Hazard assessment of ethylene oxide

209 Pages·1986·14.217 MB·English

by  Golberg, Leon

Hazard Assessment
of
Ethylene Oxide
Author
Leon Golberg, M.B., D.Sc., D. Phil.
Professor
Division of Community and Occupational Medicine
Duke University Medical Center
Durham, North Carolina
Boca Raton London New York
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Library of Congress Cataloging-in-Publication Data
Golberg, Leon.
Hazard assessment of ethylene oxide.
Bibliography: p.
Includes index.
1. Ethylene oxide—Toxicology. 2. Ethylene oxide—
Physiological effect. I. Title. [DMLM: 1. Ethylene
Oxide—adverse effects. QD 305.E7 G617h]
RA1242.E72G65 1986 615.9’5135 86-4186
ISBN-0-8493-6525-2
A Library of Congress record exists under LC control number: 86004186
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ISBN 13: 978-1-315-89372-3 (hbk)
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FOREWORD
Hazard assessment of EO has involved consideration of the chemical composition,
characteristics, and reactivity of this material. In spite of the readiness with which EO
is transformed within the body to ethylene glycol and ethylene chlorohydrin, EO—
with a biological half-life of about 10 min—is distributed throughout most organs of
the body. It is an alkylating agent, reacting with cellular macromolecules such as DNA,
RNA, and protein, including globin of hemoglobin. By virtue of the formation of
chloroacetaldehyde from chlorethanol, EO shares some metabolic pathways with vinyl
chloride, although quantitatively these pathways are likely to account for only a small
proportion of the total biotransformation of EO.
In view of these properties, it is not surprising that EO gives rise to gene mutations
and chromosomal aberrations in various short-term test systems. Genotoxic effects
observed in vivo include dominant lethality and heritable translocations. The biological
significance of increased sister chromatid exchanges (SCEs) in circulating lymphocytes
remains to be determined.
Teratogenic effects of EO are only seen under extreme conditions that render the
results questionable. Reproductive effects of minor severity occur only at high levels
of exposure. Positive results in carcinogenicity tests have been obtained by subcuta-
neous injection in mice, intragastric administration in rats, and in two separate inhal-
ation studies of EO in rats. While the interpretation of the results of each of these
studies may be subject to criticism, the overall conclusion of carcinogenicity in animals
seems justified.
Another serious effect of this highly irritant material is its neurotoxic potential, ex-
pressed in the central and peripheral nervous systems of man and animals exposed to
high levels of EO. Repeated and prolonged exposures appear to be necessary for this
effect to be manifested.
Epidemiological and other studies of occupational exposure to EO in men and
women have revealed no substantial evidence of potential to produce cancer in the
workplace. We are concerned with two modes of exposure: a fairly constant, continu-
ous level in producer/ethoxylator units; and intermittent peaks of exposure in steriliz-
ing units employing EO, often together with other agents. Early reports of leukemia
and stomach cancer referred to conditions of occupational exposure that are unlikely
to occur in the U.S. Certainly all other epidemiological studies, including several car-
ried out subsequently, have failed to substantiate these suggestions of cancer risk aris-
ing from exposure to EO. Studies reporting an increased incidence of spontaneous
abortions and/or gynecological disorders in women exposed to EO have failed to pro-
vide convincing evidence in support of these claims.
Hazard assessment cannot be based on measurements of SCE levels in people or
animals exposed to EO because the health significance of such findings is increasingly
uncertain. Equally, attempts to apply the concept of radiation equivalence, as a meas-
ure of hazard presented by EO, are unjustified. Hazard assessment, based on the de-
velopment of tumors in rats exposed to EO by inhalation, may be approached mathe-
matically by applying various models to the dose-response data for each type of tumor.
In the case of EO, however, the expression of carcinogenic potential takes the form of
low-level enhancement of the incidence of spontaneous tumors, rendering the data
inadequate for this traditional approach to prediction of risk to man.
A further approach to hazard assessment involves the application of scientific judg-
ment, "with all its frailties".1 Conclusions are based on the qualitative and quantita-
tive aspects of the various biological phenomena considered. Three exposure zones are
postulated, in terms of uniform 8-hr-daily, 5-day-a-week exposure conditions (or
equivalent work periods) as generally used for TWA calculations. The first is a zone
of increased probability of adverse health effects in man, perhaps extending down to
levels above 10 ppm—even though no adverse health effect has been reliably demon-
strated in man following exposure to 10 ppm EO. The second is a zone of uncertain
consequences, which may exist for TWAs within the range of 5 to 10 ppm, 3 to 10
ppm, or perhaps 1 to 10 ppm. At present, the extent of uncertainty is such that it is
difficult to select one or the other of these ranges with any confidence. The third zone
is considered to involve inconsequential exposure, with no apparent hazard being pre-
sented by levels at or below 1 ppm TWA.
PREFACE
During the past 4 years, a growing number of federal and state regulatory agencies
have taken an active interest in ethylene oxide (EO). Federal regulatory initiatives re-
lating to EO have been promulgated or proposed under several different statutes. At
the same time, state regulation of EO has also increased.
Occupational exposure to EO, which is the principal focus of this Hazard Assess-
ment, is regulated primarily by the Occupational Safety and Health Administration
(OSHA). On January 26, 1982, OSHA issued an Advanced Notice of Proposed Rule-
making stating that the then-current occupational safety and health standard for EO—
50 parts per million (ppm) measured as an 8-hr, time-weighted average (TWA)—ap-
peared inadequate to protect exposed employees from significant risk. On April 21,
1983, OSHA published a Notice of Proposed Rulemaking proposing a new standard
for EO, A final standard for EO, including, among other provisions, a permissible
exposure limit (PEL) of 1 ppm (TWA), was issued by OSHA on June 22, 1984. At that
time, OSHA reserved judgment as to the need for, and appropriateness of, a short-
term exposure limit for EO. On January 2, 1985, following scientific peer review and
public comment on the issue of a short-term exposure limit, OSHA published its deter-
mination that the available evidence did not support the imposition of such a limit, in
addition to the 1 ppm (TWA) PEL. At the current time (July 1985), two petitions for
judicial review of the standard—one challenging the OSHA decision not to require a
short-term exposure limit and the other asserting that the PEL should be no lower than
10 ppm (TWA)—have been consolidated and are pending in the U.S. Court of Appeals
for the District of Columbia Circuit. A decision on the two petitions is anticipated in
late 1985.
The Environmental Protection Agency (EPA) is currently in the process of deciding
whether EO should be listed and regulated as a hazardous air pollutant under section
112 of the Clean Air Act. In 1984, a draft health assessment document for EO was
prepared by the relevant EPA program offices and was reviewed by the EPA Science
Advisory Board (SAB). The health assessment document is currently being revised in
light of the SAB review and public comments, and estimates of human exposure are
being prepared. At least a tentative decision on whether to list EO is expected from
EPA during 1985. Various state air pollution control agencies are already requiring
stringent control of EO as part of their permitting processes.
Sterilant uses of EO are also subject to regulation by EPA under the Federal Insec-
ticide, Fungicide and Rodenticide Act, and the agency has placed EO in its Special
Review process. This process may result in amended labeling for EO and/or further
restriction on the conditions for its use as a sterilant or pesticide.
ACKNOWLEDGMENTS
The preparation of this report has been carried out under the auspices and with the
support of the Ethylene Oxide Industry Council (EOIC), a special program of the
Chemical Manufacturers Association (CMA). Initially the work was a collaborative
effort, to which many scientists have contributed. It is a great pleasure to acknowledge
the hard work and persistence of the colleagues listed below.
Don L. Heywood (Union Carbide Corporation) chaired the Risk Assessment Task
Force and contributed the major part of a draft of Chapter 2. Carol R. Stack was the
Program Administrator assigned by the CMA to keep the project moving effectively.
Susan G. Austin (Consultant, formerly with Union Carbide Corporation) contrib-
uted a draft of Chapter 10, which is a distillate of Appendix A, a critical analysis of
epidemiological and other health effects data prepared by the joint efforts of the fol-
lowing members of the Medical and Epidemiology Task Forces of the EOIC: Susan G.
Austin, Chairman, Shirley Andersen (HW Andersen Products), Douglas S. Bondor
(Lederle Laboratories, American Cyanamid), Mary Coleman (Abbott Laboratories),
James J. Collins (American Cyanamid), Thomas A. Lincoln (Union Carbide Corpo-
ration), Michael Utidjian (American Cyanamid), and Stanley C. White (Travenol Lab-
oratories, Inc.).
Bryan Ballantyne (Union Carbide Corporation) contributed a draft of Chapter 5,
Douglas S. Bondor a draft of Chapter 9, and Frank W. Carlborg (Consultant) a draft
of the statistical section of Chapter 11. Among the first drafts, that of Chapter 7 was
the work of C. Clifford Conaway (Clement Associates, Inc.); that of Chapter 6 was
prepared by Ninfa Indacochea-Redmond (Searle Recherche et Developement), and
that of Chapter 8, as well as of Appendix B, by Roger T. Keefe (General Foods).
William M. Snellings (Bushy Run Research Center) contributed a part of the draft of
Chapter 4. Finally, Chapters 1 and 3 and parts of Chapters 2, 10, and 11 are the results
of my efforts.
We appreciate the fine contribution by R. Julian Preston (Oak Ridge Naitonal Lab-
oratory) on the subject of radiation-equivalence. Norman W. Gaines (Union Carbide
Corporation), R. D. Mullineaux (Shell Oil Co.) and Carrol S. Weil (Bushy Run Re-
search Center) attended meetings of the Task Force and made helpful comments and
suggestions. Drafts of Chapter 8 were kindly reviewed by Trent R. Lewis (National
Institute of Occupational Safety and Health) and R. R. Maronpot (National Toxicol-
ogy Program), for whose comments we are grateful. An earlier draft was reviewed by
Joe W. Grisham (University of North Carolina School of Medicine) and Robert A.
Squire (Johns Hopkins University), whose helpful comments are much appreciated.
Appendix C is entirely the work of Robert L. Sielken, Jr. (Texas A & M University),
who kindly permitted his penetrating analysis to be included here.
Preparation of the final revised and updated manuscript was undertaken by me, and
I am responsible for the scientific judgments expressed in this report.
Leon Golberg
THE EDITOR
Leon Golberg, M.B., D.Sc., D. Phil., FRCPath., Duke University Medical Center.
After receiving a Doctorate in Organic Chemistry from the University of Oxford, Leon
Golberg went on to earn a Doctorate of Science in Biochemistry from the University
of Witwatersrand, a Master's degree in Anatomy and Physiology from the University
of Cambridge, and a degree in Medicine from the University of Cambridge and Uni-
versity College Hospital Medical School in London. Golberg is currently a professor
of Community and Occupational Medicine at Duke University Medical Center. Prior
to accepting that position, he was responsible for creating the Laboratories of the
Chemical Industry Institute of Toxicology and was its first President. In addition, he
has been on the faculty of the University of North Carolina and Albany Medical Col-
lege. A former President of the Society of Toxicology, Golberg established and was
the first Director of the British Industrial Biological Research Association. Besides
being a member of numerous professional organizations, Golberg has chaired govern-
ment and other scientific committees. For example, he was chairman of the WHO
Scientific Group on Procedures for Investigating Intentional and Unintentional Food
Additives; Chairman of the NAS Ad Hoc Subcommittee on Clinical Relevance of Car-
cinogenicity Testing of Drugs; and Chairman of the Human Effects Subcommittee of
the Secretary's (of HEW) Committee on Pesticides. A variety of papers and publica-
tions, authored by Golberg, have appeared in the international scientific literature. He
serves as Editor, or Associate Editor, of a number of scientific journals in the field of
Toxicology.
TABLE OF CONTENTS
Chapter 1
Introduction 1
Chapter 2
Chemical and Physical Properties 3
I. Physical Properties 3
II. Structure 3
III. Specifications of EO 3
IV. Chemical Reactivity of EO 3
V. Reactivity of EO with Biological Nucleophiles 7
VI. Reactivity of EO with Hemoglobin 7
A. Endogenous Formation of EO 9
Chapter 3
Metabolism and Pharmacokinetics 11
Chapter 4
Acute, Subchronic, and Chronic Effects 15
I. Effects of Exposure to EO Vapor: Relevance for Risk Assessment 15
II. Analysis of Available Data 16
Chapter 5
Neuropharmacologic and Neurotoxic Effects 19
I. Introduction 19
II. Observations 19
A. Acute Exposure of Animals 19
B. Repeated Exposure of Animals 20
C. Acute Exposure of Humans 23
D. Repeated Exposure of Humans 24
E. Conclusions 26
Chapter 6
Reproductive and Teratogenic Effects 29
I. Introduction 29
II. Reproduction Studies 29
A. Animal Studies 29
B. Human Studies 30
C. Teratogenicity Studies 31
D. The NIOSH Study 32
Chapter 7
Mutagenicity Studies — Genotoxic Effects of Ethylene Oxide in
Experimental Models 33
I. Introduction 33
II. Nonmammalian Test Systems 33
III. Mammalian Test Systems 33
A. Unscheduled DNA Synthesis 33
B. Cytogenetics: SCEs 34
C. Micronucleus Test 35
D. Cytogenetics: Chromosomal Aberrations 36
E. Dominant Lethal Assay 38
F. Heritable Translocation Test 39
G. Sperm Motility and Morphology 40
IV. Specific-Locus Test 40
V. Risk Estimation Methods 41
A. Alkylation of Proteins and DNA 41
B. Mutagenesis Data Evaluation 41
Chapter 8
Carcinogenicity Studies 45
I. Introduction 45
II. Indirect Evidence for EO Carcinogenicity 45
III. Direct (Noninhalation) Studies of EO Carcinogenic Potential 46
IV. Intragastric Administration of EO 47
V. First Inhalation Carcinogenicity Study 48
VI. Second Inhalation Study „ 50
VII. Third Inhalation Study 51
VIII. Evaluation and Conclusions 52
A. Local Sarcomas and Gastric Lesions 52
B. Tumors Associated with EO Irritancy 53
C. Tumors of the Forestomach 53
D. Subcutaneous Sarcomas 54
IX. Hyperplasia Associated with EO Irritancy or Possible Infection 55
A. Nasal Metaplasia 55
B. Adrenal Cortical Hyperplasia 55
X. Inhalation Studies 56
Chapter 9
Industrial Hygiene Aspects 59
I. Introduction 59
II. Personal Monitoring 59
III. Biological Monitoring 60
IV. Area Sampling 61
V. EO Production and Use 61
VI. Producer/Ethoxylator Industries 61
A. Control Measures 62
VII. Health Care Industry 62
A. Control Measures 62
Chapter 10
Epidemiologic Studies 65
I. Introduction 65
II. Carcinogenicity 65
III. Discussion 68
IV. Other Health Effects 68
A. Lymphocytosis 68
B. Reproductive Effects 69
C. Cardiovascular Diseases 69
V. Cytogenetic Studies 69
A. Chromosomal Aberrations 69
B. SCEs 72