ppb). DCE has been detected in groundwater samples taken at 9.5X of the 2,793 hazardous waste sites in the U.S. participating in EPA's Contract Laboratory Program. The compound was detected at a geometric mean concentration of 1.38 mg/L (EPA 1988c). 5.4.3 Soil No information is available on ambient concentrations of DCE in soil, although this chemical is often found at hazardous waste sites. Because of the tendency of DCE to partition into the atmosphere, with remaining material to percolate into groundwater sources, ambient concentrations in surface soil are expected to be low. SL 064541 91 5. POTENTIAL FOR HUMAN EXPOSURE 5.4.4 Other Media DCE copolymers are used in the manufacture of films used in food packaging. Residual DCE monomer has been detected at concentrations of less than 0.02-1.26 ppm in retail food packaging films containing polyvinylidene chloride; residues in a variety of foodstuffs wrapped with the films were in the range of less than or equal to 0.005-0.01 ppm (Gilbert et al. 1980). Concentrations of residual DCE in household films were reported by Birkel et al. (1977) to be 6.5-10.4 ppm (average 8.8 ppm). No information on the levels of DCE in humans was located, although the chemical was tentatively identified as occurring in one of 46 samples of human adipose tissue measured as part of the National Human Adipose Tissue Survey (EPA 1986e). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Information on exposure of various populations to DCE is limited to information on potential exposures in workers. The National Occupational Hazard Survey (NOHS), conducted by the National Institute for Occupational Safety and Health (NIOSH), estimated that 56,857 workers in 3,853 plants were potentially exposed to DCE in the workplace in 1970 (NIOSH 1976). These estimates were derived from observation of the actual use of DCE (IX), the use of tradename products known to contain DCE (19X), and the use of generic products suspected of containing the compound (80X). The largest numbers of exposed workers were special trade contractors or in the fabricated metal products industry or wholesale trade industry. The occupational groups with the largest numbers of exposed workers were carpenters, warehousemen (not . otherwise classified) and miscellaneous machine operators. Preliminary data from a second workplace survey, the National Occupational Exposure Survey (NOES), conducted by NIOSH from 1980 to 1983, indicated that 2,679 workers, including 291 women, in 97 plants were potentially exposed to DCE in the workplace in 1980 (NIOSH 1984). The greatest number of exposed workers were chemical technicians. All estimates were derived from observations of the actual use of the compound. Neither the NOHS nor the NOES databases contain information on the frequency, concentration, or duration of exposure of workers to any of the chemicals listed therein. Rather, they only provide estimates of workers potentially exposed to the chemicals. Varying occupational exposure levels can be found in the literature. Ranges of concentrations associated with the monomer and polymer plants have been reported as approximately 23-25 ppb and 6-12 ppb, respectively (Wapora 1982). Exposure concentrations as high as 1,900 ppm have been reported in a copolymer monofilament fiber production plant (Ott et al. 1976). However, in polymer manufacturing plants, worker exposure has been reported as <5 ppm (Ott et al. 1975; Jaeger 1975). SL 064542 92 5. POTENTIAL FOR HUMAN EXPOSURE DCE was found to be produced in significant amounts from the thermal degradation of 1,1,1-trichloroethane (TCA) (Glisson et al. 1986). This implies that inadvertent exposure to DCE may occur in many industrial situations when TCA is used in the vicinity of operations involving heat, such as welding or soldering and metal cleaning, This is of particular concern because TCA has become the solvent of choice in many industries for routine operations such-as degreasing. DCE has also been detected as a pyrolysis product of the pesticide endosulfan in tobacco smoke (Chopra et al. 1978). The Occupational Safety and Health Administration (OSHA) recently reduced the 8-hour time-weighted average permissible exposure level (8-hour TWA PEL) to 1 ppm (OSHA 1989), which should limit future workplace exposures to low levels of this compound. 5.6 POPULATIONS WITH UNUSUALLY HIGH EXPOSURES Human exposure to DCE is potentially highest in workplace settings and among populations residing in the vicinity of hazardous waste sites where the compound may contaminate environmental media. The presence of residual monomeric DCE in polymeric food wraps and other consumer products is another potential source of human exposure. Exposure from these sources is difficult to estimate. However, there is no evidence in the literature to istplicate consumer products as major sources of DCE exposure (EPA 1985a). In addition to releases from hazardous waste sites, ambient air and water may be contaminated with DCE by releases from industrial production and polymerization processes (EPA 1977; EPA 1985a; Wang et al. 1985a, 1985b). Levels are significantly higher in areas surrounding production sites (EPA 1977; EPA 1985a). 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in c nsultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of DCE is available. Where adequate information is not available, ATSDR, in cooperation with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine these health effects (and techniques for developing methods to determine such health effects). The following discussion highlights the availability, or absence, of exposure and toxicity information applicable to human health assessment. A statement of the relevance of identified data needs is also included. In a separate effort, ATSDR, in collaboration with NTP and EPA, will prioritize data needs across chemicals that have been profiled. SL 064543 93 5. POTENTIAL FOR HUMAN EXPOSURE 5.7.1 Data Needs Physical and Chemical Properties. Available data adequately characterize the physical and chemical properties of DCE. Environmental Fate. Data which describe the degradation and transformation processes of DCE in surface water and soil are limited. More information is needed to define these processes and to quantify degradation rates. Such information would be helpful in understanding the fate of nonvolatilized DCE in these media. Exposure Levels in Environmental Media. Data on the concentrations of DCE in surface water, soil, food, and human tissues are limited. More data are needed to provide a more complete characterization of human exposure. Exposure Levels in Humans. Most of the data on exposure levels of DCE are based upon occupational studies conducted under controlled environmental conditions. More current information on the potential exposure resulting from residence in the vicinity of hazardous waste sites would be useful to provide a more accurate characterization of human exposure in the U.S. Exposure Registries. There is no exposure registry for DCE currently available. Such a registry would have to monitor both duration and intensity of exposure. 5.7.2 On-going Studies Long-term research studies on the environmental fate of DCE were not identified. However, remedial investigations and feasibility studies on the 112 NPL sites which are known to have DCE contamination (EPA 1988c) should be completed in the near future and may add to the current knowledge regarding the transport and degradation of DCE in the environment. Environmental monitoring conducted in conjunction with Remedial Investigation/Feasibility Studies at hazardous waste sites on the NPL should add to the current data base on environmental levels of DCE. As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental health Laboratory Sciences Division of the Center for Environmental Health and Injury Control, Centers for Disease Control, will be analyzing human blood samples for DCE and other volatile organic compounds. These data will give an indication of the frequency of occurrence and background levels of these compounds in the general population. SL 064544 94 5. POTENTIAL FOR HUMAN EXPOSURE 1 SL 064545 95 6. ANALYTICAL METHODS The purpose of this chapter is to briefly describe the analytical methods that are available for detecting and/or measuring and to some extent monitoring DCE in environmental media and in biological samples. Our intent here is not to provide an exhaustive list of a variety of analytical methods that would be applicable to detection and quantification. Rather, we intend to identify well-established methods that are used as the standard methods of analysis by various Federal agencies. Many of the analytical methods listed under the heading of analytical methods for DCE in environmental samples are the methods approved by Federal Agencies such as the Environmental Protection Agency (EPA) and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by a trade association such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). A third category of analytical methods emphasizes research and development activities, where efforts are underway to refine previously used methods, to obtain better resolution, and to increase accuracy and precision. The analytical methods used to quantify DCE in biological and environmental samples are summarized below. Table 6-1 lists the applicable analytical methods for determining DCE in biological specimens and Table 6-2 lists the methods used for determining DCE in environmental samples. 6.1 BIOLOGICAL MATERIALS DCE and/or its metabolites are eliminated from the body primarily in the expired air and the urine. Therefore, DCE exposure can be monitored by measuring the levels in expired air and urine. DCE also distributes to liver, kidney, and to a lesser extent, adipose tissue. Methods are available to measure DCE and/or its metabolites in these tissues as well. The GC/MS procedure is the most commonly used method to detect DCE in biological samples. This technique allows the detection of compound at the parts-perbillion (ppb) level. Capillary GC affords the highest resolution of complex mixtures, even when other volatile organic compounds are present that could conceivably mask or interfere with the detection of DCE. Furthermore, specific GC-detectors as well as mass selective detectors enable the quantitation of DCE even when it is not fully separated from other compounds. It is difficult to accurately measure biological concentrations of DCE and correlate these measurements to actual exposure concentrations because of the chemical's short half-life and conversion into metabolites. The concentration of DCE in biological media is continually changing by virtue of its rapid release into the air or biotransformation into other compounds. Also, detection of DCE is more difficult in biological media because it is a low molecular weight volatile compound in a matrix of very large organic molecules. SL 064546 96 6. ANALYTICAL METHODS TABLE 6-1. Analytical Mathoda for DCE In Biological Semplaa Sample Matrix Semple Praparation Analytical Method* Sample Dataetioa Limit Accuracy Rafarancaa Hunan tiaaua (adipoaa, kidnay, liver, and brain) Braatb Flab tiaaua Mince tiaaua, add laooctana/water; extract, purge and trap Thermal deaorptioo 9C/ECD OC/MB Hoeogenlaa, add liquid Hj 6* prevent evapor ation of volatilaa. vaoutM dietillation Purse aid trap method to rolaaaa volatile cempounda trapped in tha fiah tiaaua GC/MB uaing a fuaed-ailica capillary colm OC/MB Approximately SOpf l e8/m3 Hot available io ps/k* *301 recovery *0-601 recovery Hot available 70X recovery Lin at al. 1982 Wallace at el 1984; Pelliaari at al. 1983 Hiatt 1983 Eaaley at al. 1981 *GC taa chromatography; MB aui apactraetry; BCD alactron capture datactor. SL 064547 97 6. ANALYTICAL METHODS Sampla Matrix Air TABLE 6-2. Analytical Methods for DCE in Enviroomental Sasqslas Sample Preparation Analytical* Method Sampla Detection Limit Accuracy^ (tfg/L) Adaorb (char coal) ; daaorb carbon diaulfida Solid aorbant collection GC/FID GC/FID 1 mg/m3 831 recovery 7 ug/iampla >802 References HIOSH 1884 (method 1013); Taylor 1878; Foerat 1878 Foerst 1878 Watar Ravaraible adsorption Purge-and-trap method Purge-and-trap nathod GC/tC GC/HECD GC/MS Hot available 0.13 pg/L 2.8 pg/L Hot available 0.B8C-0.87 1.12C+0.61 Coutant 1884 EFA 1884a (method 601) EPA 18840 (method 824) Groundwater Solidt/sludges/ aoila/aadimanta / waiter Isotope dilution Purge-end trap nathod Purge-and-trap method Furga-and trap method GC/MS GC/HECD GC/MS GC/MS Soil/chaoiical waata Food (potato criapa, cakaa, snack producta, biscuits) Packaging films Haxana extraction; taoiparatura programed QC determination Crush or grind and heat food tables Beat bypovials containing film aa 120*C; col lect headspace vapor GC/MS GC/ECS GC/ECD 10 ng/L Rot available 0.13 g/L 3 tfg/L 0.88C-0.87 1.12C+0.61 Soil, sediment 3 ag/L (w) wattes 0.3 mg/kg (ww) 10 ppm 1.12C+0.81 ao-floi recovery EPA 1884c (method 624) EPA 1886a (method 8010) EPA 1986b (method 8240) EPA 1886b (method 6240) DeLeon et al. 1880 <0.003 ppm Hot available Gilbert et al. 1880 0.0* pps Hot available Gilbert et al. 1860; Crosby 1882 *GC " 9u chromatography; FID - flam* ionization dataetlon; MS mass apactrcmatry; ECD " aiactron captura dataction. bZxpresaad a raeovary aa a function of 0*true value for the concentration. SL 064548 98 6. ANALYTICAL METHODS ** Environmental exposure to DCE at hazardous waste sites may include exposure to other chlorinated hydrocarbons as well. DCE exposure can be monitored by direct measurement of the parent compound or its metabolites. It is difficult to distinguish metabolites of DCE in the body because the same metabolites may be formed as a result of exposure to other chlorinated hydrocarbons. Determination of DCE in breath samples by GC/MS method is the most commonly used method of monitoring exposure to DCE (Pellizzari et al. 1985). Various other techniques are be' - studied and developed to monitor DCE in expired air using reversible ac rtion (Contant et al. 1984) and impregnated t-~e methods f continue s mor ring (Denenberg and Miller 1974). The r. surement of Z adducts with ... >A in lymphocytes or hemoglobin may also be u ful in moni^jring exposure to DCE. Such a method has been established in hemoglobin for another volatile organic compound, ethylene oxide (Tornqvist et al. 1986). Because human hemoglobin has a half-life of about 60 days (although half-lives of hemoglobin adducts are somewhat reduced), monitoring of DCE adducts with hemoglobin can be a valuable tool for estimating the daily and weekly exposure. 6.2 ENVIRONMENTAL SAMPLES The analytical methods required by EPA (1984a,b,c) for the analysis of DCE in water and wastewater are delineated in procedures 601 (GC/ECD), 624 (GC/MS), and 1624 (GC/MS). These are testing procedures required under the Clean Water Act for sites discharging municipal and industrial wastewater. The method required by the EPA Contract Laboratory Program (CLP) for analysis of DCE and other volatile organic compounds is hexadecane extraction, followed by determination of approximate concentration using gas chromatography and flame ionization detection (GC/FID) and final quantitative analysis using GC/MS (EPA 1986a, 1986b). GC/FID is used to detect DCE in air samples; the GC/MS procedure is used to determine DCE in water, wastewater discharges, and soil samples. Gilbert et al. (1980) detected DCE in food at levels less than 5 ppm using head space GC/ECD. These food products were packaged in PVC films. 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of DCE is available. Where adequate information is not available, ATSDR, in cooperation with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine these health effects (and techniques for developing methods to determine such health effects). The following discussion highlights the availability, or absence, of exposure and toxicity information applicable to human health assessment. A statement of the relevance of identified data needs is also included. In a SL 064549 99 6. ANALYTICAL METHODS separate effort, ATSDR, in collaboration with NTP and EPA, will prioritize data needs across chemicals that have been profiled. 6.3.1 Data Needs Methods for Determining Parent Compounds and Metabolites in Biological Fluids. There are few analytical methods used to determine DCE in biological samples. The current emphasis is on (a) measuring the compound of interest at the parts-per-billion level accurately and consistently, (b) refining sample preparation techniques, and (c) modifying the GC/MS procedure to obtain better resolution. An analytical methodology to distinguish exposure to DCE from compounds with similar metabolic profiles is not available. Accuracy, precision, and recovery data are also lacking since the existing effort concentrates on the extension of detection limits of DCE rather than meeting quality control objectives necessary for analytical method standardization. Methods for Biomarkers of Exposure. None of the available studies allow a quantitative correlation between monitored levels in tissues or fluids to exposure levels or toxic effects in humans. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. There are media-specific standardized methods available for detecting DCE in environmental samples. Accuracy data and sample detection limit data are available for the EPA-approved methods; however, this information is incomplete for other analytical methods. This may be due to the lack of adequate data to determine method accuracy, precision, or recovery values. There is a growing need for achieving lower detection limits. Kirshen (1984) reported that better resolution and sensitivity are achievable with the application of the proper GC capillary column and selection of the correct detector or detector combination. 6.3.2 On-going Studies No on-going studies concerning techniques for measuring and determining DCE levels in biological samples were identified. However, the Division of Environmental Health Laboratory Services of the Center for Environmental Health and Injury Control of the Centers for Disease Control in Atlanta, Georgia is developing methods for the analysis of DCE and other volatile organic compounds in blood. These methods use purge and trap methodology and magnetic mass spectrometry which gives detection limits in the low parts per trillion range. No on-going studies concerning techniques for measuring and determining DCE in environmental samples were identified. SL 064550 100 6. ANALYTICAL METHODS ** SL oe^1 *. 101 7. REGULATIONS AND ADVISORIES DCE is on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" (EPA 1987c). The international, national, and state regulations and guidelines pertaining to DCE in air, water, and food are summarized in Table 7-1. SL 064552 Agency WHO OSHA EFA COW ETA (MS 102 7. REGULATIONS AND ADVISORIES TABLE 7*1. Regulations and Guidelines Applicable to DCE Description Value References International Guideline for Drinking Hater 0.3 sg/L National WBO 1884 Proposed Medical Records Rule Unit for Air Contaeiinents Merisel Contaminant Level (MCL) in Drinking Hater General permits under the National Discharge Elimination SystM (NPCE3) Criteria ad Standarda for the NTDES General Pretreatment Regulations for Existing and Nee Sources of Pollution Hasteeater; Effluent Guidelines for Point Source Categories HA* 1 ppm 0.007 ng/L HA OSHA 1882 OSHA 1888 EPA 1883 (40 CFR 141) EPA 1883b (40 CFR 122.28) HA EPA 1878 (40 CFR 123) KA EPA lBSBd (40 CFR 403) EPA 1887b (40 CFR 414) Rayon fibers, other fibers, thermoplastic rosins, thermo setting resins, ceoadlty organic chadcals, bulk organic chemicals, specialty organic chadoala: sarlaa for one day s(aa for iwnthly average Direct discharge point sources that use end-of-pipe biological treatment (effluent limitations **BAI end NSF8): maxima for one day naTlaa for monthly average Diraet discharge point aourcaa that do not use end-of-pipe biological treatment (BAT sfflusnt limitationa and HSF3): aaxisaa for ona day maxima for monthly sveraga 80 sg/L 22 sg/L 23 sg/L 18 sg/L 60 Sg/L 22 sg/L Qbl SV Agency FDA EPA OERR EPA OSH EPA OTS flui del Ihm HIOSH acsh EPA OOH HAS 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Description Value Fropoaad uaaa of vinyl chlorlda polpaara: delation of vinyl ehlorida-DCI copolyaMC* from the list of aateriale that nay ha uaad on frulta Reportable quantity Reportable quantity (proposed) Designation of basardoua aubatancaa Listing aa toxic wastes: discarded cooBarclal chemical products, offipeclfieatimi species, container residues, and spill residues of DCS Listing as a hasardous waste constituent (Appendix Till) Toxic Cheaical Release Reporting (proposed) HA 3000 lh ioo lb HA HA HA IA Refersnces FDA 1886 EPA 1083c (40 CFR 302. EPA 1867b EPA 1083b EPA 1880a (40 CFR 281.33 (f>) EPA 1086o (40 CFR 281) EPA 1887c RecinuiauJsd Exposure Liait Riom 1078 TWA 1 ng/n3 Threshold Llalt Talua (TIT) ACGIB 1886 THA ST& S pjn 20og/a3 20 ppa * 80 at/a3 Maxlaw Confinant Laval Goal (MELS) 0.007 at/L EPA 1083c (10 CPU 141) Haalth Advisories 1 dap 10 dap 2.0 ng/L 1.0 a/L EPA 1087a Longer Tara Adult Child 3.3 as/L 1.0 ng/L Lifeline 0.007 ag/L Suggested Ro-Adverae-Effect Laval (SKARL) Chronic 100 as/L HAS 1083 SL 064554 104 7. REGULATIONS AND ADVISORIES TABLE 7*1 (Continued) Aganc7 EFA OWNS IAXC EPA DateriptIon Ambient Watar Quality Crltarla to Protact Hunan Health Infeatina watar and Oriaslaaa Inaeatin* aquatic orsanlaaw only Carcinoaenie claaeification Reference doae (RfD) (oral) q^* (oral) q^ (Inhalation) Carcinoaenie claaaification Value Reference*** EFA 1980 0.033 m/L; 0.33 m/L, 3.3 m/L for 10'. 10'5, 10'*, riak level*, raapoctlvaly 1.83 m/L; 18.5 m/L, 183 m/L for IQ'8, 10's, 10'* riak lavola, reapectively Group 3 IARC 1982 axlO"3 M/ka/day EFA 1988a 0.8 (M/ka/day) 3 EPA 1988a 1.2 (M/ka/day) 1 EFA 1988a Group C EFA 1988a Stata environmental **enciee California Halna Miuneeota Haw Jeraey Raw Mexico Vermont Stata environmental atanelaa Connecticut Illlnoia Indiana Kanaaa Maaaachuaatta North Carolina Havada Naw York Faimayivania Virslnla Stata Rafulatiana and Ouidalinaa Drlnklna watar quality atandarda and auidallnea for eeveral atataa FSIRAC 1988 Acceptabla aabiant conoantratloo auidallnea or Standarda 8 m/4 7 M/4 7 m/l 2 m/l 3 m/L 7 m/L KAIICH 1987 20 m/w3 (8 hour avf.) 0 200 M/n3 (8 hour *v*-) 0.238 M/n3 (Annual avj-) 0,2000 at/mr (24 boor *vg.) 8000 M/n3 (13 nln. ovr.) 0.1760 */n3 (8 hour avf.) 66.7 M/n3 (1 yr- *v.) 2* m/3 (1 yr. *vr.) 3.S M/n3 (2A hour *v.) *NA " Not applicable. **BAS " Boat available technology. NSPS - Now aource peronnanee atandarda. 064555 SL 105 8. REFERENCES ACGIH. 1986. Documentation of the threshold limit values and biological exposures indices. 5th ed, American Conference of Governmental Industrial Hygienists. Adeniji SA, Kerr JA, Williams MR. 1981. Rate constants for ozone-alkene reactions under atmospheric conditions. Intern J Chem Kinetics 13:209-217. Andersen ME, Jenkins J. 1977. Oral toxicity of 1,1-dichloroethylene in the rat: Effects of sex, age, and fasting. Environ Health Perspect 21:157-163. Andersen ME, Jones RA, Jenkins LJ. 1978. The acute toxicity of single, oral doses of 1,1-dichloroethylene in the fasted male rat: Effect of induction and inhibition of microsomal enzyme activities on mortality. Toxicol Appl Pharmacol 46:227-234. Andersen ME, Thomas OE, Gargas ML, et al. 1980. The significance of multiple detoxification pathways for reactive metabolites in the toxicity of 1,1,-dichloroethylene. Toxicol Appl Pharmacol 52:422-432. Anderson D, Hodge MCE, Purchase IFH. 1977. Dominant lethal studies with the halogenated olefins vinyl chloride and vinylidene dichloride in male CD-I mice. Environ Health Perdpect 21:71-78. Anon. 1968. Gas chromatographic determination of impurities in vinyl chloride. J Chromatog 34:394-398. Apfeldorf R, Infante PF. 1981. Review of epidemiologic study results of vinyl chloride-related compounds. Environ Health Perspect 41:221-226. Balmer MF, Rampy LW, Quast JF. 1976. 90-Day repeated inhalation toxicity study of vinylidene chloride in rats. Unpublished study. Toxicology Research Laboratory, Health and Environmental Research, Dow Chemical U.S.A., Midland, MI. Barnes D, Beilin J, DeRosa C, et al. 1987. Reference dose (RfD): description and use in health risk assessments. Volume I, Appendix A: Integrated risk information system supportive documentation. Washington, D.C: U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. EPA/600/8-86/032a Barrio-Lage G, Parsons FZ, Nassar RS, et al. 1986. Sequential dehalogenation of chlorinated ethenes. Environ Sci Technol 20:96-99. Cited in text SLl 064556 106 8. REFERENCES Barrio-Lage G, Parsons F2, Nassar RS, et al. 1987. Biotransformation of trichloroethene in a variety of subsurface materials. Environ Technol Chem 6:571-578. Bartsch H, Malaveille C, Barbin A, et al. 1979. Mutagenic and alkylating metabolites of halo-ethylenes, chlorobutadienes and dichlorobutenes produced by rodent and human liver tissues. Arch Toxicol 41:249-277. Bartsch H, Malaveille C, Montesano R, et al. 1975. Tissue-mediated mutagenicity of vinylldene chloride and 2-chlorobutadiene in Salmonella tvphimurluin. Nature 255:641-643. *Birkel TJ Roach JAG, Sphon JA. 1977. Determination of vinylidene chloride in Saran i_-ms by electron capture gas-solid chromatography and confirmation by mass spectrometry. J Assoc Official Anal Chemists 60(5):1210-1213. Bouwer EJ, Rittman BE, McCarthy PL. 1981. Anaerobic degradation of halogenated 1- and 2-carbon organic compounds. Environ Sci Technol 15:596-599. Bronzetti G, Bauer C, Corsi C, et al. 1981. Genetic activity of vinylidene chloride in yeast. Mutat Res 89:179-185. Brown HS, Bishop DR, Rowan CA. 1984. The role of skin absorption as a route of exposure for volatile organic compounds (VOCs) in drinking water. Am J Public Health 74:479-484, Burke DP. 1987. Chemical Week's Buyers' Guide, 1988. McGraw-Hill Publishing Co, Washington, DC, 529. Busch JT. 1985. Final report on the safety assessment of p-hydroxyanisole. J Amer Coll Toxicol 4(5):31-63. Carlson GP, Fuller GC. 1972. Interaction of modifiers of hepatic microsomal drug metabolism and inhalation toxicity of 1,1-dichloroethylene. Res Comrnun Chem Pathol Pharmacol 4(3):553-560. Carpenter CP, Smith HPJ, Pozzani UC. 1949. The assay of acute vapour toxicity, and the grading and interpretation of results on 96 chemical compounds. J Ind Hyg Toxicol 31:343-346, Chieco P, Moslen MT, Reynolds ES. 1981. Effect of adminstrative vehicle on oral 1,1-dichloroethylene toxicity. Tox Appl Pharmacol 57:146-155. Chieco P, Moslen MT, Reynolds ES. 1982. Histochemical evidence that plasma and mitochrondrial membranes are primary foci of hepatocellular injury caused by 1,1-dichloroethylene. Lab Invest 46(4):413-421. 4 SL 064557 V 107 8. REFERENCES *Chopra NM, Campbell BS, Hurley JC. 1978. Systematic studies on the breakdown of endosulfan in tobacco smokes: Isolation and identification of the degradation products from the pyrolysis of endosulfan I in a nitrogen atmosphere. J Agric Food Chem 26(1):255-258. Clark RM, Goodrich JA, Deininger RA. 1986. Drinking water and cancer mortality. Sci Total Environ 53:153-172. Clayton GD, Clayton PB, eds. 1981. Patty's industrial hygiene and toxicology. Vol. 2B, 3 ed. New York: John Wiley & Sons, 3545-3550. *CMA 1989. Chemical Manufacturers Association. Written communication. Public comment on Toxicological Profile for 1,1-Dichloroethene. Washington, DC: (May 12). *Cole RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the priority pollutant monitoring project of the nationwide urban runoff program. J Water Poll Control Fed 56:898-908. *Coniglio WA, Miller KMD. 1980. The occurrence of volatile organics in drinking water. *Conkle JP, Camp BJ, Welch BE. 1975. Trace composition of human respiratory gas. Arch Environ Health 30:290-295. Contant RW, Lewis RG, Mulik JD. 1984. Passive sampling device with reversible adsorption mechanics of sampling. In: Proc Natl Symposium on Recent Advances in Pollutant Monitoring' of Ambient Air and Stationary Sources. PB85-144053., 67-73. Cotruvo JA. 1985. Organic micropollutants in drinking water: an overview. Sci Total Environ 47:7-26. *Crosby NT. 1982. Headspace Analysis. Anal Proc 19:428-430. *Cupitt LT. 1980. Fate of toxic and hazardous materials in the air environment. Environmental Sciences Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park NC. *Dallas CE, Weir FW, Feldman S, et al. 1983. The uptake and disposition of 1,1-dichloroethylene in rats during inhalation exposure. Toxicol Appl Pharmacol 68:140-151.* *DeLeon IR, Maberry MA, Overton EB, et al. 1980. Rapid gas chromatographic method for the determination of volatile and semivolatile organochlorine compounds in soil and chemical waste disposal site samples, J Chromatogr Sci 18:85-88. SL 064558 108 8. REFERENCES *Denenberg BA, Miller RW. 1974. A continuous monitor for vinyl chloride monomers based upon an impregnated paper tape. Technical papers, regional technical conference. Society of Plastics Engineers, Palisades Section., 146-162. *Dilling WL, Bredeweg CJ, Tefertiller NB. 1976. Organic photochemistry: simulated atmospheric photodecomposition rates of methylene chloride, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene, and other compounds. Environ Sci Technol 10:351-356. Dilling WL, Tefertiller NB, Kallos GJ. 1975. Evaporation rates and reactivities of methylene chloride, chloroform, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene, and other chlorinated compounds in dilute aqueous solutions. Environ Sci Technol 9:833-837. *Drevon C, Kuroki T. 1979. Mutagenicity of vinyl chloride, vinylidene chloride and chloroprene in V79 Chinese hamster cells. Mutat Res 67:173-182. *D'Souza RW, Andersen ME. 1988. Physiologically based pharmacokinetic model for vinylidene chloride. Toxicol Appl Pharmacol 95:230-240, Dyksen JE, Hess AF. 1982. Alternatives for controlling organics in groundwater supplies. J Am Water Works Assoc 74:394-403. Easely DM, Kleopfer RD, Carasea AM. 1981. Gas chromatographic-mass spectrometric determination of volatile organic compounds in fish. J Assoc . Off Anal Chem 64(3):653-656. Edney EO, Kleindienst TE, Corse 'EW. 1986. Room temperature rate constants for the reaction of OH with selected chlorinated and oxygenated hydrocarbons. Intern J Chem Kinetics 18:1355-1371. *EPA. 1975. National Interim Primary Drinking Water Regulations. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 141. Federal Register 40(December 24, 1975):59570. EPA. 1977. Market Input/Output Studies Task 1. Vinylidene Chloride. Washington, DC: Office of Toxic Substances, US Environmental Protection Agency. PB-273-205, EPA. 1979. Criteria and Standards for the National Pollutant Discharge Elimination System. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 125. Federal Register 44(June 7, 1979):32948-32956.* *EPA. 1980a. Identification and Listing of Hazardous Waste. Discarded commercial chemical products, off-specification species, container residues, and spill residues thereof. US Environmetal Protection Agency. Code of Federal Regulations. 40 CFR 261.33(f). Federal Register 45(November 25, 1980):78543. SL 064559 * 4 109 8. REFERENCES EPA. 1980b. Water quality criteria documents: Availability. US Environmental Protection Agency. Federal Register 45:79318-79379. *EPA. 1980c. Guidelines and methodology used in the preparation of health effect assessment chapters of the consent decree water criteria documents. US Environmental Protection Agency. Federal Register 45:79347-79357 EPA. 1981. Treatability Manual. Treatability data. Washington, DC: of Research and Development, US Environmental Protection Agency. 600/2-82-001a. Office *EPA. 1983a, Atmospheric chemistry of several toxic compounds. Research Triangle Park, NC: US Environmental Protection Agency, Office of Research and Development. EPA-600/S3-82-092. *EPA. 1983b. Administered Permit Programs: The National Pollutant Discharge Elimination System: General Permits. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 122.28. Federal Register 48(April 1, 1983):14153-14178. EPA. 1984a. Method 601 guidelines establishing test procedures for the analysis of pollutants under the Clean Water Act (40 CFR 136) purgeable Halocarbons. US Environmental Protection Agency. Federal Register 49:43261-43271. *EPA. 1984b. Method 608 guidelines establishing test procedures for the analysis of pollutants under the Clean Water Act (40 CFR 136) purgeables. US Environmental Protection Agency. Federal Register 49:43373-43383. *EPA. 1984c. Method 1624, revision B guidelines establishing test procedures for the analysis of pollutants under the Clean Water Act (40 CFR 136) volatil organic compounds by isotope dilution GC/MS. US Environmental Protection Agency. Federal Register 49:43407-43415. *EPA. 1985a. Health assessment documents for vinylidene chloride; final report. Washington, DC: US Environmental Protection Agency, Office of Health and Environmental Assessment. EPA/600/8-83-031F. EPA. 1985b. National Primary Drinking Water Regulations; volatile synthetic organic chemicals; Final Rule and Proposed Rule. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 141 & 142. Federal Register 50:46900. *EPA. 1985c. Designation, Reportable Quantities, and Notification. Designation of Hazardous Substances. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 302.4. Federal Register 50(April 4, 1985):13488.* *EPA. 1986a. Method 8010 test methods for evaluating solid wastes. SL 064560 110 8. REFERENCES Laboratory Manual Physical/Chemical Methods. Washington, DC: US Environmental Protection Agency, Office of Solid Waste and Emergency Response. SW-846. *EPA. 1986b. Method 8240 test methods for evaluating solid wastes. Laboratory Manual Physical/Chemical Methods. Washington, DC: US Environmental Protection Agency, Office of Solid Waste and Emergency Response. SW-846. EPA. 1986c. Appendix VIII. Hazardous Waste Managment System: Identification and Listing of Hazardous Waste: Hazardous Constit* nts. US Environmental Protection Agency. Code of Federal Regu 'ions. J CFR 261. Federal Register 51(August 6, 1986):28308. *EPA. 1986d. General Pretreatment Regulations for Existing and New Sources. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 403. Federal Register 51(June 4, 1986):20429. *EPA. 1986e. National Human Adipose Tissue Survey. National Human Monitoring Program. US Environmental Protection Agency., 122. *EPA. 1986f. Guidelines for carcinogen risk assessment. US Environmental Pr tection Agency. Federal Register 51(185):33992-34003. EPA. 1987a. Health advisory for 1,1-dichloroethylene. Washington, DC: US Environmental Protection Agency, Office of Drinking Water. *EPA. 1987b. Organic Chemicals and Plastics and Synthetic Fibers Category Effluent Limitations Guidelines Pretreatment Standards, and New Source Performance Standards. US Environmental Protection Agency. Code of Federal Regulations. 40 CFR 414. Federal Register 52(November 5, 1987):42571-42582. *EPA. 1987c. Toxic chemical release reporting: Community right-to-know. US Environmental Protection Agency. Federal Register 52:21152-21208. EPA. 1987d. Reportable quantity adjustments. US Environmental Protection Agency. Federal Register 52:8140-8171. *EPA. 1988a. Integrated Risk Information System (IRIS) (database). Cincinnati, Ohio: US Environmental Protection Agency, Environmental Criteria and Assessment Office. EPA. 1988b. Contract Laboratory Program Statistical Database. Contract Laboratory Program, US Environmental Protection Agency. EPA. 1988c. National Priorities Listing Technical Database. National Priorities Listing. US Environmental Protection Agency. * SL 064561 ** Ill 8. REFERENCES *EPA. 1989. Toxic Release Inventory [database]. Available from the National Library of Medicine, TOXNET system. *FDA, 1986. Proposed uses of vinyl chloride polymers. US Food and Drug Administration. Federal Register 51:4177-4188. *FIelder RJ, Dale EA, Williams SD. 1985. Toxicity Review 13. Vinylidene Chloride. Her Majesty's Stationary Office. London, England. Fishbein L. 1979. Potential halogenated industrial carcinogenic and mutagenic chemicals: I. Halogenated unsaturated hydrocarbons. Sci Total Environ 11:111-161. *Foerst D. 1979. A sampling and anlytical.method for vinylidene chloride in air. Am Ind Hyd Assoc J 40:888-893. *Fogel MM, Taddeo AR, Fogel S. 1986. Biodegradation of chlorinated ethenes by a methane-utilizing mixed culture. Appl Environ Microbiol 51:720-724. Forkert PG, Forkert L, Farooqui M, et al. 1985. Lung injury and repair: DNA synthesis following 1,1-dichloroethylene. Toxicology 36:199-214. Forkert PG, Hofley M, Racz WJ. 1977. Metabolic activation of 1,1,-dichloroethylene by mouse lung and liver chromosomes. Can J Physiol Pharmacol 65(7):1496-1499. Forkert PG, Stringer V, Troughton KM. 1986. Pulmonary toxicity of 1,1-dichloroethylene: correlation of early changes with covalent binding. Can J Physiol Pharmacol 64:112-121. FSTRAC. 1988. Summary of State and Federal drinking water standards and guidelines. Federal-State Toxicology and Regulatory Alliance Committee. Gage JC. 1970. The subacute inhalation toxicity of 109 industrial chemicals. Br J Ind Med 27:1-18. Gay BWJ, Hanst PL, Bufalini JJ, et al. 1976. Atmospheric oxidation of chlorinated ethylenes. Environ Sci Technol 10:58-66. Gilbert J, Shepherd MJ, Startin JR, et al. 1980, Gas chromatographic determination of vinylidene chloride monomer in packaging films and in foods. J Chromatogr 197:71-78. Glisson BT, Craft BF, Nelson JH, et al. 1986. Production of vinylidene chloride from the thermal decomposition of methyl chloroform. Am Ind Assoc J 47:427-435. SL 064562 8. REFERENCES Going JE, Spigarelli JL. 1977. Environmental monitoring near industrial sites: vinylidene chloride. Washington, D.C: US Environmental Protection Agency, Office of Toxic Substances. EPA 560/6-77-026. Grayson M ed. 1983. Kirk-Othmer Concise Encyclopedia of Chemical Technology. Vol. 23, 3rd ed. New York: John Wiley & Sons, 764-94. Grayson M ed. 1985. Kirk-Othmer Concise Encyclopedia of Chemical Technology. New York: John Wiley & Sons, 1223-4. *Greim H, Bonse G, Radwan Z, et al. 1975. Mutagenic! / in vitro and potential carcinogenicity of chlorinated ethylenes as function of metabolic oxirane formation. Biochem Pharmacol 24:2013-2017. Grimsrud EP, Rasmussen RA. 1975. Survey and analysis of halocarbons in the atmosphere by gas chromatography- mass spectrometry. Atmos Environ 9:1014-1017. Hall LW, Hall WS, Bushong SJ, et al. 1987. In situ striped bass (Morone saxatilis) contaminant and water quality studies in the Potomac River. Aquatic Tox 10:73-99. Hannah SA, Austem BM, Eralp AE, et al. 1986. Comparative removal of toxic pollutants by six wastewater treatment processes. J WPCF 58:27-34. Harris RN, Anders MW. 1980. The effect of 2-propanol (PR) and phenobarbital (PB) treatment on the hepatotoxicity and lethality of carbon tetrachloride (CC14) and 1,1-dichloroethylene (VDC). Pharmacologist 22:223 (Abstract). *Henck JW, Quast JF, Rampy LW. 1979. A comparison of four mouse strains exposed to subchronically inhaled vinylidene chloride (VDC). Unpublished study. Toxicology Research Laboratory, Health and Environmental Science, Dow Chemical U.S.A., Midland, MI. Henschler D. 1979. [Vinylidene chloride. Hazardous substances compiled by Establishment of MAK values and fixing of limit values for dusts working groups]. In: Commission for the testing of hazardous substances of the Deutsche Forschungsgemeinschaft. Verlag Chemie GmbH 3 U-Z:l-19. (German; as cited in Fielder et al. 1985). Henschler D, Broser F, Hopf HC. 1970. Polyneuritis cranialis following poisoning with chlorinated acetylene while handling vinylidene chloride copolymers. Arch Toxicol 26:62-75. Hewitt WR, Plaa GL. 1983. Dose dependent modification of 1,1-dichloroethylene toxicity by acetone. Toxicol Lett 16:145-152. 113 8. REFERENCES *Hiatt MH. 1983. Determination of volatile organic compounds in fish samples by vacuum distillation and fused silica capillary gas chromatography/mass spectrometry. Anal Chem 55:506-515. Hoar SK, Santodonato J, Cameron TP, et al, 1985. Monographs on human exposures to chemicals in the workplace. J Occup Med 27:585-588. Hong CB, Winston JM, Thornburg LP, et al. 1981. Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice: tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health 7:909-924. HSDB. 1988. Hazardous Substance DataBank. National Library of Medicine, Toxicology Information Program, Bethesda, MD. July 1988. IARC. 1982. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans; chemicals, industrial processes and industries associated with cancer. International Agency for Research on Cancer l-29(suppl 4):262-264. IARC. 1986. IARC monographs on the evaluation of the carcinogenic risk of ch mical to humans: Chemicals, industrial processes and industries associated with cancer. International Agency for Research on Cancer 39:195-215. Irish DD. 1963. Aliphatic halogenated hydrocarbons. Vinylidene chloride. In: Patty A ed. Patty's Industrial Hygiene and Toxicology. Vol. II, 2 ed. New York, NY 1305-1307. *ITII. 1982. Toxic and hazardous industrial chemicals safety manual. Tokyo, Japan: International Technical Information Institute, 555 IS. Iwan GR. 1987. Drinking water quality concerns of New York City, past and present. Annals NY Acad Sci 502:183-204. Jackson NM, Conolly RB. 1985. Acute nephroxicity of 1,1-dichloroethylene in the rat after inhalation exposure. Toxicol Lett 29:191-199. Jaeger RJ. 1975. Vinyl chloride monomer: comments on its hepatotoxicity and interaction with 1,1-dichloroethylene. Ann NY Acad Sci 246:150-151. Jaeger RJ. 1977. Effect of 1,1-dichloroethylene exposure on hepatic mitochondria. Res Commun Chem Pathol Pharmacol 18(l):83-94. Jaeger RJ, Conolly RB, Murphy SD. 1973a. Diurnal variation of hepatic glutathione concentration and its correlation with 1,1-dichloroethylene inhalation toxicity in rats. Res Commun Chem Pathol Pharmacol 6:465-471. SI 64564 114 8. REFERENCES f Jaeger RJ, Trabulus MJ, Murphy SD. 1973b. Biochemical effects of 1,1-dichloroethylene in rats: dissociation of its hepatoxicity from a lipoperoxidative mechanism. Toxicol Appl Pharmacol 24:457-467. *Jaeger RJ, Trabulus MJ, Murphy SD. 1973c. The interaction of adrenalectomy, partial adrenal replacement therapy, and starvation with hepatotoxicity and lethality after 1,1-dichloroethylene intoxication. Toxicol Appl Pharmacol 25:491 (Abstract 133). Jaeger RJ, Conolly RB, Murphy SD. 1974. Effect of 18-hour fast and glutathione depletion on 1,1-dichloroethylene- induced hepatotoxicity and lethality in rats. Exper Mol Pathol 20:187-198. *Jaeger RJ, Conolly RB, Reynolds ES, et al. 1975a. Biochemical toxicology of unsaturated halogenated monomers. Environ Health Perspect 11:121-128. Jaeger RJ, Conolly RB, Murphy SD. 1975b. Short term inhalation toxicity of halogenated hydrocarbons effects on fasting rats. Arch Environ Health - 30:26-31. Jaeger RJ, Shoner LG, Coffman U. 1977a. 1,1-Dichloroethylene hepatotoxicity: Proposed mechanism of action and distribution and binding of [UC] radioactivity following inhalation exposure in rats. Environ Health Perspect 21:113-119. Jaeger RJ, Szabo S, Coffman U. 1977b. 1,1-Dichloroethylene hepatotoxicity. Effect of altered thyroid function and evidence for the subcellular site of injury. J Toxicol Environ Health 3:545-555. Jafvert CT, Wolfe NL. 1987. Degradation of selected halogenated ethanes in anoxic sediment-water systems. Environ Toxicol Chem 6:827-837. Jenkins J, Trabulus MJ, Murphy SD. 1972. Biochemical effects of 1.1-dichloroethylene in rats: comparison with carbon tetrachloride and 1.2-dichloroethylene. Toxicol Appl Pharmacol 23:501-510. Jenkins U, Andersen ME. 1978. 1,1-Dichloroethylene nephrotoxicity in the rat. Toxicol Appl Pharmacol 46:131-141. John JA, Murray FJ, Smith FA, et al. 1978. Teratogenic evaluation of vinyl choride, vinylidene chloride, and styrene in laboratory animals. Teratology 17:48A. Jones BK, Hathway DE. 1978a. Differences in metabolism of vinylidene chloride between mice and rats. Br J Cancer 37:411-417. Jones BK, Hathway DE. 1978b. Tissue-mediated mutagenicity of vinylidene chloride in Salmonella typhimurium TA1535. Cancer Lett 5:1-6. SL 064565 115 8. REFERENCES Jones BK, Hathway DE. 1978c. The biological fate of vinylidene chloride in rats. Chem Biol Interact 20:27-41. *Kanz MF, Reynolds ES. 1986. Early effects of 1,1-dichloroethylene on canalicular and plasma membranes: ultrastructure and stereology. Exp Molec Pathol 44:93-110. Keisel L, Liszka M, Rutkowski M. 1975. Gas chromatographic determination of trace impurities in distillates of vinyl chloride monomer. Chem Anal (Warsaw) 20:555-562. Kirshen N. 1984. Analysis of trace volatile organic chemicals in water. Am Lab 16(12):60, 62-67. Kleopfer RD, Easley DM, Haas BB, et al. 1985. Anaerobic degradation of trichloroethylene in soil. Environ Sci Technol 19:277-280. Klimisch HJ, Deckardt K, Mitea D. 1979. Subchronic toxicity of vinylidene chloride in rats after 6 weeks exposure. BASF Aktiengesellschaft, Ludwigshafen:31. (German; as cited in Fielder et al. 1985). Klimisch HJ, Freisberg KO. 1979a. [Report on the determination of acute toxicity (LC50) by inhalation of vinylidene chloride in Chinese striped hamsters (fed) during a 4*hour exposure period]. BASF Aktiengesellschaft, Ludwigshafen 14 pp. (German; as cited in Fielder RJ et al. 1985). Klimisch HJ, Freisberg KO. 1979b. [Report on the determination of acute toxicity (LC50) by inhalation of vinylidene chloride in Chinese striped hamsters (fasting) during a 4-hour exposure period], BASF Aktiengesellschaft, Ludwigshafen. 11 pp. (German; as cited in Fielder et al. 1985). Kramer CG, Mutchler JE. 1972, The correlation of clinical and environmental measurements for workers exposed to vinyl chloride. Am Ind Hyg Assoc J 33:19-30. Krijgsheld KR, Gram TE. 1984a. Selective induction of renal microsomal cytochrome P450-linked monooxygenases by 1,1-dichloroethylene in mice. Biochem Pharmacol 33:1951-1956. Krijgsheld KR, Lowe MC, Mimnaugh EG, et al. 1984b. Selective damage to nonciliated bronchiolar epithelial cells in relation to impairment of pulmonary monooxygenase activities by 1,1-dichloroethylene in mice. Toxicol Appl Pharmacol 74:201-213. Krill RM, Sonzogni WC. 1986. Chemical monitoring of Wisconsin's groundwater. J Am Water Works Assoc (September):70-75. SL 064566 116 8. REFERENCES Kurginyan KA, Shirinyan VT. 1969. Identification and quantitative determination of some impurities in chloropyrene. Arm Khim Zh (USSR) 22:61-65. *LaRegina J, Bozzelli JW, Harkov R, et al. 1986. Volatile organic compounds at hazardous waste sites and a sanitary landfill in New Jersey. Environ Progress 5:18-27. Lee CC, Bhandari JC, Winston JM, et al. 1977. Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 21:25-32. Lee CC, Bhandari JC, Winston JM, et al. 1978. Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 4:15-30. Liebler DC. 1984. Formation and disposition of reactive metabolites in the biotransformation of vinylidene chloride. Diss Abst Int 45(5):1445-1448. *Liebler DC, Meredith M J, Guengerich FP. 1985. Formation of glutathione conjugates by reactive metabolites of vinylidene chloride in microsomes and isolated hepatocytes. Cancer Res 45:186-193. *Liebler DC, Latwesen DG, Reeder TC. 1988. S-(2-Chloroacetyl)glutathione, a reactive glutathione thiol ester and a putative metabolite of 1,1dichloroethylene. Biochemistry 27:3652-3657. Lin SN, Fu FW, Bruckner JV, et al. 1982. Quantitation of 1,1- and 1,2-dichloroethylene in body tissues by purge-and-trap gas chromatography. Chromatography 244(2):311-320. J Luthra R, Kyle GM, Mehta PS, et al. and 1,1-dichloroethylene on rat hepmagnesium-stimulated ATPase. Bioch 34. Effects of carbon tetrachloride microsomal calcium- and/or iiarmacol 33:3295-3298. Mabey WR, Smith JH, Podoll RT, et ai, 1982. organic priority pollutants. Washington, DC: Agency. EPA-440/4-81-014., 434. Aquatic fate process data for US Environmental Protection Mackay D, Paterson S. 1981. Calculating fugacity. Environ Sci Technol 15:1006-1014. Maltoni C. 1977. Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect 21:1-5. Maltoni C, Cotti G, Morisi L, et al. 1977. Carcinogenicity bioassays of vinylidene chloride; research plan and early results. Medicine del Lavora 68 (4):241- 262. SL 064567 * 117 8. REFERENCES Maltoni C, Ciliberti A, Carretti D. 1982. Experimental contributions in identifying brain potential carcinogens in the petrochemical industry. Ann NY Acad Sci 381:216-249. Maltoni C, Lefemine P, Cotti, et al. ed. 1985. Experimental research on vinylidene chloride carcinogenesis. Archives of Research on Industrial Carcinogenesis. Vol. 3, Princeton, NJ: Princeton Scientific Publishers. Masuda Y, Nakayama N. 1983. Protective action of diethyldithiocarbamate and carbon disulfide against acute toxicities induced by 1,1-dichloroethylene in mice. Toxicol Appl Pharmacol 71:42-45. McCarty PL, Siegrist H, Vogel TM, et al. 1986. Biotransformation of groundwater contaminants; final report. Department of Civil Engineering, Stanford University, Stanford, CA. McKenna MJ. 1977. The fate of [14C]-vinylidene chloride following inhalation exposure and oral administration in rats. Toxicol Appl Pharmacol 41. McKenna MJ, Watanabe PG, Gehring PG. 1977. Pharmacokinetics of vinylidene chloride in the rat. Environ Health Ferspect 21:99-105. McKenna MJ, Zempel JA, Madrid E0, et al. 1978a. The pharmacokinetics of [14C] vinylidene chloride in rats following inhalation exposure. Toxicol Appl Pharmacol 45:599-610. McKenna MJ, Zempel JA, Madrid E0, et al. 1978b. Metabolism and pharmacokinetic profile of vinylidene chloride in rats following oral administration. Toxicol Appl Pharmacol 45:821-835. Merck. 1983. The Merck Index. In: Windholz M ed. 10th ed. New Jersey: Merck & Co, Inc., 1430. Mill T, Mabey UR. 1980. Test protocols for evaluating the fate of organic chemicals in air and water. Athens, GA: Office of Research and Development, Environmental Protection Agency. Moore L. 1980. Inhibition of liver microsome calcium pump by in vivo administration of CC14, CHC13, and 1,1-dichloroethylene (vinylidene chloride). Biochem Pharmacol 29:2505-2511. Mortelmans K, Haworth S, Lawlor T, et al. 1986. Salmonella mutagenicity tests: II, Results from the testing of 270 chemicals. Environ Mutagen 8(suppl 7):1-119. Moslen MT, Reynolds ES. 1985. Rapid, substrate - specific, and dose-dependent deactivation of liver cytosolic glutathione S-transferase in vivo by 1,1-dichloroethylene. Res Commun Chem Pathol Pharmacol 47(i):59-72. SL 064568 118 8. REFERENCES *Moslen MT, Poisson LR, Reynolds ES. 1985, Cholestasis and increased biliary excretion of inulin in rats given 1,1-dichloroethylene. Toxicology 34:201-209. *Moslen MT, Dunsford HA, Karaasata C, et al. 1987. Immunocytochemical and histochemical evidence of earlier and more severe bile canalicili alterations after 1,1-dichloroethylene (DCE) in fasted rats than in fed rats [abstract]. Fed Proc 46(3) 408. Murray FJ, Nitschke KD, Rampy LW, et al. 1979. Embryotoxicity and fetotoxicity of inhaled or ingested vinylidene chloride in rats and rabbits. Toxicol Appl Pharmacol 49:189-202. Nakajima T, Koyama Y, Sato A. 1982. Dietary modification of metabolism and toxicity of chemical substances-- with special reference to carbohydrate. Biochem Pharmacol 31(6):1005-1011. *NAS. 1983. Drinking water and health. Washington, DC: National Academy of Sciences. NATICH. 1987. NATICH data base report on State, local, and EPA air toxics actvities. National Air Toxics Information Clearinghouse (NATICH). US Environmental Protection Agency, Office of Air Quality Planning and Standards, Research Triangle Park, NC. July 1987. *Neufeld ML, Sittenfield M, Wolk KF, et al. 1977. Market input/output studies--Task I: vinyl chloride. Washington, DC: Office of Toxic Substances, Environmental Protection Agency. EPA 560/6-77-003. NIOSH. 1976. National Occupational Hazard Survey. Cincinnati, Ohio: US Department of Health and Human Services, National Institute of Occupational Safety and Health. NIOSH. 1978. Vinyl halides carcinogenicity. Current Intelligence Bulletin. Washington, DC: US Department of Health, Education, and Welfare, National Instititute for Occupational Safety and Health. 79-102. *NI0SH. 1984. NIOSH Manual of Analytical Methods. Method 1015. Vol. 2, 3 ed. Cincinnati, OH: US Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health. Nirmalakhandan NN, Speece RE. 1988. Prediction of aqueous solubility of organic chemicals based on molecular structure. Environ Sci Technol 22:328-338. SL 064569 119 8. REFERENCES *Nitschke KD, Smith FA, Quast JM, et al. 1983. A three-generation rat reproductive toxicity study of vinylidene chloride in the drinking water. Fund Appl Toxicol 3:75-79. *Norris JM. 1977. Toxicological and pharmacological studies on inhaled and ingested vinylidene chloride in laboratory animals. Pep Synth Conf (Prept):45-50 as cited in Fielder, RJ et al. 1985. *Oesch F, Protic-Sabljic M, Friedberg T, et al. 1983. Vinylidene chloride: changes in drug metabolizing enzymes, mutagenicity and relation to its targets for carcinogenesis. Carcinogenesis 4(8):1031-1038. *0kine LK, Goochee JM, Gran TE. 1985. Studies on the distribution and covalent binding of 1,1-dichloroethylene in the mouse. Effects of various pretreatments on covalent binding in vivo. Biochem Pharmacol 34(22):4051-4057. *OSHA. 1982. Access to employee exposure and medical records; proposed modification; request for comments and notice of public hearing. Occupational Safety and Health Administration. Federal Register 47:30420-30438. *0SHA. 1989. Occupational Safety and Health Administration. 29 CFR Part 1910. Air Contaminants. Federal Register 54(12):2332-2929 (January 19, 1989). *Ott MG, Langner RR, Holder BB. 1975. Vinyl chloride exposure in a controlled industrial environment; a long-term mortality experience in 594 employees. Arch Environ Health 30:333-339. *Ott MG, Fishbeck WA, Townsend JC, et al. 1976. A health study of employees exposed to vinylidene chloride. J Occup Med 18:735-738. Pankov JF, Rosen ME. 1988. Determination of volatile compounds in water by purging directly to a capillary column with whole column cryotrapping. Environ Sci Technol 22(4):398-405. *Parsons F, Lags GB. 1985. Chlorinated organics in simulated groundwater environments. J Amer Waterworks Assoc 77(5):52-59 *Patterson JW, Kodukala PS. 1981. Emission and effluent control: Biodegradation of hazardous organic pollutants. Chem Eng Progress April:48-55. Pearson CR, McConnel G. 1975. Chlorinated Cl and C2 hydrocarbons in the marine environment. Proc R Soc Lond B (Great Britain) 189:305-332. SL 064570 120 8. REFERENCES *Pellizzari ED, Zweidinger RA, and Sheldon LS. 1985. GC/MS determination of volatile hydrocarbons in breath samples. In: Environmental carcinogensselected methods of analysis. Ed: Fishbein L, O'Neill IK. Vol. 7. Lyon, France: International Agency for Research on Cancer., 413-431. Politziki GR, Beiniek D, Lahaniatis ES, et al. 1982. Determination of vapor pressures of nine organic chemicals adsorbed on silicagel. Chemosphere 11:1217-1229. Ponomarkov V, Tomatis L. 1980. Long-term testing of vinylidene chloride and chloroprene for carcinogenicity in rats. Oncology 37:136-141. *Prendergast JA, Jones RA, Jenkins LJ, et al. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1.1.1- trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol Appl Pharmacol 10:270-289. *Putcha L, Bruchner JV, D'Soyza R, et al. 1986. Toxicokinetics and bi availability of oral and intravenous 1,1-dichloroethylene. Fund Appl Toxicol 6:240-250. Quast JF. 1976. Pathology report on male and female rats exposed to vinylidene chloride vapors- for 6 hours per day, 5 days per week during a 30-day period. Unpublished report. Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical U.S.A., Midland, MI. Quast JF, Humiston CG, Wade CE, et al. 1983. A chronic toxicity and oncogenicity study in rats and subchronic toxicity study in dogs on ingested vinylidene chloride. Fundam Appl Toxicol 3(l):55-62. Quast JF, McKenna MJ, Rampy LW, et al. 1986. Chronic toxicity and oncogenicity study on inhaled vinylidene chloride in rats. Fund Appl Toxicol 6:105-144. Rampy LW, Quast JF, Humiston CG, et al. 1977. Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ Health Perspect 21:33-43. Reichert D, Henschler D. 1978. Uptake and hepatotoxicity of 1.1- dichloroethylene by the isolated blood- perfused rat liver. Occup Environ Health 41:169-178. Int Arch Reichert D, Werner HW, Henschler D. 1978. Role of liver glutathione In 1,1-dichloroethylene metabolism and hepatotoxicity in intact rats and isolated perfused rat liver. Arch Toxicol 41:169-179. SL 064571 121 8. REFERENCES *Reichert D, Werner HE, Metzler M, et al. 1979. Molecular mechartism of 1,1-dichloroethylene toxicity: Excreted metabolites reveal different pathways of reactive intermediates. Arch Toxicol 42:159-169. *Reitz RH, Watanabe PG, McKenna MJ, et al. 1980. Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse; a comparative study with dimethylnitrosamine. Toxicol Appl Pharmacol 52:357-370. Reynolds E, Moslen M. 1977. Damage to hepatic cellular membranes by chlorinated olefins with emphasis on synergism and antagonism. Environ Health Perspect 21:137-147. Reynolds ES, Moslen MT, Szabo S, et al. 1975. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Am J Pathol 81:219-236. Reynolds ES, Moslen MT, Boor PJ, et al. 1980. 1,1-Dichloroethylene hepatotoxicity. Am J Pathol 101(2):331-342. Reynolds ES, Kanz MF, Chieco P, et al. 1984. 1,1-Dichloroethylene: apoptotic hepatotoxin? Environ Health Perspect 57:315-320. an Sasaki M, Sugimura K, Yoshida MA, et al. 1980. Cytogenetic effects of 60 chemicals on cultured human and Chinese hamster cells. La Kromosomo II 20:574-584. Sato A, Nakajima T, Koyama Y. 1983. Interaction between ethanol and carbohydrate on the metabolism in rat liver of aromatic and chlorinated hydrocarbons. Toxicol Appl Pharmacol 68:242-249. Sawada M, Sofuni T, Ishidate M. 1987. Cytogenetic studies on 1,1-dichloroethylene and its two isomers in mammalian cells in vitro and in vivo. Mutat Res 187:157-163. Schuetzle D, Cronn D, Crittenden AL, et al. 1975. Molecular composition of secondary aerosol and its possible origin. Environ Sci Technol: 9:838. Shah J, Heyerdahl E. 1988. National ambient volatile organic compounds (VOCs) data base update. Prepared for the US Environmental Protection Agency. Research Triangle Park, NC: Atmospheric Sciences Research Laboratory. January 1988. Shah J, Heyerdahl E. 1988. National ambient volatile organic compounds (VOCs) data base update. Prepared for the US Environmental Protection Agency. Research Triangle Park, NC: Atmospheric Sciences Research Laboratory. January 1988. Shamat NA, Maier WJ. 1980, Kinetics of biodegradation of chlorinated organics. J Water Poll Control Fed 52:2158-2166. SL 064572 122 8. REFERENCES Short RD, Minor JL, House WB, et al. 1976. Continuous inhalation of 1.1- dichloroethylene (DCE) by rats and mice during gestation. The Pharmacologist 18:245. Short RD, Minor JL, Winston JM, et al. 1977a. Toxicity studies of selected chemicals; Task II: The development of vinylidene chloride inhaled by rats and mice during gestation. Washington, DC: US Environmental Protection Agency. Publication No EPA-560/6-77-022. Short RD, Minor JL, 'nston JM, et al. male rats after repe. i exposures to J Toxicol Environ Hea 3:965-968. 1977b. A dominant lethal study in 1 chloride or vinylidene chloride, Short RD, Winston JM, tinor JL, et al. 1977c. Effect of various treatments on toxicity of inhaled vinylidene chloride. Environ Health Perspect 21:125-129. Short RD, Winston JM, Minor JL, et al. 1977d. Toxicity of vinylidene chloride in mice and rats and its alteration by various treatments. J Toxicol Environ Health 3:913-921. Siegel J, Jones RA, Coon A, et al. 1971. Effects on experimental animals of acute, repeated and continuous inhalation exposures to dichloroacetylene mixtures. Toxicol Appl Pharmacol 18:168-174. Siletchnik LM, Carlson GP. 1974. Cardiac sensitizing effects of 1.1- dichloroethylene: Enhancement by phenobarbital pretreatment. Arch Int Pharmacodyn 210:359-364, Singh HB, Salas LJ, Smith AL, et al. 1981. Measurements of some potentially hazardous organic chemicals in urban environments. Atmos Environ 15:601-612. Singh HB, Salas LJ, Stiles RE. 1982. Distribution of selected gaseous organic mutagens and suspect carcinogens in ambient air. Environ Sci Technol 16:872-880. Spain MA, Middleditch BS, Bafus DA, et al. 1985. Dehydrohalogenation of atmospheric contaminants in the space cabin. Aviation Space Environ Med 56:262-264. SRI. 1987. SRI International Directory of Chemical Producers, Menlo Park, CA: SRI International. SL 064573 8. REFERENCES Szabo S, Jaeger RJ, Moslen MT, et al. 1977. Modification of 1,1-dichloroethylene hepatotoxicity by hypothyroidism. Toxicol Appl Pharmacol 42:367-376. Tabak HH, Quave SA, Mashni Cl, et al. 1981. Biodegradability studies with organic priority pollutant compounds. J Water Poll Control Fed 53:1503-1518. Taylor DG. 1978. NIOSH manual of analytical methods. Vol. 4, 2 ed. Department of Health, Education, and Welfare, National Institute for Occupational Safety and Health. Thiess AM, Frentzel-Beyme R, Penning E. 1979. Mortality study of vinylidene chloride exposed persons. In: Hien C, Kilian DJ ed. Proceedings of the 5th Medichem congress. San Francisco CA: University of California at San Francisco, 270-278. Tierney DR, Mackwood TR, Piana MR. 1979. Status assessment of toxic chemicals: vinylidene chloride. Cincinnati, Ohio: US Environmental Protection Agency. EPA 600/2-79-2100 (PB80-146442). Tornqvist M, Osterman-Golkar S, Kautiainen A, et al. 1986. Tissue doses of ethylene oxide in cigarette smokers determined from adduct levels in hemoglobin. Carcinogenesis 7(9):1519-1521. Tuazon EC, Atkinson R, Aschamnn SM, et al. 1988. Atmospheric reactions of chloroethenes with the OH radical. Intern J Chemical Kinetics 20:241-265. Van Duuren BL, Goldschmidt BM, Loewengart G, et al. 1979. of halogenated oleflnic and aliphatic hydrocarbons in mice. Inst 63(6):1433-1439. Carcinogenicity J Natl Cancer Van't Hof J, Schairer LA. 1982. Tradescantia assay system for gaseous mutagens; a report of the US Environmental Protection Agency Gene-Tox Program. Mutat Res 99:303-315. Veith GD, DeFoe D, Knuth M. 1985. Structure-activity relationships for sere ning organic chemicals for potential ecotoxicity effects. Drug Metabo1ism Reviews 15:1295-1303. Verschueren K. 1983. Handbook of environmental data of organic chemicals. 2 ed. New York: Van Nostrand Reinhold Co. Viola PL, Caputo A. 1977. Carcinogenicity studies on vinylidene chloride. Environ Health Perspect 21:45-47. Vlasov SM, Bodyagin GN. 1970. Gas chromatographic analysis of trichloroethylene. Tr Khim Khim Teknol (USSR) 1:161-162. SL 064574 124 8. REFERENCES Vogel TM, McCarty PL. 1985. Biotransformation of tetrachloroethylene to trichloroethylene, dichloroethylene, vinyl chloride, and carbon dioxide under methanogenic conditions. Appl Environ Microbiol 49:1080-1083. Vog 1 TM, Criddle CS, McCarty PL. 1987. Transformations of halogenated aliphatic compounds. Environ Sci Technol 21:722. Wallace L, Zweidinger R, Erickson MCS, et al. 1982. Monitoring individual exposure. Measurements of volatile organic compounds in breathing-zone air, drinking water, and exhaled breath. Environ Int 8:269-282. Wallace LA, Pellizzari E, Hartwell T, et al. 1984. Personal exposure to volatile organic compounds. I. Direct measurements in breathing-zone air, water, food, and exhaled breath. Environ Res 35:293-319. Wallace L, Pellizzari E, Hartwell T, et al. 1986. Concentrations of 20 volatile organic compounds in the air and drinking water of 350 residents of New Jersey compared with concentrations in their exhaled breath. J Occup Med 28:603-608. Wallace LA, Pellir.zari E, Hartwell T, et al. 1987. The TEAM study: personal exposures to toxic substances in air, drinking water, and breath of 400 residents of New Jersey, North Carolina, and North Dakota. Environ Res 43:290-307. Wang T, Lenahan R, Kanik M. 1985a. Impact of trichloroethylene contaminated groundwater discharged to the Main Canal and Indian River Lagoon, Vero Beach, Florida. Bull Environ Contam Toxicol 34:578-586. Wang TC, Lenahan R, Kanik M, et al. 1985b. The removal of trichloroethylene contaminated groundwater at Vero Beach, Florida. Arch Environ Contam Toxicol 14:719-723. Wapora I. 1982. The utility of distributed air volume sets when sampling ambient air using solid absorbents. Atmos Environ 18:555-559, Watanabe PG, Hefner RE, Gehring PJ. 1976. Vinyl chloride-induced depression of hepatic nonprotein sulfhydryl content and effects on bromosulphalein (BSP) clearance in rats. Toxicology 6:1-8. Watanabe PG, Reitz RH, Schumann AM, et al. 1980. Implications of the mechanisms of tumorigenicity for risk assessment. The Scientific Basis of Toxicity Assessment 6:69-81. Waxweiler R. 1981. Epidemiologic problems associaed with exposure to several agents. Environ Health Perspect 42:51-56. Sl> 125 8. REFERENCES *Weiss G ed. 1980. Hazardous Chemicals Data Book, Environmental Health Review No 4. Park Ridge, NJ: Noyes Data Corporation, 914. *Weiss G ed. 1986. Hazardous Chemicals Data Book. 2nd ed. Park Ridge, NJ: Noyes Data Corp, 1018. Westrick JJ, Mello JW, Thomas RF. 1984. The groundwater supply survey. J Amer Waterworks Assoc p.52-59. (May). *WHO, 1984. Guidelines for drinking-water quality. Recommendations. Geneva: World Health Organization. *Wilson BH, Smith GB, Rees JF. 1986. Biotransformations of selected alkylbenzenes and halogenated aliphatic hydrocarbons in methanogenic aquifer material: a microcosm study. Environ Sci Technol 20:997-1002. Wilson JT, McNabb JF. 1983. Biological transformation of organic pollutants in groundwater. EOS August:501-505. Wils n JT, Enfield CG, Dunlap WJ, et al. 1981. Transport and fate of selected organic pollutants in a sandy soil. J Environ Qual 10:501*506. *Zeller H, Klimisch HJ, Freisberg KO. 1979a. [Report on the determination of acute toxicity (LC50) of vinylidene chloride in Sprague-Dawley rats (fed) during a 4-hour exposure]. BASF Aktiengesellschaft, Ludwigshafen FRG (German; as cited in Fielder 1985). *Zeller H, Klimisch JH, Freisberg KO. 1979b. Report on the determination of acute toxicity (LC50) by inhalation of vinylidene chloride in vapour form in Sprague Dawley rats (fasting) during a 4 hour exposure. BASF Aktiengesellschaft, Ludwigshafen (German; as cited in Fielder et al. 1985). Zeller H, Klimisch HJ, Fresbierg KO. 1979c. Report on the determination of acute toxicity (LC50) by inhalation of vinylidene chloride in NMRI mice (fasting) during a 4-hour exposure. BASF Aktiengesellschaft, Ludwigshafen (German; as cited in Fielder et al. 1985). SL 064576 126 8. REFERENCES SL 06^577 127 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling value (DL) -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception ( ither parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in th life span of the organism. Embryotoxicity and Fetotoxieity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EFA Health Advisory --An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is SL 064578 9. GLOSSARY not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days as specified in the Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In vivo -- Occurring within the living organism. Lethal Coneentration(L0) (LC^, -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration^, (LC^) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose(L0, (LD^,) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose(30, (LD30) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time(30, (LT^) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level --An estimate of daily human exposure to a chemical that is likely to be without an appreciable risk of deleterious effects (noncancerous) over a specified duration of exposure. 129 9. GLOSSARY Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Vater Partition Coefficient (Kow) -- The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. Permissible Exposure Limit (PEL) --An allowable exposure level in workplace air averaged over an 8-hour shift. qx* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The qt* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and /ig/m3 for air). Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 lb or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Vater Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are SL 064580 130 9. GLOSSARY < ik allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-weighted Average (TWA) --An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDjo) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 502 of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAE"^ data rather than NOAEL data. Usually each of these factors is set equal to 10. SL 064581 * *. 131 APPENDIX PEER REVIEW A peer review panel was assembled for DCE. The Panel consisted of the following members: Dr. Richard J. Bull, Associate Professor of Pharmacology/Toxicology, University of Washington; Dr. Dietrich Hoffman, Associate Director, American Health Foundation; and Dr. Martha Radike, Research Assoicate Professor, Department of Environmental Health, University of Cincinnati Medical Center. These experts collectively have knowledge of DCE's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in the Superfund Amendments and Reauthorization Act of 1986, Section 110. A joint panel of scientists from ATSDR and EPA has reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply their approval of the profile's final content. The responsibility of the content of this profile lies with the Agency for Toxic Substances and Disease Registry. SL 064582 94 5. POTENTIAL FOR HUMAN EXPOSURE $* \