Document YGJRQmgrr2mO74vX7xVvX70Yn
1,1 -DICHLOROETHENE
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service Agency for Toxic Substances and Disease Registry
Comment Period Ends: February 19f 1993
Fwtoral Recycling Program ^ ^ Printed on Rocyclod Papor
DRAFT TOXICOLOGICAL PROFILE FOR
1,1 -DICHLOROETHENE
Prepared by: Syracuse Research Corporation
and Clement International Corporation
Under Contract No. 205-88-0608 Prepared for:
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service
Agency for Toxic Substances and Disease Registry
October 1992
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DISCLAIMER
The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act (SARA) 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 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 CERCLA 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 lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987, on October 20, 1988, on October 26, 1989, on October 17, 1990. A revised list of 275 substances was published on October 17, 1991.
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. 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, and 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 advene health effects in humans.
This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary.
The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance's toxicological properties. Other pertinent literature is also 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 public health statement is information
concerning levels of significant human exposure and, where known, significant health effects. The adequacy of
information to determine a substance's health effects is described in a health effects summary. Data
that
are of significance to protection of public health will be identified by ATSDR and EPA. The focus of the
profiles is on health and toxicological information; therefore, we have included this information in the beginning
of the document.
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Foreword 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 as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to:
Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E*29 Atlanta, Georgia 30333
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, the Centers for Disease Control and other federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR.
Administrator Agency for Toxic Substances and
Disease Registry
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CONTENTS
FOREWORD ......................................................................................................................................................
LIST OF FIGURES ........................................................................................................................................... a
LIST OF TABLES............................................................................................................................................... xi
1. PUBLIC HEALTH STATEMENT............................................................................................................. 1.1 WHAT IS 1,1 -DICHLOROETHENE? ........................................................................................... 1.2 WHAT HAPPENS TO 1,1-DICHLOROETHENE WHEN IT ENTERS THE ENVIRONMENT? .................................................................................................................. 1.3 HOW MIGHT I BE EXPOSED TO 1,1-DICHLOROETHENE?.............................................. 1.4 HOW CAN 1,1-DICHLOROETHENE ENTER AND LEAVE MY BODY? ......................... 1.5 HOW CAN 1,1-DICHLOROETHENE AFFECT MY HEALTH?.............................................. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,1-DICHLOROETHENE?....................................................................... 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ............................................................................................. 1.8 WHERE CAN I GET MORE INFORMATION?.........................................................................
1 1
2 2 3 4
5
5 6
1 HEALTH EFFECTS .................................................................................................................................... 7 2.1 INTRODUCTION .............................................................................................................................. 7 12 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE.................................. 7 2.2.1 Inhalation Exposure ........................................................................................................... 19 111.1 Death.................................................................................................................... 19 111.2 Systemic Effects____ 2.2.1.3 Immunological Effects 111.4 Neurological Effects . 111.5 Reproductive Effects 2.2.1.6 Developmental Effects 2.2.1.7 Genotoxic Effects ... 111.8 Cancer....................... 112 Oral Exposure........................... 1111 Death......................... 1112 Systemic Effects_____ 1113 Immunological Effects 1114 Neurological Effects . 1223 Reproductive Effects 12.16 Developmental Effects 222.7 Genotoxic Effects ... 222.8 Cancer....................... 113 Dermal Exposure ..................... 113.1 Death......................... 2.13.2 Systemic Effects____ 113.3 Immunological Effects 123.4 Neurological Effects . 1133 Reproductive Effects 113.6 Developmental Effects 113.7 Genotoxic Effects ... 113.8 Cancer.......................
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23 TOXICOKINETICS........................................................................................................................... 39 2.3.1 Absorption ............................................................................................................................ 39 23.1.1 Inhalation Exposure............................................................................................ 39 2.3.13 Oral Exposure ..................................................................................................... 41 23.13 Dermal Exposure................................................................................................ 41 23.2 Distribution ........................................................................................................................... 41 23.2.1 Inhalation Exposure............................................................................................ 41 23.2.2 Oral Exposure ..................................................................................................... 42 2.3.23 Dermal Exposure................................................................................................. 42 23.2.4 Other Routes of Exposure................................................................................. 42 233 Metabolism............................................................................................................................. 42 23.4 Excretion ............................................................................................................................... 47 23.4.1 Inhalation Exposure............................................................................................ 47 23.4.2 Oral Exposure ..................................................................................................... 4$ 23.43 Dermal Exposure................................................................................................. 48 23.4.4 Other Routes of Exposure ................................................................................ 48 2.3.5 Mechanisms of Action........................................................................................................... 49
2.4 RELEVANCE TO PUBLIC HEALTH......................................................................................... 49 2.5 BIOMARKERS OF EXPOSURE AND EFFECT....................................................................... 59
2.5.1 Biomarkers Used to Identify or Quantify Exposure to 1,1-Dichloroethene................ 59 2.5.2 Biomarkers Used to Characterize Effects Caused by1,1-Dichloroethene .................... 60 2.6 INTERACTIONS WITH OTHER CHEMICALS....................................................................... 60 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE................................................ 61 2.8 METHODS FOR REDUCING TOXIC EFFECTS..................................................................... 62 2.8.1 Reducing Peak Absorption Following Exposure.............................................................. 62 2.8.2 Reducing Body Burden....................................................................................................... 63 2.83 Interfering with the Mechanism of Action for Toxic Effects.......................................... 63 19 ADEQUACY OF THE DATABASE............................................................................................. 63 2.9.1 Existing Information on Health Effects of 1,1-Dichloroethene..................................... 64 2.9.2 Identification of Data Needs .............................................................................................. 64 2.93 On-going Studies.................................................................................................................... 69
3. CHEMICAL AND PHYSICAL INFORMATION.................................................................................. 3.1 CHEMICAL IDENTITY ................................................................................................................ 3.2 PHYSICAL AND CHEMICAL PROPERTIES............................................................................
71 71 71
4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL............................................................ 4.1 PRODUCTION ................................................................................................................................ 4.2 IMPORT/EXPORT ......................................................................................................................... 43 USE...................................................................................................................................................... 4.4 DISPOSAL...........................................................................................................................................
75 75 75 75 77
5. POTENTIAL FOR HUMAN EXPOSURE.............................................................................................. 5.1 OVERVIEW ..................................................................................................................................... 5.2 RELEASES TO THE ENVIRONMENT ..................................................................................... 5.2.1 Air.......................................................................................................................................... 5.12 Water..................................................................................................................................... 5.13 SoU......................................................................................................................................... 5.3 ENVIRONMENTAL FATE............................................................................................................ 53.1 Transport and Partitioning ................................................................................................ 53.2 Transformation and Degradation....................................................................................... 53.11 Air.......................................................................................................................... 53.12 Water.....................................................................................................................
79 79 79 79 82 82 82 82 83 83 84
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53.23 Sediment and Soil ............................................................................................. 84 5.4 LEVELS MONITORED OR ESTIMATED INTHE ENVIRONMENT................................. 85
5.4.1 Air......................................................................................................................................... 85 5.4.2 Water.................................................................................................................................... 85 5.43 Sediment and Soil................................................................................................................ 86 5.4.4 Other Environmental Media ............................................................................................. 86 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE....................................... 86 5.6 POPULATIONS WITH POTENTIALLYHIGHEXPOSURES................................................ 87 5.7 ADEQUACY OF THE DATABASE........................................................................................... 87 5.7.1 Identification of Data Needs ............................................................................................. 88 5.7.2 On-going Studies.................................................................................................................. 89
6. ANALYTICAL METHODS...................................................................................................................... 6.1 BIOLOGICAL MATERIALS......................................................................................................... 6.2 ENVIRONMENTAL SAMPLES .................................................................................................. 63 ADEQUACY OF THE DATABASE........................................................................................... 6.3.1 Identification of Data Needs ............................................................................................. 63.2 On-going Studies..................................................................................................................
91 91 93 93 93 96
7. REGULATIONS AND ADVISORIES.................................................................................................... 97
8. REFERENCES ........................................................................................................................................... 101
9. GLOSSARY................................................................................................................................................. 121
APPENDICES
A. USER'S GUIDE.................................................................................................................................... A-l
B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS.................................................................... B-l
C PEER REVIEW .................................................................................................................................... C-l
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USTOF FIGURES
2-1 Levels of Significant Exposure to 1,1-Dichloroethene - Inhalation................................................... 15 2-2 Levels of Significant Exposure to 1,1-Dichloroethene - Oral ............................................................ 33 2-3 Percentage Systemic Uptake of 1,1-Dichloroethene During Inhalation
Exposures.................................................................................................................................................... 40 2-4 Metabolic Pathway for 1,1-Dichloroethene in Animals....................................................................... 43 2-5 Physiologically Based Pharmacokinetic Model for 1,1-Dichloroethene............................................ 44 2-6 General Proposed Scheme for Oxidative and Conjugative Metabolism of
1,1-Dichloroethene not Metabolized via the Epoxide Intermediate................ .................................... 46 2-7 Existing Information of Health Effects of 1,1-Dichloroethene .......................................................... 65 5-1 Frequency of NPL Sites with 1,1-Dichloroethene Contamination..................................................... 81
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LIST OF TABLES
2-1 Levels of Significant Exposure to 1,1-Dichloroethene - Inhalation....................................................... 8 2-2 Levels of Significant Exposure to 1,1-Dichloroethene - Oral .............................................................. 29 2-3 Genotoxicity of 1,1-Dichloroethene In Vitro........................................................................................... 56 2- 4 Genotoxicity of 1,1-Dichloroethene In Vivo........................................................................................ 57 3- 1 Chemical Identity of 1,1-Dichloroethene............................................................................................. 72 3- 2 Physical and Chemical Properties of 1,1-Dichloroethene ................................................................. 73 4- 1 Facilities That Manufacture or Process 1,1-Dichloroethene ............................................................. 76 5- 1 Releases to the Environment from Facilities That Manufacture or
Process 1,1-Dichloroethene...................................................................................................................... 80 6- 1 Analytical Methods for Determining 1,1-Dichloroethene in BiologicalMaterials .......................... 92 6- 2 Analytical Methods for Determining 1,1-Dichloroethene in Environmental Samples .................. 94 7- 1 Regulations and Guidelines Applicable to 1,1-Dichloroethene........................................................ 98
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1. PUBLIC HEALTH STATEMENT
This Statement was prepared to give you information about 1,1-dichloroethene and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,300 hazardous waste sites as the most serious in the nation. These sites comprise the "National Priorities List" (NPL): Those sites which are targeted for long-term federal cleanup activities. 1,1-Dichloroethene has been found in at least 466 of the sites on the NPL. However, the number of NPL sites evaluated for 1,1-dichloroethene is not known. As EPA evaluates more sites, the number of sites at which 1,1-dichloroethene is found may increase. This information is important because exposure to 1,1-dichloroethene may cause harmful health effects and because these sites are potential or actual sources of human exposure to 1.1- dichloroethene.
When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. This release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking substances containing the substance or by skin contact with it.
If you are exposed to a substance such as 1,1-dichloroethene, many factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, gender, nutritional status, family traits, life-style, and state of health.
1.1 WHAT IS 1,1-DICHLOROETHENE?
1.1- Dichloroethene, also known as vinylidene chloride, is a chemical used to make certain plastics (such as packaging materials, flexible films like SARAN wrap) and flameretardant coatings for fiber and carpet backing. It is a clear, colorless liquid that evaporates quickly at room temperature. It has a mild, sweet smell like chloroform and bums quickly.
1.1- Dichloroethene is a man-made chemical and is not found naturally in the environ ment. Although 1,1-dichloroethene is manufactured in large quantities, most of it is used to make other substances or products such as polyvinylidene chloride. For information on the chemical and physical properties and use of 1,1-dichloroethene, see Chapters 3 and 4.
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1.2 WHAT HAPPENS TO 1,1-DICHLOROETHENE WHEN IT ENTERS THE ENVIRONMENT?
1.1- Dichloroethene can enter the environment when it is released to the air during its production or released to surface water or soil as a result of waste disposal. Most 1.1- dichloroethene evaporates quickly and mainly enters the environment through the air, although some enters into rivers or lakes. 1,1-Dichloroethene may enter soil, water, and air in large amounts during an accidental spill. 1,1-Dichloroethene can also enter the environment as a breakdown product of other chemicals in the environment.
1.1- Dichloroethene behaves differently in air, water, and soil. 1,1-Dichloroethene evaporates to the air very quickly from soil and water. In the air, 1,1-dichloroethene is broken down by reactive compounds formed by sunlight. 1,1-Dichloroethene remains in the air for about 4 days.
From water, 1,1-dichloroethene evaporates into the air, it breaks down very slowly in water. It is not readily transferred to fish or birds, and only very small amounts enter the food chain. We do not know exactly how long 1,1-dichloroethene stays in water, but we do know that it stays longer in lakes than in rivers.
In soil, 1,1-dichloroethene either evaporates to the air or percolates down through soil with rainwater and enters underground water. Small living organisms in soil and groundwater may change it into other less harmful substances, although this happens slowly.
More information on what happens to 1,1-dichloroethene in the environment can be found in Chapter 5.
1.3 HOW MIGHT I BE EXPOSED TO 1,1-DICHLOROETHENE?
You may be exposed to 1,1-dichloroethene by breathing it when it is in the air or eating food or water that contains it. You may also be exposed to 1,1-dichloroethene if it touches your skin. In addition to the high-level exposures that may occur in factories where 1,1-dichloroethene is made, low-level exposures to 1,1-dichloroethene may also occur in the environment. 1,1-Dichloroethene is found at very low levels in indoor and outdoor air (estimated as less than 1 part per trillion parts of air [ppt]). Therefore, the potential for exposure in the environment is extremely low. The amounts are somewhat higher near some factories that make or use 1,1-dichloroethene (those that make food packaging films, adhesives, flame-retardant coatings for fiber and carpet backing, piping, and coating for steel pipes), hazardous waste sites, and areas near accidental spills. The exact amount of 1,1-dichloroethene in the air near these factories is not known. In air around waste sites where it has been identified, the amount of 1,1-dichloroethene ranges from 0.39 to 36.4 parts 1,1-dichloroethene per billion parts of air (ppb, 1 ppb is 1,000 times more than 1 ppt). The levels of 1,1-dichloroethene in air around waste sites are usually much lower than those that have caused health effects in animals. We estimate that 1,1-dichloroethene contaminates the air around 97 chemical factories throughout the
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3 1. PUBLIC HEALTH STATEMENT
United States. Factories that make 1,1-dichloroethene are located in Texas and Louisiana. Measured air levels inside manufacturing plants range from less than 5 to 25 parts 1,1-dichloroethene per million parts of air (ppm, 1 ppm is 1,000 times more than 1 ppb).
A small percentage (3%) of the drinking water sources in the United States contains low amounts of 1,1-dichloroethene (0.2-0.5 ppb with an estimated average of 0.3 ppb). The amounts are very low compared with levels that are expected to affect human health. The average level was 1.38 ppm in groundwater samples from hazardous waste sites where 1,1-dichloroethene was found.
Since 1,1-dichloroethene is used to make some consumer products, exposure might occur while these products are made or used. For example, the estimated average amount of 1,1-dichloroethene in plastic food-packaging films was 1.26 ppm. The measured average amount in food wrapped in these films was less than 0.01 ppm. Not every tested food sample contained 1,1-dichloroethene, so these numbers only represent the levels found in food samples that did contain 1,1-dichloroethene. The Food and Drug Administration (FDA) regulates the use of plastic packaging films. The FDA has determined that the films can contain no more than 10 ppm 1,1-dichloroethene and that the low levels of 1.1- dichloroethene found in food wrapped in these films present no health risk to the consumer. More information on human exposure can be found in Chapter 5.
1.4 HOW CAN 1,1 -DICHLOROETHENE ENTER AND LEAVE MY BODY?
1.1- Dichloroethene can easily enter the body through the lungs as an air pollutant or through the stomach and intestines if you eat or drink contaminated food or water. Based on the physical and chemical properties of 1,1-dichloroethene, we think that 1.1- dichloroethene can enter the body through the skin. Harmful effects have occurred in animals after 1,1-dichloroethene was applied to their skin. Breathing air that contains 1,1-dichloroethene is the most likely way for humans to be exposed.
Animal studies indicate that within a few hours of exposure, 1,1-dichloroethene begins to leave the body through the lungs. The remaining 1,1-dichloroethene breaks down into other substances that leave the body in the urine within 1-2 days. Some of the breakdown products of 1,1-dichloroethene such as dithioglycollic acid, are more harmful than 1,1-dichloroethene. The way 1,1-dichloroethene and its breakdown products leave the body depends on the amount of 1,1-dichloroethene that enters the body. Low or moderate levels breathed in (25-200 ppm) or taken by mouth (up to 50 milligrams of 1.1- dichloroethene per kilogram of body weight) leave the body mainly as breakdown products in the urine. As the amount of 1,1-dichloroethene that enters the body increases, more and more 1,1-dichloroethene leaves the body in the exhaled breath. 1.1- Dichloroethene inhaled or taken by mouth leaves the body in about the same way. We do not know how 1,1-dichloroethene leaves the body if it enters through the skin. 1,1-Dichloroethene is not stored very much in the body when low to moderate amounts (up to 300 ppm) enter the body. More information on how 1,1-dichloroethene enters and leaves the body is found in Chapter 2.
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1. PUBLIC HEALTH STATEMENT
1.5 HOW CAN 1,1-DICHLOROETHENE AFFECT MY HEALTH?
How a chemical affects your health depends on how much you are exposed to and for how long. As the level and length of your exposure increase, the effects are likely to become more severe. Information on the health effects in humans after breathing 1,1-dichloroethene is insufficient. People who breathed high amounts of 1,1-dichloroethene in a closed space lost their breath and fainted. Some people who breathed 1,1-dichloroethene at work for several years had abnormal liver function. However, exposure to other chemicals may have also contributed to this effect. Available information indicates that inhaled 1,1-dichloroethene can induce adverse neurological effects and is possibly associated with liver and kidney damage in humans. Studies in animals indicate that 1,1-dichloroethene can affect the normal functions of the liver, kidneys, and lungs. However, the amount of 1,1-dichloroeth in the air to which the animals were exposed was much higher than the amounts ir. air that the general public usually breathes. Some animals that breathed high ai its of 1,1-dichloroethene died within a few days, but we do not know the cause of dea The liver and kidneys of animals were affected after the animals breathed air that contained 1,1-dichloroethene for days, months, or years. After pregnant rats breathed 1,1-dichloroethene in air, some of the newborn rats had birth defects.
We have no information on the health effects in humans who ate food or drank water that contained 1,1-dichloroethene. Animals fed food that contained 1,1-dichloroethene or that had 1,1-dichloroethene placed experimentally in their stomachs developed liver and kidney disease, and some even died. These amounts, however, are veiy much higher than those in drinking water supplies. Birth defects did not occur in the newborn of female rats that drank 1,1-dichloroethene.
Spilling 1,1-dichloroethene on your skin or in your eyes can cause irritation. We do not know what other health effects might occur if 1,1-dichloroethene comes into contact with your skin for long periods. However, no serious effects or deaths occurred in mice after small amounts of 1,1-dichloroethene were put on their skin over a period of months. We do not know whether spilling 1,1-dichloroethene on your skin can cause birth defects or affect fertility.
We do not know whether coming into contact with 1,1-dichloroethene increases the risk of cancer in humans. Several studies examined the possibility that 1,1-dichloroethene may increase the risk of cancer in animals. Only one of these studies indicated that mice breathing 1,1-dichloroethene for 1 year developed kidney cancer, but the particular type of mouse used may be especially sensitive to 1,1-dichloroethene.
The Department of Health and Human Services has not classified 1,1-dichloroethene with respect to carcinogenicity. The International Agency for Research on Cancer has determined that 1,1-dichloroethene is not classifiable as to its carcinogenicity to humans.
The EPA has determined that 1,1-dichloroethene is a possible human carcinogen.
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1. PUBLIC HEALTH STATEMENT
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,1 -DICHLOROETHENE?
1.1- Dichloroethene can be measured in the breath, blood, urine, and body tissues of individuals who come in contact with the chemical. However, only relatively high levels of 1,1-dichloroethene in body tissues and fluids can be measured. 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 1,1-dichloroethene. Other medical tests can tell if you have been exposed to 1,1-dichloroethene by detecting changes in blood cells. One of its breakdown products, dithioglycollic acid, can also be measured in urine. None of these tests are regularly available at a doctor's office because they require special equipment, but your doctor can tell you where you can get the tests done. Although these tests can prove that a person has been exposed to 1,1-dichloroethene, they cannot tell if any health effects will occur. Since 1,1-dichloroethene leaves the body within a few days, these methods are best for finding exposures that have occurred within the last several days. Levels of 1,1-dichloroethene or its breakdown products measured in the body may not necessarily mean that exposure to 1,1-dichloroethene alone has occurred. People exposed to 1,1-dichloroethene at hazardous waste sites were probably also exposed to other organic compounds, which produce breakdown products similar to those of 1,1-dichloroethene. Other methods for measuring the effects associated with exposure to 1,1-dichloroethene (such as reduced enzyme levels) are not specific enough to detect effects caused by exposure to 1,1-dichloroethene alone. More information on the tests to find 1,1-dichloroethene in the body is found in Chapter 6.
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH?
The federal government has developed regulatory guidelines and standards to protect people from the possible health effects of 1,1-dichloroethene. The Occupational Safety and Health Administration (OSHA) requires workplace exposure limits of 1 ppm or less for an 8-hour workday to protect workers from noncancer harmful health effects. To guarantee the maximum protection for human health from the possible cancer effects of drinking water or eating fish or shellfish that contain 1,1-dichloroethene over a lifetime, the EPA recommends that the level of 1,1-dichloroethene in lakes and streams should not exceed 0.003 ppm. EPA has determined that drinking water containing 3.5 ppm (3.5 parts of 1,1-dichloroethene per million parts of water) for adults and 1 ppm for children is not expected to cause noncancerous harmful health effects.
The EPA limits the amount of 1,1-dichloroethene permitted in publicly owned waste water treatment plants. To minimize human exposure to 1,1-dichloroethene, EPA requires that industry tell the National Response Center when 100 pounds or more of 1.1- dichloroethene have been released to the environment.
For more information on federal and state recommendations, see Chapter 7.
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1. PUBLIC HEALTH STATEMENT
1.8 WHERE CAN I GET MORE INFORMATION?
If you have any more questions or concerns, please contact your community or state health or environmental quality department or:
Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 (404) 639-6000
This agency can also provide you with information on the location of occupational and environmental health clinics. These clinics specialize in the recognition, evaluation, and treatment of illness resulting from exposure to hazardous substances.
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2. HEALTH EFFECTS
2.1 INTRODUCTION
The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of 1,1-dichloroethene. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.
A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE
To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure -- inhalation, oral, and dermal; and then by health effect -- death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects, These data are discussed in terms of three exposure periods -- acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more).
Levels of significant exposure (LSE) for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowestobserved-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. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious* and "serious" effects. The distinction between "less serious" effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary 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 in the LSE tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.
Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of 1,1-dichloroethene are indicated in Table 2-1 and Figure 2-1. Because cancer effects could occur at lower exposure levels, Figures 2-1 and 2-2 also show a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10~* to 10"7), as developed by EPA
Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for 1,1-dichloroethene. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncardnogenic) over a specified
DRAFT FOR PUBLIC COMMENT ***
SL 064206
2. HEALTH EFFECTS DRAFT FOR PUBLIC COMMENT
Key to figure* Spoclaa ACUTE EXPOSURE
death
1 Rat
2 Rat 3 Rat 4 Rat 5 Rat
6 Houae
7 Houae
1 Route 9 Mouse 10 Mouse
TAKE 2-1. Lmli of Stnifleant
ta 1,1-DicMoroethene - MaUtlan
Exposure duration/ frequency
fyst
MOREL
(ppa)
LQAEL (offact)
Laaa aarloua
(PP)
Sarloua
(pfxO
Reference
1d 4hr/d
1d 4hr/d
td 4hr/d
1d 4hr/d
1d 4hr/d
4d 22-23 hr/d
1d 4hr/d
7d 23hr/d
1-8 d 6hr/d
1d 4hr/d
SL 64207
8800 (LCSO IB)) 7100 (LC50m) 10300 acsotm
10000- (LCSO) 15000c
600b (LC50) 15000' (LC50)
500- (LC50) 2500b
2010b (LCSO[B]) 415b (LCSOIN])
6545b (LCSOtF])
40 (70* orteUtyW]}
Henschler 1979 (as cited In Fielder et el. 1985)
Jaeger et at. 1973c
Jaeger et al. 1974
Jaeger et al. 1973c
Zelter et al. 1979b (as cited in Ffetder et al. 1985)
Short et al. 1977c
115' (LC50IM]) 205c (LCS0[F1)
96 (LCSOOD) 105 (LC50EF1)
SO (69X eortaUtylMl)
40b (LC50(N]) 115" (LC50IF))
Henschler 1979 (as cited in Fielder et at. 1985)
Short et at. 1977c
Oesch et al. 1983
Henschler 1979 (as cited In Fielder et al. 1985)
z, health DRAFT FOR PUBLIC COMMENT
TABLE 2-1. Levels of Significant Exposure to 1,1-Oichloroethene - 1(flotation (continued)
Key to figure* Species
duration/ frequancy
System
MOAEL (PP">
tOAEL (effect) Less serious
<PP>
Serious (Pi*)
Reference
11
Hamster
1d
4hr/d
12
Hamster
1d
i 4hr/d
1660 (LC501K]) 2945 (LC501FJ)
150b (LC50(H1) 455b (LCSOlfJ)
Klisiisch and Freisbierg 1979a (as cited in Fielder et al. 1985)
Klimisch and Freisbierg 1979b (as cited in Fielder et al. 1985)
Systemic 13
Rat
1d 4hr/d
Renal
250b {swelling in renal cortex)
300b (cortical tubular necrosis)
Jackson and Conolly 1985
14 Rat
1d 6tir/d
Hepatic Renal
200e 200c
McKenna et al. 1978a
15 Rat
1-3 d 23hr/d
Renal Hepatic
60 60 (centrllobular
1 degeneration)
16 Rat
1d 4hr/d
Hepatic
250b (decreased mitochondrial
glutathione
level)
Short et at. 1977a
Jaeger 1977
17 ftftt
1d 4hr/d
Hepatic Hepatic
2000 (Increased serua
All) 150 (Increased aerua
ALT)
Jaeger et al. 1974
18 Rt
1d 6hr/d
Hepatic Renal
200b (necrosis) 200b (hmaoglobinurea.
ttiMilsr degeneration)
McKenna et al. 1978a
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TAHLE 2*1. Levels of Significant Exposure to 1,1-0ichloroethene - Irtialatlon (continued)
Key to figure* Species
19 Rat
20 Rat 21 Mouse
22 House 23 Mouse
Mouse Reproductive 25 Mouse PevelopMntal 26 Rat 22 Rat
Exposure durstIon/ frequency
Syste
NOAEL <PP">
LUAEL (effect) Less serious
(W*>
Serious (PP*>
Reference
6 hr Ix/d
Resp
1d 10 arin
1d *hr/d
Cardlo Resp
5d 23hr/d
10 d 5d/uk 6hr/d
Mapetic Renal Hepatic
Renal
1d 6hr/d
Hepatic Renat
25600 (cardiac erryttaalss)
15 (cellular dagensration)
100 ([Flcentrilobuler suelllng and pleoanrphiaaO
55 (increased kidney ueitfit)
10 50 (cantrt lobular suelllng)
5000 (scute suelling, hesnrrhagic areas, awrked congestion of lungs)
Henschler 1979 (as cited in Fielder et el. 1985)
Siletchnik and Carlson 1976
76 (idnsa of lieigs)
Zeller et el. 1979c (aa cited In Fielder et el. 1985)
15 (tifcular nephrosis)
Short et el. 1977c
200 (tFJhepatoceltular degeneration end necrosis)
200 ([MJrenal failure)
Nenck et el. 1979
10 (nephrosis)
Reiti et al. 1960
5d 6hr/d
30
Anderson et si. 1977
11 d Sd6-16 Z3hr/d
10 d 6d6-15 7h/d
15 (lateral ventrical hydrocephalus)
Short et al. 1977a
20 80 (uavy ribs and delayed oaafficatlon)
Murray et al. 1979
oe^09
*
2. HEALTH
DRAFT FOR PUBLIC COMMENT ***
TABLE 2-1. Levels of Signifleant Exposure to 1,1-Diehloroethene - legislation (continued)
Key to figure* Species
Exposure duration/ frequency
Systen
HOAEL (ppn)
LOAEL (effect)
Less serious <PP>
Serious <PP">
Reference
28 House
29 Mouse
30 House
31 Rabbit
INTERMEDIATE EXPOSURE Death 32 Gn pig 33 Monkey Systsnic 34 Rat
35 Rat
11 d 806-16 23hr/d
4d 8d12-15 23hr/d
8d fidB-15 23hr/d
13 d Gd6-18 7h/d
90 d 24hr/d
90 d 24hr/d
90 d Sd/Mk 6hr/d
4 uk 7d/uk 24hr/d
Hepatic Hepatic
80
25 (cytopiasntc vacuolization)
50 (fatty changes) and focal necrosis)
15 (unossified incus,
Short et al.
incoapletely
1977s
ossified stemebrae)
54 (fatal resorption)
Short et al. 1977a
41 (unosslfled incus, incoapletely ossified supraocctpttel)
160 (fetal annan lies and resorptions)
Short et al. 1977a
Murrey et al. 1979
15 (3/15 died) 25 (2/3 died)
Prendergast et al. 1967 Prendergast et al. 1967
Balner et al. 1976
Plusner et al. 1990
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TABLE 2-1. Lewis of Significant Exposure to 1,1-Bichloroethane - Irfielation (continued)
Kay to figure
Specie*
36 Rst
37 Rat 38 Rat
39 Rat
AO Rst 41 On pig
Exposure
durst ton/ frequency
Sy*t
NOAEL Cppe)
LOAEL (effect) Less terioue
<PP*>
Serious (pps)
6 mo 5d/wfc Ahr/d
30 d 5d/wk Ahr/d
5 wk 5d/wk Ahr/d
Rasp Hemto Hepatic
DerWoc Hepatic
Heauto Hepatic Renal
90 d 24hr/d
Reap Hepatic
Renat
3 uk Sd/uk Ahr/d
Reap Hepatic
90 d 24hr/d
Reap Hepatic
75 75
25 (fatty changes in tdional hepatic lobule)
75
125 (centrltobutar and nidzonal cytoplasaric vacuolization)
200 (necrosis)
100 (increased plasae phosphate levels)
100 (increased liver weight)
100 (Increased kidney weight, desqusatlon of nephric epithelial cells)
48 25 48 (focal necrosis
and haanstderln deposition) 15 48 (nuclear hypertropy of tubular epitheltua)
200 (slight nasal Irritation)
500 (degeneration of liver cells)
48 5 48 (increased SOFT and W anzyeae activity.
decreased itptd content)
Reference Ouast et el. 1986
Quest 1976
Kllnisch et al. 1979 (as cited in Fielder et si. 1985
Prendergast et al. 1967
Gage 1970
Prendergast et al. 1967
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Z HEALTH *** DRAFT FOR PUBUC
TABLE 2-1. Levels of Significant Exposure to 1,1-Dfchloroethene - I(flotation (continued)
Key to figure* Species 42 Gn pig 43 Monkey
Reproductive 44 Ret CHRONIC EXPOSURE tysteaic 45 Rat
46 Mouse
47 House
Exposure
duration/ frequency
Systen
NCMEL (Pt)
L0AEL (effect) Lest serious
(ppo
Serious <Pf>
6 ufc 5d/uk 8hr/d
90 d 24hr/d
Rasp
Reap Hepatic
Other
100
48 25 48 (focal necrosis,
henosidertn deposition) 5 48 (decreased body weight)
11 ufc Sd/uk
6hr/d
55
18 no 5d/uk 6hr/d
Reap Hanato Hepatic
t yr 5d/uk 6hr/d
1 yr 5d/uk 4hr/d
Renal
Hanato Hepatic Renal Renal
75 75
25 (decreased liver weight; fatty changes In the nldxonal region)
75
55 55 (hspatoceltutor necrosis) 55 (ttAular necrosis)
10 25 (tubular nephrosis)
Reference Prendergast et at. 1967 Prendergast et el. 1967
Short et al. 1977b
Quast et al. 1986
Lee et al. 1977
Maltoni et al. 1985
06^212 SL
TABLE 2-1. Levels of tfpiificant
to 1,1-Mdiloraethene - Irhalation (continued)
Key to figure* Species
Exposure duration/ frequency
Systas
HOAEl <PP*>
LOAEL (effect) Less serious
<W>
Serious (PP)
Reference
Cancer 48
House
52 uk Sd/ufc 4hr/d
25 (CEL, renal edenocarc(nose)
Haltonl et el. 1985
*The nudter corresponds to entries In Figure 2-1. *Anleels were fasted prior to eiiposure. `AntesIs Mere fed prior to exposure (non-fasted).
AIT alanine e-Letogtut arete transaslnese; both sexes; Cardto cardiovascular; CEl cancer effect Level; d day(s); Dtrm/oc denael/ocular; Gn pig Guinea pig; F if ' (*); Gd gestation day(s); Heseto * heeatologfcal; hr * hour(s); LC50 lethal concentration, 50* kill; LOAEL lout served-adverse-effect level; N = sale(s); sin * sinute(s); so sonth(s); MQAEL no-observed-adverse-effect level; keep respiratory; * * ueek(s).
l
2. HEALTH DRAFT FOR
SL 064213
h it v x -z
drwt ro *
FIGURE 2-1. Levels of Significant Exposure to 1,1 -Dichloroethene - Inhalation
ACUTE (i14 Pay)
SL 064214
2. HEALTH
*** DRAFT FOB PUBLIC
FIGURE 2-1. Levels of SlgnMcant Exposure to 1,1-Dlchlorosthena - Inhalation (continued)
ACUTE ________________________ __________________________________
SL 064215
K1TV3H 1
DRAFT FOR PUBLIC
FIGURE 2-1. Levels of Significant Exposure to 1,1-Dlchlorothene - Inhalation (continued)
SL 642l6
Z HEALTH
FIGURE 2-1. Levels off Significant Exposure to 1,1 -Dtchloroethene - Inhalation (continued)
CHROISC fejgPgg
// / /
SL 064217
19
2. HEALTH EFFECTS
duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure.
Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised.
A User's Guide has been provided at the end of this profile (see Appendix A). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.
2.2.1 Inhalation Exposure
Table 2-1 and Figures 2-1 describe the health effects observed in laboratory animals associated with exposure level and duration.
2.2.1.1 Death
No studies were located regarding death in humans after inhalation exposure to 1,1-dichloroethene. However, animal studies indicate that 1,1-dichloroethene is lethal following inhalation exposure.
The lethality of 1,1-dichloroethene in animals following inhalation exposure varies considerably and is influenced by such factors as species, strain, sex, and food intake. Differences between strains could account for the range in reported 4-hour LC50 values in rats with access to food (nonfasted rats) (-6,000-8,000 ppm in males, and 10,000 ppm in females) (Henschler 1979; Siegel et al. 1971; Zeller et al. 1979a, 1979b). Higher 4-hour LCS0 values (10,000-15,000 ppm) have been reported for non-fasted rats (sex not specified), but the animals were observed for only 24 hours (Jaeger et al. 1973c, 1974).
The LC;0 values reported for rats that were fasted for 16 hours were generally lower than those reported for nonfasted rats. For instance, the reported 4-hour LC^ was 415 ppm in fasted male rats (Zeller et al. 1979b). In fasted female rats, which appear to be more resistant to the detrimental effects of starvation, the 4-hour LCj,, was 6,545 ppm (Zeller et al. 1979b). A study by Jaeger et al. (1974) compared the effects of food intake on the lethality of male rats exposed to 1,1-dichloroethene for 24 hours. The results, of the study revealed that the LCj0 for fasted animals was almost 30 times lower than that for nonfasted animals. The proposed mechanism by which fasting increases the toxicity of 1,1-dichloroethene is discussed in Sections 23 and 2.4.
Identical trends are seen in mice and hamsters (i.e., nutritional status and sex influence the lethality of 1,1-dichloroethene following inhalation exposure). Mice, however, are considerably more susceptible to the lethal effects of 1,1-dichloroethene than are rats. Reported 4-hour LCS0 values in nonfasted mice range from 40 (males) to 200 ppm (females) (Henschler 1979; Oesch et aL 1983; Short et al. 1977c) and in fasted mice from 40 (males) to 115 ppm (females) (Henschler 1979). Similarly, fasted male Chinese hamsters are more susceptible than fasted females to the lethal effects of inhaled 1,1-dichloroethene (Henschler 1979; Klimisch and Freisberg 1979a, 1979b). Death was also reported in squirrel monkeys exposed to 25 ppm 1,1-dichloroethene following intermediate-exposure (Prendergast et al. 1967).
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20
2. HEALTH EFFECTS
LCS0 values and all LOAEL values from each reliable study 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 1,1-dichloroethene in humans. This information comes primarily from case reports and/or insufficiently detailed mortality studies in which the concentration and duration of exposure to 1,1-dichloroethene was not 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 1,1-dichloroethene can induce neurotoxicity after short-term exposure (Henschler et al. 1970; Tierney et al. 1979) and that 1,1-dichloroethene is possibly associated with hepatoand nephrotoxicity after repeated, low-level exposure in humans (Ott et al. 1976; Tierney et al. 1979).
Considerable information is available on the systemic effects of 1,1-dichloroethene following both shortand long-term e' isure in laboratory animals. The target organs or systems of 1,1-dichloroethene toxicity are reported to the central nervous system, liver, kidney, and lungs, with adverse effects occasionally being noted in trie heart.
No studies were located regarding gastrointestinal or musculoskeletal effects in humans or animals after inhalation exposure to 1,1-dichloroethene. The systemic effects observed following inhalation exposure are discussed below.
The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1.
R spiratory Effects. Only one study was located regarding respiratory effects in humans after inhalation exposure to 1,1-dichloroethene. The study reports irritation of the upper airway (inflammation of mucous membranes) in acutely exposed individuals (1711 1982).
Irritation of the mucous membranes and pulmonary edema/congestion and hyperemia are consistently seen at necropsy in rodents acutely exposed to high levels of 1,1-dichloroethene (500-15,000 ppm) via inhalation (Henschler 1979; Klimisch and Freisberg 1979a; Zeller et al. 1979b); the severity of these effects was increased in fasted rats (Zeller et al. 1979b).
Nasal irritation was observed in rats exposed to 200 ppm for 4 weeks (Gage 1970). Inflammation of the trachea was reported in rats exposed to 75 ppm 1,1-dichloroethene for 6 months (Quast et al. 1986). Other pulmonary effects seen in rats, guinea pigs, and dogs exposed to 48 ppm of 1,1-dichloroethene continuously for 90 days included discoloration and morphological changes in the lungs (Prendergast et al. 1967). These effects appear to be nonspecific in nature and are primarily due to 1,1-dichloroethene's local irritating properties. No histopathological effects attributed to treatment were observed in rats, monkeys, dogs, rabbits, or guinea pigs exposed to 100 ppm 1,1-dichloroethene intermittently for 6 weeks (Prendergast et al. 1967) or in rats similarly exposed to 75 ppm 1,1-dichloroethene for 18 months (Quast et al. 1986). The data suggest that any possible respiratory effects associated with inhalation exposure to 1,1-dichloroethene (particularly acute) in humans are Ukely to be a consequence of local, nonspecific irritation.
Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after inhalation exposure to 1,1-dichloroethene.
Few studies are available that describe adverse cardiovascular effects of 1,1-dichloroethene following inhalation exposure in laboratory animals. Acute exposure of rats to extremely high concentrations (25,600 ppm for 10 minutes) produced arrhythmias mediated by the sympathetic nervous system (Siletchnik and Carlson 1974). These authors also found that 1,1-dichloroethene at 25,600 ppm increased the
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51 os,2lg
21
2. HEALTH EFFECTS
sensitivity of the myocardium to epinephrine, thereby providing a mechanism for the electrocardiographic changes. These effects are better characterized as nonspecific neurological effects.
Cardiac effects such as contraction of the main vessels, dilation of the right side (most likely secondary to pulmonary congestion) and hyperemia were observed following acute, high-level exposure (500-15,000 ppm) to 1,1-dichloroethene (Kiimisch and Freisberg 1979a, 1979b; Zeller et al. 1979b). Cardiovascular toxicity was not generally observed after more prolonged, lower-level exposure, and is, therefore, most likely not a concern for prolonged low-level exposure in humans.
H matologlcal Effects. No studies were located regarding hematological effects in humans after inhalation exposure to 1,1-dichloroethene.
The available studies did not evaluate the hematological parameters following acute and intermediate exposure to 1,1-dichloroethene. No hematological alterations were observed in male rats (Quast et al. 1986) or in mice (Lee et al. 1977) exposed to 75 ppm 1,1-dichloroethene for 18 months or to 55 ppm 1.1- dichloroethene for 12 months, respectively.
H patlc Effects. Hepatotoxicity has been observed in humans after repeated exposure to 1.1- dichloroethene, presumably by the inhalation route. Preliminary clinical findings of workers exposed to 1.1- dichloroethene for 6 years or less in a 1,1-dichloroethene polymerization plant revealed a high incidence of hepatotoxicity. Liver scans and measurements of liver enzymes revealed 50% or greater loss in liver function in 27 (59%) of the 47 exposed workers (EPA 1985a; Tierney et al. 1979). These findings must be considered only qualitative in nature, since the study provided few details, and no follow-up study has been reported.
In laboratory animals, the liver is a major target organ of 1,1-dichloroethene toxicity following acute and chronic inhalation exposure. Hepatotoxicity is evident by the appearance of both biochemical changes (alterations in serum enzyme levels indicative of liver injury and induction of hepatic enzymes) and marked histological changes (e.g., midzonal and centrilobular swelling of liver, degeneration, and necrosis of hepatocytes). These effects appear to follow a dose-response relationship and may also be influenced by duration of exposure. Mice exposed to 50 ppm 1,1-dichloroethene 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 1,1-dichloroethene for 23 hours/day for 5 days induced an increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which is indicative of liver injury. Under the same exposure regimen, hepatic degeneration was seen at 60 ppm (Short et al. 1977c). Similar results were obtained in four strains of mice that were exposed to 55,150, or 200 ppm 1,1-dichloroethene for 6 hours/day, 5 days/week, for 10 days. Hepatotoxic effects characterized by hepatocellular degeneration and necrosis with centrilobular hepatocellular swelling and pleomorphism at 100 and 200 ppm were observed in all strains. These effects were more severe in females (Henck et al. 1979). Severe effects were seen at higher doses in rats for even shorter-duration exposures. After inhalation exposure of rats to 200-250 ppm 1,1-dichloroethene for 4 hours the following effects were observed: increased liver weight, increased serum activities of sorbitol dehydrogenase and ornithine carbamoyl transferase (Jackson and Conolly 1985; Jaeger 1977), and massive histological injury of the liver (Reynolds et al. 1980).
The food intake of the organism prior to exposure influences the degree of 1,1-dichloroethene-induced hepatotoxicity, with more severe effects displayed by animals fasted overnight prior to exposure. This suggests that a relationship exists between chemical toxicity and depletion of reduced glutathione (GSH) (Reynolds et al. 1980). For example, results from acute studies in male rats demonstrate that inhalation exposures to low levels (60-200 ppm) of 1,1-dichloroethene for periods ranging from 75 minutes to 23 hours induced increases in serum enzyme levels indicative of liver dysfunction--aspartate aminotransferase (AST), alanine alpha-ketoglutarate transaminase (AKT), and alanine aminotransferase (ALT)--in fasted animals, but not in nonfasted animals (Andersen and Jenkins 1977; Jaeger et al. 1974). Only a slight increase in the serum enzymes was observed in nonfasted rats exposed to 2,000 ppm or more
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SL 064220
22 2. HEALTH EFFECTS
1,1-dichloroethene (Jaeger et al. 1974). Gross and microscopic histopathological, and biochemical evidence of hepatotoxicity occurs earlier and is more extensive in fasted rats following short-term inhalation exposure to 1,1-dichloroethene. Exposing fasted rats to 200 ppm 1,1-dichloroethene for 4 hours or less resulted in aberrations in hepatic GSH levels that preceded and/or accompanied major histological changes (Jaeger et al. 1975a; McKenna et al. 1978a; Reynolds et al. 1980). As mentioned above, the increased hepatotoxic effects of 1,1-dichloroethene following inhalation exposure seen in fasted versus nonfasted animals may be related to depletion of hepatic GSH levels in the fasted animals. GSH is known to be involved in 1,1-dichloroethene metabolism (see Section 2.3). GSH levels in rats fed ad libitum exhibited a marked diurnal rhythm; levels were minimal at 1,900-2,200 hours and maximal at 700-1300 hours (Jaeger et al. 1973a). This increase was prevented in fasted rats, with maximal levels reduced by 50%. Furthermore, the 1,1-dichloroethene-induced hepatotoxicity coincided with the reduction in liver GSH levels (Jaeger et al. 1973a). Nonfasted rats exposed to 1,1-dichloroethene via inhalation for 1.000- 1,400 hours exhibited no signs of hepatotoxicity, but when they were exposed to similar levels of 1.1- dichloroethene during the diurnal period of minimal GSH levels, 40% died and serum enzyme markers increased markedly.
The hepatotoxic effects of 1,1-dichloroethene following intermediate or chronic exposure in animals are similar to those described above for acute exposure (Gage 1970; Lee et al. 1977; Plummer et al. 1990; Quasi et al. 1986). Many of the studies that describe the longer-term effects of 1,1-dichloroethene in animals are limited in that only a few experimental details were provided or only one or two doses were studied. These limitations often prevent an adequate assessment of the quality of the results. Male and female rats exposed for 6 hours/day, 5 days/week, over a 30-day period, to 125 or 200 ppm 1,1-dichloroethene exhibited liver changes. These changes were more severe in female, and were characterized by a minimal degree of centrilobular fatty degeneration or hepatocellular necrosis (Quast 1976). Mild dose-related hepatotoxic effects consisting of cytoplasmic vacuolation were observed in male and female rats exposed to 25 or 75 ppm 1,1-dichloroethene 6 hours/day, 5 days/week for either 30 or 90 days (Balmer et al. 1976). The authors considered these changes reversible. Fatty infiltration of the liver was reported in rats exposed to 25 ppm of 1,1-dichloroethene 6 hours/day, 5 days/week, for 6 months (Quast et al. 1986).
Animals appear to be much less tolerant of continuous (23-24 hours per day) than intermittent exposure
to 1,1-dichloroethene. There was no evidence of toxicity in beagle dogs exposed to 100 ppm of
1,1-dichloroethene for 8 hours/day, 5 days/week, for 43 days, but continuous exposure to 48 ppm of
1,1-dichloroethene for 90 days caused marked liver da' ?e (Prenderrvt et al. 1967). Similarly, squirrel
monkeys continuously exposed to 48 ppm l,l-dichlor< me for 90
exhibited marked evidence of
liver damage (i.e., focal necrosis and hemosiderin dep< ;on). How* , no liver toxicity was apparent
following 42 days of intermittent exposure to 100 ppm i.l-dichloroethene (Prendergast et al. 1967). It
would appear that when animals are exposed to 1,1-dichloroethene 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 1,1-dichloroethene-induced
hepatotoxicity.
Hepatotoxic effects similar to those discussed above are seen fallowing chronic inhalation exposure to 1,1-dichloroethene in laboratory animals (Lee et al. 1977; Quast et al. 1986). Female rats exposed to 1.1- dichloroethene via inhalation at a concentration of 25 ppm for 6 hours/day, 5 days/week, for 18 months, exhibited fatty changes in the liver (Quast et al. 1986). The results of these studies are only suggestive because of the poor presentation of the data.
Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1.1- dichloroethene.
Adverse effects have been observed in the kidneys of laboratory animals following acute, intermediate, and chronic inhalation exposure to 1,1-dichloroethene. These effects are manifested as enzyme changes
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(decreases in kidney monooxygenase and epoxide hydrolase levels) (Oesch et al. 1983), tubular alterations (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; Watanabe et al. 1980). Following acute exposure, the range of 1,1-dichloroethene 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 1,1-dichloroethene than female mice or both sexes of rats. Severe histological lesions of the kidney were observed in mice following acute inhalation exposure to 10-50 ppm of 1,1-dichloroethene (Reitz et al. 1980; Short et al. 1977c; Watanabe et al. 1980). Similar results were obtained in four strains of mice exposed to 55,100, or 200 ppm for 6 houis/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 male mice (Henck et al. 1979). There is evidence that kidney damage in animals after acute inhalation exposure to 1,1-dichloroethene is reversible, though this may depend on the dose level and duration of exposure. Tubular regeneration was evident in mice 48 hours after a single 6*hour exposure to 50 ppm 1,1-dichloroethene (Reitz et al. 1980). However, reversibility of kidney damage at higher exposure concentrations has not been demonstrated.
As was seen with hepatotoxicity, the amount of food intake of the animal appears to be an important determinant of 1,1-dichloroethene-induced nephrotoxicity. Fasted male rats exposed once to 200 ppm 1,1-dichloroethene for 6 hours exhibited delayed hemoglobinuria and marked tubular degeneration, while fed male rats similarly exposed displayed no treatment-related toxic effects (McKenna et al. 1978a). GSH depletion may play an indirect role in the exacerbation of 1,1-dichloroethene-induced nephrotoxicity in the fasted rat
The bulk of the information on 1,1-dichloroethene-induced nephrotoxicity in animals comes from acute experiments and evidence of nephrotoxicity after intermediate exposure is limited. Continuous inhalation exposure of rats to 48 ppm 1,1-dichloroethene for 90 days resulted in nuclear hypertrophy of the renal tubular epithelium (Prendergast et at 1967). Severe nephrotoxicity occurred in male mice exposed to 25 ppm 1,1-dichloroethene 4 hours/day, 4-5 days/week, for 1 year (Maltoni et al. 1985). Hie reversibility of this effect was not determined. No treatment-related effects were noted in the kidneys of rats chronically exposed to a concentration of 25 or 75 ppm 1,1-dichloroethene for 6 hours/day, 5 days/week, for 18 months (Quast et al. 1986). Species differences may account for the differential susceptibility to 1,1-dichloroethene exposure.
Dermal/Ocuiar Effect*. No studies were located regarding dermal/ocular effects in humans followinginhalation exposure to 1,1-dichloroethene.
No eye irritation was observed in rats exposed to an average concentration of 75 ppm 1,1-dichloroethene for 18 months (Quast et al. 1986).
Other Systemic Effects. No studies were located regarding other systemic effects in humans after inhalation exposure to 1,1-dichloroethene.
A decrease in body weight was reported in rabbits exposed to 25 ppm 1,1-dichloroethene continuously for 90 days or to 100 ppm 1,1-dichloroethene intermittently for 6 weeks (Prendergast et aL 1967). Similar results were reported in monkeys exposed to 15 or 48 ppm 1,1-dichloroethene continuously for 90 days or intermittently to 100 ppm 1,1-dichloroethene for 6 weeks (Prendergast et al. 1967). Food consumption data were not provided. A decrease in body weight was also reported in rats exposed to 500 ppm 1,1-dichloroethene intermittently for 3 weeks, but the magnitude of the effect was not provided (Gage 1970).
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2.2.1.3 Immunological Effects
No studies were located regarding immunological effects in humans or animals after inhalation exposure to 1.1- dichloroethene.
2.2.1.4 Neurological Effects
Central nervous system depression and symptoms of inebriation, which may progress to convulsions, spasms, and unconsciousness, have been observed in humans after acute exposure to high airborne concentrations (-4,000 ppm) of 1,1-dichloroethene (Tierney et al. 1979). Complete recovery generally occurs if exposure is not prolonged. However, two cases of persistent cranial nerve disorders were observed following acute inhalation exposure to 1,1-dichloroethene. These cases primarily involved 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 eye muscles (Henschler et al. 1970). These two patients were involved in manually cleaning tanks used in the transport of an aqueous dispersion 1.1- dichloroethene copolymers. The effects were most likely a result of dichloroacetylene format from 1.1- dichloroethene due to heat and the presence of alkali from the soaps used; chloroacetylenes highly neurotoxic (Fielder et al. 1985). There is no direct evidence that 1,1-dichloroethene can produce adverse neurological effects, but it is a possibility that similar conditions may occur (i.e., heat and an alkali environment) which could generate chloroacetylenes from 1,1-dichloroethene at hazardous waste sites.
Signs of central nervous system toxicity were observed in animals after acute inhalation exposure. The toxic signs are similar across species and consist primarily of central nervous system depression, lacrimation, dyspnea, tremor, convulsions, uncoordinated motor response, and narcosis, ultimately resulting in death (Henschler 1979; Klimisch and Freisberg 1979a, 1979b; Zeller et al. 1979a, 1979b). These signs can also be accompanied by lethargy, rough coats, and a hunched appearance (Zeller et al. 1979b). Acute exposure of rats to extremely high concentrations (25,600 ppm for 10 minutes) induced increased sympathetic activity, resulting in cardiac arrhythmia (Siletchnik and Carlson 1974).
No studies were located regarding neurological effects in humans or animals following intermediate or chronic inhalation exposure.
2.2.1.5 Reproductive Effects
No studies were located regarding reproductive effects in humans following inhalation exposure to 1.1- dichloroethene.
Premating exposure of male rats to 55 ppm 1,1-dichloroethene 6 hours/day, 5 days/week, for 11 weeks, did not affect their fertility (Short et al. 1977b; no pre- or post-implantation losses occurred in untreated pregnant females mated to treated males. Similarly, inhalation exposure of male mice to 10 or 30 ppm 1.1- dichloroethene for 6 hours/day for 5 days had no adverse effect on fertility (Anderson et al. 1977). Decreased fertility was observed in rats following inhalation exposure to 50 ppm 1,1-dichloroethene for 5 days. However, the authors attributed the decrease to infertility in males that ordinarily might not have been used but had to be included in the study in order to establish a sufficient group size.
The highest NOAEL value from each reliable study for reproductive effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1.
2.2.1.6 Developmental Effects
No studies were located regarding developmental effects in humans following inhalation exposure to 1.1- dichloroethene.
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1.1- Dichloroethene appears to produce weak teratogenic effects in laboratory animals (Short et al. 1977a). 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 developmental^ toxic doses. Doses of 1,1-dichloroethene used in these studies ranged from IS to 449 ppm. Increased mortality was observed in both pregnant and nonpregnant mice exposed to 144 ppm or more and rats exposed to 57 ppm or more. Skeletal anomalies in rats and mice and soft tissue anomalies in rats were observed at IS ppm. Because of the high incidence of fetal resorptions observed in these initial experiments, Short et al. (1977a) conducted additional studies in mice. Pregnant animals were exposed via inhalation to various concentrations of 1,1-dichloroethene ranging from 41 to 112 ppm. The experiments were performed over different exposure durations that covered various phases of fetal development. Statistical analysis by two sample rank tests demonstrated that 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, deft palate, and hydronephrosis. Skeletal anomalies were also observed.
A statistically significant increase in the incidence of minor skeletal anomalies was observed in the litters of rats exposed to 80 and 160 ppm 1,1-dichloroethene and in the litters of rabbits exposed to 160 ppm 1.1- dichloroethene (Murray et al. 1979). Developmental toxicity was evidenced by wavy ribs and delayed ossification in rat fetuses and by increased resorptions 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 exposed to 20 ppm or in rabbits exposed to 80 ppm 7 hours daily during pregnancy. A NOAEL for developmental toxicity following continuous inhalation exposure was not identified.
The highest NOAEL values and all LOAEL values from each reliable study for developmental effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1-
2.2.1.7 Genotoxlc Effects
No studies were located regarding genotoxic effects in humans after inhalation exposure to 1.1- dichloroethene.
Inhalation of 1,1-dichloroethene vapors in animals has resulted in dominant lethal gene mutations (Anderson et al. 1977; Short et al. 1977b) and has produced deoxyribonucleic add (DNA) damage, as indicated by a slight increase in repair rates in mouse kidney cells in which normal replicative DNA synthesis bad been inhibited (Reitz et al. 1980). Inhalation of 1,1-dichloroethene 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 1,1-dichloroethene 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 exposure levels are capable of inducing a low inddence of DNA damage in the kidney cells of mice and minimal alkylation in liver and kidney.
Other genotaxidty studies are discussed in Section 2.4.
2.2.1.8 Cancer
No relationship between the occurrence of cancer in humans and occupational exposure (primarily chronic inhalation exposure) to 1,1-dichloroethene has been demonstrated. However, only three studies were available for analysis.
Chronic occupational exposure to 1,1-dichloroethene was not associated with the occurrence of angiosarcoma in rubber-plant workers (Waxweiler 1981). Similarly, no assodation was found between occupational exposure and cancer mortality in 1,1-dichloroethene production and polymerization plant
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workers (Ott et al. 1976; Thiess et aL 1979). 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 1,1-dichloroethene. 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, risk was underestimated. The Ott et al. (1976) study described liver enzyme changes in two workers and gave clinical chemistry findings comparing two cohorts. None of the clinical chemistry values were significantly different between the two cohorts.
The carcinogenicity of 1,1-dichloroethene 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 1,1-dichloroethene in these studies ranged from 10 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 1,1-dichloroethene exposure.
In a study reported by Maltoni et al. (1985), male and female Swiss mice wer xposed by inhalation to 0, 10, or 25 ppm 1,1-dichloroethene 4 hours/day, 4-5 days/week, 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 occurred; however, no dose-response was evident. Lung tumors (most of which were benign pulmonary adenomas) increased in males at 10 ppm and in 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 highdose 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 or the 186 control males. Renal adenocarcinomas are rare tumors in the Swiss mouse. The kidney tumors were accompanied by severe nephrotoxic effects including nephrosis. Moreover, an increased incidence of renal tumors in the male mice was only observed at doses that induced toxicity and which approximated the acutely lethal concentration. Only one female developed kidney tumors, but there appeared to be no difference between the sexes with regard to the incidence of regressive changes in the kidney. Thus, it is difficult to assess whether the occurrence of nephrosis predisposes the animal to the development of kidney tumors. This study can only be used to provide suggestive evidence of 1,1-dichloroethene-induced carcinogenicity in animals because of the inadequate exposure duration.
An increased incidence of malignant mammary tumors and leukemia was reported in rats exposed to 100 ppm 1,1-dichloroethene 7 hours/day, 5 days/week, for 104 weeks (Cotti et aL 1988; Maltoni et al. 1985). Pregnant female rats were exposed on gestation day 12; the exposures continued in dams and "50% of the offspring (in 12-day and older embryos via transplacental exposure, followed by inhalation exposure for all progeny from this group) for 104 weeks. The remaining 50% were exposed for 15 weeks only. The highest tumorigenic response was seen in offspring treated for 104 weeks. The authors concluded that under these exposure conditions (high doses during and after embryonal development), 1,1-dichloroethene is carcinogenic in rats. However, the results of this study are not definitive since the authors did not present statistical analyses and used ambiguous terminology (i.e., `total malignant tumors") to present the results.
Results of other inhalation studies with laboratory animals were negative regarding carcinogenicity (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 to 0 or 55 ppm 1,1-dichloroethene for 1 year. Few hepatic hemangiosarcomas, hepatomas, bronchioalveolar adenomas, and skin keratoacanthomas were observed in experimentally treated mice; but some of the rats exposed to 55 ppm 1,1-dichloroethene developed hemangiosarcomas of the mesenteric lymph nodes and the subcutaneous tissu . The incidence of these lesions, however, was not statistically significant In a follow-
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up study, carcinogenicity was examined in rats and mice during a 12-month period (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 1,1-dichloroethene. Though the increased tumor incidences observed in Lee et al. (1977,1978) and Hong et al. (1981) were not statistically significant, these studies provide evidence of the differences in species and strain sensitivity to the effects of 1,1-dichloroethene exposure.
Male and female rats were exposed to 0, 25, or 75 ppm 1,1-dichloroethene via inhalation for 18 months (Quast et al. 1986). A statistically significant increase (p<0.05) in adenocarcinomas of the mammary gland was noted in the low-dose females (25 ppm). The authors did not consider this increase related to 1.1- dichloroethene exposure because the incidence of mammary gland adenocarcinomas in the treatment groups was within the range of historical control data and was not dose-related.
Both female and male rats were exposed to 0,10, 25, 50,100, or 150 ppm 1,1-dichloroethene for 1 year (Maltoni et al. 1985). The incidence of total mammary tumors (fibroadenomas, carcinomas, sarcomas, carcinosarcomas) increased in females in the 10- and 100-ppm exposure groups. However, evidence for a carcinogenic effect from inhalation exposure to 1,1-dichloroethene in this study was inconclusive because there was no clear dose-related increase in total mammary tumor incidence, the latency time for mammary tumor incidence was similar in all treated and control groups, the incidence (62%) of spontaneous mammary tumors in controls was high, and the incidence of mammary gland carcinomas in treated groups was lower than that of controls.
The effects of chronic inhalation exposure of CD-I mice and CD rats to 55 ppm 1,1-dichloroethene 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 none were found in the controls. The authors claimed that rats were more resistant than mice to the carcinogenic effects of 1.1- dichloroethene, 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 turnon that have a longer latency period.
In a follow-up study, CD-I mice and CD rats were exposed to 55 ppm 1,1-dichloroethene 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). The mortality incidence was high; in mice exposed for 6 months and rats exposed for 10 months, 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 of tumors in any of the treated animate compared to untreated animals. However, the study was limited by the following factors: the small number of animate used in each group which decreased the ability of the study to detea a tumorigenic response, and the exposure durations were considerably less than the expected lifetime of the mice.
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, small numbers of animate, and/or HmimH 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). These limitations can impair the sensitivity of a test to detea a carcinogenic response.
EPA has derived an inhalation unit risk of 5x10'* /tg/m3 for cancer risk associated with inhalation exposure to 1,1-dichloroethene based on the study by Maltoni et aL (1985) in mice (IRIS 1992). EPA indicates, however, that it may not be appropriate to use this inhalation unit risk if the air concentration exceeds 0.05 ppm. The air concentrations associated with the upper bound for an individual lifetime cancer risk of 1C4 to 10'7 are 5x1c4 to 5xl0`7 ppm, respectively. This range is plotted in Figure 2*1. The
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exposure concentration associated with an increase incidence of kidney adenocarcinoma (25 ppm) in male mice is presented in Table 2-1 and plotted in Figure 2-1.
2.2.2 Oral Exposure
2.2.2.1 Death
No studies were located regarding death in humans after oral exposure to 1,1-dichloroethene.
Death has been observed in laboratory animals following oral exposure to 1,1-dichloroethene. The database on the lethality of ingested 1,1-dichloroethene in animals consists primarily of gavage studies in fasted rats. However, there were a few studies located regarding the lethality of mice or other species.
Reported oral LD50 values in rats are -1,500 mg/kg (Jenkins et al. 1972; Jones and Hathway 1978a). The threshold for mortality in male rats is 50 mg 1,1-dichloroethene/kg in corn oil (Andersen and Jenkins 1977). The limited data available for mice indicate that this species is considerably more sensitive than rats to the lethal effects of ingested 1,1-dichloroethene. Reported LD50 values in mice are -200 mg/kg (Jones and Hathway 1978a).
Since all available data are from fasted animals, it is not possible to determine whether the amount- of food intake of the animal influenced the lethality of ingested 1,1-dichloroethene, as it did during inhalation exposure. It has been demonstrated by Jenkins et al. (1972) that adrenalectomy in rats exacerbates the lethal effects of ingested 1,1-dichloroethene. These investigators reported an oral LD50 of 80 mg/kg for 1,1-dichloroethene in adrenalectomized rats. The mechanism and significance of this effect is undear but may involve a compromise in the animal's response to stress.
Oral administration of a single dose of 1,1-dichloroethene to fisted rats revealed that young male rats (100-200 g) appeared to be more susceptible than older rats to its lethal effects (Andersen and Jenkins 1977). This age-dependent difference in toxicity was not seen in females, although male mice fasted before inhalation exposure showed signs of enhanced 1,1-dichloroethene toxicity compared to nonfasted rats.
In summary, ingested 1,1-dichloroethene is' moderately toxic in at least two spedes of laboratory animals. Young animals and those with compromised stress responses appear to be most susceptible to these effects.
All LDS0 values and LOAEL values from each reliable study for death in each spedes and duration category are recorded in Table 2-2 and plotted in Figure 2-1
2.2.2.2 Systemic Effects
No studies were located regarding systemic effects in humans following oral exposure. 1,1-Dicfaloroethene has been shown to adversely affect several organ systems in laboratory animals. The major target organs of 1,1-dichloroethene toxicity in animals are the liver and kidney. In addition, some studies suggest that 1,1-dichloroethene may induce adverse effects on the respiratory and gastrointestinal systems following oral exposure.
No studies were located regarding cardiovascular, musculoskeletal or dermal/ocular effects in animals following oral exposure to 1,1-dichloroethene. The systemic effects observed after oral exposure are discussed below.
The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2.
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TABLE 2-2. levels of Significant Exposure to 1,1-DfcMoroethene - Oral
Key to
duration/
figure* Species Route frequency
HOAEL Systea (ag/kg/day)
lGAEL (effect)
Less serious (ag/kg/day)
Serious (ag/kg/day)
Reference
ACUTE EXPOSURE
Death 1
Kftt
(6) 1 d
3 2 Rat (G) 1 d
3 Rat (G) 1 d
1500* (1050) 80* (1050adrenal ectoay) 50* (LDlo, 10X died)
1550 (LD50)
Jenkins et al. 1972
Anderson and Jenkins 1977
Jones and Hathuay 1978a
4 House (G) 1 d
Syateaiic 5 Rat
(GO) 1 d Ix/d
6 Rat (6) 1 d Ix/d
7 Hat (G) 1 d Ix/d
8 Rat (G) 1 d Ix/d
9 Rat (GO) 1 d Ix/d
194 (ID50EF1) 217 (ID50 Dll)
Hepatic Hepatic Hepatic Hepatic
Hepatic
50 (Increased seru* alanine aalnotraneferase)
200b 400* (Increased triglycerides)
200* (Increased SCOT and SGPT activity)
200* (decreased blle flow. Increased plasaa levels of GOT and LDH)
50 (bile canalleutl Injury In the centrHobular tone)
Jones and Hathuay 1978
Hoslen et al. 1989b
Jaeger et at. 1973b Chleco et at. 1981 Hoslen et at. 1985
Hoslen et al. 1989a
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TAOLE 2-2. Iml* of Significant Exposure to 1,1-Didiloroethene - Oral (continued)
Key to
duration/
figure* Species Route frequency
HOAEL Systeai (ag/kg/day)
IQAEt (effect)
Lest serious (ng/kg/day)
Serious (g/kg/day)
Reference
10
Rot (GO) .1 d
Hapotic
11
Hit (C) 1 d
Renal
Ix/d
Hapotic
12
Rot (6) 1 d
Reap
Ix/d
Cordlo
Gastro
Nepotic
Other
13
Mouse (G) 1 d
Keep
Developawntal 14 Rat
(W) 10 d Gd6-IS od lib
200* 100*
100 (centrolobular and Idzonal necrosis)
400* (Increased serua levels of LDH and SDH)
400* (tubular necrosis. Increased serial creatinine)
200 200
200 (edaaa of forestcoach)
200 (Increased haaoglcbin level)
200* (granular "hene1* costs In Nanle,s loop)
200
200* (henorrhegic liver and nidioneI necrosis)
200 (reversible and disruption of Clsrs cells)
Kent et el. 1991 Jenkins and Andersen 1978
Chieco et ol. 1981
Forkert et et. 1985
40 Murray et at. 1979
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2 HEALTH
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TABLE 2-2. Level* of Significant
to 1,1-Dichloroethene - Oral (continued)
Key to figure*
Exposure duration/ Species Route frequency
NQAEL Syste* (sg/kg/day)
LQAEL (effect)
Less serious (eg/kg/dey)
Serious (ng/kg/day)
INTERMEDIATE EXPOSURE
Systeefc
15 Dog <U) 97 d ad (lb
CHRONIC EXPOSURE Systenlc 16 Rat
(U) 2 yr ad (lb
17 Rat (U) 2 vr ad (lb 3 gen
HaaMto Hepatic Renal
Haaato Hepatic Renal Hepatic
10
Rat (U) 2 yr
Heaaito
ad (lb
Hepatic
3 gen
19
Rat (U) 2 yr
lleneto
ad (lb
Hepatic
Renat
25 25 25
19.3 10
19.3
19.3 (cytoplasatic vacuo!IxatIon)
9 (hepatocellular fatty changes, accentuated hepatic lobular pattern)
30 9C (hepatocellular suet ting, aldxonat fatty changes)
25.6 12.6
25.6
25.6 (cytoplasalc vacuolization)
Reference
Quest et at. 1963
Raspy et al. 1977
Hitschke et al 1983
Quest et al. 1983
Raspy et al. 1977
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TABLE 2-2. Levels of Significant Exposure to 1,1-Dichloroethene - Oral (continued)
Key to figure'
Species
Route
Exposure duration/ frequency
N0AEL Systeai (ag/kg/day)
LOAEL (effect)
Less serious (ag/kg/day)
Serious (ag/kg/day)
Reference
Reproductive 20 Nat
(W) 2 yr ad lib 3 gen
30
Nitschke et at. 1983
*The mater corresponds to entries In Figure 2-2. *Antaels were fasted prior to exposure. `Used to derive e chronic Hlntaal Risk Level (NHL) of 0.009 ag/kg/day; dose divided by on uncertainty factor of 1,000 (10
for the use of s LOAEL, 10 for extrapolation fra* anisMls to huaans, and 10 for huaan variability).
ad lib * ad tibitua; Cardio cardiovascular; d * day(s); F * feasle(a); (6) gavage; Gastro * gastrointestinal; Gd = gestation day(s); gen * generations; (00) gavage oil; Heaato hesMtologlcal; LD50 lethal dose, SOX kilt; IDH lactate dehydrogenase; LOU * lowest lethal dose; LOAEL * lowest-observed-adverse-effect level; N * aaie(s); M0AEL no-observed-adverse-effect level; Rasp * respiratory; SDH * sorbitol dehydrogenase; (U) drinking water; wk * week(s); x * tiae(s); yr * year(s).
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FIGURE 2-2. Levels of Significant Exposure to 1,1 -Dlchloroethene - Oral
ACUTE
<*140y)
////
/
1.000 -
Oim O'* O'* O* O'* Oo*** Oo*'" o*
2 8r 8:"
O'" 0> O'*
o*
ai aoi aooi
si
FIGURE 2-2. Levels of Significant Exposure to 1,1-Oichloroethene - Oral (continued)
MTERMEDIATE (15-364 Dy)
CHROtSC _____________ fe 363 Dy)
// /
14000 f>
tjQOQ
/ / V/
I On 0- 0-
8it '" 3m nifc 8lS o*>
2. HEALTH DRAFT FOR
&1
non
r Rtf m Sour d Dog
LOOOAjCOO lOAELkroodoo-
0 ICMLtorlMO
0 NCAaiMMd
Kw |^
`j _.. "**>
1 MMiarnwRarix oftocfeadarOionooncar 1 w
ThOflMdOMrttoMdll
DortrtottaTdUtML
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36 2. HEALTH EFFECTS
Respiratory Effects. No histopathological changes were observed in the lungs of nonfasted or fasted rats administered a single gavage dose of 200 mg/kg 1,1-dichloroethene in either corn oil, mineral oil, or an aqueous solvent (Chieco et al. 1981).
Pulmonary injury was observed in mice exposed to a single oral dose of 200 mg/kg (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; cellular regeneration was evident within 5 days of treatment. The relevance of these findings to human exposure is questionable.
Gastrointestinal Effects. Edema of the forestomach was observed in fasted and nonfasted rats after a single gavage dose of 200 mg/kg (Chieco et al. (1981). However, this alteration was not associated with any discernible degenerative changes, and its relevance to human exposure is unknown. No short-term studies of 1,1-dichloroethene administered in food were located.
H matologlcal Effects. A significant increase (p<0.001) in plasma free hemoglobin was observed in fasted rats administered a single dose of 200 mg/kg 1,1-dichloroethene in mineral oil or in corn oil (Chieco et al. 1981). The effect was not as marked, although still significant (p<0.05), when 1,1-dichloroethene was given to nonfasted rats in either vehicle. According to the investigators, the effect does not represent a true hematological effect but is due to hemolysis of red cells trapped in the congested sinusoids of. the injured liver.
No significant changes in hematological or clinical chemistry parameters were observed in dogs exposed to 25 mg/kg/day 1,1-dichloroethene in drinking water for 97 days (Quast et al. 1983). Similar results were observed in rats exposed to *30 mg/kg/day in drinking water for 2 years (Quast et al. 1983; Rampy et aL 1977).
Hepatic Effects. 1,1-Dichloroethene is hepatotoxic in laboratory animals, particularly after ingestion of an acute dose. A complete spectrum of effects indicative of liver toxicity has been observed in animals following acute oral administration of 1,1-dichloroethene, and their incidence and severity tend to be dose related. Significant increases in serum enzyme markers of liver damage or dysfunction (ALT and AST) have been noted in fasted rats after the ingestion of a single dose of 50 mg/kg or more (Andersen and Jenkins 1977; Andersen et al. 1980; Jenkins and Andersen 1978; Moslen et al. 1989b). Acute exposure to 50 mg/kg induced bile canalicular injury in rats (Moslen et al. 1989a). Histological evidence of liver damage (i.e., necrosis, hemorrhage) was noted following oral administration of 100 mg/kg to rats (Kanz et al. 1991). Ultrastructural changes in hepatocellular organelles have also been noted in fasted rats after a single dose of 25 mg/kg (Kanz and Reynolds 1986).
The food intake of animals and the dosing vehicle influence the hepatotoxidty of orally administered 1.1- dichloroethene in animals. Fasting exacerbates 1,1-dichloroethene-induced hepatotoxitity, nonfasted 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 and Andersen 1978). The hepatotoxic effects of 1,1-dichloroethene in rats tend to be more severe when administered in mineral or corn oil than in 0.5% aqueous Tween 80 (Chieco et al. 1981). These authors have suggested that an aqueous solution of Tween 80 facilitates the clearance of 1,1-dichloroethene from the body.
One study was located regarding hepatic effects in animals after intermediate exposure to 1.1- dichloroethene. No exposure-related gross or histopathological changes were observed in the livers of beagle dogs given 25 mg/kg/day in drinking water for 97 days (Quast et al. 1983).
Chronic studies have been performed in rats ingesting low levels (9-20 mg/kg/day) of 1,1-dichloroethene for 2 years. The results indicated few treatment-related changes. After 1 year of treatment, only a
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minimal increase in cytoplasmic vacuolation of hepatocytes was noted (Rampy et al. 1977). After 2 years, a minimal amount of hepatocellular swelling with midzonal fatty change was reported (Quast et al. 1983). Slight hepatocellular changes were observed in rats exposed to 1,1-dichloroethene in the drinking water at levels of 9 mg/kg/day in utero, during lactation, and through weaning into adulthood (Nitschke et al. 1983). A chronic oral MRL of 0.009 mg/kg (Quast et al. 1983) was calculated for 1,1-dichloroethene, as described in the footnote in Table 2-2.
Renal Effects. Evidence for 1,1-dichloroethene-induced kidney dysfunction has been observed in laboratory animals following acute oral exposure. Fasted rats given single gavage doses of 200 mg/kg or more in corn oil exhibited increased plasma urea and creatinine levels (at 400 mg/kg) (Jenkins and Andersen 1978). Histopathological changes (vacuolization, pigmentation, tubular dilation, and necrosis) were observed at 400 mg/kg. These changes were more severe in females, though some recovery was evident in females 96 hours after exposure. The histological changes such as granular heme casts in Henle's loop were observed in the kidneys of nonfasted and fasted rats administered single doses of 200 mg/kg by gavage in either corn oil, mineral oil, or an aqueous solvent (Cbieco et al. 1981). As noted for hepatic effects, fasting exacerbates 1,1-dichloroethene-induced nephrotoxicity in animals; no renal effects were observed in nonfasted animals administered single doses of 400 mg/kg (Jenkins and Andersen 1978).
No renal effects were noted in animals following intermediate (Quast et al. 1983) or chronic (Rampy et al. 1977) oral exposure to 1,1-dichloroethene at doses of 30 mg/kg/day or less.
2.2.2.3 Immunological Effect*
No studies were located regarding immunological effects in humans or animals after oral exposure to 1.1- dichloroethene.
2.2.2.4 Neurological Effect*
No studies were located regarding neurological effects in humans after oral exposure to 1,1-dichloroethene.
No adverse neurological effects on were identified after oral administration of 1,1-dichloroethene for any exposure duration in animals. The appearance and demeanor of the test animals were not affected in either an intermediate feeding study in dogs (25 mg/kg/day for 97 days) or a chronic study in rats (30 mg/kg/day or less for 2 years) (Quast et al. 1983). However, these results are only suggestive because no sensitive neurological tests were performed.
2.2.2.5 Reproductive Effect*
No studies were located regarding reproductive effects in humans after oral exposure to 1,1 -dichloroethene.
1.1- Dichloroethene (99.5% purity) was administered in the drinking water of rats at dosages of 30 mg/kg/day or less for three generations. No dose-related changes were seen in reproduction or neonatal development (Nitschke et al. 1983). The NOAJEL value for reproductive effects is listed in Table 2-2 and plotted in Figure 2-2.
2.2.2.G Developmental Effects
No studies were located regarding developmental effects in humans after oral exposure to 1.1- dichloroethene.
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No effect on the number of implantations, live fetuses, or resorptions, sex ratio, or fetal weight were observed among the offspring of rats administered 40 mg/kg/day in the drinking water on gestation days 6 through IS (Murray et al. 1979). The incidence of malformations, considered individually or collectively, among the rats given 1,1-dichloroetbene was not significantly different from that of controls. There was, however, a marginal increase in crown-rump length in treated rats; the significance of this effect is unclear.
The highest NOAEL values for developmental effects in rats after acute exposure is listed in Table 2-2 and plotted in Figure 2-2.
2.2.2.7 Genotoxlc Effects
No studies were located regarding genotoxic effects in humans or animals after oral exposure to 1.1- dichloroethene.
Genotoxicity studies are discussed in Section 2.4.
2.2.2.S Cancer
No studies were located regarding cancer in humans after oral exposure to 1,1-dichloroethene.
A number of chronic studies in rats and mice have evaluated the carcinogenicity of 1,1-dichloroethene by oral exposure (Maltoni et al. 1982, 1985; NTP 1982; Ponomarkov and Tomatis 1980; Quast et al. 1983; Rampy et al. 1977). Dosages of 1,1-dichloroethene in these studies ranged from 0.5 to 30 mg/kg/day. Administration was by gavage with the exception of two studies in which 1,1-dichloroethene 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, 1,1-dichloroethene exposure has not produced statistically significant changes in the tumor incidence of treated animals.
A trend toward increased incidence of malignant and nonmalignant tumors in 1,1-dichloroethene-treated animals was reported by NTP (1982), Ponomarkov and Tomatis (1980), and Quast et al. (1983). For example, rats given weekly gavage doses of 50 mg/kg 1,1-dichloroethene from weaning until 120 weeks of age had an increased incidence of meningiomas and liver cell adenomas and carcinomas compared to controls, but the difference was not statistically significant (Ponomarkov and Tomatis 1980). However, hyperplastic nodules of the liveT in these animals were significantly increased (p=0.04). A different study showed that male rats treated by gavage with 5 mg/kg 1,1-dichloroethene for 2 years had an increased incidence of pheochromocytomas, but when compared with control animals, the difference was not statistically significant (NTP 1982).
Statistically significant increases in certain types of tumors and cancers have been reported in bioassays in which rats and beagles were orally exposed to 1,1-dichloroethene (Quast et al. 1983); however, investigators discounted these results for various reasons. In a 2-year study by Quast et al. (1983), doses of 7,10, and 20 mg/kg/day and 9,14, and 30 mg/kg/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 was within the normal range of historical control data and because these tumors were not observed in higher-dose females or in treated males, the authors did not consider these increases related to 1,1-dichloroethene ingestion. Thus, the results of the study are of questionable biological significance.
Clinical signs of toxicity were not generally observed in the various oral carcinogenicity studies on 1.1- dichloroethene; consequently, maximum tolerated doses may not have been achieved (NTP 1982; Ponomarkov and Tomatis 1980, Quast et al. 1983; Rampy et al. 1977). Long-term animal studies at or***
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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); however, the animals were observed for 136 or 147 weeks allowing an adequate latency period for the development of late-appearing tumors (Maltoni et al. 1982, 1985).
EPA has derived an oral cancer slope factor (qj*) of 0.6 (mg/kg/day)'1 for cancer risk associated with oral exposure to 1,1-dichloroethene based on the study by NTP (1982) in rats (IRIS 1992). The doses associated with the upper bound for individual lifetime cancer risk of 10^ to 10*7 are UxlO"4 to 1.7xl0'7 mg/kg/day, respectively. This range is plotted in Figure 2-2. At the highest dose level tested, 5 mg/kg/day, the incidence of pheochromocytomas increased in male rats, but the increase was not statistically significant.
2.2.3 Dermal Exposure
2.2.3.1 Death
No studies were located regarding death in humans or animals after dermal exposure to 1,1-dichloroethene.
2.2.3.2 Systemic Effects
No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to 1,1-dichloroethene. The dermal/ocular effects observed after dermal exposure are discussed below.
Dermal/Oeular Effects. Liquid 1,1-dichloroethene is irritating when applied to the sldn of humans (Tierney et al. 1979) and animals (Torkelson and Rowe 1981) 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 (MEHQ), present in these formulations. MEHQ is an antioxidant which on contact results in skin depigmentation at concentrations of 0.25% or more (Busch 1985). Similarly, 1,1-dichloroethene is an ocular irritant in humans (Tierney et al. 1979); this effect has also been ascribed to MEHQ.
No studies were located regarding the following health effects in humans or animals after dermal exposure to 1,1-dichloroethene:
2.2.3.3 2.2.3.4 2.2.3.5 2.2.3.6 2.2.3.7
Immunological Effects Neurological Effects Reproductive Effects Developmental Effects Qenotoxlc Effects
Genotoxicity studies are discussed in Section 2.4.
2.2.3.S Cancer
No studies were located regarding cancer in humans after dermal exposure to 1,1-dichloroethene.
The carcinogenicity of 1,1-dichloroethe
Uowing dermal exposure has been evaluated by Van Duuren et
al. (1979). In this study, 1,1-dichloroe
doses of 40 or 121 mg (1,333 or 4,033 mg/kg, respectively) in
acetone were applied three times week
595 days or less to the skin of Swiss mice. No skin tumors
were noted in treated animals. Increase . .ncidences of pulmonary papillomas and squamous-cell
carcinomas of the forestomach were observed in treated mice; the incidences of these tumors, however,
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were not statistically different from controls. The results suggest 1,1-dichloroethene is inactive as a complete carcinogen (an agent, which if applied in sufficient concentrations, can induce tumors by itself) when applied repeatedly to the mouse skin.
The ability of 1,1-dichloroethene to act as a tumor initiator in the skin of Swiss mice was evaluated by Van Duuren et al. (1979). In 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. 1,1-Dichloroethene (121 mg or 4,033 mg/kg) in acetone was applied to the skin once, followed 2 weeks later by dermal application of the tumor promotor, phorbol myristate acetate (TPA) three times a week for 576 days or less. Untreated, vehicle-treated, and TPAonly-treated animals served as negative controls. A statistically significant (p<0.005) increase in the incidence of skin papillomas was recorded in treated mice compared to controls. These results indicate that 1,1-dichloroethene is a tumor-initiating agent.
2.3 TOXICOKINETICS
Data regarding toxicokinetics of 1,1-dichloroethene in humans are not available. Studies in animals indicate that 1,1-dichloroethene is readily absorbed and rapidly distributed in the body following inhalation and oral exposure. The oral absorption rate greatly depends on the type of vehicle used. Oily vehicles facilitate uptake. Uptake of 1,1-dichloroethene vapors is duration and dose-dependent. However, the percentage of 1,1-dichloroethene uptake decreases as the exposure concentration increases, until an equilibrium is reached. 1,1-Dichloroethene distributes mainly to the liver and kidney and does not appear to be stored or accumulated in the tissues. It is metabolized by the hepatic microsomal cytochrome P-450 system. This process gives rise to several possible reactive intermediates thought to be responsible for 1,1-dichloroethene toxicity. The major detoxification route for these intermediates are hydroxylation and conjugation with GSH. Therefore, metabolic interventions that deplete glutathione (GSH) (treatment with drugs, fasting, etc.) tend to increase 1,1-dichloroethene toxicity. Excretion of metabolites and parent compound occurs primarily via the urine and exhaled air. At high doses or exposures, greater percentages of the dose are exhaled as unchanged 1,1-dichloroethene. The physical/chemical properties of 1,1-dichloroethene indicate that absorption of the liquid form of 1,1-dichloroethene via dermal exposure is possible in humans. Information on the disposition and metabolism of 1,1-dichloroethene following long term exposures were not available.
2.3.1 Absorption
2.3.1.1 Inhalation Exposure
No studies were located regarding the absorption of 1,1-dichloroethene in humans following inhalation exposure.
Studies in laboratory animals have demonstrated that 1,1-dichloroethene was rapidly absorbed following inhalation exposure (Dallas et al. 1983; McKenna et al. 1978a). No studies were located that described transport mechanisms for 1,1-dichloroethene absorption. Since 1,1-dichloroethene is a small organic molecule with chemical and physical properties similar to lipid soluble anesthetics, it is expected to penetrate pulmonary membranes easily and to enter the blood stream rapidly. 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 1,1-dichloroethene was duration- and dose-dependent, as shown in Figure 2-3. The percentage of systemic uptake decreased with time from the onset of exposure until an equilibrium was reached within 1 hour. Once equilibrium was reached, percentage uptake varied inversely with dose. The cumulative uptake of 1,1 -dichloroethene following inhalation exposure was linear for levels of 150 ppm or less. However, at 300 ppm level of 1,1-dichloroethene exposure, steady-state was never achieved. This finding indicates that 1,1-dichloroethene absorption following inhalation exposure was
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FIGURE 2-3. Percentage Systemic Uptake of 1,1-Dlchloroethene During Inhalation Exposures
100-1 io ,
Y\oo H
25 ppm O 75 ppm A 150 ppm 300 ppm
80 H
A
t
8*i22i22222 2222
70 H
DO
60 a D0f
50 H
1--------------1--------------1--------------1--------------1--------------1 30 00 90 120 150 180
TIME (min)
Rats were exposed to 25,75,150, or 300 ppm DCEfor 3 hours. Percentage uptake was determined at 0-minute intervals. Each point represents the mean percentage uptake In four animate per group. Standard deviation brackets are omitted for the sake of darty. Reproduced trom DaHas et at 1963.
f i r' I f * 1
41
Z. HEALTH EFFECTS
saturable at high levels, and the kinetics at these levels are best described by a cubic curve (Dallas et al. 1983).
2.3.1.2 Oral Exposure
No studies were located regarding absorption in humans after oral exposure to 1,1-dichloroethene.
Studies in animals clearly indicated that doses of 1,1-dichloroethene ranging from 10 to 100 mg/kg were rapidly and almost completely absorbed from the gastrointestinal tract of rats and mice following oral administration in com oil (Jones and Hathway 1978a; McKenna et al. 1978b; Putcha et al. 1986). Rapid absorption occurred following oral administration of 200 mg/kg 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/kg of radiolabeled 1,1-dichloroethene was given to female rats, -10% of the parent compound was recovered in the expired air by 1 hour after exposure, indicating that oral absorption was rapid (Reichert et al. 1979). After oral administration of radiolabeled 1.1- dichloroethene to rats, 81-99.8% of the administered radioactivity was recovered within 72 hours (i.e., 21% was recovered in the expired air, 53.9% in urine, 14.5% in feces, 2.8% in the carcass, and 7.5% in the cage rinse following oral administration of 5 mg 14C-l,l-dichloroethene/kg) (Reichert et al. 1979). These results suggest that 1,1-dichloroethene may be rapidly and completely absorbed in humans following oral exposure (e.g., via ingestion of contaminated groundwater).
2.3.1.3 Dermal Exposure
No studies were located regarding absorption in humans or animals after dermal exposure to 1.1- dichloroethene. Nonetheless, the physical/chemical properties of 1,1-dichloroethene indicate that dermal absorption of the liquid form of 1,1-dichloroethene is possible. 1,1-Dichloroethene is a small organic molecule with properties similar to the lipid-soluble anesthetics. Thus, liquid 1,1-dichloroethene is expected to readily penetrate the skin, which is a lipid-rich tissue.
2.3.2 Dlatrlbutlon
2.3.2.1 Inhalation Exposure
No studies were located regarding distribution in humans after inhalation exposure to 1,1-dichloroethene.
Following inhalation exposure of rats to 10 or 200 ppm of 14C-labeled 1,1-dichloroethene, the highest level of radioactivity was found in the liver and kidneys after 72 hours, with only very small amounts present in other tissues (McKenna et al. 1978a). These authors found that the tissue burden/g of tissue (mg equivalents of14C-1,1 -dichloroethene/g of tissue/total mg equivalents recovered per rat) in the liver, kidneys, and lungs of fasted rats were significantly greater than in non-fasted rats at both exposure levels, even though the total accumulation of l4C in fasted rats was less than in non-fasted rats. The results of this study suggest that in fasted rats the 14C is retained in specific target tissues and not distributed randomly in all tissues.
Preferential accumulation of radioactivity was reported in the kidney and liver of rats exposed to 2,000 ppm radiolabeled 1,1-dichloroethene for 2 hours (Jaeger 1977). Fasted rats had higher levels of label than non-fasted rats in these tissues. Examination of *4C activity at the subcellular level in these two tissues revealed that significantly more water-soluble 14C activity was present in the cytosolic fractions of fasted rats. This observation suggest that distribution pathways for metabolism differ according to the amount of food ingested by the animals.
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2.3.Z2 Oral Exposure
No studies were located regarding distribution in humans after oral exposure to 1,1-dichloroethene.
1.1- Dichioroethene was rapidly distributed to all tissues examined following a single oral dose of the 14C-labeled compound to rats (Jones and Hathway 1978c). The highest amount of radioactivity was found 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 3% or less of the administered dose present in the body 72 hours after exposure. At that time, the highest levels were found in liver and kidneys, with very little remaining in other tissues, including fat (Jones and Hathway 1978c).
2.3.2.3 Dermal Exposure
No studies were located regarding distribution in humans or animals 1,1 -dichloroethene.
' dermal exposure to
2.3.2.4 Other Routea of Expoaure
In a study by Okine et al. (1985) in which mice were administered a single intraperitoneal injection of 125 mg/kg of l4C-1,1-dichloroethene, radioactivity was distributed to some extent to all examined tissues 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
2.3,3 Metabolism
No studies were located regarding metabolism in humans following inhalation, oral, or dermal exposure to 1.1- dichloroethene.
Some evidence from animal studies suggests that at least the initial metabolic transformations in humans may be similar to those described in animals. Liver cells from a human subject together with arochlor pretreated S-9 activated 1,1-dichloroethene induced unspecified mutagenic metabolites in Salmonella typhimumun (Jones and Hathway 1978b). This suggests that reactive metabolites may also be produced in humans.
The metabolism of 1,1-dichloroethene following oral administration in rats has been extensively studied (Jones and Hathway 1978a, 1978c; McKenna et al. 1978b; Reichert et al. 1979). These studies demonstrate that 1,1-dichloroethene undergoes biotransfonnation processes, and several metabolites have been identified. An overall summary of the metabolic pathway of 1,1-dichloroethene in animals is presented in Figure 2-4.
A physiologically based pharmacokinetic model for 1,1-dichloroethene based on its oxidative metabolism by the P-450 cytochrome system and subsequent conjugation with GSH, a principal pathway was developed by D'Souza and Anderson (1988) (see Figure 2-5). Their model demonstrates that because 1.1- dichloroethene has a low blood-to-air partition coefficient and saturable metabolism, the metabolism of 1,1-dichloroethene is sensitive to the rate of absorption. Furthermore, 1,1-dichloroethene's metabolic pathway (i.e., the percentage of 1,1-dichloroethene 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 potential toxicity of 1,1-dichloroethene under various exposure conditions.
An initial step in the metabolism of 1,1-dichloroethene may be the formation of the epoxide (oxirane) intermediate, 1,1-dichloroethylene oxide; however, this reactive compound has never been isolated after
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FIGURE 2-4. Metabolic Pathway of 1,1 -Dlchloroethene In Animals *
0 1
-c- OH
\
HOCHjCOOH QLYCOUJC ACID
*** ORAFT FOR PUBLIC
(COOH)
OXMJCACtD
N - ACETYL CYSTEINE DERIVATIVE
IHO - CH2CHjSHCH
V'_._ ~~
-C__O_|O_s H^
?
S - (2 - HYDROXYETHYL) - N -ACETYLCYSTEINE (20%; 50%)
a - CH tCCNHCHaCHtOH
CHjSCHfCONHCHjCHjOH METHYL THOACETYLAMNOETHANOL
|0%;O%)
S - 2 (CARBOXYMETHYL) CYSTEINE dacarbcncyteion
COa (3%; 35%)
HOOC-CHj-S- CHj- CHCOOH NHCOCH,
N - ACETYL S (2 - CARBOXYMETHYL) CY3TEME (0%;4%)
Potcontege vteuw gMn In brodwti ora o< do--d motertte axcrated (rat mou--)toioAr>o----mmte>50mgAflby lh route. Principal mataboMea only v ahown. Raproducad front Ftektof at al. 1065
HOOC-CHa-S-CHa-COOH THIOOKJLYCOLUC ACID (22%; 3%)
j JMNomaa
H - S -CHj- COOH THIOOIQLYCOUJC ACID
(3%; 9%)
*
S -CHjCOOH
S -CHjCOOH
DITHIOGLYCOUJC ACID (5%; 23%)
S6
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FIGURE 2-5. Physiologically Based Pharmacokinetic Model for 1,1-Dlchloroethene*
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OSH GMutrtiiooe ooncrrtraton Ffcemrdet rrte conrtwttw tomHon ot MAT.
If,** Fkst-ontor rati comtanl tor tonmion o( QCM. FVd-wdM rale constant to* cMoroacatyl craonos votmMofi.
Km MMweleoonsMfcradiMvepsOwMy. If. Zero-order dMrttow eynOteale. <m> nd
OSH dependent
If, Flrat-ofde* rale constant to* glunaNone bfsakdown. If,. FMdMrMoomMtodtaMliloM
eynOwleee traafcduML HAT MetshoWe ninOabts lor toddty V'm. M"^imifrrtyiif iMlileti pt6t--y
Reproduced from D'Souza and Anderson (1968)
Parameters UMd In The 1,1-DlcMofoetiene P8-PK Modal
Portion Coefficients
Uvecbtood
1.1
Richly pe<1used:ttood
1.1
Sknriy pertusedbtood
o.e
Fafcbtood
IS .4
Bloodialr
5.0
Kinetic Constant*
vmm <mhf1) *, (mger'i
(eM 'lr'1)
*. *0
2.6 0.25 0.33 SO 9000
H,0 (M)
1.62 X 10" 55
Ob^1*3
45
2, HEALTH EFFECTS
1,1-dichloroethene administration in laboratory animals (Jones and Hathway 1978c; McKenna et al. 1977; Reichert et al. 1979).
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 1,1-dichloroethene in the rat may 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 1,1-dichloroethene depletes GSH levels in the liver (Jaeger et al. 1974; Reichert et al. 1979; Reynolds et al. 1980). For example, Reynolds et al. (1980) reported a linear relationship in rats between intraperitoneally administered 1,1-dichloroethene and GSH depletion over the range of 20-100 mg/kg; above this level GSH depletion reached a plateau. The maximum reduction seen (70%) occurred 4 hours after the dose, with a subsequent gradual recovery to normal levels within 24 hours. These findings have led several investigators to suggest that 1,1-dichloroethene-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 detoxified, ultimately leading to cell death (Jaeger et al. 1974; McKenna et al. 1977; Reynolds et al. 1980).
Conjugation with monochloroacetic acid followed by fi-thionase activity appeared to be the major metabolic route on a quantitative basis in rats, since thiodiglycollic add was the predominant urinary metabolite (Jones and Hathway 1978a). Other metabolites identified in this pathway indude monochloroacetic add itself, thioglycolic add, and dithioglycollic add. 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.
Evidence suggests that enzymatic hydration of the epoxide by epoxide hydrolase is a minor pathway in the metabolism of 1,1-dichloroethene in rats, since exacerbation of 1,1-dichloroethene-induced toxidty in rats by diethyl maleate and various epoxide inhibitors following inhalation exposure was directly related to their ability to decrease GSH levels, rather than their ability to competitively inhibit epoxide hydrolase (Andersen et al. 1980).
An alternative metabolic pathway (i.e., one not involving GSH conjugation) to account for the presence of the metabolite methylthioacetylaminoethanol was proposed by Reichert et al. (1979). 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 1,1-dichloroethene 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 1,1-dichloroethene was metabolized per given dose level by the mouse than the rat) (Jones and Hathway 1978a). The predominant urinary metabolite of 1,1-dichloroethene 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, S-thionase activity was more pronounced since more dithioglycollic arid was found than thioglycolic arid (Jones and Hathway 1978a). In addition, Oesch et al. (1983) pointed out that 1,1-dichloroethene may have different effects on cytosolic GSH transferase activity and that this difference may have contributed to the species differences observed.
14C-l,l-Dichloroethene covalently binds preferentially to liver and kidney tissues following administration, which may provide a basis for the toxic effects seen in these organs (Jaeger et al. 1977; McKenna et
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FIGURE 2*6. General Proposed Scheme lor Oxidative Conjugate Metabolism of 1,1-Dtehloroethene Not Metabolized Via the Epoxide Intermediate*
_ a FMSO H* " c a-------
h c--c--a
II
q1 ai
OSH
HC --ch --a H* QS -- cj --CHCI*.
H
S-(2.2hcNmo-1-hydroxy) elhytglutalhlona
W
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2. HEALTH EFFECTS
al. 1977). A linear increase in the amount of covalently bound radioactivity in the liver of rats exposed to 5-200 ppm l4C-l,l-dichloroethene by inhalation for 6 hours was reported by McKenna et al. (1977). However, GSH depletion 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 1,1-dichloroethene in the mouse, 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 in the rat following exposure to the same dose of 1,1-dichloroethene (McKenna et al. 1977). The mouse exhibited greater 1.1- dichloroethene-induced 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, compared to the rat kidney. Similar results were reported by Short et al. (I977d) when a single dose of 14C-l,l-dichloroethene was injected intraperitoneally into 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 1.1- dichloroethene and increase the extent of its detoxification. Thus, with respect to genotoxicity, conjugation of reactive intermediates of 1,1-dichloroethene with GSH is a major detoxification mechanism in laboratory animals because it reduces the amount of reactive material available to covalently bind to cellular macromolecules.
1.1- Dichloroethene can also potentially form.adducts with hemoglobin, similar to what has been observed with ethylene oxide (Tomqvist et al. 1986). Electrophilic intermediates, such as the epoxide formed in 1.1- dichloroethene metabolism, can likely bind to proteins in hemoglobin, similar to reactions demonstrated for liver and kidney.
2.3.4 Excretion
2.3.4.1 Inhalation Expoaure
No studies were located regarding excretion in humans following inhalation exposure to 1.1 -dichloroethene.
Elimination of 1,1-dichloroethene following inhalation exposure in rats is rapid, with the bulk of the absorbed material eliminated as metabolites in the urine, and very little (1% of the administered dose) of the parent compound is eliminated unchanged in the expired air at low levels of exposure (McKenna et al. 1978a). Steady-state levels of 1,1-dichloroethene in the expired air are achieved within 30-45 minutes after exposure to low (25-150 ppm) levels of 1,1-dichloroethene, 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 steady-state levels of 1,1-dichloroethene in expired air are never readied. Since 1,1-dichloroethene is volatile and relatively insoluble in blood, increased amounts can easily be eliminated unchanged via the lung once metabolic processes become saturated. Upon cessation of exposure, concentrations of 1,1-dichloroethene in both blood and breath fell rapidly (Dallas et al. 1983). Similar results were reported by McKenna et al. (1978a).
1.1- Dichloroethene 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 1,1-dichloroethene 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. Food intake did not appear to affect the elimination kinetics of 1,1-dichloroethene following inhalation exposure in rats (McKenna et al. 1978a).
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Information is limited on elimination in mice after inhalation exposure to 1,1-dichIoroethene. However, McKenna et al. (1977) reported that at low levels of exposure (10 ppm for 6 hours), somewhat lower levels of unchanged 1,1-dichloroethene were eliminated in the expired air of mice and higher levels of watersoluble metabolites were found in the urine of mice, compared to levels in the rat. This indicates that mice metabolize 1,1-dichloroethene at a greater rate than rats.
2.3.4.2 Oral Exposure
No studies were located regarding excretion in humans following oral exposure to 1,1-dichloroethene.
Elimination of 1,1-dichloroethene and its metabolites following oral administration in rats is very similar to that seen following inhalation exposure. Following oral administration of 1 mg/kg 14C1,1-dichloroethene in com oil, less than 1% of the administered dose was excreted unchanged in the expired air, with 5-14% of the administered dose recovered as 14C-carbon dioxide. The bulk of the administered 14C-l,l-dichloroethene (44-80% of the administered dose) was eliminated in the urine within 3 days, most within the 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/kg 14C-l,l-dichloroethene), 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 carbon dioxide (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 become saturated at rather low dose levels.
The elimination of orally administered 1,1-dichloroethene is triphasic according to Putcha et al. (1986); however, 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 the two phases of elimination after inhalation exposure were 20 minutes and 1 hour in the breath, and 6 hours and 17 hours in the urine.
The amount of food ingested in tbe previous 24 hours slightly modifies the elimination of 1,1-dichloroethene by rats after oral administration. It was found that 19% of a 50-mg/kg dose was excreted unchanged via the lungs of nonfasted rats, whereas 29% was excreted by fasted rats McKenna et al. (1978b). This finding provides evidence that fasted rats eliminate unchanged 1,1-dichloroethene to a greater extent than non-fksted rats. However, elimination of nonvolatile metabolites was slightly greater in fed animals than in fasted animals, indicating a reduced capacity for metabolism in fasted rats.
Mice eliminate more 1,1-dichloroethene as water-soluble metabolites in the urine than do rats at comparable doses (Jones and Hathway 1978a). These results suggest that mice also metabolize orally administered l.l-dicbloroethene to a greater extent than rats.
2.3.4.3 Dermal Exposure
No studies were located regarding the excretion of 1,1-dichloroethene in humans or animals following dermal exposure to 1,1-dichloroethene.
2.3.4.4 Other Routes of Exposure
Using the physiologically based pharmacokinetic model developed for 1,1-dichloroethene discussed in Section 2.3.3, D'Souza and Anderson (1988) demonstrated that the half-life of 1,1-dichloroethene in blood is not representative of metabolism rates, but rather more closely corresponds to reequilibration of
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1.1- dichIoroethene from fat Consequently, rats with higher fat content were verified to have lunger 1.1- dichloroethene blood half-lives following intravenous administration. This could have important implications for obese individuals exposed to high levels of 1,1-dichloroethene.
2.3.5 Mechanisms of Action
The specific mechanism by which 1,1-dichloroethene is transported across the gastrointestinal wall or across the pulmonary epithelium is not known. However, because of its high lipid solubility, it is expected that 1,1-dichloroethene will easily penetrate biological membranes following a concentration gradient. Similarly, no information was found regarding the mechanism by which 1,1-dichloroethene is transported in the blood, however, it is reasonable to assume that 1,1-dichloroethene will dissolve in the lipid fraction of the blood.
It is well known that the toxicity of 1,1-dichloroethene is due to chemicals derived from the biotransformation of 1,1-dichloroethene and not to the parent compound (Andersen et al. 1978, I98U; Jaeger et al. 1977a; Jones and Hathway 1978b). 1,1-Dichloroethene is initially oxidized by the hepatic cytochrome P-450 system with the formation of reactive and electrophilic products such as oxiranes, acyl chlorides, and halogenated aldehydes, which are responsible for the liver toxicity by alkylating macromolecules (Forkert et al 1986). These reactive intermediates form GSH 5-conjugates by the action of glutathione 5-transferases located in the hepatic cytosol and microsomes. GSH 5-conjugates that are primarily secreted from the hepatocytes into, plasma and S-conjugates entering the circulation after reabsorption from the small intestine are ultimately delivered to the kidney where they may undergo glomerular filtration (Dekant et al. 1989). In the kidney, GSH 5-conjugates may be metabolized to the corresponding cysteine 5-conjugate, which may be acetylated to form the corresponding mercapturic acid and excreted in the urine (Vamvakas and Anders 1990). However, cysteine 5-conjugates may also he metabolized by 8-lyase, located in the proximal tubule cells, to unstable thiols that yield ciectrophilic products whose interactions with macromolecules is associated with nephrotoxicity. In summary, GSH 5conjugate formation of nephrotoxic haloalkenes competes with hepatic cytochrome P-450 for substrates. The relative extent of these reactions in vivo appears to be decisive for the initiation of adverse effects either in the liver (oxidations by P-450) or in the kidney (formation and renal processing of 5-conjugates).
2.4 RELEVANCE TO PUBLIC HEALTH
A combination of inhalation and dermal routes represent the most likely routes of exposure to 1,1-dichloroethene in an occupational setting. The general population is most likely to be exposed to 1.1- dichloroethene by inhalation and oral consumption of contaminated food or water. Limited information is available on the human health effects following exposure to 1,1-dichloroethene. This information comes primarily from case reports and/or insufficiently detailed mortality studies wherein the concentration and duration of exposure to 1,1-dichloroethene was not quantified. Concurrent exposure to other toxic substances cannot be ruled out in most of these cases. Nevertheless, the information available indicates that relatively high concentrations of inhaled 1,1-dichloroethene can induce adverse neurological effects after short-term exposure, and that 1,1-dichloroethene is possibly associated with liver and kidney toxicity after repeated, low-level exposure in humans. Considerable information exists regarding the effects of 1,1-dichloroethene in animals after inhalation and oral exposure. The liver and kidney, and possibly the lungs, can be considered target organs for 1,1-dichloroethene by both routes of exposure. In addition, cardiovascular, neurological, developmental, and genotoxic effects were reported after inhalation of 1.1- dichloroethene, and gastrointestinal effects occurred after oral exposure. The evidence for 1.1- dichloroethene carcinogenicity is inadequate in humans and is limited in animals. Information regarding toxicokinetics in animals suggests that 1,1-dichloroethene does not tend to accumulate in the body. Background levels found in air and drinking water supplies (see Section 5.4) are not likely to cause adverse health effects in humans. For populations living near waste sites and/or facilities that manufacture or store 1,1-dichloroethene, the most likely routes of exposure are inhalation and oral (through contaminated water) routes.
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There is convincing evidence from animal studies to indicate that 1,1-dichloroethene toxicity is mediated by metabolism to reactive intermediates that act at the cellular level to ultimately compromise the viability of the target tissues. While the metabolic pathways for 1,1-dichloroethene are similar in the rat and mouse, the rate of metabolism is greater in the mouse, resulting in greater concentrations of toxic metabolites. Thus, the severity of 1,1-dichloroethene-induced toxicity in humans may depend on the extent to which 1,1-dichloroethene is metabolized and which intermediates are formed.
Groups of people who should be specifically cautioned against exposure to 1,1-dichloroethene include the very young; the elderly, pregnant women; those who ingest alcohol; people using phenobarbital (or possibly other hepatic enzyme-inducing drugs); people who, for whatever reason, are fasting; and those with cardiac, hepatic, renal, and certain central nervous system dysfunctions.
Inhalation MRLs
An MRL has not been derived for acute inhalation exposure (14 days or less) to 1,1-dichloroethene. A study by Reitz et al (1980) reported adverse kidney effects in mice exposed to 10 ppm for 6 hours. This appears to be the most sensitive end point identified; however, study limitations, such as the small number of animals used (three to six males) and the ambiguous description of the incidence of the lesions (0-20% of the animals) precluded derivation of an acute-duration inhalation MRL.
An MRL has not been derived for intermediate inhalation exposure (15-364 days) to 1,1-dichloroethene. The adverse hepatic effects were observed in rats exposed to a concentration of 25 ppm 1,1-dichloroethene 6 hours/day, 5 days/week, for 6 months (Quast et al. 1986). The liver is a known target organ for 1,1-dichloroethene and the results of Quast et al. (1986) are supported by numerous studies in various animals species that described similar hepatic effects at comparable doses. Other end points such as respiratory and hematological effects were affected at higher exposure concentrations. However, a serious LOAEL of 15 ppm for developmental effects in rats and mice following acute exposure to 1,1dichloroethene was reported by Short et al. (1977a) which precluded derivation of an intermediateduration inhalation MRL.
An MRL has not been derived for chronic inhalation exposure (365 davs or more) to 1,1-dichloroethene.
The adverse hepatic effects were observed in rats exposed to a concer on of 25 ppm 1,1-dichloroethene
6 hours/day, 5 days/week for 18 months (Quast et al. 1986). Few clr
inhalation studies were
identified, and the one conducted by Quast et al. (1986) provided ti ost complete information and
identified the most sensitive end point. However, a serious LOAEL . 15 ppm for developmental effects in
rats and mice following acute exposure to 1,1-dichloroethene was reported by Short et al. (1977a) which
precluded derivation of a chronic-duration inhalation MRL.
Oral MRU
An MRL of 0.009 mg/kg/day has been derived for chronic-duration oral exposure (365 days or more) to 1,1-dichloroethene. This MRL is based on the development of hepatocellular changes observed in rats exposed to 50 ppm 1,1-dichloroethene (converted by the investigators to a dose of 9 mg/kg/day based on body weight and water consumption data) in utero, during lactation, and through weaning into adulthood (Quast et al. 1983). These results are supported by several other chronic-duration studies that found similar hepatic effects in rats at comparable doses of 1,1-dichloroethene.
An MRL has not been derived for acute oral exposure (14 days or less) to 1,1-dichloroethene. With the exception of a developmental study in rats (Murray et al. 1979), all the acute-duration studies administered a single dose of 1,1-dichloroethene, and although Murray et al. (1979) defined a NOAEL of 40 mg/kg/day, this NOAEL is too close to the 50-mg/kg dose that caused death in fasted rats (Andersen and Jenkins 1977).
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An MRL has not been derived for intermediate oral exposure (15-364 days) to 1,1-dichloroethene. Only one study reported data after intermediate-duration exposure to 1,1-dichloroethene (Quast et al. 1983). This study could not define a dose-response relationship for any examined end point and reported a NOAEL of 25 mg/kg/day.
D ath. Though no deaths have been reported in humans following 1,1-dichloroethene exposure, 1,1-dichloroethene was lethal to animals following acute exposures to high levels via the inhalation or oral routes. 1,1-Dichloroethene-induced lethality appeared to be influenced by the nutritional status of the animal regardless of exposure route, with LDJ0 values for fasted animals generally significantly lower than those reported for fed animals (e.g., Chieco et al. 1981; Jaeger et al. 1973c; Jenkins and Andersen 1978; Siegel et al. 1971). Young males 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 reactive intermediates of 1,1-dichloroethene available for binding to macromolecules in target tissues after fasting (McKenna et al. 1978a). Non-fasted rats that were exposed to 20,000 or 32,000 ppm of 1.1- dichloroethene by inhalation for ! hour survived for at least 24 hours (Carlson and Fuller 1972). However, when comparable animals were pretreated with the microsomal enzyme inducers phenobarbital or methylcholanthrene, these exposure levels were lethal to nearly all of the animals within 2 hours, suggesting that lethality was due to increased formation of toxic metabolites. However, Carlson and Fuller (1972) found that pretreating 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 1,1-dichloroethene also reduced the survival time. Other inhibitors of microsomal metabolism (carbon disulfide and diethyldithiocarbamate) were found to protea mice against all 1.1- dichloroethene-induced toxic effects at low doses following intraperitoneal injection (Masuda and Nakayama 1983). These results indicate that biotransfbrmation plays an important role in the expression of 1,1-dichloroethene-induced effects. Increased susceptibility of tested animate to the lethal effects of 1.1- dichloroethene may occur, because testing depleted GSH in the target tissues, and less GSH was available to bind to the active intermediate (Jaeger et al. 1973a).
Mice are more sensitive than rats to the lethal effects of inhaled 1,1-dichloroethene (see Figure 2-1) (Jaeger et al. 1974). This differential sensitivity also has been observed by the oral exposure route (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 the increased levels of electrophilic species capable of reacting with intracellular macromolecules (McKenna et al. 1977; Reitz et al. 1980).
Though animal studies indicate that amount of food ingested affects 1,1-dichloroethene-induced lethality, how the amount of food ingested prior to exposure affects the susceptibility of humans to the toxic effects of 1,1-dichloroethene is not known. Human subpopulations most likely exist with differing biochemical capacities for 1,1-dichloroethene 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 1,1-dichloroethene-induced lethality. Orally ingested 1,1-dichloroethene at sufficiently high doses is likely to cause death in humans, and younger members (particularly males) of the population may be at higher risk.
Systemic Effects
Respiratory Effects, information regarding respiratory effects in humans was limited to reports of upper
airway irritation after acute inhalation exposure (mi 1982). 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 1,1-dichloroethene via inhalation (Henschler 1979; Klimisch and Freisberg 1979a; Rylova 1953; Zeller et al. 1979b). Chronic inhalation exposure to 1,1-dichloroethene was associated with similar adverse respiratory effects (Gage 1970; Prendergast et al. 1967; Quast et al. 1986). These effects appeared to be rather nonspecific and most likely resulted from
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1.1- dichloroethene's irritating properties. Therefore, these data suggest that any possible non-genotoxic respiratory effects associated with inhalation exposure to 1,1-dichloroethene (particularly acute exposure) 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 1,1-dichloroethene. The effects seen included histopathological changes in Clara cells, pulmonary edema, hemorrhage, and focal atelectasis. These effects were considered 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 1.1- dichloroethene (Forkert et al. 1985,1990; Krijgsheld et al. 1984). The relevance of these findings to prolonged human exposure is not known because the findings in the one oral study are not substantiated by other studies, and intraperitoneal administration is not a relevant route of administration in humans.
Cardiovascular Effects. No information was located regarding cardiovascular effects of 1,1-dichloroethene in humans. F >s obtained in experimental animals suggest that the at high concentrations the cardiovascular cm is a target for 1,1-dichloroethene, since the effects described (cardiac arrhythmia, increase a sens tty to epinephrine) are known to occur with a number of similar chlorohydrocarbons Insel 1990). However, relevance of these findings to prolonged human exposure is not known because the finding in one acute inhalation study are not substantiated by other studies.
Hematological Effects. No information was found regarding hematological effects of 1,1-dichloroetliene in humans. Increased hemoglobin levels were reported in an acute oral study in rats (Chieco et al. 1981). Given the lack of effects noted in animals in long-term studies by the inhalation (Lee et al. 1977; Quast et al. 1986) and oral routes (Quast et al. 1983; Rampy et al. 1977), it seems unlikely that 1,1-dichloroethene would cause adverse hematological effects in humans unless definite liver toxicity is observed.
Hepatic Effects. Information regarding hepatic effects of 1,1-dichloroethene in humans was limited to a reports of increased serum enzymes (indicative of liver injury) in occupationally exposed workers (Ott et al. 1976; Tierney et al. 1979). However, because of the incomplete reporting of the results, a clear relationship between exposure to 1,1-dichloroethene and development of adverse hepatic effects could not be established. Results from animal as well as human studies indicate that the liver is a primary target organ for 1,1-dichloroethene-induced toxicity. Hepatotoxicity following both inhalation and oral exposure to 1,1-dichloroethene 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 and/or centrilobular vacuolization, swelling, degeneration and necrosis). More severe hepatotoxic effects were seen in fasted animals (particularly males), compared to fed animals (Andersen and Jenkins 1977; Andersen et al. 1978, 1980; Chieco et al. 1981; Jaeger et al. 1974, 1975b; Jenkins and Andersen 1978; McKenna et al. 1978; Reynolds et al. 1980). The increased susceptibility to 1,1-dichloroethene-induced hepatotoxicity seen in fasted rats may be related to the depletion of GSH levels. The hepatotoxic effects of 1,1-dichloroethene were also found to be dependent on the vehicle used. For example, increased liver toxicity was observed in fasted rats given 1,1-dichloroethene in mineral oil or corn oil compared to administration of 1,1-dichloroethene in an aqueous solution (Chieco et al. 1981). This information has important implications with regard to humans, since oral exposure to 1,1-dichloroethene, particularly in individuals in close proximity to hazardous waste sites, will most likely be from groundwater.
Indirect evidence of the role of GSH in 1,1-dichloroethene-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 1,1-dichloroethene via inhalation. Decreased levels of hepatic GSH were also reported in mice treated with 1,1-dichloroethene intraperitoneally (Forkert et al. 1991). In addition, thyroidectomy, a surgical procedure that results in increased liver GSH levels, has protected against 1,1-dichloroethene-induced hepatotoxicity and lethality, whereas thyroxine replacement restored or even potentiated the susceptibility of thyroidectomized animals to 1,1-dichloroethene-induced hepatotoxicity (Jaeger et al. 1977b; Szabo et al. 1977).
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Results from in vivo studies suggest that 1,1-dichloroethene-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 P-450 mixed function oxidase system (Forkert et al. 1986).
Other subcellular mechanisms of 1,1-dichloroethene-induced toxicity have been proposed. For example, it has been suggested that 1,1-dichioroethene-induced inhibition of calcium-dependent 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 1,1-dichloroethene metabolism reduces the 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). Phospholipase A2 activation may also be part of the sequence of events (Glende and Recknage! 1992).
In conclusion, 1,1-dichloroethene induces hepatotoxicity in animals following both inhalation and acute and repeated oral exposures. The limited information available in humans also indicates that 1.1- dichloroethene is hepatotoxic (Ott et al. 1976). Thus, humans particularly those exposed by inhalation to high levels of 1,1-dichloroethene in occupational settings or in areas surrounding hazardous waste sites and those with compromised hepatic function, are at risk for 1,1-dichloroethene-induced liver toxicity.
Renal Effects. No studies were located regarding renal effects in humans after exposure to 1.1- dichloroethene. 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 1,1-dichloroethene in animals (Jackson and Conolly 1985; Lee et al. 1977; McXenna et al. 1978; Oesch et al. 1983; Short et al. 1977c). Fasted animals (particularly males) were again more susceptible to these effects than non-fasted animals (Chieco et al. 1981; McKenna et al. 1978a), and mice were more susceptible than rats, as was seen for 1,1-dichloroethene-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 1,1-dichloroethene may be reversible (Jenkins and Andersen 1978; Reitz et al. 1980), but this may be concentration or duration dependent As indicated in Section 2.3.5, kidney toxicity has been attributed to the formation of cysteine S-conjugates that may be metabolized by 6-lyase, located in the proximal tubule cells, to unstable thiols that yield electrophilic products that interact with macromolecules.
Though data on kidney toxicity in humans following exposure to 1,1-dichloroethene do not currently exist, evidence from animal studies in two species suggest that nephrotoxicity may also occur in humans, particularly following acute exposure to 1,1-dichloroethene. The fact that adverse renal effects were rarely seen following more prolonged exposure to 1,1-dichloroethene (except in male mice), coupled with the observation that the acute nephrotoxic effects were reversible, suggest that repair mechanism* may be operating. The renal effects of long-term exposure to 1,1-dichloroethene in humans are not known, but are probably minimal at concentrations generally experienced.
Immunological Effects. No studies were located regarding immunological effects in humans and animal* after 1,1-dichloroethene exposure by any route. Therefore, the potential for 1,1-dichloroethene to cause immunological effects in humans exposed in the environment or at hazardous waste sites cannot be assessed.
Neurological Effects, Central nervous system toxicity has been observed in humans acutely exposed to high concentrations (-4,000 ppm) of inhaled 1,1-dichloroethene (Tierney et al. 1979). Complete recovery occurred if exposure was not prolonged. In addition, signs of central nervous system toxicity were the predominant effects observed in animals after acute inhalation exposure to high concentrations of 1,1-dichloroethene. These signs and symptoms observed in humans and in animals are consistent with a
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narcotic effect of 1,1-dichloroethene, which is observed with many other organic solvents. Effects on the nervous system were not observed following oral or repeated inhalation exposures to 1,1-dichloroethene in animals. However, these studies did not utilize comprehensive neurological testing that may have detected subtle neurological effects. The available information is insufficient to predict whether or not exposure to low levels of 1,1-dichloroethene by the inhalation, oral, or dermal routes of exposure represents a neurological hazard for humans.
Reproductive Effects. No studies were located regarding reproductive effects of 1,1-dichloroethene in humans. Premating exposure of male rats to 1,1-dichloroethene by the inhalation route had no effect on r productive endpoints (Anderson et al. 1977; Short et al. 1977b). Similarly, no reproductive effects were reported in a 3-generation drinking water study with 1,1-dichloroethene in rats (Nitschke et al. 1983). The biological significance of these findings in animals with regard to potential reproductive effects of 1,1-dichloroethene in humans is not known.
Developmental Effects. No studies were located regarding developmental effects of 1,1-dichloroethene in humans. However, an increased incidence of congenital cardiac malformations was observed in infants born to mothers who had consumed water contaminated mainly with trichloroethylene and to a lesser extent with 1,1-dichloroethene and chromium during the first trimester of pregnancy (Goldberg et al. 1990). Although exposure to other chemicals was simultaneous, this finding may be relevant since 1,1-dichloroethene induced a dose-related increase in various congenital cardiac defects in rat fetuses after intrauterine administration of 1,1-dichloroethene to the dams (Dawson et al. 1990). Since 1,1-dichloroethene was not supplied by a natural route of exposure, the results of this study should be interpreted with caution (Dawson et al. 1990). Based on studies by Short et al. (1977a), 1,1-dichloroethene has weak teratogenic effects in laboratory animals (rats and mice). Developmental toxicity was enhanced following inhalation exposure to 1,1-dichloroethene, compared to oral exposure. Developmental toxicity was often observed at doses of 1,1-dichloroethene that also induce maternal toxicity in animals. Studies by Murray et al. (1979) demonstrated that the sensitivity of pregnant rats to 1,1-dichloroethene was greater by inhalation than by ingestion. After inhalation exposure at 80 and 160 ppm for 7 bours/day on gestation days 6-18,1,1-dichloroethene produced maternal toxicity, increased resorption and skeletal alterations. Except for a marginal increase in mean fetal crown-rump length in the offspring, no adverse effects were noted in rats receiving 40 mg/kg/day in drinking water. The author hypothesized a possible mechanism to explain the route-dependent differences in 1,1-dichloroetbene-induced toxicity was as follows: since detoxication of 1,1-dichloroethene occurred 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/kg administered in drinking water over a 24-hour period, but not when the animals were exposed via inhalation between 830 am and 3:30 pm. When 1,1-dichloroethene doses are converted into equivalent units, animals exposed by inhalation received -76.6 and 153 mg/kg/day (assuming all 1,1-dichloroethene was absorbed by the lungs) compared to 40 mg/kg/day in drinking water. Thus, a difference in total dose may also explain the greater toxicity seen following inhalation exposure.
Based on studies in laboratory animals, it is prudent to consider that potential adverse maternal and developmental effects could occur in humans exposed to 1,1-dichloroethene.
G notoxlc Effect*. The available data suggest that 1,1-dichloroethene produces genotoxic effects in a number of test systems. The results of in vitro and in vivo studies indicate that 1,1-dichloroethene 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 widely mutagenic in plants without activation by mammalian metabolic systems. 1,1-Dichloroethene induced chromosome aberrations and sister chromatid exchanges in cultured mammalian cells in vitro and DNA damage in mioe in vivo.
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1,1-Dichloroethene was 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 plant cells (Bartsch et al. 1975, 1979; Bronzetti et al. 1981; Greim et al. 1975; Jones and Hathway 1978b; Oesch et al. 1983; Van't Hof 1982), and it induced gene conversion in yeast (Bronzetti et al. 1981; Koch et al. 1988). Both base-pair substitution and frameshift mutations were reported in Salmonella typhimurium after continuous exposure to 1,1-dichloroethene vapors (Bartsch et al. 1975, 1979; Jones and Hathway 1978b; 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 1,1-dichloroethene into the warmed incubation medium instead of exposing the bacteria continuously to vapor. Given that 1,1-dichloroethene is very volatile and would be expected to escape from the culture, continuous exposure to vapor is considered a more reliable method. 1,1-Dichloroethene was mutagenic in Salmonella after metabolic activation with an exogenous activation system derived from human liver cells (Jones and Hathway 1978b), thus supporting the concept that the human liver is capable of activating 1,1-dichloroethene into mutagenic metabolites.
In cultured mammalian cells, 1,1-dichloroethene was 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 (Sawada et al. 1987) and in mouse lymphoma cells (McGregor et al. 1991) in the presence of a metabolic activation system.
1,1-Dichloroethene has 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). 1.1- Dichloroethene inhalation was associated with low rates of DNA alkylation in the livers and kidneys of mice and rats, compared to dimethylnitrosamine-treated controls. 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, 1,1-dichloroethene was mutagenic and induced gene conversion in yeast (Bronzetti et al. 1981).
There is no direct evidence that exposure to 1,1-dichloroethene causes genotoxic effects in humans; however, the fact that a metabolizing enzyme system derived from human liver could activate 1.1- dichloroethene into mutagenic metabolites (Jones and Hathway 1978b) suggests that 1,1-dichloroethene may be considered a potential genotoxic threat to humans. It must be mentioned, however, that human liver cells overlaid with mammalian tissue post-mitochondrial S9 (prepared from Arodor-1254 induced rats) were activated, and human tissue not overlaid with S9 did not activate 1,1-dichloroethene into mutagenic metabolites.
Cancer. Data regarding carcinogenic effects of 1,1-dichloroethene in humans were limited to results from two occupational exposure studies (Ott et al. 1976; Thiess et al. 1979). The assumption is made that exposure occurred mainly via inhalation, although dermal contact cannot be ruled out Limitations in these studies, such as small cohort size and short observation periods greatly diminished their usefulness for assessing the carcinogenic potential of 1,1-dichloroethene in humans.
The carcinogenicity of 1,1-dichloroethene 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; NTP 1982; 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
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Specks (lest system)
End point
Results
With activation
Without activation
Prokaryotic organisms: Salmonella typhimurium (desiccator test for exposure to gases) S. typhimurium (gas exposure) S. typhimurium (gas exposure) S. typhimurium (gas exposure) S. typhimurium (liquid preincubation test) S. typhimurium (liquid preincubation test) Escherichia coli WP2 E coli K12
Gene mutation
Gene mutation Gene mutation Gene mutation Gene mutation Gene mutation Gene, mutation Gene mutation
+
+ + +
-
+ + +
Eukaryotic organisms: Fungi: Saccharomyces cerevisiae D7 S. cerevisiae D7 S. cerevisiae D7 5. cerevisiae D7 S. cerevisiae D61.M
Plant: Ttadescantia clone 4430
Mammalian cells: Chinese hamster V79 cells Chinese hamster CHL cells Chinese hamster CHL cells Mouse L5178Y lymphoma cells
Gene mutation Gene conversion Gene conversion Gene mutation Mitotic mabegregaiion
+ +
-
+ +
Gene mutation
No data
Gene mutation Chromosomal Sister chromatid exchange Gene mutation
+
(+) +
No data
-
No data -
-
-
+
(+) No data
-
(+)
- = negative result; + = positive result; (4-) = weakly positive result
SL
Reference
Bartsch et ai. 1979
Oesch et al. 1983 Bartsch et al. 1973 Jones and Halhway 1978b Mortelmans el al. 1986 Roldan-Arjona et al. 1991 Oesch et al. 1983 Greim et aL 1973
Bronzetti et al. 1981 Bronzetti et al. 1981 Koch et al. 1988 Koch et al. 1988 Koch et al. 1988
Van'l Hoff 1982
Drevon and Kuroki 1979 Sawada el al. 1987 Sawada el al. 1987 McGregor el al. 1991
TABLE 2-4. Genotoxlclty of 1,1 -Dlchloroethene In Vivo
Spedes (test system)
Mammalian cells: Mouse Rat Mouse bone marrow Mouse fetal liver and blood Mouse kidney (DNA repair)
Host-mediated assays: Saccharomyces cerevisiae (mouse host-mediated assay) S. cerevisiae (mouse host-mediated assay)
End point
Dominant lethals Dominant lethals Micronudei Micronuclei DNA damage
Gene mutation Gene conversion
Results
-
(+)
+ +
Reference
Anderson et al. 1977 Short et al. 1977b Sawada et al. 1987 Sawada et al. 1987 Reitz et al. 1980
Bronzetti et al. 1981 Bronzetti et al. 1981
| - - negative result; + = positive result; (+) *= weakly positive result; DNA = deoxyribonudeic add
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1,1-dichloroethene exposure. In this study, increases in renal adenocarcinomas were noted in male Swiss mice exposed to 25 ppm 1,1-dichloroethene via inhalation. 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; NTP 1982; 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.
The carcinogenicity of 1,1-dichloroethene in mice treated by dermal application and by subcutaneous injection was evaluated by (Van Duuren et al. 1979). 1,1-Dichloroethene was inactive as a complete carcinogen when applied repeatedly for a lifetime to the skin of mice, and did not induce local malignancies when administered chronically to mice by subcutaneous injection. However, a dermal initiation-promotion study with Swiss mice has shown that -dichloroethene was active as a tumorinitiating agent. A statistically significant increase in the incidence of skin papillomas was noted in Swiss mice treated dermally with both 1,1-dichloroethene 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), 1,1-dichloroethene 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 1,1-dichloroethene 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 1,1-dichloroethene 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).
In experimental studies with mice, it has been observed that doses of 1,1-dichloroethene 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 finding 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 1,1-dichloroethene may be the result of the chemical's toxic effect upon nongenetic carcinogenic mechanisms (Reitz et al. 1980). However, 1,1-dichloroethene 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 1,1-dichloroethene 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 1,1-dichioroethene 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 1,1-dichloroethene activation to electrophilic species capable of reacting with intracellular macromolecules (McKenna et al. 1977; Reitz et aL 1980).
NTP described the carcinogenic effects of oral administration of 1,1-dichloroethene in both sexes of Fischer-344 rats and B6C3Fj mice as negative. This term has subsequently been changed to no evidence. EPA (IRIS 1992) has classified 1,1-chloroethene as a Group C agent (possible human carcinogen). This category applies to chemicals for which there is limited evidence of carcinogenicity in animals and inadequate evidence in humans. IARC (1987) has classified 1,1-dichloroethene as a Group 3 chemical (not classifiable as to human carcinogenicity). 1,1-Dichloroethene is not included in the Sixth Annual
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Report on Carcinogens, which is a list of compounds that may reasonably be anticipated to be carcinogens published by the U.S. Public Health Service (NTP 1991).
2.5 BIOMARKERS OF EXPOSURE AND EFFECT
Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).
A biomarker of exposure is a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target moIecule(s) or celi(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 1,1-dichloroethene are discussed in Section 2.5.1.
Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by 1,1-dichloroethene are discussed in Section Z52.
A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, Populations That Are Unusually Susceptible.
2.5.1 Biomarkers Used to Identify or Quantify Exposure to 1,1 Dlehloroethene
Exposure to 1,1-dichloroethene can be determined by the appearance of 1,1-dichloroethene in exhaled air and/or the appearance of metabolites such as dithiogtycollic acid in urine (see Section 6.1). However, because 1,1-dichloroethene is rapidly eliminated from the body, such determinations can prove useful only for detecting recent exposure (within days). Furthermore, because other structurally similar compounds such as vinyl chloride can give rise to the same metabolic products as 1,1-dichloroethene, formation of adducts with hemoglobin and detection of urinary metabolites cannot be considered as specific biomarkers of exposure to 1,1-dichloroethene.
Data from available studies have been insufficient to correlate levels of 1,1-dichloroethene in the environment with levels in breath. In an investigation of trace organic compounds in human breath, a 60minute sampling period yielded 13.0 /ig of 1,1-dichloroethene in the breath (volume unspecified) of one individual (Conkle et al. 1975). This value was corrected for the amount of 1,1-dichloroethene in the air supplied to the individual during the sampling period. The authors attributed the amount of 1,1-dichloroethene in the individuals's breath to previous exposure; however, no levels of previous
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exposure to 1,1-dichloroethene were reported for the test subject The breath of 1 out of 12 subjects tested by Wallace et al. (1984) contained 1,1-dichloroethene (levels not specified). No environmental levels of 1,1-dichloroethene were reported for this study. Twelve percent of breath samples from 350 residents of New Jersey contained measurable amounts of 1,1-dichloroethene, ranging from -0.2 to 2 jxg/m3 of expired air (Wallace et al. 1986). Increased liver enzyme (AST, ALT) activities were reported in two workers exposed to 1,1-dichloroethene. However, these enzyme markers are not specific to 1.1- dichloroethene induced liver toxicity.
2.5.2 Biomarker* Ueed to Characterize Effect* Caused by 1,1-Dichloroethsne
As indicated in Sections 22 and 23, the liver and kidney are primary target organs for 1,1-dichloroethene exposure. Exposure to 1,1-dichloroethene (depending on dose and duration of exposure) increases serum levels of certain liver enzymes such as SGOT (AST), SGPT (ALT), and others, which is taken as an indication of liver injury. However, this effect is caused by other halogenated alkenes as well such as vinyl chloride, and cannot be considered as a specific indicator of 1,1-dichloroethene effects.
Occupational exposure studies have investigated health effects associated with exposure to 1.1- dichloroethene. Because of the small cohort size and concurrent exposure to other compounds, the information from these studies is not sufficient to correlate levels of 1,1-dichloroethene in the environment with health effects (Apfeldorf and Infante 1981). A study of 138 workers exposed to 1,1-dichloroethene (time-weighted-average concentrations ranging from <5 to 70 ppm) and copolymers other than 1.1- dichloroethene reported no statistically-related changes attributable to 1,1-dichloroethene in long-term mortality or health-inventory findings (Ott et al. 1976). No association between occupational exposure to 1,1-dichloroethene (with concurrent exposure to other chemicals) and incidence of angiosarcomas of the fiver in workers was found by Waxweiler (1981).
Inhalation exposure to 50 ppm 1,1-dichloroethene was associated with minimal rates of DNA alkylation in fiver and kidney cells of experimental rats and mice (Reitz et al. 1980).
Additional details regarding biomarkers of effects for 1,1-dichloroethene may be found in the CDC/ATSDR Subcommittee Report on Biological Indicators of Organ Damage (CDG/ATSDR 1990) or in the OTA report on neurotoxicity (1990). A more detailed discussion of health effects attributed to exposure to 1,1-dichloroethene can be found in Section 22 of Chapter 2 in this document
2.6 INTERACTIONS WITH OTHER CHEMICALS
As discussed in previous sections, it is apparent that the toxicity of 1,1-dichloroethene is largely due to the formation of toxic intermediates during metabolism in vivo. The production and biotransfonnation of toxic metabolic intermediates of 1,1-dichloroethene can be greatly influenced by various metabolic inhibitors and inducers, and by the availability of precursors of compounds involved in detoxication, such as GSR
Microsomal mixed-function oxidases (MFOs) are a group of enzymes involved in the biotransfonnation and detoxication of xenobiotjcs such as 1,1-dichloroethene. 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 1,1-dichloroethene in the liver, probably by inhibiting the enzymes responsible for the formation of reactive toxic intermediates (Masuda and Nakayama 1983; Shon et al. 1977c, 1977d). Inhibitors of metabolic enzymes responsible for the breakdown of these reactive intermediates may also enhance the toxicity of 1,1-dichloroethene. For example, 1,1,1-trichloropropane and other inhibitors of epoxide hydrolase can potentiate the toxicity of 1,1-dichloroethene (Jaeger 1977). Other chemicals that reduce the activity of metabolic enzymes and show some protective effects against the toxicity of 1,1-dichloroethene include pyrazole, 3-aminotriazol (Andersen et al. 1978).
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Pretreatment of rats with acetaminophen greatly increased lethality and the hepatotoxic effects of 1.1- dichloroetbene (Wright and Moore 1991). Although the depletion of glutathione was not discussed, the authors concluded that acetaminophen produces alterations that make hepatocytes more susceptible to 1.1- dichloroethene injury.
Enzyme inducers (enhancers) may either protect against or exacerbate the toxicity of 1,1-dichloroethene. Induction of enzymes involved in the formation of toxic intermediates potentiates 1,1-dichloroetheneinduced toxicity following 1,1-dichloroethene exposure; conversely, induction of enzymes responsible for the biodegradation of the toxic intermediate(s) decreases toxicity. Examples of compounds that induce MFOs and increase toxic effects upon exposure to 1,1-dichloroethene include ethanol and acetone (Hewitt and Plaa 1983; Sato et al. 1983).
Many inducers of MFO enzymes do not increase the hepatotoxicity of 1,1-dichloroethene, perhaps because they stimulate enzyme systems not involved in the metabolism of 1,1-dichloroethene. An example of this type of compound is P-450 (Carlson and Fuller 1972). The induction of metabolic enzymes by phenobarbital, even though protective against liver damage, has increased the central nervous system related effects of inhaled 1,1-dichloroethene at very high exposure levels.
Thyroidectomy protected rats from the hepatotoxic effects of 1,1-dichloroethene (Szabo et al. 1977). Thyroxine replacement in thyroidectomized rats exacerbated the liver damage seen upon subsequent exposure to 1,1-dichloroethene (Szabo et al. 1977).
Pretreatment of animals with compounds that deplete GSH levels (such as diethyl maleate) increases the amount of liver damage caused by 1,1-dichloroethene exposure (Reichert et al. 1978). Conversely, pretreatment of animals with supplements containing high concentrations of the amino adds cysteine and/or methionine, both of which are metabolic contributors of the sulfhydryl group required for OSH biosynthesis, has had a protective effect against the toxidty of 1,1-dichloroethene (Short et al. 1977d).
2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE
A susceptible population will exhibit a different or enhanced response to 1,1-dichloroethene than will most persons exposed to the same level of 1,1-dichloroethene in the environment Reasons indude genetic make-up, developmental stage, age, health and nutritional status (induding dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (induding smoking). These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (induding effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, Populations With Potentially High Exposure.
Specific information regarding human subpopulations that are unusually susceptible to the toxic effects of 1.1- dichloroethene were not located. However, animal studies have suggested that there are factors that may predispose some groups of the population to an increased risk for the toxic effects of 1.1- dichloroethene. These factors are discussed below.
The influence that dietary intake can have upon the metabolism and detoxification of xenobiotics has been well documented. Fasting 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 1.1- dichloroethene, compared to similarly exposed control (carbohydrate-fed) animals (Nakajima et al. 1982). Fasting prior to 1,1-dichloroethene exposure resulted in both an earlier appearance of hepatic
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lesions and a more extensive distributi n of lesions, compared to control (fed) rats (Jaeger et al. 1974; Reynolds and Moslen 1977).
Sex differences in the toxic response to 1,1-dichloroethene have been observed in animals. For example, in a chronic inhalation exposure study in rats, hepatotoxic effects occurred at lower 1,1-dichloroethene concentrations in female rats than in male rats (25 and 75 ppm, respectively) (Quast et al. 1986). Fasted male animals, particularly young males, appear to be more susceptible to the toxic effects of 1.1- dichloroethene than fasted females, as evidenced by their enhanced responses at lower doses of 1.1- dichloroethene.
Individuals taking certain drugs or who have pre-existing liver, kidney, thyroid, or cardiac disease may be at greater risk for 1,1-dichloroethene-induced toxicity. Acetaminophen is prescribed to some rheumatic patients at doses up to 4 grams per day (Insel 1990). Such individuals may be highly susceptible to the effects of 1,1-dichloroethene (Wright and Moore 1991). Pbenobarbital, even though somewhat protective against 1,1-dichloroethene-generated liver damage (Carlson and Fuller 1972), has sensitized the heart to 1.1- dichloroethene-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 1,1-dichloroethene. Ethanol increases the amount of 1,1-dichloroethene-induced hepatotaxicity observed in rats, which suggests that alcohol ingestion could exacerbate 1,1-dichloroethene-induced toxicity in exposed individuals. Therefore, individuals taking medicine that contains alcohol or individuals drinking alcoholic beverages may be more susceptible to the trade effects of 1,1-dichloroethene. Thyroidectomy, either chemical or surgical, can protea against the hepatotaxicity associated with inhalation of 1.1- dichloroethene. Conversely, thyroxine treatment to replace or supplement normal thyroid function increases the amount of liver damage upon subsequent exposure to 1,1-dichloroethene in animals (Szabo et al. 1977). Individuals with liver or kidney disease or those with an acute hypersensitivity to 1.1- dichloroethene should avoid exposure to 1,1-dichloroethene.
Specific data concerning teratogenicity in humans exposed to 1,1-dichloroethene were not found in the reviewed literature. 1,1-Dichloroethene has been described as a possible teratogen responsible for softtissue anomalies in rats and skeletal defects in mice, rats, and rabbits, often at levels that produced dear evidence of toxicity in the dam. It would be prudent for pregnant women to avoid exposure to 1.1- dichloroethene.
To conclude, groups of people who should be specifically cautioned against exposure to 1,1-dichloroethene include the very young the elderly, the pregnant; those ingesting large amounts of acetaminophen as medication; those that ingest alcohol; people using phenobarbital (or possibly other hepatic enzymeinducing drugs); those receiving thyroid replacement therapy or those who are hyperthyroid; people who, for whatever reason, are fastings; and those with cardiac, hepatic, renal, and certain central nervous system dysfunctions.
2.8 METHODS FOR REDUCING TOXIC EFFECTS
This section will describe clinical practice and research concerning methods for reducing trade effects of exposure to 1,1-dichloroethene. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to 1,1-dichloroethene. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice.
2.8.1 Reducing Peak Absorption Following Exposure
Treatment for exposure to 1,1-dichloroethene is essentially supportive after the individual is removed from the contaminated environment (Haddad and Winchester 1990). The following steps arc taken in an acute
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exposure situation to reduce the possibility of 1,1-dichloroethene absorption. If 1,1-dichloroethene js swallowed and the victim is conscious, water or milk can be administered to minimize mucosal irritation (Anonymous 1991). Administer activated charcoal to inhibit absorption in the intestine. Empty gastric content by use of ipecac or lavage. Following dermal contact the affected areas are flushed with water. No specific information was located regarding reducing peak absorption of 1,1-dichloroethene following inhalation exposure.
2.8.2 Reducing Body Burden
No information was located regarding retention of 1,1-dichloroethene or its metabolites in humans exposed to 1,1-dichloroethene. However, if the toxicokinetic mechanisms described in animals are suggestive for humans, the metabolites are eliminated mainly in the urine. Therefore, increasing diuresis may be a way of reducing the body burden of 1,1-dichloroethene metabolites.
2.8.3 interfering with the Mechanism of Action for Toxic Effects
No information was located in the available literature regarding clinical or experimental methods that can block the mechanism of toxic action of 1,1-dichloroethene in humans.
Although the exact mechanism of action of 1,1-dichloroethene in humans is not known, both humans and animal studies have identified the liver as the target organ for 1,1-dichloroethene. In experimental animals, 1,1-dichloroethene-induced hepatotoxicity is primarily due to reactive metabolic products that arise from biotransformation reactions initiated by the cytochrome P-450 enzymatic system. It js, therefore, not unreasonable to assume that 1,1-dichloroethene-induced liver toxicity in humans is also caused by 1,1-dichloroethene metabolites. If this premise is accepted, then two general types of biochemical manipulations could be envisioned to reduce 1,1-dichloroethene-induced toxicity. The first one would be to prevent biotransformation into reactive intermediates. This could be done by inhibiting enzymes responsible for these processes. The second alternative would be to ensure that adequate amounts of GSH are available (for example by administering precursors of GSH) in the liver in order to form 5-conjugates with metabolic intermediates that can be eliminated in the urine. In fact, such interventions have been shown to protect against 1,1-dichloroethene-induced liver damage in rats (Moslen et al. 1989b). Based on the fact that 1,1-dichloroethene does not appear to accumulate in tissues, these experimental procedures are likely to be more useful shortly after exposure to 1,1-dichloroethene rather than after prolonged exposure to low levels of 1,1-dichloroethene, which may occur to populations near waste sites.
2.9 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to whether adequate information on the health effects of 1,1-dichloroethene is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,1-dichloroethene.
The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed.
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2.9.1 Existing Information on H alth Effocts of 1,1 -Dlchloroethene
The easting data on health effects of inhalation, oral, and dermal exposure of humans and animals to 1,1-dichloroethene are summarized in Figure 2-7. The purpose of this figure is to illustrate the existing information concerning the health effects of 1,1-dichloroethene. Each dot in the figure indicates that one or more studies provide information associated with that particular effect The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as 'data needs.' A data need, as defined in ATSDR's Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature.
Figure 2-7 depicts the existing health effects information on 1,1-dichloroethene for a specific route and duration of exposure. There is little information available conce; - ng the long-term health effects of 1,1-dichloroethene in humans following inhalation exposure. Mo of the information concerning health effects in hums ' is reported in occupational studies that are diff Jit to interpret, due to limitations in study design (e exposure levels and duration cannot be quantified and concurrent exposure to other toxic substance^ tnnot be ruled out). No information concerning oral or dermal exposure to 1,1-dichloroethene in humans was found in the reviewed literature.
The systemic effects of 1,1-dichloroethene in animals following inhalation and oral exposure have been studied in a variety of species following acute, intermediate, and chronic exposure durations. No studies were located regarding immunological effects in humans or animals following inhalation or 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 or behavioral 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 Identification of Data Needs
Acute-Duration Exposure. No data were located indicating specific organs or systems as targets for 1,1-dichloroethene in humans by any route of exposure. The data in experimental animals such as rats and mice suggest that the liver and kidneys are the primary targets for acute-duration exposure to 1,1-dichloroethene by inhalation and oral routr of exposure (Anderson et ah 1980; Chieco et al. 1987; Henck et al. 1979; Jenkins and Anderson 1978; McKenna et al. 1978a; Moslen et al. 1989b; Reynolds et al. 1980). Data regarding the dermal route of exposure were not located. Although the kidney was identified as the most sensitive organ in acute inhalation studies (Henck et al. 1979; McKenna et al. 1978a; Reitz et al. 1980), these studies were considered inadequate for derivation of an acute inhalation MRL, largely because of the small numbers of animals used and lack of clarify in the presentation of the results. The data in experimental animals were insufficient to derive an acute oral NOIL mainly because the lowest dose associated with systemic effects (Moslen et al. 1989a) was also found to cause lethality in lasted rats (Anderson and Jenkins 1977). Information regarding the cause of death in the acute-duration studies would be useful Acute-duration studies by the dermal route using 14C-1,1-dichloroethene would provide useful information regarding absorption, distribution and kinetics of excretion. Results of these studies coupled with available knowledge on the toxicity and toxicokinetics should suffice. This information may be relevant for populations surrounding hazardous waste sites that might be exposed to 1,1-dichloroethene for brief periods. Pharmacokinetic data do not suggest route-specific target organs. Since 1,1-dichloroethene is rapidly excreted, it is not expected to accumulate in tissues.
Intermediate-Duration Exposure. No data were located that identified target organs in humans following intermediate exposure to 1,1-dichloroethene by any route of exposure. Information is available on the systemic toxicity of 1,1-dichloroethene following inhalation and oral exposure in rats, guinea pigs, dogs, and monkeys. These data indicate that the liver and kidneys are target organs for intermediate
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figure 2-7. Existing Information on Health Effects of 1,1-Dichloroethene
Inhalation Oral Dermal
Inhalation Oral Dermal
Existing Studies
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06 2. HEALTH EFFECTS
exposure to 1,1-dichloroethene (Guest et al. 1976, 1983; Prendergast et al. 1967). However, serious developmental effects occur in rats (Short et al. 1977b) at exposure levels below the levels which produce hepatic effects. Therefore, available data are inadequate to derive an inhalation MRL. Only one study was identified that described the effects of 1,1-dichJoroethene in animals (dogs) after oral intermediate exposure (Quast et al. 1983). The lack of supporting data precluded derivation of an oral MRL. Additional studies conducted in rats via oral route for intermediate exposure would be useful for setting the maximum tolerated dose for oral chronic studies. Data on dermal exposure in animals are lacking. This information may be relevant for populations surrounding hazardous waste sites that might be exposed to 1,1-dichloroethene for brief periods. There are no pharmacokinetic data that would suggest routespecific target organs.
Chronic-Duration Exposure and Cancer. No data were located that identified target organs in humans following chronic exposure to 1,1-dichloroethene by the oral and dermal routes. Hepatic effects described in occupationally exposed humans (EPA 1985a; Tierney et al. 1979) are supported by data in animals (Quast et al. 1983, 1986), but data from animal studies are sparse. An MRL was derived for oral exposure based on hepatic effects in rats (Quast et al. 1983). There are no pharmacokinetic data that would suggest route-specific target organs. Dermal exposure data are lacking and no target organ can be identified. Studies with well-designed experiments and complete dose and time protocols, and measuring all sensitive toxicological end points, would provide valuable information on the health effects associated with long term exposure to 1,1-dichloroethene. These chronic studies could provide information on subtle toxicological changes in organs associated with prolonged exposure to low levels of 1,1-dichloroethene. This information may be relevant for populations surrounding hazardous waste sites that might be exposed to 1,1-dichloroethene for long periods.
Available data are insufficient to permit an evaluation of the carcinogenic risk of 1,1-dichloroethene in humans. The data from animal studies are limited in their usefulness because of flaws in the experimental design (e.g., doses that are too low) (Maltoni et al. 1985; NTP 1982; Ponomarkov and Tomatis 1980; Quast et al. 1983; Rampy et al. 1977). An inhalation study in mice described a positive carcinogenic response in the kidney (Maltoni et al. 1985). This study, however, has been regarded as inconclusive since it appears that tumors were not observed in the absence of nephrotoxicity. Swiss mice, in fact, are much more susceptible to the nephrotoxic effects of 1,1-dichloroethene than other species, or even other strains of mice. Additional information of the carcinogenicity of 1,1-dichloroethene from well conducted animal bioassays and epidemiological studies using various routes of exposure would be useful in predicting the likelihood that such a response occurs in humans.
GenotoxIcHy. No studies were identified that evaluated genotoxic effects of 1,1-dichloroethene in humans following any route of exposure, or in animals following oral or dermal exposure. Studies by the oral and dermal routes could help develop dose-response relationships for these routes. Several in vitro studies (Table 2-3 in Section 23.1.1) suggest that 1,1-dichloroethene, only in the presence of activating systems, is mutagenic in both prokaryotic and eukaryotic organisms. These results are consistent with the idea that a reactive metabolic intennediate(s), and not the parent compound, is (are) responsible for the genotoxic properties of 1,1-dichloroethene. With the exception of a weakly positive response in mouse kidney cells (Reitz et al. 1960), 1,1-dichloroethene tested negative in in vivo rodent assays following acute and intermediate inhalation or acute oral exposure to 1,1-dichloroethene (Anderson et al. 1977; Sawada et al. 1987; Short et al. 1977b). Cytogenetic analysis of human populations exposed to 1,1-dichloroethene in occupational settings would provide an opportunity to assess the genotoxic potential of this chemical in humans.
Reproductive Toxlcft Jo information is available regarding reproductive effects of 1,1-dichloroethene
in humans following
ute of exposure or in animals following dermal exposure. Only one
multigeneration stud) identified in rats (Nitschke et al. 1983). This study was conducted by the oral
route, and the results cre negative. Studies were identified that examined the reproductive effects of
1,1-dichloroethene after acute inhalation exposure in rats (Short et al. 1977b) and mice (Anderson et al.
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1977). No adverse reproductive effects were observed in either one of these studies. Available pharmacokinetic data do not suggest route-specific target organs. Multigeneration studies by the inhalation and dermal routes would add information that could be relevant to humans.
Developmental Toxicity. No relevant information is available indicating that 1,1-dichloroethene affects development in humans by any route of exposure or in animals following dermal exposure. Numerous studies have been conducted in rats by the inhalation route (Murray et al. 1979; Short et al. 1977a, 1977b). Based on the results of these studies no-observed-effect level could not be identified because the study authors did not use concentrations below those that produced adverse effects. Therefore, studies using lower exposure concentrations of 1,1-dichloroethene would provide useful information. Only one oral exposure study in rats was located (Murray et al. 1979), and this study used only one exposure level. No pharmacokinetic data are available that would indicate the transplacental transfer of 1,1-dichloroethane. However, the available developmental toxicity studies suggest that 1,1-dichloroethane can be potentially toxic to the developing fetus. Therefore, additional oral studies using a range of doses would provide useful information.
Immunotoxlclty. No information is available indicating that the immune system is a target for 1,1-dichloroethene in humans or animals. Batteries of immune function tests have not been performed in the available acute-, intermediate-, and chronic-duration studies. Studies conducting tests for immunocompetence and histopathological observations of organs and tissues involved in immunological response would provide valuable information. Dermal sensitization studies in animals might provide information on whether 1,1-dichloroethene is likely to cause an allergic response. Available toxicokinetic data do not suggest route-specific target organs.
N urotoxlcity. Neurobebavioral toxicity studies of acute inhalation exposures to 1,1-dichloroethene in both humans (Henschler et al. 1970; Tierney et al. 1979) and animals (Henschler 1979; Klimisch and Freisberg 1979a, 1979b; Zeller et al. 1979a, 1979b) are inadequate. This limited information suggests that the nervous system can be affected by exposure to rather high concentrations of 1,1-dichloroethene, but a complete battery of neurological tests was not performed. Information by other routes of exposure is lacking. Available toxicokinetics data do not suggest route-specific target organs. Studies by the inhalation, oral, and dermal routes, as well as tests for neurological impairment in animals, might provide information that could be relevant to humans.
Epidemiological and Human Doalmetry Studlea. Most of the available information on the adverse effects of 1,1-dichloroethene 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 1,1-dichloroethene can cause central nervous system toxicity and irritation of the mucous membranes (Quast et al. 1986; Tierney et a). 1979). There is also some evidence to suggest that repeated exposure to 1,1-dichloroethene is associated with liver damage in humans (Tierney et al. 1979). Well-controlled epidemiological studies of people living in close proximity to areas where 1,1-dichloroethene has been detected in surface water and groundwater, in the vicinity of industries releasing 1,1-dichloroethene, near hazardous waste sites, and of people occupationally exposed could add to and clarify the existing database on 1,1-dichloroethene-induced human health effects. However, such 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 decreasing or difficult to define. Furthermore, a study of human populations residing near hazardous waste sites or production sites would also be difficult to conduct because of the difficulty in obtaining meaningful historical estimates of exposure, historical medical data, and comprehensive follow ups.
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Bi markers of Exposur and Effect
Exposure. Information regarding populations exposed specifically to 1,1-dichloroethene is not available; therefore, no known biomarker of exposure to 1,1-dichloroethene has been identified in humans. However, if 1,1-dichloroethene is metabolically disposed by humans in a way similar to that observed in animals, 1,1-dichloroethene in expired air could be a biomarker of recent exposure to relatively high concentrations of 1,1-dichloroethene. Similarly, urinary excretion of metabolites such as thioglycollic acid could also be considered a biomarker of recent exposure. It must be mentioned, however, that the urinary metabolites would not be specific biomarkers for 1,1-dichloroethene-exposure, since other chemicals have similar urinary metabolites. Hence, the development of methods to detect alternative biomarkers, the presence of which in body fluids or tissues can be associated with acute, intermediate, and chronic exposure levels of 1,1-dichloroethene, alone would be useful.
Effect. Information regarding populations exposed specifically to 1,1-dichloroethene is not available. Limited information indicate that serum levels of certain enzymes indicative of liver damage may be elevated in humans exposed to 1,1-dichloroethene (EPA 1985a; Tierney et al. 1979). However, the elevation of liver enzymes is triggered by exposure to many other chemicals; hence, elevation of these enzymes cannot be considered a specific biomarker for 1,1-dichloroethene. Research leading to the identification of specific DNA adducts formed after 1,1-dichloroethene exposure would be valuable. This . would facilitate medical surveillance leading to early detection of potentially adverse health effects and possible treatment.
Absorption, Distribution, Metabolism, and Excretion. There are no quantitative data regarding absorption in humans by the inhalation, oral, and dermal route. The animal data indicate that 1,1-dichloroethene is efficiently absorbed by the inhalation (Dallas et al. 1983; McKenna et al. 1978a) and oral routes (Jones and Hathway 1978a; McKenna et ai. 1978b; Putcha et al. 1986). These studies have been conducted mostly in rats and mice. Dermal absorption data are lacking, but absorption by. this route should be suspected based on the physical and chemical properties of 1,1-dichloroethene.
No data were located regarding distribution of 1,1-dichloroethene or its metabolites in humans. Data derived from inhalation exposure (Jaeger et al. 1977,1978a) and oral administration (Jones and Hathway 1978c) of 1,1-dichloroethene to animals indicate that 1,1-dichloroethene (or metabolites) distribute preferentially to the liver, kidney, and lung, and that in general, 1,1-dichloroethene does not accumulate in tissues. Additional data on the distribution of 1,1-dichloroethene following dermal exposure would be useful, since humans can be exposed via this route, as well. Studies regarding distribution through the placenta were not available.
Data regarding biotransformation of 1,1-dichloroethene in humans are not available. The use of human cell systems in culture might be considered a useful alternative to studying the metabolic fate of 1,1-dichloroethene in individuals. The metabolism of 1,1-dichloroethene has been extensively studied in rats and mice following inhalation and oral exposure (Jones and Hathway 1978a, 1978c; McKenna et al. 1977,1978b; Reichert et al. 1979). Experimental evidence indicates that the metabolic rate is a saturable process. Although information regarding metabolism following dermal exposure is lacking, there is no reason to believe that other pathways would operate after exposure by this route.
Data regarding excretion of 1,1-dichloroethene in humans are not available. Urinary excretion of metabolites is the main route of elimination of 1,1-dichloroethene metabolites in animals after inhalation (McKenna et al. 1978a) and oral exposure (McKenna et al. 1978b; Reichert et al. 1979). After exposure to high concentrations of 1,1-dichloroethene, however, elimination of unchanged 1,1-dichloroethene in expired air was observed (Jones and Hathway 1978c; McKenna et al. 1978b; Reichert et al. 1979). No studies were located regarding excretion following dermal exposure to 1,1-dichloroethene.
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Comparative Toxic kinetics. No direct information exists to assess whether humans handle 1,1-dichloroethene in a way similar to that observed in animals. Toxicokinetics studies have been performed mainly in rats and mice, and the results suggest that no differences exist between these two species, although mice seem to metabolize 1,1-dichloroethene to a greater extent than rats (Jones and Hathway 1978a, 1978c; McKenna et al. 1977, 1978b; Reichert et al. 1979). Experiments in animals (mostly rats and mice) indicate that the liver, kidney, and lungs are common target organs across species. Data from occupationally exposed humans suggest that the liver is a target organ in humans (EPA 1985a; Tierney et al. 1979). Once reliable end points are determined in species other than rats and mice, it should be important to verify that primates are affected in a similar manner, in order to ensure that no unforeseen health effects might occur in humans.
Moth ds for Reducing Toxic Effects. There are no specific established methods or treatment for reducing absorption of 1,1-dichloroethene. Studies aimed at elucidating this mechanism would provide useful information. No information is available regarding the mechanism by which 1,1-dichloroethene distributes to tissues in the body. There are no well-established methods or treatment for reducing the body burden of 1,1-dichloroethene or metabolites or for prevention of toxicity following long-term exposure. The mechanism of toxicity of 1,1-dichloroethene in humans is not known, but there is evidence that 1,1-dichloroethene toxicity in animals is due to a reactive intermediate and not the parent compound (Dekant et al. 1989; Vamvakas and Anders 1990). Experimental methods exist that can prevent the toxic action of 1,1-dichloroethene in animals (i.e., administration of precursors of GHS) (Moslen et al. 1989b), but it is not known whether these methods are relevant to humans. Studies in primates could provide information regarding the mechanism of action of 1,1-dichloroethene that may be more relevant to humans than data obtained in rats and mice. Methods for mitigation of the adverse health effects induced by 1,1-dichloroethene in animals have only been carried out by administering the substance prior to exposure (Anderson et al. 1978).
2.9.3 On-going Studies
Studies are currently being conducted by Dr. A.L. Moore's research laboratory at the Uniformed Services University at Bethesda to evaluate the role of increased ionized calcium in liver cells induced by exposure to 1,1-dichloroethene and other halogenated hydrocarbons (CRISP 1990).
Studies being conducted by Dr. E.A. Glende and coworkers at Case Western Reserve University are aimed at determining whether phospholipase A2 activation occurs during the course of action of liver toxicants such as 1,1-dichloroethene (CRISP 1989).
Studies by Dr. J.L. Poyer's research group at the Oklahoma Medical Research Foundation will determine whether free radical formation observed during the metabolism of 1,1-dichloroethene in the liver correlates with the extent of liver injury (CRISP 1989).
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3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY The chemical formula, structure, synonyms, and identification numbers for 1,1-dichloroethene are listed in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Important physical and chemical properties of 1,1-dichloroethene are listed in Table 3-2.
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TABLE 3-1. Chemical Identity of 1,1-Dlchloroethene
Characteristic
Information
Reference
Chemical name
1,1-Dichloroethene
Synonym(s)
DCE; 1,1-dichioroethylene; 1,1-DCE; asym-dichloroethylene; VDC; vinylidene chloride; vinylidene chloride (II); vinylidene dichloride; vinylidine chloride
Registered trade name(s)
No data
Chemical formula
CjH2a2
Chemical structure
a-c = c-h
11 ah
Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS DOT/UN/NA/IMCO shipping HSDB NCI
75-35-4 KV9275000 U078/D029 7216949 UN 1303; IMO 3.1 1995 C54262
HSDB 1992 HSDB 1992
Budavari et at 1989 Budavari et aL 1989
HSDB 1992 HSDB 1992 HSDB 1992 HSDB 1992 HSDB 1992 HSDB 1992 HSDB 1992
CAS m Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA a Environmental Protection Agency; HSDB * Hazardous Substances Data Bank; NCI * National Cancer Institute; NIOSH *= National Institute for Occupational Safety and Health; OHM/TADS Oil and Hazardous Materials/Technical Assistance Dam System; RTECS = Registry of Toxic Effects of Chemical Substances
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TABLE 3-2. Physical and Chemical Properties of 1,1-Dichioroethene
Property
Molecular weight Color Physical state Melting point, "C Boiling point, C Density:
at 20*C
Odor
Odor threshold: Air
Solubility: Water at 20C
Organic solvents)
Partition coefficients: LogK^ LogKoe
Vapor pressure: at 20C at 25*C
Henry's law constant: at 20-25*C
Autoignition temperature Flashpoint
Flammability limits Conversion factors
Explosive limits
Information
96.95 Colorless Liquid -122.5 31.7 at 760 mmHg
1.2129 g/cm3
Mild sweet odor resembling that of chloroform
500 ppm
2400 mg/L
Soluble in organic solvents
2.13 1.81
500 mmHg 591 mmHg
0.19 atm-m3/mol
512.8-555.0C -16C (tag open-cup) -19C (tag closed-cup) 74-16% 1 ppm x 3.97 " 1 mg/m3 1 mg/m3 x 045 * 1 ppm 5.6-11.4%
Reference
Budavari et al. 1989 Grayson 1985 Budavari et al. 1989 Budavari et al. 1989 Budavari et aL 1989
Budavari et al 1989
Budavari et aL 1989
Clayton and Clayton 1981
Clayton and Clayton 1981
Budavari et al 1969
Mabey et aL 1982 Mabey et al 1982
Verschueren 1983 Clayton and
Clayton 1981
Pankow and Rosen 1988
Weiss 1986 EPA 1985a EPA 1985a Weiss 1986 Verschueren 1983 Verschueren 1983 Sax and Lewis 1987
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4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL
4.1 PRODUCTION
1,1-Dichloroethene does not occur naturally (EPA 1985a) but it is found as the result of the breakdown of polyvinyiidene chloride products in landfills. It is produced commercially by the dehydrochlorination of 1,1,2-trichloroethane with excess lime or caustic. As an inhibitor of the polymerization reaction, 200 ppm p-hydroxyanisole is added, then later removed by distillation or washing (Grayson 1985). Typically, a commercial grade contains 99.8% 1,1-dichJoroethene (EPA 1985a).
1,1-Dichloroethene polymerizes after the addition of an initiator by either an ionic or a free radial reaction. 1,1-Dichloroethene can polymerize spontaneously at room temperature following addition of peroxides (Grayson 1985).
1.1- Dichloroethene is manufactured in chemical plants located in Texas and Louisiana. Currently, there are two major producers, Dow Chemical and Pittsburgh Paint and Glass (PPG) Industries (Burke 1987; EPA 1977; SRI 1991). Production capacity in 1985 was 178 million pounds^ear (EPA 1985a). Tliis has decreased from 1977, when production capacity was estimated at 270 million pounds (EPA 1977). In 1988, plant capacity at PPG Industries was estimated at 64 million pounds/year (PPG Industries 1988). Estimated 1989 production is 230 million pounds (CMA 1989).
According to the 1990 Toxic Chemical Release Inventory (TRI), 21 facilities manufactured or processed
1.1- dichloroethene in 1990 (TRI90 1992). All 21 of these, facilities reported the maximum amount of 1,1-dichloroethene that they would have on site. These data are listed in Table 4-1. The TRI data should be used with caution since only certain types of facilities are required to report This is not an exhaustive list
4.2 IMPORT/EXPORT
In 1984, 40,000 pounds of 1,1-dichloroethene was imported into the United States (SRI 1987). No data are available on the export levels.
4.3 USE
Monomeric 1,1-dichloroethene is used as an intermediate for captive organic chemical synthesis, and in the production of polyvinyiidene 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 polyvinyiidene chloride copolymers is the production of flexible films for food packaging (SARAN and VELON* wraps). 1,1-Dichloroethene is found in many food and other packaging materials. SARAN wrap was found to contain up to 30 ppm 1,1-dichloroethene (Birkel et al. 1977). The plastic packaging films can contain no more than 10 ppm 1,1-dichloroethene (FDA 1988). The coating applicable to fresh-citrus fruit (minimum amount required for intended use) is *25% aqueous solution (FDA 1977). Due to the instability of the polymer, 1,1-dichloroethene is usually used as a copolymer with acrylonitrile, vinyl chloride, methactylonitrile, and methacrylate (Grayson 1985; Rossberg et al. 1986). In the late 1960s and early 1970s, 1,1-dichloroethene 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).
t
F t
f
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* * ORATT FOR PUBLIC
TABLE 4-1. Facilities that Wwitetai or haem 1.1-Blebloroetbsns*
Facility
Location*
3N MONSANTO CO. KOOAK COLORADO DIV. DON CHEMICAL DALTON RITE NORTON INTERNATIONAL,INC. (RIN) SIGNAL CARLE ELI LILLY A CO. TIPPECANOE
LABORATORIES VULCAN CHEMICALS RF 8000RICH LOUISVILLE PLANT W. R. GRACE S CO. VULCAN MATERIALS CO. CHEMICALS DIV.
GEISMAR FACILITY PPG INDUSTRIES, INC.
DOW CHEMICAL CO. USA MICHIGAN DIV. RNQNE-POULENC WALSH DIV. ALLIED-SIGNAL, INC. 6ENCQRP, INC., DM GENCORP POLYMER
PROOUCTS NOGADORE PLY. OCCIDENTAL CHEMICAL CORP. VCM PLANT DOW CHEMICAL CO. TEXAS OPERATIONS
DECATUR, AL DECATUR, AL WINDSOR, CO DALTON, GA RINGWOOO, IL WAUKEGAN, IL MAOELAND, IN
WICHITA, KS LOUISVILLE, KY OWENSDORO, KY GEISMAR, LA
WESTLAKE, LA
MIDLAND, Ml GASTONIA, NC BUFFALO, NY NOGADORE, OH
DEER PARK, TX FREEPORT, TX
LAPORTE CHEMICAL CORP. HERCULES, INC. AC WEST VIRGINIA POLYOL CO.
LA PORTE, TX COVINGTON, VA
SOUTH CHARLESTON, WV
"Derived fra* TR190 (1992) Tost office state abbreviations uaad
Ratios of animal aaounts on alts in pounds
1,000-9,999 100,000-999,999
1,000-9,999 0-99
100,000-999,999 100-999
10,000-99,999
10,000-99,999 10,000-99,999 100,000-999,999 10,000-99,999
1,000,000-9,999,999
1,000,000-9,999,999 100,000-999,999 10,000-99,999 100,000-999,999
10,000-99,999 1,000,000-9,999,999
1,000-9,999 100,000-999,999 100,000-999,999
Activities and uses
Aa a reactant As a reactant Aa u reactant As a reactant As a reactant As an article coaponant As a reactant
As a reactant As a reactant As a reactant Produce; as a byproduct; as an
Impurity; as a reactant Produce; for sale/distributIon; M
byproduct; as an l^xrlty As a reactant As a reactant As a reactant As a reactant
Produce; as a byproduct Produce; for sale/dlstributIon; a* a
byproduct; as an lapurlty; as a reactant; In re-packaging; as a processing aid Produce; as a byproduct As a reactant As a reactant
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4. PRODUCTION, IMPORT, USE AND DISPOSAL
4.4 DISPOSAL
1,1-Dichloroethene 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 regulations of 1,1-dichioroethene require dissolving it in combustible solvents and scatter spraying the solvent into a furnace with an afterburner and alkaline scrubber. However, the criteria for land treatment and burial is undergoing significant revision (HSDB 1992). The waste mother liquor probably contains higher concentrations (>200 ppm) of the inhibitor, (p-hydroxyanisole) MEHQ.
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5.1 OVERVIEW
The primary sources of 1,1-dichloroethene in the environment are related to the synthesis, fabrication, and transport of 1,1-dichloroethene and the fabrication of its polymer products. Because of the volatile nature of the chemical, releases to the atmosphere are the greatest source of ambient 1,1-dichloroethenc. Smaller amounts of the chemical are released to surface water and soil, primarily as a result of waste disposal. 1,1-Dichloroethene in waste water should partition to the atmosphere as a result of volatilization during treatment processes. Most of the 1,1-dichloroethene released to the environment partitions to air or water, including groundwater.
1,1-Dichloroethene has been identified in at least 466 of the 1300 hazardous waste sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HAZDAT 1992). However, the number of sites evaluated for 1,1-dichloroethene is not known. The frequency of these sites can be seen in Figure 5-1. Of these sites, 1 is located in the Commonwealth of Puerto Rico (not shown).
1.1- Dichloroethene is rapidly transformed in the troposphere, where oxidation by hydroxyl radicals is the dominant transformation process. Biotransformation is believed to be the dominant transformation process for 1,1-dichloroethene in groundwater, although this process is probably not important in aerobic surface waters. Biotransformation in soil has not been studied extensively, but it has been shown to occur by methanogenic organisms. Biotransformation will be more important in subsurface soils, because 1.1- dichloroethene in surface soils will volatilize to the atmosphere. 1,1-Dichloroethene 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, landfills, hazardous wastes sites).
The potential for human exposure to 1,1-dichloroethene is greatest for those at its point of production, formulation, or transport. Occupational exposure to 1,1-dichloroethene may occur by inhalation or dermal contact Members of the general public may be exposed by inhalation or by ingesting contaminated drinking water. Those who live near hazardous waste sites contaminated with 1,1-dichloroethene. especially those who receive their drinking water from underground sources, may potentially be exposed to high levels of 1,1-dichloroethene. Quantitative data that address levels of human exposure to 1,1-dichloroethene are limited.
5.2 RELEASES TO THE ENVIRONMENT
5.2.1 Air
Air releases are the largest source of 1,1-dichloroethene releases to the environment, and emissions from polymer synthesis and fabrication industries contribute most to overall atmospheric loading. Singh et at. (1981) have estimated that air emissions of 1,1-dichloroethene from polymer synthesis in the United States range between 2% and 5% of the annual production. EPA (1985a) estimated total annual air emissions of 1,1-dichloroethene of -650 tons/year, which was 0.8% of the production volume for that year. Over one-half of that total (355 tons) was from the polymer production/fabrication industries. The remaining emissions were from monomer synthesis (223 tons/year; 34%) and monomer storage, handling, and transportation (73 tons/year, 11%). Small amounts of 1,1-dichloroethene (not quantified) were estimated to be released during the incineration (disposal) of polymer products containing the 1,1-dichloroethene monomer, 1,1,1-trichloroethane, and other chlorinated solvents (Oki et al. 1990; Yasuhaka and Morita 1988). However, more recent data indicate that both the number of emission point sources and the total amount of 1,1-dichloroethene 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
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TAKE 5-1. M*hm to tho Bwlnnmt froa Facilities that Manufacture or Process 1,mcMomt>--*
* * DRAFT FOR PUBLIC
Reported aaquite released In pounds
Facility
Location*
Underground Air Injection
Water
Total Land emi rorawnt*
POTW* transfer
Off-site waste
transfer
3N
MONSANTO 00.
KODAK 001
!>IV.
DOU CNBUtt.
SITE
NORTON IMTERNATIONAL,
INC. (RIN)
SIGNAL CARLE
ELI LILLY TIPPECANOE
LABORATORIES
WLCAN CHEMICALS
RF ROOMICH LOUISVILLE
PLANT
W. R. GRACE 8 CO.
WLCAN MATERIALS CO.
CHEMICALS DIV. GEISMAR
FACILITY
PPG IMUSTRIES, INC.
ROW CHEMICAL CO. USA
MICHIGAN OtV.
RNONE-POULENC UALSH DIV.
ALLIED-SIGNAL, INC.
GENCORP, INC. DRA GENCORP
POLYMER PROOUCTS
OCCIDENTAL CHEMICAL
CORP. VCM PLANT
DOW CHEMICAL CO. TEXAS
OPERATIONS
LAPORTE CHEMICAL COM.
HERCULES, INC.
AC NEST VIRGINIA POLYOL
CO.
DECATUR, AL DECATUR, AL WINDSOR, CO DALTON, GA RINGHOOD, IL
WAUKEGAN, IL SMKLAMD, li
WiCNITA, KS LOUISVILLE, KV
OUENSRONO, KY GEISMAR, LA
WESTLAKE, LA MIDLAND, MI
GASTONIA, NC DUFFALO, NY NOGADORE, OH
DEER PARK, TX
FREEPORT, TX
LA PORTE, TX COVINGTON, VA SOUTH CNARLEST, WV
Totals
1,330 1,600
670 3,730 13,200
2S5 500
19 270
36,000 170
199,366 22,269
1,006 932
1,000
0
10,400
50 1,712 1,123
303,602
0 0 0 1,330
0 100
0 1,700
0 20 0 690
0 0 200 3,990
0 0 0 13,200
0 0 20 200 0 0 0 500
0 0 0 169 0 0 0 270
0 7 4 36,011 0 1 0 171
00 00 00 0 130,800 05
0 250 0 1,700
00 00
00 00
0 48 0 46
00 00 00
00
0 29
00 00 00
2 199,416 0 22,315
0 25 0 258
0 1,006 0 932 0 1,000
0 0
54
0 0
5
0 0 00
0 18,429 0 0
0 50 0
0 1,712
0
0 1,123 932
0 0
0
0 251 226 304,234 986 133,043
Wived froo TRIM (1992) "Foot Office state abbreviations UMd cTha m of all ralMaas of tho chaotcal to air, land, wotor, and underaround Injection walla by a given facility.
*POTW pU>llcly owned treatawnt worka
su 6''216
1
FIGURE 5-1. FREQUENCY OF NPL SITES WITH 1,1 -DICHLOROETHENE CONTAMINATION *
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1 TO 6 SITES 23 TO 31 SITES
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and improvements in control technology. For example, survey data submitted by the Chemical Manufacturers Association to EPA indicate that -103.4 tons of 1,1-dichloroethene per year are released from manufacturing and processing facilities (CMA 1989).
According to the TRI, an estimated total of 303,602 million pounds (137.7 metric tons) of 1.1- dichloroethene, amounting to 99.8% of the total environmental release, was discharged to the air from manufacturing and processing facilities in the United States in 1990. Hie data listed in TRI should be used with caution since only certain types of facilities are required to report This is not an exhaustive list.
Hazardous waste sites and landfills where 1,1-dichloroethene have 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 Water
Industrial releases of 1,1-dichloroethene to surface water contribute to the overall environmental loading of the chemical, but to a much lesser extent than atmospheric emissions. Liquid effluents produced during polymerization operations are estimated to contribute -2 tons of waste 1,1-dichloroethene each year (Neufeld et al. 1977). Other potential industrial sources of waste 1,1-dichloroethene in surface water are metal finishing and nonferrous metals manufacturing industries, soap and detergent manufacturers, electric coil coating and battery manufacturers, coal mines, laundries, and industries involving paint and ink formulation. 1,1-Dicfaloroethene has been measured in raw waste water from these industries at mean concentrations of 3-760 pg/L (EPA 1981).
According to TRI90 (1992), an estimated total of 251 pounds (0.11 metric tons) of 1,1-dichloroethene, amounting to 0.0008% of the total environmental release, was discharged to water from manufacturing and processing facilities in the United States in 1990 (TRI90 1992). An estimated total of 986 pounds (0.45 metric tons), amounting to 0.0032% of the total environmental release, was discharged to publicly owned treatment works. The TRI data should be used with caution since only certain types of facilities are required to report This is not an exhaustive list
Hazardous waste sites where 1,1-dichloroethene has been improperly disposed are additional potential sources of the chemical, although there are no quantitative data available to address how much 1.1- dichloroethene enters the environment from this source. In addition, surface water or groundwater contaminated with 1,1,1-trichloroethane, tetrachloroethylene, 1,1,2-trichloroethylene, and 1.2- dichloroethane can be an additional source of 1,1-dichloroethene through biotic or abiotic elimination or dehydrochlorination transformations (Back et al. 1990; Cline and Viste 1985; Lesage et al. 1990; McCarty et al. 1986). Hydrolysis of 1,1,1-trichloroethane in water or water/sediment systems will result in the formation of 1,1-dichloroethene by elimination, although it is a very slow process, with a half-life of -1 year (Haag and Mill 1988). Total releases of 1,1-dichloroethene from these sources have not been quantified or estimated.
5.2.3 Soil
Limited information is available on the releases of 1,1-dichloroethene to soil. An estimated total of 180 pounds/year of 1,1-dichloroethene are disposed of in municipal landfills as residual monomer in some consumer products on a national basis (Neufeld et al. 1977).
5.3 ENVIRONMENTAL FATE
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/cfaemical properties. Based on a vapor pressure of 592 mmHg (Verschueren 1983), most of the
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1.1- dichloroethene released into the environment will ultimately partition into the atmospheric compartment as shown by the vapor partitioning model of Mackay and Paterson (1981) although other factors such as water solubility may affect the rate at which the partitioning will occur. In localized situations, intervening processes such as biotransformation, may alter this outcome.
As the magnitude of the Henry's law constant for 1,1-dichloroethene, 0.19 atmospheres m3/mole (Pankow and Rosen 1988), indicates, 1,1-dichloroethene is likely to partition readily into the atmosphere from water. Because of this, 1,1-dichloroethene is generally not found in surface water in high concentrations. Studies on atmospheric removal processes indicate that once in the atmosphere, 1,1-dichloroethene is unlikely to be removed by physical processes such as wet deposition (e.g., rain) or by adsorption to atmospheric particulates (Cupitt 1980).
1.1- Dichloroethene spilled onto surface soil will also tend to partition to the atmosphere, while some of the chemical may percolate into the subsurface soil. Once in the subsurface soil, 1,1-dichloroethene will partition between soil and water. 1,1-Dichloroethene has high water solubility and a small log soil organic carbon sorption coefficient (K^ value of 1.81 (Mabey et al. 1982), indicating that 1,1-dichloroethene will migrate through soil without significant retardation by adsorption to organic carbon. Similarly, 1.1- dichloroethene will migrate relatively freely within groundwater.
1.1- Dichloroethene in surface water is unlikely to partition significantly into aquatic organisms. Although measured bioconcentration factors were not located in the available literature, partitioning of 1.1- dichloroethene from water into aquatic organisms can be predicted in pan by the magnitude of the octanol/water partition coefficient (K^J value. The chemicals with a log of <4.0 are unlikely to bioaccumulate to hazardous levels in human food chains (Veith et al. 198S). The log is 2.13 (Veith et al. 1985), and based upon this calculation, bioaccumulation in the human food chain is not expected to be significant for this compound.
5.3.2 Transformation and Degradation
Transformations of 1,1-dichloroethene can occur due to the reaction with radical species in the atmosphere, and biodegradation under anaerobic conditions in soil or water.
5.3,2.1 Air
Atmospheric degradation of 1,1-dichloroethene is expected to be dominated by gas-phase oxidation with photochemically produced hydroxyl radicals. An experimental rate constant for this process of 8.11xl0'12 cmvmolecule-second at 25eC has been determined (Tuazon et al. 1988) and has been recommended as the best value in an extensive review of the reaction of hydroxyl radicals with organic compounds (Atkinson 1989). Using an average atmospheric hydroxyl radical concentration of 5x10s molecule/cm3, a half-life of 2-3 days can be calculated for this process (Cupitt 1980; Tuazon et al 1988). A higher atmospheric concentration of hydroxyl radicals (106 molecules/cm3) will reduce the halflife of 1,1-dichloroethene to 4-20 hours (Grosjean 1990). The products from this reaction are phosgene, formaldehyde, and chloroacetyl chloride (Tuazon et al. 1988).
Atmospheric degradation of 1,1-dichloroethene may also occur by a gas-phase reaction with other atmospheric oxidants, namely ozone and nitrate radicals, although these processes are too slow to successfully compete with the reaction of 1,1-dichloroethene with hydroxyl radicals (Grosjean 1990). An experimental rate constant for the gas-phase reaction of ozone with 1,1-dichloroethene of 3.7xl0'21 cm3/molecule-second at 25eC (Atkinson and Carter 1984) translates to an atmospheric half-life of more than 10 years for this process using an average atmospheric ozone concentration of 7xlOJ1 molecule/cm3. Nitrate radicals are destroyed by sunlight, and the oxidation of organic compounds by this oxidant is only important at night The rate constant for the oxidation of 1,1-dichloroethene by nitrate radicals, 1.78X10"1 cm3/molecule-second at 25C (Sabljic and Gusten 1990), translates to a half-life
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5. POTENTIAL FOR HUMAN EXPOSURE
of 19 days in a moderately polluted atmosphere, although at nitrate concentrations of SO ppt the half-life may be reduced to 6 days (Grosjean 1990). Reaction products of 1,1-dichloroetbene with hydroxyl radicals and nitrates in air include chloroacetyl chloride, phosgene, formaldehyde, carbon monoxide, and nitric acid (EPA 1983a).
Another process for release of organic compounds in the atmosphere is by direct photolytic degradation; however, because chloroethenes do not adsorb radiation at wavelengths <300 nm to any significant extent (Cupitt 1980; Tuazon et al. 1988), this process is not important degradation pathway for 1,1dichloroethene.
5.3.2.2 Water
Biotransformation under anaerobic conditions is believed to be the dominant transformation process for 1,1-dichloroethene in groundwater. 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 1,1-dichloroethene. Several investigations (Bouwer et al. 1981; McCarty et al. 1986; Pearson and McConnel 1975) have found no evidence for biotransformation of chlorinated ethenes such as 1,1-dichloroethene under aerobic conditions. In contrast, Tabak et al. (1981) reported transformation of 54% of 5 mg/L and 30% of 10 mg/L test concentrations of 1,1-dichloroethene under aerobic conditions within 1 week after incubation with a domestic waste water seed; these removal figures were adjusted to account for volatilization losses from control flasks of 24% for the 5 mg/L and 15% for the 10 mg/L test concentrations.
Under anaerobic conditions (such as those that occur in groundwater), the importance of biotransformation is more clearly defined. McCarty et al. (1986) found that 1,1-dichloroethene was nearly quantitatively reduced to vinyl chloride under methanogenic conditions after 108 days. In another study, vinyl chloride was produced from the reductive dechlorination of 1,1-dichloroethene by microorganisms in anoxic microcosms after 1-2 weeks of incubation (Barrio-Lage et al. 1986). Wilson et al. (1986) studied the behavior of 1,1-dichloroethene 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. Baek et al. (1990) also observed the formation of vinyl chloride under anaerobic conditions when 1,1-dichloroethene was incubated with digested sludge under both fermentive and methanogenic conditions. Vinyl chloride has been classified as a human carcinogen by EPA (EPA 1985a). ATSDR has produced a toxicological profile on this compound (ATSDR 1990).
Photolysis and hydrolysis of 1,1-dichloroetbene in natural aquatic media are not significant processes (Mabey et al. 1982). The estimated half-life for hydrolysis of 1,1-dichloroethene at 25C under neutral (or slightly basic) conditions is 1.2x10s years (Jeffers et al. 1989). Similarly, oxidation is not a significant transformation mechanism for 1,1-dichloroethene in aqueous environments. Degradation rates due to reactions with singlet oxygen and the peroxy radical are not estimated to be environmentally significant in aquatic systems (Mill and Mabey 1980).
5.3.2.3 Sediment end Soil
A methane-utilizing culture isolated from lake sediment was able to degrade 600 ng/mL 1,1-dichloroethene to 200 ng/mL under aerobic conditions within 2 days. The end products were non volatile and did not include vinyl chloride which is known to be formed under anaerobic conditions (Fogel et al. 1986).
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5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
5.4.1 Air
The National Ambient Volatile Organic Compound Database, updated in 1988 to include ambient and indoor volatile organic compounds (VOCs) concentrations in urban, rural, remote, source-dominated and indoor environments, reports an ambient daily average concentration for 1,1-dichloroethene of 4.6 ppb (Shah and Heyerdahl 1988). The ambient average concentration represents contributions from rural, suburban, urban, and source-dominated sites. In a survey of the indoor air of 26 homes and apartments near Research Triangle Park, North Carolina, 1,1-dichloroethene was found in 4 of IS summer samples at a mean concentration of 47.3 ppb and 4 of 16 winter samples at a mean concentration of 7.1 ppb (EPA 1985).
The results of an on-site field data collection program based on short-term studies conducted in seven U.S. cities indicated that 1,1-dichloroethene was present in air at an average concentration range of 0.005-0.03 ppb in various cities (Singh et al. 1981, 1982). 1,1-Dichloroethene was detected in 24 of 79 ambient air samples (collected from 1986 to 1987 in the Kanawha Valley, West Virginia; Los Angeles, California; and Houston, Texas) at a mean concentration of 0.84 ppb (Pleil et al. 1988). It was also found in 33 of 35 ambient air samples (collected in Newark, New Jersey, July-August 1981) at a geometric mean concentration of 0.38 ppb (Harkov et al. 1987). Corresponding values for Elizabeth and Camden, New Jersey, were 33 of 34 samples at a mean concentration of 0.35 ppb and 28 of 30 samples with a mean concentration of 0.36 ppb, respectively (Harkov et al. 1987).
1,1-Dichloroethene has been measured in air in the vicinity of five of six hazardous waste sites as well as a sanitary landfill in New Jersey (1983-1984), with arithmetic mean concentrations ranging from 0.39 to 38.9 ppb measured at waste sites, and an arithmetic mean concentration of 2.6 ppb measured at the sanitary landfill. The highest concentration measured at these six sites was 97 ppb (Harkov et al. 1985; LaRegina et al. 1986). Although quantitative information on the air concentrations of 1,1-dichloroethene at hazardous waste sites on the NPL is not available, 1,1-dichloroethene 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
1,1-Dichloroethene concentrations >5 mg/L have been measured in raw waste water from the metal finishing and nonferrous metals manufacturing industries (EPA 1981). Lower concentrations (<1 mg/L) have been measured in raw waste water from industries involving paint and ink formulation, soap and detergent manufacturing, coil coating, battery manufacturing, coal mining and laundries (EPA 1981). Treated waste waters from all these industries ranged from <1 to 4 mg/L (EPA 1981). According to the STORET database maintained by the EPA 1,1-dichloroethene has been detected in 33% of 1350 effluent samples monitored nationwide (Staples et al. 1985).
1.1- Dichloroethene has been detected in surface waters sampled near industrial sites at concentrations ranging from less than 1 to 550 jtg/L (Going and Spigarelli 1977). According to the STORET database maintained by the EPA 1,1-dichloroethene has been detected in 6% of 8,714 surface water samples monitored nationwide (Staples et al. 1985). However, no 1,1-dichloroethene was detected in raw surface water during a 105-city survey of U.S. cities (Coniglio and Miller 1980). 1,1-Dichloroethene has been detected infrequently at low concentrations in urban runoff that will contribute to surface water concentrations. The Nationwide Urban Runoff Program (NURP), initiated to evaluate the significance of priority pollutants in urban storm water runoff, report a detection frequency of only 3%, with a range of concentrations of 1.5-4 /ig/L (Cole et al. 1984).
About 3% of the drinking water supplies in the United States have been found to contain 1.1- dichloroethene at 0.2-0.5 ng/L (estimated mean 03 jjg/L) concentration in a survey conducted by EPA
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5. POTENTIAL FOR HUMAN EXPOSURE
(EPA 1985a). 1,1-Dichloroethene was also detected (quantification limit of 0.2 ppb) in 23% 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 1,1-dichloroethene detected in the positive samples was 6.3 jig/L (subset median values were 0.28-1.2 ng/L). 1,1-Dichloroethene was detected in 9 of 466 U.S. drinking water wells sampled in the 1982 Ground Water Supply Survey at a median concentration of 0.3 ng/L (Cotruvo 1985).
1.1- Dichloroethene has been detected in 25.2% of 178 contaminated sites monitored under the Comprehensive Emergency Response, Compensation, and Liability Act (CERCLA) making it the fifth most frequently detected organic contaminant at these sites (Plumb 1987). Contamination of groundwater at an industrial site in Waite Park, MN, resulting from the mishandling of waste product, paint, and solvent led to a maximum 1,1-dichloroethene concentration of 88 pg/L in deep monitoring wells and 22 ng/L in shallow weUs (ATSDR 1990). This aquifer contamination led to a maximum 1,1-dichloroethene concentration of 94 jig/L in Waite Park municipal wells resulting in this city's water supply being listed as an NPL site. The disposal of organic chemicals in trenches at a waste disposal site near Ottawa, Canada, resulted in 1,1-dichloroethene groundwater concentrations ranging from 0.9 to 60 ng/L in 43% of samples taken from a 37-well monitoring network in 1988 (Lesage et al. 1990). 1,1-Dichloroethene has also been detected in groundwater sampling surveys conducted in New Jersey (Cain et al. 1989; Fusillo et al. 1985).
The concentration of 1,1-dichloroethene in leachate from the Moyer Landfill in Collegeville, Pennsylvania, classified as an NPL site by the EPA in 1982, ranged from 1 to 2 ppb (Varma 1985). In a 1987-1988 survey of groundwater contamination at 19 municipal and 6 industrial landfills in Wisconsin, 1.1- dichloroethene was detected at one site at an average concentration of 3.4 jig/L (Battista and Connelly 1988).
5.4.3 Sediment end Soil
No information is available on ambient concentrations of 1,1-dichloroethene in soil, although this chemical is often found at hazardous waste sites. Because of the tendency of 1,1-dichloroethene to partition into the atmosphere, with remaining material having the potential to percolate into groundwater, ambient concentrations in surface soil are expected to be low. No information is available on the concentration of 1.1- dichloroethene in sediment.
5.4.4 Other Environmental Media
1.1- Dichloroethene copolymers are used in the manufacture of films used in food packaging. Residual 1.1- dichloroethene monomer has been detected at concentrations of <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 *0.005-0.01 ppm (Gilbert et al. 1980). Concentrations of residual 1.1- dichloroethene in household films used to package food were reported by Birkel et al. (1977) to be 6.5-10.4 ppm (average 8.8 ppm). Some films contained as much as 30 ppm 1,1-dichloroethene (Birkel et al. 1977). No information on the levels of 1,1-dichloroethene in humans was located.
1.1- Dichloroethene was detected in a composite sample of Rigolets clams obtained from Lake Pontchartrain, Louisiana, in 1980 at a concentration of 4.4 ppb wet weight (Ferrario et al. 1985).
5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE
Information on exposure of various populations to 1,1-dichloroethene is limited to information on the potential exposures of 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 1,1-dichloroethene in the workplace in 1970 (NIOSH 1976). These estimates were derived from observation of the actual use of 1,1-dichloroethene (1%), the use of trade-
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name products known to contain 1,1-dichloroethene (19%), and the use of generic products suspected of containing the compound (80%). 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.
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 1,1-dichioroethene 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. Reported ranges of concentrations associated with the monomer and polymer plants are -23-25 ppb and 6-12 ppb, respectively (Wapora 1982). Exposure concentrations %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 (Jaeger 1975).
1,1-Dichloroethene was produced in significant amounts that under certain conditions may approach 100%, from the thermal degradation of methyl chloroform (Glisson et al. 1986). This implies that inadvertent exposure to 1,1-dichloroethene may occur in many industrial situations when methyl chloroform is used in the vicinity of operations involving heat, such as welding or soldering and metal cleaning. 1.1- Dichloroethene 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-weightedaverage 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 POTENTIALLY HIGH EXPOSURES
Human exposure to 1,1-dichloroethene 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 1,1-dichloroethene 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 implicate consumer products as major sources of 1,1-dichloroethene exposure (EPA 1985a).
In addition to releases from hazardous waste sites, ambient air and water may be contaminated with 1.1- dichloroethene by releases from industrial production and polymerization processes (EPA 1977, 1985a; Wang et al. 1985a, 1985b). Levels are significantly higher in areas surrounding production sites (EPA 1977, 1985a).
5.7 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
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5. POTENTIAL FOR HUMAN EXPOSURE
adequate information on the health effects of 1,1-dichloroethene is available. Where adequate information is not available, ATSDR, in conjunction with the NTT, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,1-dichloroethene.
The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed.
5.7.1 Identification of Data Needs
Physical and Chemical Properties. Available data adequately characterize the physical and chemical properties of 1,1-dichloroethene (HSDB 1992; Merck 1983; see Chapter 3).
Production, Import/Export, Use, and Disposal. 1,1-Dichloroethene is produced commercially. The estimated production of the compound in 1989 totalled 230 million pounds, up from an estimated production capacity of 178 million pounds/year in 1985. 1,1-Dichloroethene is used as an intermediate in the synthesis of other organic chemicals and polymers, including flexible films for food packaging. Monomeric 1,1-dichloroethene has been detected in many food packaging materials and foodstuffs. 1.1- Dichloroethene is released mainly to the atmosphere. EPA requires compliance with the regulations of the Resource Conservation and Recovery Act when producing, treating, storing, or disposing of 1.1- dichloroethene. Current disposal regulations require dissolving the compound in combustible solvents and scatter spraying the solvent into a furnace with an afterburner and alkaline scrubber. Additional information on the current criteria for land treatment and burial and on the amounts of 1,1-dichloroethene disposed of by incineration versus landfilling would be helpful.
According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1990, became available in May of 1992 This database will be updated yearly and should provide a list of industrial production facilities and emissions.
Environmental Fata. The available data suggest that 1,1-dichloroethene can undergo transformation due to the reaction with radical species in the atmosphere and biodegradation under anaerobic conditions in water and under aerobic conditions in soil (Foget et al. 1986; Grosjean 1990; Tabak et al. 1981; Tuazon et al. 1988). The atmospheric half-life of 1,1-dichloroethene in air following hydroxyl radical reaction is estimated to be 4-20 hours, and the products of this reaction are phosgene, formaldehyde, and chioroacetyl chloride (Tuazon et al. 1988). The estimated half-life for hydrolysis of 1,1-dichloroethene at 25C under neutral conditions is 1.2x10s years (Jeffers et al. 1989). 1,1-Dichloroethene is reduced to vinyl chloride under methanogenic conditions (McCarty et al. 1986). In a methane-utilizing culture from lake sediment, 1,1-dichloroethene was degraded under aerobic conditions within 2 days; the end products, although unspecified, did not include vinyl chloride. More information is needed to define these processes and to quantify degradation rates. Such information would be helpful in understanding the fate of nonvolatilized 1,1-dichloroethene in these media.
Bioavallablllty from Environmental Media. The monitoring data available indicate that 1.1- dichloroethene is present in some samples of air, water, soil, and foodstuffs (EPA 1981, EPA 1985a, Gilbert et al. 1980, Shah and Heyerdahl 1988, Singh et al. 1981, Verma 1985). Animal studies indicate that 1,1-dichloroethene is absorbed following inhalation and oral routes. 1,1-Dichloroethene and its metabolites can be measured in the breath, blood, urine, and adipose tissue of humans. Thus, it can be concluded that 1,1-dichloroethene is bioavailable from the environment. What is lacking is good
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5. POTENTIAL FOR HUMAN EXPOSURE
quantitative data that correlate varying levels in the environment with levels in the body and health effects and the extent to which 1,1-dichloroethene can be absorbed from various media (i.e., soil). This may be difficult to obtain since environmental levels can fluctuate widely and exposure may be sporadic.
Food Chain Bioaccumulation. No information was found regarding the bioconcentration of 1,1-dichloroethene in plants, aquatic organisms, or animals. On the basis of the log octanol/water partition coefficient value of 2.13 (Mabey et al. 1982), bioconcentration of the compound to significant levels by terrestrial or aquatic organisms is not expected. No data were located regarding the biomagnification of 1,1-dichloroethene in terrestrial or aquatic food chains. Given the expected limited bioconcentration (Barrio-Lage et al. 1986; Wilson et al. 1986) of the compound in the tissues of terrestrial and aquatic organisms, and the extent to which 1,1-dichloroethene undergoes biotransformation, biomagnification in terrestrial and aquatic food chains is not expected. Additional experimental data to confirm this predicted limited food chain bioaccumulation of 1,1-dichloroethene would be helpful in evaluating the relative significance of this route of exposure.
Exposure Levels in Environmental Media. Data on the concentrations of 1,1-dichloroethene in surface water, soil, and food, are limited (EPA 1981, EPA 1985a, Gilbert et al. 1980, Shah and Heyerdahl 1988, Singh et al. 1981, Verma 1985). More data are needed to provide a more complete characterization of human exposure. The concentration of 1,1-dichloroethene in the air above hazardous waste sites and in groundwater near them is not well documented. The available data indicate that human exposure may occur because of 1,1-dichloroethene's presence in these environmental media. Additional monitoring data will better address the degree to which it occurs.
Reliable monitoring data for the levels of 1,1-dichloroethene in contaminated media at hazardous waste sites are needed so that the information obtained on levels of 1,1-dichloroethene in the environment can be used in combination with the known body burden of 1,1-dichloroethene to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites.
Exposure Levels in Humsns. Although analytical method is available to detect 1,1-dichloroethene in human tissue. No studies were found that measured its levels in human tissues. Most of the data on exposure levels of 1,1-dichloroethene are based on occupational studies conducted under controlled environmental conditions (Wapora 1982), and these data are not current More current information on the potential exposure resulting from residence in the vicinity of hazardous waste sites would provide a more accurate characterization of human exposure in the United States.
This information is useful for assessing the need to conduct health studies on these populations.
Exposure Registries. No exposure registries for 1,1-dichloroethene were located. This substance is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to exposure to this substance.
5.7.2 On-going Studies
Long-term research studies on the environmental fate of 1,1-dichloroethene were not identified. However, remedial investigations and feasibility studies at NPL sites known to have 1,1-dichloroethene contamination (NPLTD 1988) should be completed in the near future and may add to the current knowledge regarding the transport and degradation of 1,1-dichloroethene in the environment.
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S. POTENTIAL FOR HUMAN EXPOSURE
Environmental monitoring conducted in conjunction with remedial investigation/feasibility studies at hazardous waste sites on the NPL should add to the current database on environmental levels of 1,1-dichloroethene.
As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health Laboratory Sciences Division of the National Center for Environmental Health and Injury Control, Centers for Disease Control, will be analyzing human blood samples for 1,1-dichloroethene 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.
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6. ANALYTICAL METHODS
The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring 1,1-dichloroethene, its metabolites, and other biomarkers of exposure and effect to 1,1-dichloroethene. The intent is not to provide an exhaustive list of analytical n mods. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision.
6.1 BIOLOGICAL MATERIALS
The analytical methods used to quantify 1,1-dichloroethene in biological samples are summarized below. Table 6-1 lists the applicable analytical methods for determining 1,1-dichloroethene in biological specimens.
1.1- Dichloroethene and/or its metabolites are eliminated from the body primarily in expired air and the urine. Therefore, 1,1-dichloroethene exposure can be monitored by measuring the levels in expired air and urine. 1,1-Dichloroethene also distributes preferentially to liver, kidney, and to a lesser extent, adipose tissue. Methods are available to measure 1,1-dichloroethene and/or its metabolites in these tissues as well. The gas chromatography/mass spectrometry (GC/MS) procedure is the most commonly used method to detect 1,1-dichloroethene in biological samples. This technique allows the detection of compound at the ppb level. Capillaiy 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 1.1- dichloroethene. Furthermore, specific GC-detectors, as well as mass selective detectors, enable the quantitation of 1,1-dichloroethene even when it is not fully separated from other compounds. It is difficult to accurately measure biological concentrations of 1,1-dichloroethene and correlate these measurements to actual exposure concentrations because of the chemical's short half-life and conversion into metabolites. The concentration of 1,1-dichloroethene in biological media is continually changing by virtue of its rapid release into the air or biotransformation into other compounds. More information on methods for the analysis of 1,1-dichloroethene in biological materials, including sample preparation techniques, can be found in the references cited in Table 6-1.
Environmental exposure to 1,1-dichloroethene at hazardous waste sites may often include exposure to other chlorinated hydrocarbons. 1,1-Dichloroethene exposure can be monitored by direct measurement of the parent compound or its metabolites. It is difficult to distinguish metabolites of 1,1-dichloroethene in the body because some of the same metabolites may be formed as a result of exposure to some of other chlorinated hydrocarbons.
Determination of 1,1-dichloroethene in breath samples by GC/MS is the most commonly used method of monitoring exposure to 1,1-dichloroethene (Pellizzari et al. 1985). Various other techniques are being studied and developed to monitor 1,1-dichloroethene in expired air using reversible adsorption (Contant et al. 1984) and impregnated tape methods for continuous monitoring (Denenberg and Miller 1974). Recently, a portable device for measuring 1,1-dichloroethene in alveolar breath was described (Raymer et al. 1990). TTie measurement of 1,1-dichloroethene adducts with DNA in lymphocytes or hemoglobin may also be useful in monitoring exposure to 1,1-dichloroethene. Such a method has been established in hemoglobin for another volatile organic compound, ethylene oxide (Tomqvist et al. 1986). Because human hemoglobin has a half-life of >-60 days (although half-lives of hemoglobin adducts are somewhat reduced).
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TABLE 6-1. Analytical Methods for Determining 1,1 -Dlchloroethene In Biological Materials
6. ANALYTICAL
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Sample matrix
Preparation method
Analytical method
Human tissue (adipose, kidney, liver, and brain)
Mince tissue, add isooctane/water; extract, purge and trap
GC/ECD
Breath
Thermal desorption
GC/MS
Alveolar breath
Fbl: >e
Rat urine Fish tissue
Breath collection in evacuated 1.8 L canister using a spirometer, cryogenic concentration
Gv.
Homogenize, add liquid N2 to prevent evapor ation of volatiles, vacuum distillation
GC/MS using a fusedsilica capillary column
None
GC/MS
Purge and trap method to release volatile compounds trapped in the fish tissue
GC/MS
Sample detection
limit
Percent recovery
Reference
-50 pg
>50 Lin et aL 1982
1 pg/m3 <5 Mg/m3
40-60 95
Wallace et aL 1984; Pelllzari et aL 1985
Raymer et aL 1990
No data
No data Hiatt 1983
No data 10 Mg/kg
.35 70
McKenna et aL 1978b Easley et aL 1981
BCD electron capture detector, OC - gas chromatography, MS
spectrometry, N2 nitrogen
93
6. ANALYTICAL METHODS
monitoring of 1,1-dichloroethene adducts with hemoglobin can be a valuable tool for estimating exposure over longer periods.
6.2 ENVIRONMENTAL SAMPLES
The analytical methods used to quantify 1,1-dichloroethene in environmental samples are listed in Table 6-2. The analytical methods required by EPA (1984a, 1984b, 1984c) for the analysis of 1,1-dichloroethene in water and waste water are described 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 waste water. The method required by the EPA Contract Laboratory Program (CLP) for analysis of 1,1-dichloroethene and other volatile organic compounds is hexadecane extraction, followed by determination of approximate concentration using GC and flame ionization detection (FID), and final quantitative analysis using GC/MS (EPA 1986a, 1986b).
GC/FID is used to detect 1,1-dichloroethene in air samples; the GC/MS procedure is used to determine 1,1-dichloroethene in water, waste water discharges, and soil samples; GCVion trap detection (ITD) is used for drinking water. Complete descriptions of these techniques can be found in the references cited in Table 6-2. Gilbert et al. (1980) detected 1,1-dichloroethene in food at levels <5 ppm using headspace GC/ECD. These food products were packaged in polyvinylchloride films.
6.3 ADEQUACY OF THE DATABASE
Section 104(i)(5) of CERCLA, as amended, 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 1,1-dichloroethene is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,1-dichloroethene.
The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed.
6.3.1 Identification of Data Needa
Methods for Determining Blomarkers of Exposure and Effect. Except for the measurement of 1,1-dichloroethene in breath within a short period after exposure, there are no other biomarkers of exposure or effect unique to 1,1-dichloroethene. Present analytical techniques for the determination of 1,1-dichloroethene in breath (Pellizzari et al. 1985; Raymer et al. 1990, Wallace et al. 1984) have acceptable quantification limits and are capable of determining exposure.
There are few analytical methods used to determine 1,1-dichloroethene in biological samples. The current emphasis is on (a) measuring the compound of interest at the ppb level accurately and consistently, (b) refining sample preparation techniques, and (c) modifying the analytical procedure to obtain better resolution with higher sensitivity. Analytical methodology to distinguish exposure to 1,1-dichloroethene 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 1,1-dichloroethene rather than meeting quality control objectives necessary for analytical method standardization.
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TABLE 6-2. Analytical Methods for Determining 1,1-Dichloroethene In Environmental Samples
Sample matrix
Preparation method
Analytical method
Air
Adsorb (charcoal);
GC/F1D
desorb carbon disulfide
Air Air Water
Solid sorbent collection GC/FID Reversible adsorption GC/MS Purge and trap method GC/HECD
Water
Purge and trap method GC/MS
Water
Isotope dilution
GC/MS
Drinking water Groundwater
Purge and trap on solid absorbent, thermal desorption, capillary column GC separation
Gc/rro
Purge and trap method GC/HECD
Sample detection
limit
Percent recovery*
Reference
1 mg/m3
7 pg&unple No data 0.13 fig/L 2.8 fig/L 10 ftg/L <0.2 fig/L
85
>80 No data 0.980 0.87 1.12C+ 0.61 No data
87
NIOSH 1984 (method 1015); Taylor 1978; Foerst 1979
Foerst 1979
Coutant 1984
EPA 1984a (method 601)
EPA 1984c (method 624)
EPA 1984c (method 624)
Eichelberger et al. 1990 (EPA method 524.2)
0.13 fig/L
0.980 0.87
EPA 1986a (method 8010)
06k*90 Si-
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TABLE 6-2. Analytical Methods for Determining 1,1-Dlchloroethene In Environmental Samplea (continued)
Sample matrix Groundwater
Preparation method
Analytical method
Purge and trap method GC/MS
Solids/sludges/ soils/sediments/ wastes
Purge and trap method GC/MS
Soil/chemical waste
Hexane extraction; temperature programmed GC determination
GC/MS
Food (potato crisps, cakes, snack products, cheeses, biscuits)
Crush or grind and heat food samples
GC/ECD
Packaging films
Heat hypovials containing film at 120*0; collect headspace vapor
GC/ECD
Sample detection
limit
Percent recovery*
Reference
5 pg/L
1.12C+ 0.61
Soil, sediment 5 ngfL (ww); wastes 0.5 mg/kg
1.12C+ 0.61
10 ppm
80-90
EPA 1986b (method 8240) EPA 1986b (method 8240)
DeLeon et ai. 1980
<0.005 ppm No data Gilbert et al. 1980
0.04 ppm
No data
Gilbert et al. 198(1, Crosby 1982
`Expressed a recovery as a function of C true value for the concentration
ECD = electron capture detection; FID = flame ionization detection; OC - gas chromatography, HECD = Hall electrolytic conductivity detector; ITD = ion trap detection; MS = mass spectrometry, ww - wet weight
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6. ANALYTICAL METHODS
Methods for Determining Parsnt Compounds and Degradation Products In Environmental Media. There are media-specific standardized methods available for detecting 1,1-dichloroethene 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. A better resolution and sensitivity are achievable with the application of the proper GC capillary column and selection of the correct detector or detector combination (Kirshen 1984).
Methods are available to detect 1,1-dichloroethene in air, water, sediment, soil, sludge, liquid waste, food, and fish. The standardized methods can detect 1,1-dichloroethene levels *ppt in air and *ng/L in water. In addition, numerous techniques for the analysis of 1,1-dichloroethene are reported in the open literature (Constant et al. 1984; EPA 1986a, 1986b; Gilbert et al. 1980; Pellizzari et al. 1985; Tornqvist et at. 1986).
The known degradation products of 1,1-dichloroethene containing chlorine are volatile organic compounds and are often detected and quantified along with 1,1-dichloroetb i in monitoring experiments (although they likely arose from anthropogenic sources). Thus, experime nethods used to detect 1,1-dichloroethene are sufficient to quantify its chlorinated deg: :ion products.
6.3.2 On-going Studios
No on-going studies concerning techniques for measuring and determining 1,1-dichloroethene in nvironmental samples were identified.
The Environmental Health Laboratory Sciences Division of the National Center for Environmental Health and Injury Control, Centers for Disease Control, is developing methods for the analysis of 1,1-dichloroethene and other volatile organic compounds in blood. These methods use purge and trap methodology, high resolution gas chromatography, and magnetic sector mass spectrometry which gives detection limits in the low parts per trillion (ppt) range.
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7. REGULATIONS AND ADVISORIES
Table 7-1 summarizes international, national, and state regulations and guidelines on human exposure to 1,1-dichloroethene.
ATSDR has derived an MRL of 0.009 mg/kg/day derived for chronic-duration oral exposure in rats; this MRL is based on a LOAEL of 9 mg/kg/day (Quast et al. 1983).
A reference dose (RfD) of 0.009 mg/kg/day has been verified by EPA for 1,1-dichloroethene (IRIS 1992). The RfD is based on a LOAEL of 50 ppm of 1,1-dichloroethene in the drinking water for liver effects in rats (Quast et al. 1983). EPA has given 1,1-dichloroethene a Group C weight-of-evidence carcinogenicity classification, probable human carcinogen (IRIS 1992).
The Clean Water Effluent Guidelines regulate 1,1-dichloroethene for the following industrial point sources: electroplating, organic chemicals production, rubber manufacturing, asbestos product manufacturing, timber products processing, metal finishing, paving and roofing, paint formulating, ink formulating, gum and wood chemicals manufacturing, carbon black manufacturing, coil coating, and electrical and electronic components manufacturing (EPA 1988).
The FDA has limited the amount of 1,1-dichloroethene that can be present in foodwrap to 10 ppm (FDA 1988).
t
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TABLE 7-1. Ftegulatl ns and Guidllns Applicable to l,1-Oichk>i thn
Agency INTERNATIONAL IARC WHO NATIONAL Regulations: a. Air
OSHA b. Water
EPAODW EPAOWRS
FDA
c. Other EPAOERR EPAOSW
Description
Carcinogenic classification Guideline for drinking water
Information
Reference*
Group 3* 03 sg/L
IARC 1987 WHO 1984
Limit for air contaminant* 8-hour TWA
1 ppm
MCL in drinking water
0.007 mg/L
General permit* under the NPDES
No
Criteria and atandard* for the NPDES
No
General pretreatment regulation* for existing and new aoureea of pollution waste water effluent guideline* for point aource categories
Rayon fiber*, other fiber*, thermoplastic resins. thermosetting resins, commodity organic chemicals, bulk organic chemicals,
specialty organic chemicals:
Maximum for one day Maximum for monthly avenge Direct discharge point source* that uae end-of-pipe
biological treatment (effluent limitations BAT snd NSPS):
Maximum for one day Maximum for moodily average Direct discharge point aoureea that do not use
end-of-pipe biological treatment (BAT effluent limitation* and NSPS): Maximum for ooc day Maximum for monthly average Piopoaed uses of vinyl chloride polymen: deletion of vinyl dtioride-DCE copoiymen from the list of materials that may be used on fruits
applicable to fresh dtrus fruit (minimum required for Intended uae)
ob ptatic ptcfctftaf flint
No
60 xg/L 22 *g/L
25 ng/L 16 Xg/L
60 xg/L 22gg/L No
25% or leas aqueous aohttion 510 ppm
Reportable quantity
Reportable quantity (proposed) Designation of hazardous substances Listing as ttzoc wastes: discarded commercial
chemical products, off-specification species, container residues, and spill residues of DCE Listing as a hazardous waste constituent (Appendix VIII)
5000 pounds 100 pounds No No
No
OSHA 1989 (29 CFR 1910.1000)
EPA 1985c (40 CFR 141)
EPA 1983b (40 CFR 12228)
EPA 1979 (40 CFR 125)
EPA 1966d (40 CFR 403)
EPA 1987b (40 CFR 414)
EPA 1967b (40 CFR 414)
EPA 1967b (40 CFR 414)
EPA 1967b (40 CFR 414)
FDA 1966
FDA 1977 (21 CFR 1172210); FDA 1968 (21 CFR 177)
EPA 1985c (40 CFR 3024)
EPA 1967b EPA 1963b EPA 1960s (40 CFR
26133)
EPA 1985c (40 CFR 261)
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TABLE 7-1. ftogulstlons and QutdUf>M AppHcabto to 1,1>DlchlorottiwM (continued)
A*ency
Description
Information
NATIONAL (com) EPAOTS
Guidelines; a. Air
ACGIH b. Water
EPAODW
EFA OWRS
NAS c. Other.
EPA
STATE Refutation*
OuiMiao: a. Air
Arizona Connecticut lirftmf Kanaaa Maine Maryland Maeaartmsrtti Nevada New York North Carolina North Dakota Oklahoma Penmytvania T Virginia
Tone Chemical Release Reportable; Community Right-to-Know (proposed)
TLVTWA STEL
MCLG
Health Advisoriea 1 day 10 days Loafer Term Adult Child
Ambient water quality criteria for protection of human health; Ingesting water and organisms:
wr5 w*
IVs IV* SNARL (chronic)
RID (oral) Carcinogen classification
q,*(oral) Inhalation unit risk
Acceptable ambient air concentrations (24 hour average) (8 hour average) (8 hour avenge) (annual average)
(24 hour average) (8 hour average) (1 year average) (24 hour average) (8 hour average) (24 hour average) (1 year average) (1 year average) (24 hour average)
No
5ppm 20 ppm
0.007 mg/L
2.0 mg/L 1.0 mg/L
3-5 mg/L 1.0 mg/L 0.007 mg/L
23 kf/L 033 gg/L 0X33 gg/L
185 gg/L 184 gg/L 135 gg/L 100 gg/L
0.009 mg/tg/day Group C* 04 (mf/kfWay)'1 5x1O'5 (gg/to3)'1
110 gg/m3 400 gg/m1 200 gg/m3 0.02 gg/m3 0.0 0.0 1.08 ggAn3 476 gg/m3 66.7 gg/m3 0.12 mg/m3 02 mg/m3 198 gg/m3 24 gg/m3 4 gg/m3 330 gg/m3
References
EPA 1987c
ACGIH 1986 EPA 1985c (40 CFR
141) EPA 1987a
EPA 1980
NAS 1983 IRIS 1992 IRIS 1992 DUS 1992 DUS 1992
NATICH 1967
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TABLE 7-1. Regulations and Guidelines Applicable to 1,1-Dlchloroethene (continued)
Agency
DcKxiption
Information
References
STATE (com.)
b. Water; Alabama Arizona California Connecticut Maine Massachusetts Minnesota New Jersey Rhode Island Vermont
Drinking water quality standards
7gg/L
7/L 6 ag/L 7 ag/L 7 ag/L 7 ag/L 7 ag/L 2 ag/L 7 ag/L 7/L
FSTRAC 1990
Group 3: Not dassifsbie as to human cardnogenidty kGroup C PoaaiUe human carcinogen
ACGIH - American Conference of Governmental Industrial Hygkntists; BAT Best Available Technology; EPA * Environmental Protection Agency, FDA < Food and Drug Administration; 1ARC - International Agency far Research on Cancer, MCL - Maximum Contaminant Level; MCLG * Maximum Contaminant Level Goal; NAS " National Academy of Sciences; NPDES - National Pollutant Discharge Elimination System; NSPS - New Source Performance Standards; ODW " Office of Drinking Water, OERR Office of Emergency and Remedial Response; OSHA - Occupational Safety and Health Administration; OSW - Office of Solid Waste; OTS - Office of Ttnic Substances; OWRS - Office of Water Regulations and Standards; RID - Reference Dose; SNARL Suggested No-Adverse Effect Level; STEL - Short-term Exposure Limit; TLV a Threshold Limit Value; TWA " Time-Weighted Average; WHO - World Health Organization
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8. REFERENCES
`ACGIH. 1986. Documentation of the threshold limit values and biological exposures indices. 5th ed. American Conference of Governmental Industrial Hygienists. Cincinnati, OH.
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 Perspect 21:71-78.
Anonymous. 1968. Gas chromatographic determination of impurities in vinyl chloride. J Chromatog 34:394-398.
`Anonymous. 1991. Hazardous materials: 1,1-Dichloroethylene. Dangerous Properties of Industrial Materials Report II(3):235-251.
`Apfeldorf R, Infante PF. 1981. Review of epidemiologic study results of vinyl chloride-related compounds. Environ Health Perspect 41:221-226.
`Atkinson R. 1989. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic compounds. Journal of Physical and Chemical Reference Data, Monograph no. 1.
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9. GLOSSARY
Acute Exposure - Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles.
Adsorption Coefficient (K^) - 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 - 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 (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity -- 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, indude malformations and variations, altered growth, and in utero death.
EPA Health Advisory - An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is 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.
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9. GLOSSARY
In Vitro - Isolated from the living organism and artificially maintained, as in a test tube.
In Vivo - Occurring within the living organism.
Lethal Concentration^ (LC^) - The lowest concentration of a chemical in air which has been reported to have caused death m humans or animals.
Lethal Concentration^ (LCjq) - 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(LO) (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^ (LDjq) - The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population.
Lethal Time(S0 .Tjq) - A calculated period of time within which a specific concentration of a chemical is expected to caL 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 adiwrse 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 dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure.
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 follow exposure to chemical.
No-Observed-Adverse-Effect Level (NOAEL) - The dose of chemical at which t.re were no statistically or biologically significant increases in frequency or severity of adverse effects seen oetween the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse.
Octanol-Water Partition Coefficient (K^) - 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 8hour shift.
qt* - The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q:* can be used to calculate an estimate of carcinogenic potency, the increir ntal excess cancer risk per unit of exposure (usually *ig/L for water, mg/kg/day for food, and ng/m3 for ait
Reference Dose (RID) - 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
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9. GLOSSARY
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 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water 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 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 (TD^ - A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% 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 LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10.
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APPENDIX A USER'S C.UIDE
Chapter 1
Public Health Statement
This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance.
The major headings in the Public Health Statement are useful to find specific topics of concern. The topics arc written in a question and answer format The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic.
Chapter 2
Tables and Figures for Levels of Significant Exposure (LSE)
Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELs) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species. Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Hie LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text
The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in tbe left column of the legends correspond to the numbers in the example table nd figure.
LEGEND
See LSE Table 2-1
(1). Route of Exposure One of tbe first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, three LSE tables and two LSE figures are presented in the document The three LSE tables present data on tbe three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1,2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes.
(2). Exposure Duration Three exposure periods: acute (14 days or less); intermediate (IS to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported.
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(3) ,
Health Effect The major categories of health effects included in LSE tables and figures arc death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects arc further defined in the "System* column of the LSE table.
(4) .
Kev to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1).
(5) . Species Tbe test species, whether animal or human, are identified in this column.
(6) .
Exposure Freauencv/Duration Tbe duration of the study and tbe weekly and d-dly exposure regimen are provided in this column. This permits comparison of NO \ELs and LOAEL m different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for . weeks, 5 days per week, for 6 hours per day.
(7) .
System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g, a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated in this study.
(8) .
noart. a No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 repans a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "c").
(9) .
LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in tbe study that caused a harmful health effect LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which advene health effects first appear and the gradation of effects with increasing dose. A brief description of die specific end point used to quantify the advene effect accompanies the LOAEL The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm.
(10) . Reference Tbe complete reference citation is given in Chapter 8 of the profile.
(11) . CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset ofcarcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer.
(12) . Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in tbe footnotes. Footnote "c" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm.
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LEGEND
See LSE Figure 2-1
LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration.
(13) . Exnosure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated.
(14) . Health Effect These are the categories of health effects for which reliable quantitative data exist The same health effects appear in the LSE table.
(13). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mgAn1 or ppm and oral exposure is reported in mg/kg/day.
(16) . NOAEL in this example, I8r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat). The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table).
(17) . CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table.
(18) . Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived front EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,*).
(19) . Kev to LSE Figure The Key explains tbe abbreviations and symbols used in the figue.
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TABLE 2-1. Until of Significant byrntn to IOwli.il XI - IiMetlan
Key to figure* Spocloo
INTERMEDIATE EXPOSURE
s- Systonlc
B-* ID
T
Rot
Expoouro frequency/
duration
Syotno
Ejp
13 ok 3d/uk tfhr/d
[p
Roop
NOAEL (W*)
P
LOAEL (Offoct)
Low oorlouo <PPt)
Sorlouo <>
10 (hyporptwlo)
Reference
[ip
Nltochko et ol. 1981
CHRONIC EXPOSURE Concor
38 Rot
18 n> 5d/uk 7hr/d
39 Rot
89*104 uk 5d/Hk Ahr/d
AO Nouoo
79*103 uk 3d/uk
Ahr/d
* The nudber corraaponde to ontrlM In Fifun 2*1.
f
20 tL
.Ipt#
orflono)
Wong et at. 1982
10 (CEL, lung tiworo, NIP 1982 nowl tuooro)
10 (CEL, lung tuooro, NIP 1982 haoong 1 owrccnw)
CEL cancor offoct lovol; <1 diyd); hr fcour(i); LOAEL * loweet-obeerved-edveree-effect lovol; mo oonth(i); NOAEL noobeorvod-adverse-effect lovol; hoop reeptrotory; uk Mokd)
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FIGURE 2--1
of significant Exposure to (cbenioal X]-Inhalation
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Chapter 2 (Section 2^4) Relevance to Public Health
APPENDIX A
The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinedc information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions.
1. What effects are known to occur in humans?
2. What effects observed in animals are likely to be of concern to humans?
3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites?
The section discusses health effects by end point Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included.
The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinedc, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate sectkm(s).
Limitations to existing scientific literature that prevent a satisfactory evaluation of die relevance to public health are identified in the Identification of Data Needs section.
Interpretation of Minimal Risk Levels
Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g,, Inhalation acute, -intermediate, -chronic; Oral - acute, -intermediate, - chronic). These MRLs are not meant to suppari regulatory action, but to aquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure.
MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "Populations that are Unusually Susceptible" provide important supplemental information.
MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by tbe Environmental Protection Agency (EPA) (Barnes andDourson, 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure.
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A-7 APPENDIX A To derive an MRL, ATSDR generally selects die end point which, in its bestjudgement represents the most sensitive human health effect fora given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential effects (c.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELs for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point arc available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables.
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APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS
ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F
Fl FAO FEMA FIFRA fpm ft FR
g GC gen HPLC hr IDLH IARC ILO in Kd
kg kkg
Kow L LC
LClo
LCjo
American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors
Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and liability Act
Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodentidde Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration, low lethal concentration, 50% kill
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LDlo LD50 LOAEL LSE m mg min mL mm mmHg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC
ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL
Pg pmol PHS PMR ppb ppm ppt REL RID RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA U.S. UF
lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogratn picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor
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yr WHO wk
> _>
< < % a & 6 y nm MS
APPEND*B
year World Health Organization week
greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram
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APPENDIX C
PEER REVIEW
A peer review panel was assembled for 1,1-dichloroethene. The panel consisted of the following members: Dr. C Clifford Conaway, Research Scientist, American Health Foundation, Valhalla, New York; Dr. Arthur Gregory, Private Consultant, Techto Enterprises, Sterling, Virginia; Dr. Nancy Tooney, Associated Professor of Biochemistry, Department of Chemistry, Polytechnic University, Brooklyn, New York. These experts collectively have knowledge of 1,1-dichloroethene'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 Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended.
Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have 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 its approval of the profile's final content The responsibility for the content of this profile lies with the ATSDR.
'A'U.S. Government Printing Office, 1992! 638-237
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