Review of Inhalants:

Euphoria to Dysfunction

Editors:

Charles Wm. Sharp, Ph.D.

Mary Lee Brehm, Ph.D.

NIDA Research Monograph 15

October 1977

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

Alcohol, Drug Abuse, and Mental Health Administration

National Institution on Drug Abuse

Office of Science

5600 Fishers Lane

Rockville, Maryland 20857

Review of Inhalants:

Euphoria to Dysfunction
ACKNOWLEDGMENT

The Research Triangle Institute organized and conducted the

conference on June 7-8, 1977, in San Francisco, for which the

papers in this monograph were written; assembled the bibliography; and prepared the monograph for publication. The work was

done under NIDA contract 271-75-1016.

Library of Congress catalog number 77-089150

NIDA Research Monographs are indexed in the Index Medicus. They

are selectively included in the coverage of Biosciences Information Service, Chemical Abstracts, Psychological Abstracts, and

Psychopharmacology Abstracts.

DHHS Publication No. (ADM) 85-553

Printed 1977 Reprinted 1979, 1985

iv
FOREWORD

Inhalant abuse presents somewhat unique challenges to drug

abuse research, treatment, and prevention.Inhalants, or volatile

solvents, do not show up in large or alarming percentages in

national surveys, nor until recently were they taken very seriously--"glue-sniffing" has been the rather innocuous sounding

popular description of the practice.

But, such solvents are often the first drugs used by preteenagers to produce a state of altered consciousness (a "high").

Under certain conditions (poverty, minority, rural situations),

solvents are the most readily available intoxicants.Users tend to

be young (mean age 14, range 7-17), and the seriousness of the

problem becomes apparent when one finds that continued inhalation of industrial solvents--including lacquer thinner--can result

in paralysis or even death.

By virtue of the youth and vulnerability of the primary using

population, the ready accessibility and increasing prevalence of

these intoxicants for other common uses, and the nagging possibility that our survey techniques may not adequately be capturing

the actual extent of use, we have a special responsibility, in my

view, to be sure that we are doing all we can.

This monograph provides a thorough review of the literature and

critical assessment of the state of our knowledge in the several

papers presented, and an important post-1970 selected bibliography on the topic. It should prove a useful text and reference.

William Pollin, M.D.

Director

National Institute on Drug Abuse

v

PREFACE

Inhaling psychotropic substances and vapors for mind altering

and recreational purposes is older than pharmacognosy. Although

one of the oldest and simplest forms of producing an intoxicated

state, inhalation of volatile solvents has provoked only limited

efforts to define its basic elements, to evaluate the consequences,

or to deal with the problem in a systematic way.

There are many reasons for this lack of interest and support.

One of the primary reasons is a derogatory attitude towards the

majority of the population of inhalers not only on the part of the

general populace but also on the part of those from other drug

cultures. Use of inhalants has no mystical or religious associations . Many users, themselves, refer to inhalants as a second

choice of drug for producing an altered consciousness. Statements range from, “Anybody who would inhale that stuff must be

a nut," to "I'd rather have alcohol or marihuana if I could get

it. " This view may be reinforced by frequent harassment and

debasement by law officials, school authorities, parents, and even

siblings or fellow drug users.

Another important reason for lack of focus on the problem may

have resulted from calling the practice “glue sniffing.’ Although

there was an apparent upsurge in the use of glue during the

sixties, other forms of inhalant abuse were almost ignored and

this labeling may have led to a limited approach to the problem.

There is good reason to believe that most other substances which

are being used today were used extensively then. Although the

predominant product may change, the use of many mixtures may

vary less than expected. A general attack on the use of glue led

people to believe that this was an effective deterrent to "glue

sniffing." However, distribution and availability may be more

likely to influence the choice of substances used than the deterrent forces of press and legal attacks. Contributing to the

availability of substances has been the capability of the petroleum, chemical, and related industries, to provide an increasing

array of volatile organic substances to choose from during the

past 50 some years. Also, the greater the diversity of substances, the less any one government agency or consumer group

will be able to focus on the total problem. Although these different mixtures may have several uses in industry and in the home

and may manifest distinctly different toxicological actions, most

have a common chemical and biological action dependent on their

lipophilic nature.

Another important reason for not focusing on inhalant abuse may

be due to the type of products abused. Many of these "solvents"

vii
have been used for several decades and are generally considered

“safe” by the average user. Agencies charged to control their

safety and hazard in industry and the home have been concerned

mainly with the acute toxic phase of the physiological insult.

Attention has been directed more recently towards chronic and

continuous long-term exposure, especially towards carcinogenicity .

Also, many other "pollutants" are considered more toxic, and

therefore, less attention has been focused on the more common

solvents. In drug abuse circles, opiates, barbiturates, amphetamines, hallucinogens, and, more recently, marihuana, cocaine,

and phencyclidine have been considered the major drugs of abuse.

Solvent abuse is still generally considered a "minor" problem.

The data here show that its use may be as much or more prevalent than that of several of the substances mentioned above.

Further, the toxicity of many of these solvents exceeds that of

other drugs of abuse.

Possibly the oldest form of this type of abuse is associated with

the field of anesthesiology. Although scientists in the field have

studied most aspects related to these drugs, they have not carefully evaluated the recreational use of anesthetics. Not only are

some of the abused inhalants used as anesthetics, the state of

intoxication is comparable to Phase I-II (or "light") anesthesia.

It is therefore very appropriate for those in this field to apply

their techniques and knowledge to the study of inhalant abuse,

especially now that they are concentrating on analogous problems

associated with the repeated administration of anesthetics.

One of the first attempts to survey the inhalant problem was by

Bass in 1970. Although the National Institute on Drug Abuse has

included the use of inhalants in surveys, no thorough evaluation

of the prevalence of solvent abuse exists. Despite these deficiencies , this publication has been assembled through the efforts

of several qualified scientists to review that information which is

presently available and to discuss the relevant issues associated

with inhalant abuse. Hopefully, many investigators will be stimulated to study this problem. Also, clinicians and others in the

community may be able to make use of this information and increase their efforts and cooperation in resolving the problem.

Because of the more complete treatment elsewhere, inhalants such

as cocaine, marihuana, and other drugs taken intranasally or

otherwise inhaled as a second route of administration are not

covered here. Also not discussed is the misuse of many of the

inhaled substances through accidental or purposeful ingestion.

This effort has been a culmination of many people's effort,

thought, and reports. It is the intention that this compendium

be the basis for energizing thought and action in this area not

only in interest but also in support at all levels of our society.

viii
Perhaps society can begin to look on this group, as it is beginning to look on alcoholics, with less disdain and view them as a

group needing more positive consideration in home, school, and

the community at large.

Charles Wm. Sharp, Ph.D.

Research Biochemist

Division of Preclinical Research

National Institute on Drug Abuse

ix
CONTRlBUTORS

Dr. Domingo M. Aviado

Senior Director of Biomedical

Research

Allied Chemical Corporation

P.O. Box 1021R

Morristown, New Jersey 07960

Dr. Robert E. Bowman

Professor of Psychology

Department of Psychology

Primate Laboratory

University of Wisconsin

22 North Charter Street

Madison. Wisconsin 53706

Dr. Mary Lee Brehm

Research Psychologist

Center for the Study of Social Behavior

Research Triangle Institute

Research Triangle Park, North Carolina

Dr. James V. Bruckner

Assistant Professor of Pharmacology

Department of Pharmacology

University of Texas Medical School

at Houston

P.O. Box 20708

Houston, Texas 77025

27709

Dr. Eric G. Comstock

Director, Institute of Clinical

Toxicology

1802 Medical Towers

1709 Dryden

Houston, Texas 77030

Ma. Eleanor Carroll

Research Sociologist

Division of Research

National Institute on Drug Abuse

11400 Rockville Pike, Room 610

Rockville, Maryland 20852

Dr. Daniel Couri

Professor of Pharmacology

Director of Toxicology

Department of Pharmacology,

Toxicology Division

Ohio State University College

of Medicine

1645 Neil Avenue

Columbus, Ohio 43210

Dr. Maynard B. Chenoweth Dr. Maurice Korman

Research Scientist Professor and Chairman

Biomedical Research Division of Psychology

Health and Environmental Research University of Texas Health

Dow Chemical Company Science Center at Dallas

607 Building 5323 Harry Hines Boulevard

Midland, Michigan 48640 Dallas, Texas 75235

Dr. Sidney Cohen

Director, Council on Alcohol

and Drug Abuse and

Principal Investigator,

Marijuana Research Project

13020 Sky Valley Road

Los Angeles, California 90049

Dr. Betsy S. Comstock

Associate Professor of Psychiatry

Baylor College of Medicine

Houston, Texas 77025

x
Mr. Joseph P. Nachtman

Graduate Research Associate

Department of Pharmacology,

Toxicity Division

Ohio State University College

of Medicine

1645 Neil Avenue

Columbus, Ohio 43210

Dr. Richard G. Peterson

Associate Professor

Department of Anatomy

Indiana University School

of Medicine

1100 West Michigan Avenue

Indianapolis, Indiana 46202

Dr. Leon Prockop

Professor of Medicine and

Chief, Neurology Section

College of Medicine

University of South Florida

12901 No. 30th Street

Tampa, Florida 33620

Dr. Charles W. Sharp

Research Biochemist

Biomedical Research Branch

Division of Research

National Institute on Drug Abuse

11400 Rockville Pike, Room 664

Rockville, Maryland 20852

x i
CONTENTS

FOREWORD v

PREFACE vii

CONTRIBUTORS x

INTRODUCTION 1

Chapter 1 Inhalant Abuse: An Overview of the Problem

Sidney Cohen

History

CIassification

Extent of the Problem

Why Solvents Are Abused

Peer Group Influences

Cost Effectiveness

Easy Availability

Convenient Packaging

Mood Elevation

The Course of the Intoxication

The Legal Issue

Social Costs

Trends

Summary

2

2

4

4

6

6

6

6

7

7

7

8

8

10

9

SOCIOCULTURAL-EPIDEMIOLOGICAL ASPECTS 13

Chapter 2 Notes on the Epidemiology of Inhalants 14

Eleanor Carroll

Ethnographic Data 14

Domestic Issues and Inhalants 16

Epidemiology of Inhalants 17

Conclusions 21

Appendix Summary of Exploratory Study of Inhalant Use and Treatment 26

CLINICAL EVALUATION 29

Chapter 3 Clinical Evaluation of Psychological Factors 30

Maurice Korman

Introduction 30

Psychological Factors Predisposing to Use 31

Personality Factors 31

Familial Disorganization and Pathology 33

Environmental Pressures 34

Mental Status of Users 36

Cognitive Difficulties 36

xii
CONTENTS (con.)

Danger to Self and others 37

Mood and Affect 38

Diagnosis and Prognosis 39

Other Drug Use 40

Personality Studies of Users 42

Long-Term Effects 44

Psychological Treatment and Prevention 45

Psychological Treatment 45

Other Control Techniques and Prevention 47

Chapter 4 Medical Evaluation of Inhalant Abusers 54

Eric G. Comstock and Betsy S. Comstock

Introduction 54

Toxicity 55

Exposure and Clinical Effects 55

n-Hexane 56

Toluene 56

Gasoline 56

Aerosols 66

Chlorinated Hydrocarbons 66

Survey of Medical Effects of Inhalant Abuse 66

Case Abstracts 67

Data Summary 70

Discussion 70

Medical Evaluation of Inhalant Users 70

Clinical Assessment 73

Chief Complaints 73

Present Illness 73

Review of Systems 74

Past Medical History 74

Employment History 74

Personal and Social History 74

General 75

Physical Examination 75

Conclusions 77

Chapter 5 Specific Neurological Evaluation of Inhalant Abusers:

Clinical and Laboratory 81

Leon Prockop

Introduction 81

Neurological Evaluation 82

General Comments 82

Neurological Physical Examination 83

Diagnostic Assessment 83

xiii
CONTENTS (con.)

Ancillary Tests for Further Neurologic Evaluation 84

Mental Status EvaIuation 84

Electroencephalography 85

Electromyography and Nerve Conduction

Velocity Studies 86

Lumbar Puncture 86

Computerized Axial Tomography 86

Nerve Biopsy 86

Appendix Neurological Evaluation Form 89

PRECLINICAL: PHARMACOLOGY AND TOXICOLOGY 97

Chapter 6 Introduction 98

Daniel Couri

Occurrences of Volatile Agents 99

Physical and Chemical Properties of

Volatile Solvents 99

Chapter 7 Abuse of Inhalation Anesthetics 102

Maynard B. Chenoweth

History 102

Agents and Actions 103

Anesthesia and Its Problems 103

Toxicity of Anesthetics 103

Sources of Anesthetic Chemicals 107

Addiction and Abuse of Anesthetics 107

Incidence and Control of Anesthetic Abuse 108

Summary 109

Chapter 8 Toxicology of Alcohols, Ketones, and Esters—Inhalation 112

Daniel Couri and Joseph P. Nachtman

Alcohols 112

Methanol 113

Symptoms of Exposure 113

Retinal and Central Nervous System

Toxicity 113

Metabolism 114

Ethanol 115

Symptoms of Exposure 115

Metabolism 115

Isopropanol 115

Symptoms of Exposure 115

Metabolism 115

xiv
CONTENTS (con.)

Acute Toxicity of Alcohols 116

Esters 116

General Features of Toxic Exposure 116

Metabolism 116

Acute Toxicity of Esters 117

Ketones 117

General Features of Source and Exposure 117

Acute Toxicity of Ketones 118

Methyl Ethyl Ketone

Acetone

118

119

Methyl n-Butyl Ketone and Ketones Derived From

Hydrocarbons 120

Solvent Mixtures 121

Chapter 9 Review of the Aliphatic and Aromatic Hydrocarbons 124

James V. Bruckner and Richard G. Peterson

Aromatic Hydrocarbons 124

Benzene 124

Absorption and Distribution 125

Metabolism 126

Acute Toxicity 126

Organ Toxicity 126

Potential Health Risks 129

Toluene 130

Absorption and Distribution 131

Acute Toxicity 131

Organ Toxicity 132

Potential Health Risks 132

Xylene 133

Acute Toxicity 133

Metabolism 134

Organ Toxicity 134

Styrene 136

Absorption and Acute Toxicity 135

Metabolism 135

Organ Toxicity 136

Potential Health Risks 136

Naphthalene 136

Acute Toxicity 137

Organ Toxicity 137

Potential Health Risks 138

Aliphatic Hydrocarbons 138

General Properties 138

Acute Toxicity 139

xv
CONTENTS (con.)

Cardiotoxicity

Neurotoxicity

n-Hexane

Absorption and Acute Toxicity

Organ Toxicity

Mixed Aliphatic/Aromatic Hycdrocarbons

Gasoline

Acute Toxicity

Inhalation Abuse

Organ Toxicity

Miscellaneous Hydrocarbon Solvents

Acute Toxicity

Potential Health Risks

Aliphatic Nitrites

Abuse

Toxicity

Chapter 10 Preclinical Pharmacology and ‘I’oxicology of Halogenated

Solvents and Propellants

Domingo M. Aviado

Introduction

Fluorinated Hydrocarbons

Cardiotoxicity of Fluorinated Propellants

Extracardiac Organs

Dichlorinated Hydrocarbons

Methylene Chloride

Cardiac Arrythmia in Mice

Cardiac Arrythmia in Dogs

Cardiac Arrythmia in Carbon Monoxide Poisoning

Interaction Between Carboxyhemoglobin and

Solvents on the Heart

Myocardial Contractility

Acetylene Dichloride

Ethylene Dichloride

Propylene Dichloride

Trichlorinated Solvents

Methyl Chloroform

Absorption, Metabolism, and Disposition

Cardiotoxicity

Pneumotoxicity

Hepatotoxicity

Nephrotoxicity

Trichloroethylene

Acute Inhalation Toxicity of Chlorlinated Hydrocarbons

Concluding Remarks

139

139

140

140

140

142

142

143

144

144

145

145

146

147

147

147

164

164

165

165

165

165

167

168

168

168

169

169

170

170

170

171

171

172

172

174

174

176

177

177

177

xvi
CONTENTS (con.)

Chapter 11 Nervous System Damage From Mixed Organic Solvents 186

Leon D. Prockop and Daniel Couri

Introduction 185

General Comments 185

Pathophysiological Considerations 186

Information Derived From Accidental or

Occupational Exposure 186

Effects of Mixed Solvents 187

General Comments and Principals 187

Clinical and Pathological Features of Huffer’s

Neuropathy Secondary to Inhalant Abuse in

Humans and Experimentally in Rats 188

Clinical Data 188

Toxicological Data

Data From In Vivo Animal Studies 189

Industrial Exposure to Mixed Solvents Relevant

to Mixed Inhalant Abuse 191

Significance of the MBK Study in

Relationship to the Inhalation Abuse

of Industrial Solvents 192

Enhanced Toxicity of MBK When Combined

with MEK 192

Kinetics of Plasma MBK and MEK After

Exposure to Solvent Vapors 193

Reports of Increased Toxicity From Mixed

Solvent Vapor Exposures 194

Reports of Increased Toxicity Attributable to the

Inhalant Abuse of Mixed Solvents 194

Additional Experimental Data Related to the

Biological Effects of Mixed Solvents 195

Concluding Remarks 196

PRECLINICAL BEHAVIORAL DYSFUNCTIONS 199

Chapter 12 Preclinical Behavioral Toxicology of Inhalant Solvents 200

Robert E. Bowman

Two Problems: Dependency and Behavioral Toxicity

Behavioral Aspects of Drug Dependency and Drug

Dependency Potential

Definitions of Terms

Preclinical Models of Drug Dependency

Behavioral Dependence

Physical Dependence

Aversive Properties of Solvents 

Properties of the Dependency Potential

200

200

200

201

201

203

203

204

xvii
CONTENTS (con.)

Behavioral Toxicity of Solvents 206

Definitions of Intoxication, Persisting Toxicity,

Irreversible Toxicity, Remote Toxicity, Covert

Toxicity, and Tolerance 206

Dose Response Curve, Dose Effect Curves, and

Threshold Limit Values 207

Anesthetic Properties of Volatile Solvents and Determination

of Anesthetic Potency (MAC or AD50) 208

Behavioral Data on Intoxication (Acute Toxicity)

With Inhalant Solvents 310

Nitrous Oxide 211

Chlorinated Hydrocarbons in Animals 213

Trichloroethylene in Humans 213

Toluene 213

Halothane 214

Cumulative Behavioral Toxicity 216

Enduring Behavioral Toxicity of Inhalant

Solvents 217

Solvent Exposures During Neural Development 217

Adult Solvent Exposure Followed by Conception

and Testing of Their Offspring 218

Adult Solvent Exposure With Subsequent Testing

of the Same Adults 218

SUMMARY 2 25

Chapter 13 Approaches to the Problem 226

Charles W. Sharp

Introduction 226

Prevention 227

Addition of Obnoxious Materials to Solvents 227

Product Composition Changes to Lessen

Euphoric Effects 228

Product Formulation Changes to Reduce Toxicity 228

Limitations of Sales and/or Use to Adults 229

Modify Labels 230

Community Action 230

Early Warning System 231

Treatment 232

General 232

Psychotherapies 233

Maintenance 234

Other Approaches 234

xviii
CONTENTS (con.)

Areas of Focus for Research 235

Epidemiological Studies 235

Deaths and Other Hazards 235

In-Depth Surveys 237

Clinical Studies 237

Impairments 238

Specific Early Symptoms of Inhalant Toxicity 238

Performance Impairments 239

Preclinical Studies 239

Development of Model Toxicity Systems 239

Mixture-Related Toxicities 240

Final Comment 242

Bibliography 243

List of Monographs 346

xix

INTRODUCTION

1
Chapter 1

INHALANT ABUSE:

AN OVERVIEW OF THE PROBLEM

Sidney Cohen

HISTORY

The efficiency of the pulmonary absorption of gases and volatile

liquids has been known since prehistoric times. The surface area

of the pulmonary epithelium and the mucous membranes of the

respiratory trace is large, and absorption is rapid. In addition

to gases and volatile fluids, smokes, snuffs, and nonvolatile

solutions in aerosol spray form can produce systemic effects

through their absorption along the airway. Further advantages

of respiratory tract absorption compared to the gastrointestinal

route is that the material is delivered directly to the target organ

without passing through the liver with its detoxifying enzyme

systems. ‘I’herefore, effects upon the brain, for example, are

more rapid and more intense than by oral administration.

The advantages of pulmonary transfer of consciousness-altering

substances have been widely exploited. The method of the ancient Greeks at Delphi was rather sophisticated. In order to

invoke the gift of prophecy, an old woman known as the Pythoness was seated on a tripod placed over a vent in a rock from

which carbon dioxide emanated, This induced a trance-like state

during which the subsequent act of divination occurred.

When the carbon dioxide vent gave out, sacred laurel leaves were

scorched in a copper bowl and inhaled by the Pythoness. A

sufficient concentration of carbon dioxide was achieved to reproduce the trance and the prophetic experience (Cohen, 1967).

2
Nitrous oxide is another gas inhaled for analgesia, anesthesia, or

fun. Ether and chloroform also had interesting histories of

recreational usage before they came to be mundane anesthetics.

Even ethyl alcohol can be inhaled in sufficient concentrations to

produce inebriation.

Opium, dimethyltryptamine (DMT), and tobacco are smoked for

the same various mind-altering changes they induce. Columbus

encountered West Indian tribes that used snuffs (probably cohaba, Piptadenia peregrina) They had elaborate snuffing tubes for

more efficient delivery of the powder. Virola, tobacco, and many

other snuffs were and are used throughout Central ‘and South

America (Efron , 1967). Of course, cocaine and good quality

heroin are also effective intranasally.

More relevant to the intentional use of commercial solvents, one of

the earliest descriptions of the phenomenon is that of Clinger and

Johnson (1951) who reported on a localized outbreak of gasoline

sniffing in Warren, Pa. During the next decade articles appeared

in the lay and scientific press about model airplane glue sniffing.

The intoxicating effects of this substance apparently were accidentally discovered by a number of adolescents while working on

their model airplane kits. Eventually, a long list of vaporizing

liquids came to be abused. These included various contact cements and adhesives, paints, lacquers and their thinners, dry

cleaning fluids and spot removers, transmission and brake fluids,

liquid waxes and wax strippers, certain shoe polishes, lighter

fluids, nail polish removers, degreasers, refrigerants, and other

volatile products.

Not long after the aerosols became popular items on the marketplace, they also were found to be intoxicating, and their use for

this purpose spread. These products contain not only a conventional solvent, but also one of the Freons, a chlorinated, fluorinated substituted methane or ethane derivative. In addition, of

course, each has an ingredient that provides it with its specific

commercial activity. Initially, the glass chillers and vegetable

nonstick frying sprays were used. Eventually, it appears, almost

every type of aerosol has been inhaled. A partial list would

include cold weather car starters, air sanitizers, window cleaners,

furniture polishes, insecticides, disinfectants, various spray

medications, deodorants, hair sprays, and antiperspirants. More

recently, the clear lacquers and the gold and bronze sprays have

become increasingly popular.

It should not be assumed that the marketed products are simple

solutions of one or a small number of solvents. Prockop (1975)

analyzed a lacquer thinner and could identify 11 solvents. In

addition, small amounts of unidentifiable impurities were found.

It also cannot be presumed that any of the commercial formulations will remain constant. They change, often without notice,

when improvements are made, when certain of the constituents

increase in price, or when some of them come into short supply.

3
A special group of volatile substances require mention. Ampules

of amyl nitrite ("poppers" or "snappers") are used medically to

dilate coronary arteries during an episode of angina pectoris.

Apparently, cerebral arteries are also dilated, rapidly producing

a suffusion of blood to the brain. The perception of time is

slowed. The recreational use of these solvents has been by

adults, almost exclusively to prolong and intensify the subjective

effects of orgasm.

More recently, advertisements for other products including Toilet

Water, Locker Room, Vaporole, Rush, Kick, Bullet, and Joc

Aroma have appeared in underground newspapers and magazines

devoted to recreational drug use. These items contain isobutyl

nitrite, isobutyl alcohol, and isopentyl nitrite. Siegel (1977), in a

study of 85 cocaine snorters, found that 7 percent of them had

used at least one of these products in 1975. Twelve months later

19 percent were found to be inhaling these "orgasm extenders"

The use of volatile substances for purposes of intoxication

appears to be worldwide. Countries that have expressed special

concerns include the United States, Canada, Mexico, a number of

Central and South American nations, and many European and

African countries. Reports from Japan and Sweden have described "thinner" problems among juveniles. Even the Australian

aborigines (Norcombe, 1970) and the Indians of arctic Manitoba

(Boecks et al. , 1976) are not exempted from the practice.

CLASSIFICATION

A list of the more common solvents that have been abused is

provided in Table 1.

EXTENT OF THE PROBLEM

Although the prevalence and demographic nature of the problem

of inhalation abuse will be dealt with in a later chapter, a few

general comments at this time might be worthwhile.

School surveys that do not specifically inquire into solvent abuse,

do not include grade and junior high schools, and do not sample

dropout populations will under-report the prevalence of solvent

inhalation. These drugs are often the first nonmedically used

psychoactive agents, sometimes antedating tobacco and alcohol.

Solvent usage tends to decrease with increasing age, one of the

few substances showing this pattern in adolescents. The fact

that the abuse of solvents occurs at an early age, and that they

may be the first of the culturally unacceptable agents to be

employed, suggests that they might serve as an introduction to a

career of drug dependence.

4
TABLE 1

A CLASSIFICATION OF ABUSED SOLVENTS

1. Aliphatic and Aromatic Hydrocarbons: 4. Ketones:

Hexane

Naphtha

Petroleum distillates

Gasoline

Benzene

Xylene

Toluene

2. Halogenated Hydrocarbons:

Trichloroethylene

1, 1, 1 , trichloroethane (methylchloroform)

Carbon tetrachloride

Ethylene dichloride

Methylene chloride

Chloroform

Halothane

Freons:

Trichlorofluoromethane (FC11)

Oichlorodifluoromethane (FC114)

Cryoflurane

Dichlorotetrafluoromethane (FC12)

Acetone

Cyclohexanone

Methyl ethyl ketone

Methyl isobutyl ketone

Methyl butyl ketone

Methyl amyl ketone

5. Esters:

Ethyl acetate

Amyl acetate

Butyl acetate

6. Alcohols:

Methyl alcohol

Isopropyl alcohol

7. Glycols

Methyl cellulose acetate

Ethylene glycol

8. Ethers

3. Aliphatic Nitrites:

Amyl nitrite

lsobutyl nitrite

9. Gases:

Nitrous oxide

Since it is young children who tend to become involved with

solvent sniffing, issues of their physical and emotional maturation

arise. It is well known that growing tissues are more sensitive to

toxic products than mature cells. Thus cellular damage can occur

in pubescents at concentrations not as likely to cause impairment

in older persons. It is also during these formative years that

techniques of coping with life stress are learned. If, instead of

dealing with the daily frustrations and problems. a youngster

dissolves them in solvent fumes. then the techniques for coping

with life’s difficulties are never learned, and he or she may

remain emotionally immature, perhaps for a lifetime.

WHY SOLVENTS ARE ABUSED

It is difficult for nonconsumers of solvents to undterstand why

these materials would be deliberately inhaled for purposes of

5
intoxication. Industrial workers are usually protected from exposure to more than a few parts per million (ppm) of these agents,

while young people will wittingly inhale concentrations 50 or 100

times greater than the maximum allowable concentration in industry. It is difficult for some people to understand why anyone

would breathe in strange compounds whose potential for harm has

hardly been studied, or if they have, art: considered unfit for

human consumption at high concentrations over long periods of

time.

In order to try to understand why the volatile inhalants are

attractive to those who indulge in them, inquiries were made of

the juveniles referred to me (1976) for interview because of a

problem with solvent dependence. Their justifications for the use

of solvents and aerosols appeared to fall into one or more of

seven categories, and these will be described.

Peer Group Influences

The peer group is a very strong factor, perhaps the strongest,

in initiating and perpetuating the use of specific intoxicants. Not

only does the group dictate whether solvents or aerosols are to

be used, but even which brand is currently favored, and how to

use them. This does not mean that novel techniques and new

products are not tried, but when the shift from paint thinner to

clear lacquer spray to gold paint aerosols takes place, usually the

whole group shifts over from one item to the other collectively.

If the crowd one goes around with are all inhaling an intoxicant,

it is very difficult for an individual group member to abstain.

Cost Effectiveness

An important factor in the decisionmaking process about whether

to use one of the inhalants is cost. Many, but by no means all,

inhalant abusers are from low income families, and the price

factor is a decisive element for some of them. Remarks like "I

can't afford anything else" or "It's cheaper than wine or pot" are

made. A 75¢ can of varnish remover can intoxicate more people

than a gallon of cheap wine. Furthermore, as one young man

said, "If you’re broke, there’s always gasoline." Simply inhaling

fumes from a car gas tank or a gasoline-soaked rag, or siphoning

off some gas for later use are widely known methods of getting

"stoned." When asked about the objectionable odor of gasoline,

they claimed that it either wasn’t so bad, or that they got used

to it quickly.

Easy Availability

Although alcohol is commonly assumed to be the most widely

available of all intoxicants, in fact, industrial solvents can be

found even in places where alcoholic beverages do not penetrate.

In poor households a stockpile of liquor hardly is to be expected,

6
but gasoline, paints, and a variety of aerosols are somewhere

around. In very remote rural areas gasoline is the only intoxicant available to juveniles, The solvents are the easiest mind--

altering substances for teenage youths to buy. In some communities there may be laws prohibiting the sale of model airplane

glue to underage youngsters. But these same teenagers can

readily purchase dozens of other solvent preparations in supermarkets, hardware stores, or pharmacies. Even the five and ten

cent stores have a large selection to choose from. It is not even

necessary to buy them; they are often displayed open shelves,

and shoplifting them is not difficult. Among certain groups the

theft of these substances is a routine practice. It is a point of

honor not to pay for these products.

Convenient Packaging

"You can put a supply in your pocket, and nobody can tell." A

tube of airplane cement or a bottle of nail polish remover can be

concealed much more successfully than a pint of wine or a six

pack of beer. The compact packaging is part particularly convenient

for those who still attend school and like to sniff’ between classes.

Mood Elevation

A number of the responses referred to the nature of the solventinduced emotional experience. "It makes me feel good," or "I like

the high," and "You aren’t afraid when you’re under" were some

of the responses. The respondents seemed to be describing

either a floaty euphoria or a blotting out of the unpleasant elements in their everyday lives. I asked them how it compared

with alcohol intoxication, and it was usually described as similar

but not identical.

It appeared to me that that the heavy, consistent users were, in

effect, treating their feelings of frustration and depression with

the state of oblivion that the vapors from some solvent can bring.

They appeared unable to enjoy their life situation sober, either,

because of some personal inadequacy, a miserable family situation,

or a deplorable social setting.

The Course of the Intoxication

In one respect solvent inebriation was treated as superior to that

produced by alcohol. "It's a quicker drunk." The inhalation

route produces a more rapid onset than drinking, and this aspect

is appreciated by those who want instant effect in their inebriant.

A further advantage mentioned by one client was that the drunk

was over in an hour or so, rather than lasting all day as with

alcohol. The solvent hangover is alleged to be less unpleasant

than the postalcoholic state. Headache and nausea were the two

7
most common complaints noted during recovery from inhalant

intoxication. It is considered more reliably intoxicating than

marihuana.

The Legal Issue

Only one person mentioned the fact that buying or being in

possession of some spray can or other solvent was not illegal.

The legality of solvents versus the illegality of marihuana or

alcohol for this age group did not seem to be an important consideration.

From the viewpoint of the consumer the use of solvents, therefore , becomes more comprehensible. They have certain advantages over other intoxicants: availability, inexpensiveness, rapid

action, and desirable consciousness change. But what about the

dangers involved? Certainly no prudent person would deliberately inhale these materials. Unfortunately, prudence or worry

about what can happen to their future health does not seem to be

a particular concern of those who use solvents for recreational

purposes.

SOCIAL COSTS

The price that some inhalant abusers pay in the form of physical

and psychological impairment will be presented in another chapter.

The costs to society will be discussed here. It is not in its

widespread use that the social losses should be counted. Cannabis, tobacco, alcohol, and the sedative-hypnotics are more. widely

abused. But some disconcerting aspects of the abuser of solvents

do exist. The youthfulness of the population involved is a matter

of apprehension both in their added vulnerability to toxic chemicals and in their future tendencies to be overinvolved in future

recreational drug-using practices.

The morbidity and mortality from acute cardiac arrest, asphyxiation, accidents . and organ failures are sufficiently numerous to

cause concern. Particularly disquieting are the recent preliminary findings by Berry et al. (1976) that indicate a wide range of

neuropsychological impairments in a group of chronic solvent

abusers If these dysfunctions are established in further studies. it could have serious implications regarding the treatability of

such individuals and their capacity to acquire the information and

values that would enable them to be productive citizens.

The burden on the families of solvent abusers only increases what

is often a tenuously organized or completely disorganized family

group. The costs to the medical and social services and to the

criminal justice system are visible, but they are not excessively

high at present. Those in the immediate vicinity of solvent-intoxicated persons may be at risk because of their unpredictable,

bizarre impulse-ridden behavior.

8
TRENDS

A number of trends in solvent-usage can be identified. Consistent with the increased involvement of females with all drugs of

abuse, the male-female ratio for solvents is decreasing. There

are greater numbers of users in the 21- to 30-year-old age group

than previously reported.

In the past few years aerosols have become more popular as

intoxicating agents, and these carry hazards beyond those accruing to the solvent itself. Among them are the inhalation of additional toxic ingredients (copper, insecticide, oil), and the cardiac

arrhythmic properties of the propellant Freons

Another recently noted tendency is to add other drugs to a

solvent habit. Alcohol and central nervous system depressants

are usually those found in this form of polydrug abuse.

A favorable trend is the increased interest by the authorities in

the solvent and aerosol problem. The National Institute on Drug

Abuse (NIDA) has begun to fund projects designed to study the

toxicity of various common solvents as used by juveniles. The

first international symposium on the deliberate inhalation of industrial solvents took place in Mexico City, June 21-24, 1976. It

was jointly sponsored by the Centro Mexicano de Estudios en

Farmacodependencia (CEMEF) and NIDA . More recently a conference of Canadian clinicians and solvent industry representatives

took place in Toronto, May 11, 1977.

There is little to report that is new in the areas of prevention

and rehabilitation. Actually, developments outside the field of

drug abuse may help the situation in time to come. If the public’s concern with damage to the troposphere results in the fluorocarbon aerosols being taken off the market, they will therefore be

unavailable for use as intoxicating agents. Whether new aerosol

propellants will be developed that do not interfere with the ozone

shield, or whether aerosols will eventually be abolished, is not

known at this time.

A second current movement that will reduce toxicity is the removal of tetraethyl lead from gasoline. Instances of lead polyneuropathy and encephalopathy will decrease when leaded gasoline

is no longer marketed.

In connection with gasoline, another development might also have

a favorable impact. Now that it has become more expensive, more

locks are seen on gasoline tanks. If locking gasoline tanks

becomes fairly universal, a reduction in this form of sniffing

should occur.

9
SUMMARY

Inhalant abuse, a youthful substance abuse problem of the past

quarter century, is difficult for many adults to understand.

When perceived from the perspective of the youth who tends to

mimic the behavior of his peers, it becomes more comprehensible.

The solvents are among the most available, inexpensive, and

convenient of the intoxicants. They are effective in producing

the desired state of transforming or obliterating sober consciousness. The fact that their dangers are either hardly studied or

actually known to be serious, deters few consumers who indulge,

because they seem to be more here and now, rather than future,

oriented.

The person who experiments once or twice with some industrial

solvent may simply be manifesting the natural curiosity or the

mimicking behavior of the young. No particular treatment is

needed for such individuals. It is the consistent consumer who is

liable to the possible illnesses, injuries, and even fatalities associated with inhaling these unusual intoxicants. The unknown

composition and the multiplicity of the products used make treatment difficult when such people appear at a medical installation.

The management of the psychic and somatic disabilities is complicated, and rehabilitation is difficult to predict. It is in preventive measures that the greatest hope of making a real impact on

the problem exists. Future strategies should focus on early,

primary preventive efforts. However, it is acknowledged that

these are the most difficult and challenging to achieve.

REFERENCES

Berry, G., et al. Neuropsychological assessment of chronic

inhalant abusers: A preliminary report. Presented at the First

International Symposium on Voluntary Inhalation of Industrial

Solvents, Mexico City, 1976.

Boecks, R., and F. Coodin. An epidemic of gasoline sniffing.

Presented at the First International Symposium on the Deliberate

Inhalation of Industrial Solvents, Mexico City, 1976.

Clinger, O., and N. Johnson. Purposeful inhalation of gasoline

vapors. Psychoanal Q, 25:557, 1951.

Cohen, S. The beyond within: The LSD story. New York:

Atheneum, 1967.

Cohen, S. Why solvents? Presented at the First International

Symposium on the Deliberate Inhalation of Industrial Solvents,

Mexico City, 1976.

10
Effron, D., B. Holmstedt, and N. Kline. Ethnographic search

for psychoactive drugs. PHS Pub. No. 1645, Superintendent of

Documents, U.S. Government Printing Office, Washington, D.C,

20402, 196’7.

Nurcombe, B. , G. Bianchi, J. Money, and J. Cawte. A hunger

for stimuli. The psychosocial background of petrol inhalation.

Br J Med Psychol, 43(4):367-74, 1970.

Prockop , L. "Huffer's" neuropathy. JAMA, 229(8):1083-4, 1974.

Siegel, R. Personal communication, 1977.

11

SOCIOCULTURAL-EPIDEMlOlOGlCAL ASPECTS

13
Chapter 2

NOTES ON THE EPIDEMIOLOGY OF INHALANTS

Eleanor Carroll

About twenty-five years ago, Aldous Huxley began an address to

the New York Academy of Sciences with the striking words,

"pharmacology is older than agriculture." He went on to say that

primitive man knew how to exploit every root, twig, berry, and

grain in his environment for their possible uses. This was not

only to satisfy such basic and fully acknowledged human needs as

hunger and thirst, but also to satisfy another human need not so

fully acknowledged, but perhaps just as basic, the need for

alteration of one's state of consciousness. Perhaps just as basic

because the Human Relations Area Files (coded for easy retrieval

of information about drug use, as well as other types of basic

information such as family organization, subsistence patterns,

treatment of illness) indicate that there are only three societies

which have not made some use of mind altering plant substances.

ETHNOGRAPHIC DATA

Even this small number of three may yet be reduced, given the

burgeoning interest in ethnopharmacology, by scholars drawn

from such diverse disciplines as botany, archaeology, and art

history. This diversity of interest is exemplified by the recent

establishment of the Ethnopharmacology Society through the joint

efforts of a psychiatrist and an anthropologist Only in about

the last 10 years have anthropologists, aided by botanists, psychopharmacologists, and psychiatrists, begun actively to record the

14
use of mind altering plant substances in communities ranging from

the fairly primitive to modern Western industrial societies. These

uses are as diverse as those of the Jivaro of Ecuador, who use

psychoactive drugs in child rearing, and the quest for greater

creative expression that has captivated some users in our own

society. Among the Jivaro, the rebellious young must use these

substances to discern the will of their ancestors, which oddly

enough corresponds to the ideas of their tribal elders. Among

our own rebellious youth, it is probably safe to say that the use

of hallucinogens less frequently results in discovering views

corresponding to those of their elders!

Psychoactive plant substances may be used to place oneself in

communication with supernatural beings, to help with divination,

to aid in the diagnosis and treatment of certain types of illnesses,

or simply to give individuals a culturally acceptable mode of

escape from everyday life. In most societies that we know of,

this way of escape was not one open to all; usually it was reserved for priests and shamans. That situation could and did

change, however, in response to certain outside economic and

social pressures--one of the best examples is the post-Conquest

spread of coca use to the common Indians after the defeat of the

Inca.

The altered state of consciousness which many of these psychoactive plant substances could produce has been perceived as such

a benison that only a god could have given the means to achieve

it. Dionvsus was worshipped in Greece because of his gift of

the grape, and in Mexico the hongos magicos are often called the

flesh of the gods. In our own time, which has been aptly called

the age of pharmacological Calvinism,’ it is difficult to imagine any

drug, either natural or synthetic, being given a divine origin.

In fact, the polar, or at least the nether, opposite would probably be true.

Richard Evans Schultes, the eminent ethnobotanist of Harvard

University, has often pointed out that the New World has many

more narcotic and hallucinogenic plants than the Old World, and

we have archaeological records to document their existence and

employment for centuries before the Conquest. In addition, there

are undoubtedly many plants, known at least at the time of

Sahagun , which now seem to have disappeared, or, at least, to

await further careful ethnographic work to document their present

use. Of particular interest are the narcotic and hallucinogenic

plants which depend on nasal ingestion, that is, sniffing, snuffing, or snorting, to produce their effects.

One of these is tobacco. In prehistoric and early historic times,

tobacco achieved fairly extensive distribution through large parts

of the tropical forest, the Andes and the Caribbean, and was

used primarily as a psychotropic agent, usually in a magicoreligious context. Tobacco can be used in many ways through

15
smoking, chewing, licking, in a liquid form, or through snuffing.

Smoking, as a method of consumption, was probably a much later

development. Of course, tobacco snuff achieved widespread

distribution in the Western world after the Conquest. In addition

to tobacco, several varieties of hallucinogenic cacti are ingested

through sniffing in various parts of South America. Sometimes,

as among the Yamamomo shamans of Ecuador, a long blowpipe is

used to deliver the drug into the nostrils of another. In many

parts of the Old World, as well as in the Far East, various

cannabis preparations were inhaled.

This brief series of examples serves to indicate that the urge to

alter one’s psychological state to secure a state of consciousness

deemed desirable is a well nigh universal phenomenon, and that

snuffing or sniffing to secure this perceived blissful state is

extremely widespread. It is ironic that we may have more widespread knowledge concerning the nature, extent, and correlates

of inhalant use in some isolated primitive groups than we do about

those in our own society. In at least one of these groups, the

Yamamomo, thanks to remarkable film footage by two anthropologists, we not only have films of shamans using the hallucinogenic

drug blowpipes, but we also have scenes of young boys imitating

their elders by blowing from the fire into the nostrils of their

same age companions. Following this, the youngsters give an

earnest, if not entirely convincing, demonstration of the effect of

the drug on the bodily movements of the male adults. Here, at

least, is one society where we do not have to worry about the

relative influence of parents or peers in the induction into this

kind of drug using behavior.

DOMESTIC ISSUES AND INHALANTS

The extent of use/abuse of inhalants in the United States, the

age, sex, racial and ethnic identification of the users, the physiological and psychological risks (either short or long term) involved in using various kinds of inhalants, with varying degrees

of intensity of exposure--all of these are areas in which solid

epidemiological data are lacking. There are several reasons for

this.

1. For too long, the generic description for inhalant use has

been “glue sniffing," because of the popularity of that particular

substance. In reality, “glue” in this context actually alludes to a

variety of substances which are sniffed and which pose a wide

range of hazards. Unfortunately, “glue sniffing” to most of the

general public does not sound terribly serious. Most, hearing it,

are more likely to dismiss the problem as one of childish

behavior, something easily outgrown and, like the smoking of

corn silk cigarettes, not a matter for serious concern. Use of

the term “inhalants” in the Mexico City Conference of 1976 was in

itself a breakthrough, because it opened the door to a much

broader and more serious consideration of the nature and extent

of the problem.

16
2. Another reason is the nature of the problem with which we

are concerned. There is little doubt that preoccupation with the

abuse of heroin and the opiates has tended to dominate our thinking concerning drug abuse, prevention, treatment, and research

for almost a decade. Allied with our concern about opiate abuse

has been a fear regarding the crimes which opiate abusers commit

to support their habits. Today, as we begin to assemble and

analyze scattered clinical and control study reports from a variety

of research sites, we begin to realize that the kind of aggression

displayed by heavy inhalant users, aggression directed either

against themselves or at others,. also makes these users a population which may have impact beyond their numbers.

3. A third problem, initially of interest primarily to those social

scientists trained in the development and administration of gathering instruments, is that of wording questions about drug use (see

contribution from Jack Elinson). Operational Definitions in SocioBehavioral Drug Use Research, a 1975 Publication resulting from

the combined interest of major NIDA grantees and the Special

Action Office, is entirely devoted to the different kinds of answers one can predict, depending on how we ask about drug use.

What, for example, does the concept “ever used” mean? And

where do we place the cutting points for designating “light,”

“moderate,” and “heavy” use of drugs? When dealing with inhalants, should there be provision for looking into the pharmacologically different attributes of the various inhalants used, so that

the potential severity of outcome of their use can be anticipated?

4. A fourth difficulty has to do with the division of bureaucratic responsibility. Who, in what parts of the bureaucracy, has

the major responsibility for dealing with inhalant use and abuse?

In the U.S. government, for example, responsibility and knowledge regarding various facets of the problem are to be found in

such agencies as the Food and Drug Administration, the Environmental Protection Agency, and the National Institute on Drug

Abuse, to name but three of the many.

Such distinctions between agencies and their responsibilities become important when we consider such aspects as prevention,

which may entail regulatory or legislative restrictions on the

availability, packaging, and distribution of potentially abusable

inhalants. It is also relevant to the assessment of the abuse

potential and hazards posed by the various inhalants. Possible

adverse effects of most industrial substances, for example, are

assessed at levels of exposure likely in industrial settings and not

under the conditions of concentrated inhalation involved in their

deliberate abuse.

EPIDEMIOLOGY OF INHALANTS

When we turn to the various surveys that have been conducted in

the United States in recent years, we are confronted with several

17
problems and sources of confusion. Many of’ the surveys conducted have focused on illicit drug abuse or with the addition of

alcohol and tobacco use, but have frequently omitted inhalant

abuse or have restricted the questioning specifically to “glue

sniffing.” As we have already indicated, however, glue sniffing

is but one form of inhalant abuse, the actual range of inhalants

that may be utilized is very large. It includes such diverse

substance:; as spray paints, spray shoe polish, gasoline, paint

thinner, various other industrial solvents and many other products packed in aerosolized form. Thus, it is by no means certain

that even the individual responding to a questionnaire with every

intent of being open will divine the intent of the questionnaire

and report his or her inhalant use accurately

There have been informal clinical reports of especially high incidence of inhalant abuse among younger minority group members,

school dropouts, truants. and others who may not be adequately

reached by the usual household survey or questionnaire administered in the school. Thus, national or even more narrowly

focused surveys may omit important abusing groups or underreport their actual level of abuse. Lower class, minority members

are also probably less likely to seek medical attention for adverse

reactions to inhalants or, if they do, their symptoms may not be

connected with inhalant abuse. This may well explain the very

small number of mentions of inhalants in the DAWN system, which

is a national drug abuse warning network to monitor emergency

rooms, drug abuse crisis centers, and other treatment facilities

that deal with drug-related emergencies,

Despite some limitations, the figures that are available concerning

inhalant abuse do provide some useful information. In the United

States, nationwide drug abuse surveys based on household interviews with a stratified random sample of the population have been

conducted since 1972. Unfortunately, the form in which the

questions regarding inhalants were posed varied in each of the

three surveys involved (1972. 1974, and 1975/76) The 1972

survey asked about “glue or other things you breathe in.” In

1974, it talked about “glue or some other inhalant," but by 1975/

76, the questioning was considerably more explicit. It was then

phrased “glue or some other substances that people inhale for

kicks or to get high. Besides glue, there are things like gasoline, some aerosols, nitrous oxide, amyl nitrite which is also

called 'poppers,' and other solvents.” Among youth from 12-17,

the most recent 1975/76 survey found that slightly less than one

in twelve (8.1 percent) reported having used inhalants with less

than one percent (0.9 percent) reporting current use. Among

those over eighteen, 3.4 percent report ever having used inhalants and only one-half of one percent report current use,

defined as use within the month preceding the survey. When one

looks at the 18-25 group of young adults, generally the peak drug

using age group, 9 percent of this group report having ever

used with again one half’ of one percent reporting current use.

18
Rates for inhalant use are on about the same level as those fore

the use of such drugs as LSD and cocaine. Although the small

percentages involved make tracing trends somewhat hazardous,

the most recent rates appear to be higher for those who have

ever used than were reported in 1972 (for youth 12-17, ever used

figures were 6.4 percent in 1973 rising to 8.1 percent in 1975/76;

among adults, comparable figures were 2.1 percent in 1972 and 3.4

percent in 1975/76). Current use rates for both youth and adults

have shown no dramatic change at less than one percent for

youth and one half of one percent in all three survey years.

However, the rather low prevalence of current inhalant use found

in the national survey samples coupled with the sample variation

likely from year to year make it difficult to be certain if small

changes are the result of sampling or reflect real changes in

national use patterns (Abelson et al. , 1976).

Data obtained from a national cross section of high school and

college students conducted from mid-1973 through 1974 (Drug

Abuse Council, 1975) are generally consistent with the three major

U.S. national surveys described. Among the high school students, the figure for ever having tried inhalants was 7 percent

as compared with the 8.5 figure obtained for youth 12-17 in the

1974 National Survey. The figure for college students, 9 percent

reporting having ever used, is identical with that found for the

18-25-year-old group in the most recent 1975/76 National Survey.

Current use figures are also comparable, lending some confidence

that the figures from these two independent sources are probably

reasonably good estimates of the actual rates of use.

Despite these rather consistent national results, it should be

emphasized that they may obscure considerable variability in the

level of use within specific communities, schools, and quite

possibly various ethnic groups. Figures from another national

high school drug study conducted in 1973 illustrate this (Columbia

University, 1973). Two of the high schools which were included

had rates for ever having used inhalants that were considerably

higher than those reported above. One of these was a large

black or ethnically mixed city school on the West Coast which

reported 16.6 percent had tried inhalants; another was a large

city, predominantly white, East Coast school, which reported a

figure of 17.1 percent. However, the percentage now using

(defined as “used 3 or more times in last two months”) was one

half of one percent in the West Coast school and 4.1 percent in

the East Coast, predominantly white school. Such figures illustrate the probable complexity of inhalant use and suggest a need

to have considerably more detailed understanding of the patterns

and implications of inhalant use for different groups.

There has been a diversity of local surveys of drug use including

that of inhalants over the past several years (summarized in

Glenn, 1976). Unfortunately, the highly varied form of the

19
questionnaires used, the times at which the studies were conducted, and the varying conditions of administration all make firm

conclusions about differences noted dubious. A set of comparable

studies of drug use which focused on the general population over

the age of 14 in several States reported former inhalant user rates

ranging from 0.1 percent in Mississippi to 1.3 percent in Arizona.

The very low rates detected in these general populations and the

small numbers of users in each make questionable any interstate

comparisons, however (Chambers et al., 1973).

Two New York State studies are of interest for the light they

cast on area differences within the State and differences in

ethnicity of adolescent users. The lowest rate of ever having

used "solvents" was in New York City (3.1 percent reported

having used). Upstate New York was highest at 6.4 percent and

the New York City suburbs were intermediate at 5.8 percent of

7-12 grade students having used inhalants (New York State,

1975). A second statewide study of 8,206 secondary school

students in 18 public schools found American Indian youth had the

highest rate of inhalant use at 12 percent and blacks the lowest

at 3 percent having ever used, White inhalant use was intermediate--S percent reported having done so (Kandel et al. , 1974).

In addition to less precise impressionistic evidence that inhalant

abuse is more common among poorer minority group children,

there is some data to support this assertion. A study of 457

lower class Mexican American children living in four East Los

Angeles public housing projects found inhalant use considerably

higher than among the national survey of adolescents alluded to

above. The children involved were randomly chosen and were

interviewed by specially trained adolescent bilingual interviewers,

themselves residents of the area studied. By contrast with the

national adolescent sample, the Mexican-American adolescents were

three times more likely to have ever used inhalants. In terms of

current use, again compared to the national sample, teenagers in

the barrios were fourteen times more likely to be currently using

inhalants. As compared with the national sample in which less

than one in a hundred (0.9 percent) reported inhalant use in the

month preceding the survey, more than one in eight (13.1 percent) of the barrio youngsters in the same age range reported

having used inhalants in the week prior to the Los Angeles

survey. While current use of marihuana and of alcohol was also

higher than in the national sample (on the order of twice as

likely), the differences in inhalant use were much greater.

Although inhalant users were often found to also use marihuana

and alcohol, users of marihuana and alcohol reported little use of

inhalants (Padilla et al., 1976).

Basing their report on interviews with 75 respondents in Arizona

"who might be expected to have experience, contact, and knowledge about inhalant abuse," Varges and Kjolseth report that

Mexican-Americans predominate among Arizona inhalant abusers

20
with Indians, and blacks also are more commonly abusers than are

whites. Their respondents, who were predominantly drug treatment program administrators, counselors, or parole and probations

officers, also described inhalant abusers as typically of lower

class origins (Vargas and Kjolseth, 1976).

Inhalant use has also been systematically studied among the

Pueblo tribes of New Mexico. Goldstein, based on a sample of

nearly 2,200 junior and senior high school age Indian children

found inhalant use in this group also far more common than in the

national sample of adolescents. Twice as many in his sample (17.2

percent vs. 8.1 percent in the national sample) had tried inhalants and fifteen times as many (13.9 percent vs. 0.9 percent)

were currently using these substances. In this group, female

users were nearly twice as common as male users, a finding the

author attributes to males have greater access to alternatives

such as alcohol and to traditional prejudices against women drinking. Those youngsters who belonged to the Native American

Church, which makes extensive use of peyote, a hallucinogenic

cactus , as a sacrament, were much less likely to abuse inhalants.

This is probably due to the Church’s strong proscriptions against

the abuse of any drug (Goldstein, 1976).

CONCLUSIONS

The overall picture of inhalant abuse that emerges from the

admittedly incomplete data available may be summarized as follows:

Use encompasses a rather large range of substances with an

almost equally wide range of potentially toxic effects. National

survey figures for inhalant abuse report levels of abuse roughly

comparable to that for the major hallucinogens such as LSD and

for the stimulant cocaine. Because such national data do not

adequately sample special populations at higher than average risk,

it is likely that these figures understate the extent of the problem, especially as it affects such minority populations as MexicanAmericans and Indians. Data from these groups as well as from

other sources suggest that chronic inhalant abuse is a phenomenon

of the young (late childhood-early adolescence) and the very

poor. This is probably because of the widespread low cost availability of substances that can so readily be abused in this fashion.

Present deficiencies in the epidemiological data concerning inhalant

abuse argue for more systematic study of the problem especially

in high risk groups. The diversity of substances employed makes

it desirable that the specific substances used by better identified

and their possible toxic effects more clearly specified.

21
REFERENCES*

Abelson, H., and P. Fishburne. Nonmedical use of psychoactive

substances. Princeton, N.J. Response Analysis Corporation,

1976.

Chambers, C., J. Inciardi, II. Siegal, and S. Newman. A n

assessment of the incidence and prevalence of drug and alcohol

use within the general population of west central Arkansas.

Washington, D.C., Miami, Fla.: and White Plains, N.Y.: Resource Planning Corporation, September 1973.

Chambers, C., J. Inciardi, H. Siegal, and W. Conway. A n

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of Florida.

Washington, D.C., Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation. August 1973.

Chambers, C., J. Inciardi, H. Siegal, and W. Conway. A n

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of Indiana.

Washington, D.C. , Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation, November 1973.

Chambers, C., J. Inciardi H. Siegal, and W. Conway. An

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of Mississippi.

Washington, D.C. , Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation , February 1974.

Chambers, C., J. Inciardi, and H. Siegal. An assessment of the

incidence and prevalence of drug and alcohol use within the

general population of the State of New Jersey. Washington,

D.C. , Miami, Fla. , and White Plains, N.Y.: Resource Planning

Corporation, July 1973.

Chambers, C., J. Inciardi, H. Siegal. and W. Conway. A n

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of North Carolina

Washington, D,C., Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation, February 1974.

Chambers, C., J. Inciardi, H. Siegal, and W. Conway. An

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of North Dakota.

Washington, D.C. , Miami, Fla. , and White Plains, N.Y.: Resource Planning Corporation, August 1973.

*For additional studies on the socio-epidemiological aspects of

inhalant abuse in Mexico see also papers reported at the First

International Symposium on Voluntary Inhalation of Industrial

Solvents, Mexico City, June 1976.

22
Chambers, C., J. Inciardi, H. Siegal, and W. Conway. An

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State of South Dakota.

Washington, D.C. , Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation, December 1973.

Chambers, C., J. Inciardi, H. Siegal, and W. Conway. A n

assessment of the incidence and prevalence of drug and alcohol

use within the general population of the State o f Utah.

Washington, D.C., Miami, Fla., and White Plains, N.Y.: Resource Planning Corporation, August 1973.

Miami, Fla., and White Plains. N.Y.: Resource Planning CorporaChambers, C., J. Inciardi, and H. Siegal. An assessment of the

incidence and prevalence of’ drug and alcohol use within the

general population of the State of Wyoming, Washington, D.C.,

tion, June 1973.

Columbia University School of Public Health. High school drug

study - spring 1973 preliminary findings. Study supported by

National Institute on Drug Abuse Grant DA00043, Columbia

University School of Public Health, New York City, June 1974.

Drug Abuse Council. Students and drugs: A report of the Drug

Abuse Council. Based on a Study by Yankelovich, Skelly and

White, Inc., 1975.

Glenn, W. Recent surveys of non-medical drug use: A compen--

dium of abstracts. Final report from Research Triangle lnstitute,

NIDA Contract HSM-42-72-169. March 1976.

Goldstein , G. Inhalant abuse among the Pueblo tribes of New

Mexico. Unpublished paper. 1976.

Kandel, D., and E. Single. The epidemiology of drug use among

New York State high school students: I-Distribution, trends and

change in rates of use. Mimeo, 52 pp., New York State Depart--

ment of Mental Hygiene and School of Public Health, Columbia

University, March 1974.

Mexico American Neighborhood Civic Association (MANCO) The

problem of toxicant inhalations in San Antonio, Texas. Unpublished paper, 1976.

New York State Office of Drug Abuse Services. A survey of

substance use among junior, and senior high school students in

New York State, Report No. 1: Prevalance of Drug and Alcohol

Use, Winter 1974/75, New York State Office of Drug Abuse Services , Two World Trade Center, New York. New York 10047,

November 1975. Also reported in: Stephens, R., et al. Sniffing

from Suffolk to Syracuse: A report on youthful solvent use in

23
New York State. Presented at the First International Symposium

on Voluntary Inhalation of Industrial Solvents, Mexico City, June

1976.

Padilla, E., A. Padilla, R. Ramirez, A. Morales, and E. Olmedo.

Inhalant, marihuana and alcohol abuse among barrio children and

adolescents. Unpublished paper, 1976.

Vargas, P., and R. Kjolseth. A special report on the abuse of

inhalants in the State of Arizona. Arizona Department of Health

Services, July 19, 1976.

24
Appendix

SUMMARY OF EXPLORATORY STUDY

OF INHALANT USE AND TREATMENT

A report under NIDA contract 271-76-4409 on a Summary of Exploratory Study of Inhalant Use and Treatment has recently become

available (General Research Corporation, Westgate Research Park,

McLean, Virginia, 22101, 1977). In this preliminary effort, nine

programs in seven field sites were visited, clients and staff were

interviewed, and the following impressions were obtained.

1.

2.

3.

4.

5.

6.

There are two major types of inhalant abusers: (1) experimenters or transitional users who move on to other drugs,

and (2) chronic abusers.

Chronic inhalant abuse is a phenomenon of the young and

the very poor.

Inhalant experimentation is extremely widespread among

young people--i.e., nearly everybody tries it.

Among the general population, committed inhalant abuse is

extremely rare.

As an established drug problem, inhalant abuse occurs in

certain neighborhoods and not in others.

Where inhalant abuse becomes popular, a system of not-forprofit distribution of the preferred product is developed.

25
7. Inhalant abusers are invisible to the educational and health

care delivery systems, but visible to the criminal justice

system.

8. Within their own neighborhoods, chronic inhalant abusers

come from the most unstable, disorganized, and problemridden families.

9. Chronic inhalant abuse in children and parental alcoholism

are related.

10. Black children are sniffers less frequently than other ethnic

groups.

11.

12.

The prevalence of sniffing is stabilized or increasing.

Sniffing among girls is increasing. But girls don’t get

caught as often as boys.

13. Children start sniffing with peers--either siblings or

friends.

14. Chronic inhalant abusing children generally have been

abused and/or neglected by their parents.

15.

16.

Children without siblings rarely sniff.

Inhalant abusers do not develop ritual or jargon--they are

not part of a drug subculture

17. In each of the sites visited, inhalant abusers number at

least in the several hundreds.

The table (on the following page) indicating regional differences

in solvent recreational use reproduced from the report.

Fashions change in the solvent employed from time to time so that

repeated surveys will show new products appearing and old ones

disappearing.

26
PREFERRED SUBSTANCE(S) AND STATED REASON FOR PREFERENCE, BY SITE

Site Favored Product Reason for Use, Comments

New York

Miami

Louisville

Los Angeles

Houston

Albuquerque

Sandoval Pueblos

Denver

Plastic cement, amyl nitrite (“Locker

Room”)

Transgo transmission fluid

Spray paint (“Toohey’s Gold”)

Clear plastic spray paint, glue, “PAM”

Spray shoeshine (“Texas Shoeshine”),

paint

Spray paint (“5-Star Gold”)

Gasoline, spray paint, spray acrylic

Clear plastic spray

“Gives longest high”

“Made in the area-goad high”

“Gives longest high-made in the

area”

No reason given

Shoeshine made in area

“Gives longest high”

No reason given

“Gives longest high”

27

CLINICAL EVALUATION

29
Chapter 3

CLINICAL EVALUATION OF PSYCHOLOGICAL FACTORS

Maurice Korman

INTRODUCTION

This section will review selected relevant literature describing

psychological factors predisposing to use; mental status of users;

personality studies of users; long-term effects; and psychological

treatment and prevention. Emphasis will be on recent research,

much of it presented at the First International Symposium on the

Voluntary Inhalation of Industrial Solvents, Mexico City, June

1976.

Characteristics of inhalant users have been described in an

impressive number of studies, with major review articles by Cohen

(1973), Done (1973), and Wyse (1973). Unfortunately, the bulk of

the literature is marred by serious methodological flaws. There is

excessive emphasis on retrospective studies; many investigators

content themselves with a purely descriptive approach, control

groups are frequently lacking, and when present, are inadequate

in that other-drug use in particular is seldom properly matched

for. Sampling problems abound with few careful attempts to

delineate the nature of a particular sample or to evaluate its

representativeness. Informational sources are nearly exclusively

restricted to the inhalant user himself; few investigators have

used an explicit theoretical framework. These methodological

considerations will be expanded upon passim.

30
PSYCHOLOGICAL FACTORS PREDISPOSING TO USE

Much of the literature on licit and illicit drug use attempts to

pinpoint the antecedent conditions that lead to substance use and

abuse. Most of this research has dealt with alcohol, psychedelics, and narcotics (Braucht et al., 1973; Lettieri, 1975; Gorsuch

and Butler, 1976) and has led to a considerable amount of speculation concerning causal relationships between psychological and

social factors on the one hand and substance abuse on the other.

The use of inhalants can be viewed in the context of overall drug

use. It is possible, of course, that no significant specific etiologic agents are at work here. Except for the very young age

distribution (which, incidentally, appears to be rapidly changing--

see Faillace and Guynn, 1976, for instance), Done (1973) finds

that “the similarity of psychosocial factors in sniffers and in

narcotic addicts or alcoholics (Coodley, 1961) suggests that there

is nothing unusual about this form of abuse from the standpoint

of possible etiology and epidemiology” (p. 112). Nonetheless, it

seems a reasonable procedure that inhalant users be contrasted to

other-drug users when one is investigating predisposing factors,

since there may be particular circumstances or specific characteristics that set the stage for inhalant use, quite aside from the

forces that lead youngsters to chemical coping generally (Gorsuch

and Butler, 1976). A critical heuristic question is: What does

the research on drug use in general tell us about such antecedent

conditions and to what extent are inhalant users different? Such

background information is particularly important with regard to

alcohol, tobacco, and marihuana , drugs which appear in the lives

of adolescents at about the same time as inhalants. We will,

therefore, try to set our discussion of the predisposing factors to

inhalant use against the background of the research literature on

the predisposing factors to the use of other such drugs.

Personality Factors

Published speculation on personality factors involved in an increased likelihood that a youngster will use inhalants has relied

primarily on information collected from confirmed sniffers. It is

likely, however, that sniffers will frequently show personality

characteristics which are the result, direct or indirect, of the

physical, psychological, or social impact of inhalant use. Under

some circumstances, sniffers will come to the attention of legal or

medical personnel during or after a crisis. As a result, some of

the data is suspect to an unknown degree. One should note that

the inhalant literature does not yet contain longitudinal studies of

the type exemplified by certain investigations on the use of

marihuana and alcohol to which we now turn.

Haagen (1970) found that students who 3 years later became marihuana users were originally more dissatisfied and nonconformist;

they were typically bright hut disaffected with school and unconcerned about the future. Smith (1973) reported that self and

31
peer ratings of rebelliousness were both predictors of subsequent

marihuana use. Jessor (1976) found that high school students

who became marihuana users later on, initially placed a lower

value on achievement and a concurrently greater value on independence; they were more given to social criticism and more

tolerant of deviation.

Somewhat similar results are reported in the longitudinal investigation of alcohol use. For example Jones (1968) found that problem drinkers were initially seen as being more unpredictable,

unstable, and impulsive than control subjects. These findings, it

is interesting to note, parallel to an appreciable extent ad hoc

studies of personality variables in young problem drinkers such

as those reported by Williams (1970). If the same holds for

inhalants, one can perhaps assume, as a working hypothesis, that

the descriptive studies cited below may be borne out by future

longitudinal or developmental investigations, especially those that

deal with young users observed under “everyday” conditions.

In an early study of 27 sniffers, Massengale et al. (1963) conjectured that inhalants were helpful in controlling the anxiety that

would otherwise have accompanied strong sexual and aggressive

impulses. Press and Done (1967) inferred from their study of 16

inhalant users that the principal personality factors at work in

inhalant users include a sense of inadequacy, bashfulness, and

feelings of frustration over inability to reach high standards set

by parents. Nylander (1962) described an “emotionally disturbed

background” in many of 20 intensively studied youngsters in

Stockholm. Nurcombe et al. (1970) studied gasoline sniffers who

came from traditionally belligerent clans in a remote part of

Australia. They posit a higher than average need for discharge

of tension associated with sexual, aggressive, and acquisitive

drives. Inhalant-promoted disinhibited behavior thus aids in

establishment and assertion of masculinity. Some confirmation of

this hypothesis was obtained through a technique based on

teacher ratings (presumably not on a blind basis) which resulted

in higher Tension Discharge scores and higher Anxiety Index

scores for inhalant users in contrast to a control group.

Richek et al. (1975) administered the Bown Self Report Inventory

to 190 middle class high school juniors and seniors. The Bown

Inventory measures positiveness of attitude towards self and

milieu. Richek reported low negative correlation coefficients

between self-reported incidence of inhalant use and the Bown Inventory scales. The pattern of correlation coefficients was roughly similar to those involving the use of other drugs. Meloff

(1970) reports on intergroup differences on the California Psychological Inventory: inhalant users scored lower on scales reflecting poise, ascendancy, self-assurance, socialization, maturity,

and responsibility. Control groups, however, were not fully

adequate, and it is unclear, as it is in most of the research here

reported, whether these differences reflect drug use in general

or inhalant use specifically.

32
The most telling criticism here is the absence of comprehensive

studies based on a useful theoretical framework rather than on

happenstance observations of a sample’s salient personality characteristics. A potentially promising approach, for instance, might

attempt to examine unsuccessful adaptation in response to important developmental tasks of adolescence. Might, for instance, the

decision to inhale be a function of repettitive failures of this type?

Alternative models (and easily more comprehensive ones) could be

evolved. Future research needs to be guided by potentially

useful notions rather than adding still more descriptive studies of

small samples. Since the antecedent conditions to marihuana and

alcohol use are beginning to be known with some reliability, they

represent a useful point of’ departure for inhalant research, As a

start, one might try to replicate the work of Haagen (1970) or

Jessor (1976) with experimental and compulsive sniffers.

Familial Disorganization and Pathology

Much of the research in this area, basically descriptive in nature,

is focused on the level of intactness of the family and overall

judgments of the family’s effectiveness of functioning. In a

sample of nine glue sniffers admitted to a psychiatric state hospital, Jackson et al. (1967) found no child living with both

parents at the time of admission, Ackerly and Gibson (1964)

reported that most of the families in their small sample of inhalers

were “multipe problem families” that had gone through considerable periods of turmoil and discord. In a sample of 32 sniffers

living as illegal squatters in Mexico, De la Garza et al. (1976)

found that nearly half of the families had a parent. missing

through abandonment or death, Massrngale et al. (1963) report

on a sample of 27 sniffers. Only seven families had both parents

living at home; one or both parents were alcoholic in a total of 13

families. Press and Done (1967) similarly note the incidence and

extent of family disorganization. They point to the excessive use

of alcohol in one or both parents. The greater use of alcohol in

sniffers' families suggested by some of these investigators is, of

course, paralleled by the literature on the families of alcohol

abusing youngsters (mcKay, 1961; Maddox, 1970; Gusfield, 1970)

Some studies report information regarding parallel control groups.

Barker and Adams (1973) found that sniffers resembled control

youngsters in a training school setting in that signs of family

disintegration were present in both groups, although they concluded that the sniffers’ families showed a greater level of clinical

deterioration, Meloff (1970) reported that over half of the families

of inhalers included separated marital couples; two control groups

yielded 25 percent and 9 percent split families respectively. A

sample of sniffers in the remote north of Australia was reported

by Nurcombe et al. (1970) to be slightly, though not significantly, more often separated from their fathers than a control group.

The better controlled studies are less conclusive on the issue of

family intactness than the clinical reports.

33
The literature generally provides little insight into the actual

pathology beyond pointing to the general turmoil and ineffectiveness of family functioning. Bonnheim and Korman (1977) videotaped structured interactions among family members of sniffers

and other-drug controls. Blind ratings of the tapes by professionals reflected a significantly more conflictual, anxious atmosphere in sniffer families, with particular problems in communication and organization. It should be noted that it is especially

important (though difficult) to differentiate family reactions to a

child’s sniffing from antecedent family conditions. Comstock

(1976), for instance, reports on a sample of families of hospitalized sniffers and describes the outrage and rejection by the

sniffers’ families in comparison to other-drug controls.

Because no longitudinal studies are available which study the

initiation of sniffing behavior, it is not possible to evaluate the

extent to which the lack of parental control and support, which

Jessor (1976) reports as antedating the use of marihuana, is

likewise present in the case of inhalants.

Furthermore, is it possible that factors that presumably precede

drug use generally, such as family instability, over- and

under-domination, parental rejection, harsh physical punishment

by one or both parents (see Gorsuch and Butler [1967] for an

extended review) are present initially in the case of inhaler

families to the same extent, but are then amplified by the almost

reflexive negative response that sniffing specifically seems to

bring out in most parents?

Future research clearly needs to focus on the possible relationship between the personality variables and familial conditions. An

adolescent’s psychological vulnerability may eventuate in an increased likelihood of inhalant use only in the context of a familial

impasse, or when accompanied by a specific constellation of sociocultural pressures. Multivariate research that examines such

variables additively, and perhaps interactionally, is needed.

Environmental Pressures

School adjustment represents one of the most frequently reported

troublesome areas for the sniffer. Ackerly and Gibson (1964) and

Massengale et al. (1963), among others, describe samples of

sniffers noted for their poor school performance and adjustment.

More recently, a number of controlled studies have suggested

much the same pattern. Barker and Adams (1973) found that

inhalant users were more significantly retarded educationally (p <

.01) than a comparable control group even though they were

roughly of the same intelligence. Meloff (1970) found that inhalant users were approximately one grade below a comparison

group; he further reports that three of the four variables that

best discriminated sniffers from others were school-related: days

absent from school last year; grade point average last year; and

school-related attitudes. Nurcombe (1970) likewise found a ten34
dency for sniffers to be slower learners than control children.

Korman et al. (1977) found that inhalant users appeared to be

significantly discriminable (p < .05) from other drug using children on the following variables: lower grades on last report card;

more suspensions at school; and overall severity of school problems. In addition, teachers were perceived by them as being

significantly stricter and controlling.

As was noted above with reference to family pathology, schools

and teachers may react to the visible signs of sniffing at least as

much as they set the stage for alienation and disaffection. Thus,

they become involved in the etiology and the consequences of inhalant use. Such a dual role for schools, frequently noted clinically, needs to be confirmed experimentally, particularly in

Mexican-American communities where increased inhalant use and

unsatisfactory educational situations coexist.

Another environmental condition present with some frequency in

the life space of inhalant users is boredom or idleness. MedinaMora and Terroba (1976) stressed their subjects’ “state of idleness” in their epidemiological survey of inhalant users in the

Federal District (Mexico City). A sociological study of sniffers in

Phoenix, Arizona (Montiel, 1976), reports a high incidence of

inhalant use when there is “nothing to do.” Stybel et al. (1976)

concluded from similar data that community programs emphasizing

recreation should be initiated. Korman et al. (1977) report simultaneously a significant lack of socially appropriate current activities in inhalant sniffers in comparison to a control group of

other-drug users and negligible interest in new activities being

made available.

Peer use represents a significant environmental press directed

towards inhalant use in that reference is persistently made to the

role that peers play in introducing youths to sniffing (Ackerly

and Gibson, 1964; Cohen, Chapter 1, this volume; Berry et al.,

1976). At the same time, it appears that only a minority of a

sniffer’s reported “best friends network” may themselves be

sniffers or even approve of sniffing (Korman et al. , 1977), which

may leave the door open to the use of “counter-models.”

No definitive information is currently available regarding the

extent to which substance use may differentially characterize the

families of eventual sniffers. In this they may parallel (or exceed) families of alcoholics (Maddox, 1970) or marihuana users

(Kandel, 1973) . Of most interest here would be longitudinal controlled studies comparing sniffers with other-drug using groups.

35
MENTAL STATUS OF USERS

Cognitive Difficulties

In the 50's and 60's a number of small sample clinical reports

were published suggesting a relationship between inhalants (particularly gasoline) and signs of acute brain damage (Courtin,

1955; Faucett and Benson, 1952; Lawton and Malmquist, 1961;

Satran and Godson, 1963; Brozovsky and Winkler, 1965; Chapel

and Taylor, 1968). Many of these studies, with some exceptions

such as Massengale et al. (1963), found abnormal EEG’s and

occasionally reported on psychological test results suggesting

impaired memory and concentration, perceptual motor difficulties,

and disorientation.

Barmen et al. (1964) evaluated 15 glue sniffers, 8 of whom were

given the Bender Gestalt test shortly after inhaling; they reported gross deviations from normal. The subjects’ performances had

much improved a week later, leaving the investigators to conclude

that the visual-motor distortions were transitory in nature. No

controls fot either initial performance or practice effects were

included. Torres-Ruiz (1976) reported on a larger sample of 30

sniffers and found attentional and memory disturbances on the

Psychopathological Appraisal Form.

Because many of the youngsters evaluated in the studies listed

above had disturbed backgrounds characterized by polydrug use,

it is impossible to ascribe findings of organic brain syndromes to

inhalant use alone without the availability of appropriate controls.

A number of investigators, however, did investigate brain

changes in inhalant users in the context of parallel data on control subjects and/or objective behavioral measures of brain involvement. Dodd and Santostefano (1964) gave 12 glue sniffers a

series of tests of concentration, continuous performance in the

face of distraction, and visual-motor coordination some 14 hours

postinhalation. These subjects had inhaled a median number of 82

times. The authors concluded that their "performances were

strikingly similar to those of the controls" (pp. 568-569).

In a well designed study still in progress, Berry et al. (1976)

evaluated 37 chronic inhalers (average number of inhalations in

excess of 7,000) with the Halstead-Reitan Neuropsychology (NP)

Battery. These subjects, who inhaled primarily metallic paints,

were compared to a control group matched on ethnicity, education, sex, age, and drug histories. On nearly half of the tests

making up the NP battery, inhalant users scored significantly

lower than controls; 40 percent of the inhalant subjects scored in

the brain damaged range on impairment indices, while none of the

control subjects did. These results were corroborated by Korman

et al. (1977), likewise reporting on work in progress. Approximately 60 percent of 59 moderate sniffers, primarily aerosal paint

36
users (average number of inhalations in excess of 50), yielded NP

battery results that were initially rated as brain damaged, in

contrast to "experimental" sniffers and other-drug controls whose

NP batteries were rated as brain damaged 30 and 35 percent of

the time, respectively. Finally, two studies report on mental

status evaluation of organic brain syndrome. Comstock (1976)

found that 55 percent of a sample of 22 primarily toluene users

demonstrated an acute organic brain syndrome characterized by

memory impairment, poor retention, and inability to perform

simple calculations. Korman et al. (1976) compared 162 inhalant.

users seen in a psychiatric emergency room to a group of 162

controls matched on age, sex, ethnicity , and drug use, and

found that they differed significantly on the following characteristics:

deficit (p < .05); greater judgment deficit (p < .001); and greater

loss of immediate recall (p < .05); greater abstraction

insight deficit (p <. 001).

Research on the impact of inhalants on the higher brain functions

has been beset by a number of deficiencies. Among these are the

frequent lack of samples of sufficient size, appropriate controls,

and systematic approaches to the measurement of dependent variables . At the very least, careful specification of type, amounts,

and duration of inhalant and other drugs used is critical. It

would be desirable if subjects were sought out whose inhalant

history is limited to severe abuse of only one inhalant. Contradictions in the literature may simply resolve themselves to issues

of sampling and types of inhalants. Also, too little is known

regarding the natural course and long-term reversibility of brainrelated behavior deficiencies; as the age range of inhalant users

becomes greater, such follow-up will become both critical and

feasible.

Danger to Self and Others

Sniffers have frequently come to the attention of authorities

because of their involvement with some form of antisocial behavior . Many clinical studies have stressed the sniffer’s sense of

grandiosity and invulnerability (Wyse, 1973) which is seen as

frequently leading to self-directed destructive behavior; others

(Cohen, 1975) have pointed out that inhalants may, like alcohol,

diminish behavioral control capabilities long before motor activity

is diminished. A representative clinical study (Press & Done,

1967) detected sniffing behavior to be "a precursor to criminality"

in about a third of the subjects. These individuals were seen as

suffering from serious deficits in their judgment and reality

perception which led them to be accident prone and to indulge in

antisocial and self-destructive acts. It is interesting to note that

in Kalogerakis’ (1971) report on a series of patient assaults at

Bellevue Hospital in New York, only one incident was due to an

intoxicant, and that was glue.

37
Tinklenberg and Woodrow (1974) contrasted groups of youthful

assaultive and nonassaultive incarcerated offenders with reference

to their history of drug use. Although inhalants were used with

low frequency by both groups, their prevalence in the assaultive

group was of suggestive proportions in contrast to the control

group.

Friedman and Friedman's (1973) large sample studies on drug use

and delinquency yielded self-reports of greater violence and

aggression on the part of drug users in contrast to non-drugusing controls.

Within-drug-group analyses suggested that “users of inhalants

reported the greatest overall amount of violence, both in order to

obtain drugs and while under the influence of drugs” (p. 468).

They also noted that, among boys with police records, some 40

percent attributed their loss of control leading to violence to drug

use. Official records implicated solvents more frequently than

any other drug.

In a psychiatry emergency room study, Korman et al. (1976)

found that their sample of 162 inhalant users differed significantly

from matched controls in that they displayed significantly more

self-directed destructive behavior as well as some degree of

recent suicidal and homicidal behavior. Mean differences in

clinical ratings, however, were small. Some interactive effects

were suggested: the non-Hispanic, postadolescent inhalant user

is particularly at risk. Another aspect of this study investigated

the question, what combination of drugs best predicts self-directed, destructive behavior? Inhalants, and no other drug with it,

appeared to be the significant predictive drug variable.

The relationship between inhalants and aggressive behavior represents an important current research issue: What psychological

mechanisms are involved? Is the problem primarily a predisposition to aggress or is it a failure of internal controls? What role

do inhalant-produced internal states play? These are some of the

important, unresolved questions.

Mood and Affect

Massengale et al. (1963) found that nearly all youths in a sample

of sniffers showed chronic depression and passive aggressiveness.

Brozovsky and Winkler (1965) summarized an investigation of 17

sniffers by postulating basic feelings of helplessness and depression which inhalers replace with euphoria. De la Garza et al.

(1976), in a careful psychiatric evaluation of 32 inhalant users in

Monterrey, Mexico, found that depression was the most frequently

exhibited symptom, being characteristic of 40 percent of the

subjects. Using the Brief Psychiatric Rating Scale, Torres-Ruiz

(1976) described a sample of 30 sniffers as being high on emotional shyness, flattening of affect, motor retardation, and depression.

38
Three studies are of particular interest because they involve

comparison groups. Comstock (1976) found that a sample of 22

hospitalized sniffers were significantly lower on the anxiety,

depressive mood, motor retardation, excitement, and suicidal

ideation components of the Brief Psychiatric Rating Scale. Furthermore, the sniffers’ Minnesota Multiphasic Personality Inventory (MMPI) neurotic triad scores tended to be lower than that of

users of barbiturates, stimulants, and psychotropics. Berry et

al. (1976) reported on a sample of 37 sniffers who had significantly higher Depression (D) scores on the MMPI than a control

group. It should be noted, however, that D was not elevated by

absolute standards (average T score of 62), and was lower than

five of the remaining seven clinical scales. Korman et al. (1976)

found that inhalant users and other-drug users were both rated

higher on depression than the general population of individuals

visiting a psychiatric emergency room. In addition, there were

no significant between-group differences on any of seven other

rating scales reflecting various dimensions of mood and affect.

There seems little question that inhalant users are more depressed

than the population at large, and that they present themselves as

having lowered mood and poor morale, particularly if seen at a

time of personal crisis. The issue of whether they show greater

affective disturbance than drug users in general is very much

open to question.

Diagnosis and Prognosis

The modal prognostic picture that any group of professionally

evaluated patients presents is primarily a function of the selection

(or self-selection) process with reference to a particular health

setting. Not surprisingly, the literature reveals much variability

on this issue. For example, Brozovsky and Winkler (1965) found

that three quarters of a small sample of sniffers are schizophrenics. By contrast, Alapin (1972) evaluated sniffers in Britain and

Poland and reported about a third of them to be schizophrenic.

Comstock (1976), describing a sample of sniffers hospitalized in a

polydrug treatment center, reports a diagnostic breakdown as

follows:

Sociopathic personality 23%

Adolescent adjustment reaction 45%

Depressive neurosis 23%

Schizophrenia 9%

In a setting that accommodates a wide range of patients, the prevailing base rates for both “drug” and “non-drug” patients are

fundamental to an assessment of the diagnostic picture of inhalant

users. Shown in the table at the top of the next page is the

diagnostic structure of inhalant (I), other-drug (O.D.), and

non-drug groups (N.D.) taken from a recently completed study

by Korman et al. (1976). Interestingly, the three groups do not

differ in the incidence of psychosis. The inhalant group appears

39
Psychotic Organic Brain Syndrome (O.B.S.)

Non-Psychotic O.B.S.

Affective Psychosis

Non-Affective Psychosis

Neurosis

Personality Disorder

Sexual Deviation

Alcoholism

Drug Dependence

Psychophysiological Disorder

Transient Situational Disturbance

Behavior Disorder of Childhood or Adolescence

Mental Retardation

No Diagnosis Made

7%

4%

4%

23%

15%

20%*

2%

6%

35%*

0%

10%

15%

1%

2%

6% 1%

2% 2%

4% 4%

19% 26%

15% 15%

0% 0%

1% 1%

1% 1%

17% 1%

0% 2%

15% 19%

10% 7%

6% 6%

5% 15%

Note: Based on N=162 psychiatric emergency room patients per group;

percentages include primary and secondary diagnoses.

*Significantly different from O.D. group.

to include a relatively large number of persons noted for their

lifelong pattern of maladaptive behavior. Does the difference in

drug dependence diagnoses reflect a more committed drug orientation on the part of inhalant users than non-sniffing polydrug

users?

Prognosis appears to be poorer for inhalant users than for otherdrug users. In Comstock’s (1976) study, for instance, sniffers

responded to a total hospital therapeutic program with "an apparent mobilization of agitation, impulsiveness, and of antisocial

manifestations as well." As seen in the emergency room (Korman

et al., 1976), inhalant users differed from other-drug users in

that the duration of their illnesses was significantly longer (p

< .01), as was the index episode’s duration (p < .05); furthermore,

the typical disposition was more frequently to hospitalize the

patient and less frequently outpatient treatment or no further

treatment (p < .05).

Other Drug Use

A number of problems exist with reference to determining the use

of other drugs by sniffers. Other-drug use is a function of the

age of the respondents, the number of years of drug use, the

current extent of involvement with inhalants and, most of all, the

"type" of sniffer--a determination most influenced by considerations of sample selection. It is instructive to look at the variability of information regarding other drugs ever used as reported in three studies describing different samples of sniffers:

40
Berry et al.

(N=37; age=18.3)

Alcohol 100%

Marihuana 100%

Barbiturates 54%

Amphetamines 73%

Heroin 24%

Hallucinogens 54%

Cocaine 38%

Comstock

(N=22; age=17.7)

Alcohol 18%

Marihuana 36%

Sedatives 59%

Stimulants 23%

Narcotics 27%

Psychedelics 14%

Psychotropics 14%

Korman et al.

(N=162; age=21.5)

Alcohol 51%

Marihuana 65%

Sedatives 39%

Stimulants 18%

Narcotics 29%

Hallucinogens 41%

Studies such as these seem to corroborate the view that inhalant

users are a heterogenous group when it comes to other-drug use.

Perhaps, as Glaser (1966) notes, they are confirmed in their primary drug orientation much like narcotic and alcohol addicts.

Reliable data are lacking on this score.

The issue of possible progression up the "drug ladder" is an

important one for inhalant users since it is a drug of early initiation. Kramer (1972) reported that nearly half of a sample of 47

heroin addicts began their drug abuse with glue sniffing. Unfortunately, so little is known about the incidence of sniffers who do

stop short of using narcotics that causal arguments derived from

studies of heroin addicts cannot be taken seriously.

In spite of the wide panoply of drugs used by most sniffers in

the samples discussed above, the prevalence of heroin ("ever

used") does not exceed 30 percent. Done's question about a

"graduation" from early inhalant use to heroin (Done, 1973, p.

114) is far from conclusively answered.

What is the order in which inhalant users move from one drug

group to another? Some preliminary findings on a sample of 37

sniffers (average age 18), would appear to give the following

sequence (Berry et al., 1976):

% Ever Used

Alcohol

Amphetamines

Marihuana

Solvents

Barbiturates

Hallucinogens

Cocaine

Heroin

Age of First Use

10.7 100%

11.3 73%

12.8 100%

12.8 100%

15.0 54%

15.8 54%

16.6 30%

16.9 24%

A younger group of sniffers (N=61; average age 15) show the

following progression: (Korman et al., 1977)

4 1
Beer

Marihuana

Spray paint

Liquor

Gasoline

Wine

Glues or cements

Lighter fluids

Heroin

Hallucinogens

Barbiturates

Stimulants

Other Sedatives

Cocaine

Hashish

Other Narcotics

First Tried

(Months ago) % Ever Used

41.7 77%

38.3 92%

33.9 77%

33.0 39%

30.5 29%

26.4 21%

25.7 21%

20.6 21%

19.5 3%

11.7 57%

17.5 30%

15.5 66%

13.4 13%

10.4 33%

6.5 3%

5.3 10%

Alcohol and marihuana seem to precede the beginning of inhalant

use by very little, if at all; a year and a half or more, however,

appears to elapse before the appearance of most street drugs.

It is interesting to note that whereas only 3 percent of the 15-

year-old inhalers tried heroin, the parallel figure for the 18-yearold is 24 percent. It will be significant if further research

supports the notion that this figure is close to the maximum level

of penetration of heroin for samples of sniffers.

PERSONALITY STUDIES OF USERS

Although some group data have been published which utilized the

California Psychological Inventory (Meloff, 1970), the most useful

data derived from objective personality tests appear to come from

studies using the Minnesota Multiphasic Personality Inventory

(MMPI). MMPIs of individuals primarily identified as sniffers that

have been collected by two investigators (Comstock, 1976; Berry

et al., 1976) were pooled into a composite profile (see Figure 1)

for the purposes of this section because of their essential similarity This composite sample (mean age of 18) includes mostly men

(85 percent), and is half Anglo and half Mexican-American or

Indian, while including slightly more nonhospitalized than hospitalized individuals.

42
Figure 1. Mean MMPI profile of 59 inhalant users.

A personality description for this profile, as derived from actuarially constructed interpretation devices for adolescents (Marks et

al., 1974) and adults (Gilberstadt and Duker, 1965; Hovey and

Lewis, 1967), might include descriptors such as (a) a predisposition to exhibit strange and not very well organized beliefs, occasionally of a delusional (persecutory) caliber, and to report sense

organ disturbances occasionally; (b) a tendency to under-control

impulses, to act out, to resist or derogate others, particularly

authority figures.

In Lachar's extensive review of polydrug use and the MMPI

(Lachar et al., in press), he concludes that "most studies reported Pd-Sc/Sc-Pd or a Pd spike with a moderate elevation on SC

mean profile." MMPI profiles that include SC/Ma elevations have

typically been regarded as reflecting somewhat greater psychopathology in patients in general (Lachar, 1974). Research that

will contrast inhalant users MMPIs with those of selected properly

matched comparison groups will be of interest in this regard.

43
Lachar and his colleagues (in press) clearly demonstrate the usefulness of using the MMPl as the tool of choice for the objective

assessment of personality and psychopathology of groups of polydrug users generally. Profile analysis, however, is called for

since mean profiles or even code types are far from adequate.

Profiles in turn will need to be related to patterns of use and

prognosis on a longitudinal basis; a number of critical variables

should be looked at, such as the context in which the inhalant

user presents himself (voluntary vs. involuntary) as well as the

customary demographic variables of sex, age, and ethnicity. One

interesting research question deals with a possible typology of

inhalant users. The MMPI might be used as the vehicle for

differentiating and then describing subtypes if they exist (Marks

et al., 1974). As Lachar et al. (in press) point out, identifying

subgroups differentiated by the success of various treatment

approaches would be an especially useful contribution.

LONG-TERM EFFECTS

The development of an apparent tolerance for inhalants, particularly toluene-based compounds, has been noted by a number of

investigators (Glasser and Massengale, 1962; Brozovsky and

Winkler, 1965; Press and Done, 1967; Preble and Laury, 1967).

Borzovsky and Winkler, for instance, noted an increase of up to

25 tubes per day in one child. A more typical progression is

that “over a one or two year period the user may experience less

effect with eight to ten tubes of plastic cement, for example, than

was noted initially with one or two” (Done, p. 109).

Not enough is reliably known concerning the antecedents of increased tolerance for the major classes of inhalants. There are

indications (Easson , 1962) that the sniffing of gasoline, for

instance, may likewise involve eventual tolerance buildup. As

increasing numbers of adults are reported to be returning to

occasional or compulsive inhalant use (cf Faillace and Guynn,

1976). prospective and retrospective research on tolerance needs

to be undertaken.

A number of investigators have commented anecdotally on sniffers'

symptoms of psychological dependency primarily in terms of the

persistence with which the goal of inhaling is pursued (Clinger

and Johnson? 1951; Ackerly and Gibson, 1964). There have also

been reports of a negative psychological state induced in confirmed inhalers when prevented from sniffing. Some investigators

(Ackerly and Gibson, 1964; Preble and Laury, 1967; De la Garza

et al., in press) have reported increases in irritability, restlessness, excitability, and anxiety under such conditions. Frequently, it has been difficult to establish the causal relationship between the inaccessibility of the drug and such psychological

states. This is particularly true when the sniffer comes to the

attention of professionals because he is apprehended or needs

44
medical care. Further research is also needed that will chart the

extent to which the deprived inhaler departs from an optimal state

of well being as a result of the nonavailability of inhalants, and

under what conditions the urge to use, or fantasize about use,

are most frequently experienced.

There has been disagreement in the literature over the existence

of a withdrawal syndrome upon abrupt cessation of long and

frequent inhalant use. Some authors specifically point to its

absence (cf Done, 1973) although there have been reported observations of a syndrome resembling delirium tremens under conditions of abrupt cessation (Merry and Zachariadis, 1962;

Nylander, 1962; Lindstrom, 1973)

In an interesting study, De la Garza et al. (1976) described an

abstinence syndrome in 22 percent of a group of sniffers characterized not only by dysphoric symptoms but by physical signs as

well : abdominal pain, general paresthesias , leg cramps, headaches, and other discomforts. Furthermore, a small group (9

percent) kept some plastic cement to inhale early the next day to

counteract deprivation symptoms. Since this is an unusual finding, its replication and further explication is highly desirable,

particularly in populations other than the one investigated.

PSYCHOLOGICAL TREATMENT AND PREVENTION

Psychological Treatment

Anecdotal accounts abound regarding the difficulties in modifying

sniffing behavior (Clinger and Johnson, 1951; Ackerly and Gibson,

1964; Chevaili, 1976). Comstock (1976) reports fewer favorable

pre-post changes on psychometric instruments for a sample of inhalant users in contrast to groups of other-drug users following a

period of hospitalization during which psychotherapy, social work,

and vocational rehabilitation were available.

Laury (1972) describes his experience with a sample of 30 sniffers, 10 of whom were seen in outpatient psychotherapy. He

stresses the need for careful diagnostic evaluation and points out

that removal of the sources of glue is insufficient. He emphasizes

the importance of helping the child secure new peer relationships,

of investigating community resources in order to find alternative

"square" activities, and particularly of changing the family interaction with the aim of increasing communication and heightening

reinforcement for appropriate behavior. Unfortunately, no outcome information is provided.

Chevaili (1976) finds inhalant users to be unreachable by traditional therapeutic methods because of the lack of verbal ability

and the unavailability of basic support systems usually provided

by family, school, and work institutions. Like Laury, he

stresses the need to work with the family, the school, and the

45
work setting while providing for an integration of verbal therapy

and corporal exercises. Campuzano (1976) focuses on the utilization of psychodrama and the inclusion of paramedical personnel in

alternating group therapy sessions. A somewhat similar attempt

to avoid the pitfalls of the verbal therapies through a very active

"reality therapy-confrontation" approach is outlined by Bratter

(1973).

A series of studies have been reported which are based on conditioning principles and other learning paradigms. Although most

of these efforts are based on very small samples, they reflect increasing interest in a specific delineation of the therapeutic

procedures and a concern with information regarding outcome.

Mecir (1971) reports on an attempt to pair inhalation of a cleaning

liquid containing trichloroethylene with discomfort produced by an

injection of apomorphine. Twenty such trials were given to a

17-year-old boy in the space of a month, followed by five booster

shots. The author reports success over a 7-year follow-up.

Skoricova and Molcan (1972) treated 22 adolescents and 10 adults

with aversive therapy, following a period of detoxification and

symptomatic treatment. They report therapy as being successful

in 50 percent of their treated cases, using resumption of sniffing

as the criterion.

Kelvin (1967) reports on the treatment of a 15-year-old gasoline

sniffer by the use of relaxation and aversive imagery techniques.

Self-report information during a 17-month follow-up period showed

no resumption of sniffing. Blanchard et al. (1973) treated a

patient with a 7-year history of spray paint inhalation with a

combination of covert sensitization and apneic aversion, with

apnea induced by an injection of succinylcholine chloride

(Anectine) . Dependent variables included two types of free

access measures. Follow-up for a year indicated a discontinuation

of sniffing and an appreciable degree of social rehabilitation.

Maletzky (1974) treated ten Army drug abusers, one of whom was

a spray paint user, with covert sensitization assisted by the inhalation of a foul but safe odor. Behavioral measures included

self-report information (incidence of drug abuse and urges to

abuse drugs), reports from the authorities, and randomly

scheduled urinalysis. The experimental group improved more

than a control group receiving counseling on all three sets of

criteria; follow-up lasted 6 months.

A group of Mexican researchers (Perez de Francisco et al. , 1976)

report useful results obtained in treating hospitalized inhalant

users with prolonged action neuroleptics (pimocide, penfluridol,

and pipotiacina) in conjunction with a total rehabilitation effort.

46
Other Control Techniques and Prevention

A number of authors reporting on psychological treatment have

indicated the importance of adjunctive methods involving the

school, the home, and work (Bratter, 1973; Laury, 1972; Chevaili,

1976).

Additional reports deal with the effectiveness of such other approaches in the absence of psychological treatment. Unfortunately, these are largely anecdotal accounts that do not report

outcome evaluation data.

Silberberg and Silberberg (1974) focus on the role of the school

and point out that a spurt in arrests for glue use sometimes

follows on the heels of a school drug education program, a fact

that seems to be in keeping with difficulties occasionally encountered with drug information programs. They emphasize the need

to initiate programs that develop self-worth within the context of

the schools. They conclude that the typical sniffer can succeed

most easily in an alternative school setting of the type where

traditional skills are not the only aptitudes necessary for success.

De Hoyos (1975; 1977, in press) organized youth groups designed

to develop positive status on the basis of attainable achievements

in sports and the arts, particularly in relationship to peers.

Simultaneously, workers facilitated the formation of formal neighborhood groups of parents (concilios) who interacted with youth

groups in drug abuse seminars. This community group also

developed audio-visual and written materials (e.g. , comic books)

as a preventative measure.

A number of attempts at prevention have been reported (Barker

and Adams, 1973) stressing the need to appeal to merchants to

control in some fashion the sale of the more popular inhalants in a

particular community. Such efforts, complicated by the patchwork of local laws regulating the sale of various inhalants, appear

not to have changed inhalant-related behavior materially. Attempts to control inhalant use through unpleasant additives or

chemical replacement (Cohen, 1973) have been thwarted by sniffers’ discoveries of other intoxicating solvents.

It might be useful, in conclusion, to review criteria for improving

inhalant treatment research, adapting recommendations suggested

by Callner (1975) among others:

1. Include more representative inhalant users by type of

inhalant used, history, and typical dose, as well as by

subject characteristics likely to interact with treatment

approach.

2. Use a larger variety of reliable and representative

dependent measures--including behavioral components of

47
2. sniffing, unobtrusive or nonreactive variables, ongoing

program performance measures, reports by collateral

informants.

3. Increase experimental control through the utilization of

baseline data and carefully chosen control groups whose

characteristics and alternate "treatment" are throroughly

described.

4. Improve follow-up procedures--adding to self-report

approaches through the use of informants and in vivo

assessments, and collecting dependent measures similar

to those used during and at the conclusion of the

experiment.

5. Apply appropriate data analysis, both graphical and

statistical.

6. Provide detailed analysis of variables affecting both

therapeutic successes and failures as a preliminary step

to refiing treatment and patient selection procedures.

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53
MEDICAL EVALUATION OF

INHALANT ABUSERS

Eric G. Comstock and Betsy S. Comstock

INTRODUCTION

Inhalant abuse describes a pattern of behavior which involves the

voluntary inhalation of gases or vapors in order to achieve a

modified state of consciousness. The usual intent is to achieve a

state of euphoria or "high." A sensation of dizziness, light-headedness, or floating ordinarily is associated with the euphoria.

The state of dissociation from one’s environment allows temporary

escape from the troubles, concerns, and stresses of everyday

living. The response induced by inhalation is dose-related and

cumulative over short periods of time. The desired alteration in

consciousness may be achieved by high concentrations of gas or

vapor in air within 1 to 2 minutes, while lower concentrations may

require 5 to 10 minutes to achieve the desired effects. Depending

upon the substance and the dose, an altered state of consciousness may persist for a few minutes to several hours. With poor

control of exposure, the intended effects may become excessive,

leading to general central nervous system (CNS) dysfunction,

depression, sedation, coma, and death due to respiratory depression or major cardiac arrhythmias. Depending upon the technique

of administration, hazard exists for reduction of oxygen content

of inhaled air with anoxia leading to unconsciousness and for

death from respiratory failure.

54
Toxicity

The deleterious acute effect of inhalant abuse represents a pharmacologic progression beyond the response desired by the host

and occurs as a result of excessive doses. Because the respiratory tract provides a portal of entry into the blood stream for

lipophilic substances that is almost equivalent to intravenous

injection, elevated concentrations of inhaled substances in the

blood are achieved almost immediately. The blood brain barrier is

readily penetrated by lipophilic substances. The concentration in

the central nervous system reflects the concentration of substances in inhaled air delayed only by the circulation time from

the lungs to the brain. The combination of ease of administration

and rapidity of response allows immediate feedback. While induction is very rapid, disappearance of effects is relatively slower

because of retention of lipophilic substances in lipid pools in the

body from which there is gradual release over a period of hours

to days. Recurrent use of inhalants over a time interval shorter

than the time required to clear fat depots of their retained substances may result in a gradual accumulation requiring many days

for dissipation after the last use of the substance.

The effects of inhaled substances may be immediate, delayed, or

remote with respect to the time frame within which the effects are

manifest . Alteration of consciousness is an immediate effect as

are cardiac conduction abnormalities. Delayed effects are manifest

by persistent organic brain syndrome, peripheral nerve injury,

reduction in hematopoietic activity, and liver and kidney damage.

Remote effects may not be manifest for 10 to 30 years and consist

of increased rate of cancer and genetic changes in germinal

tissue.

Exposure and Clinical Effects

The medical literature is spotted by case reports and reports of

series of epidemiologically related cases of injury associated with

the use of inhalants. The available medical literature cannot be

construed as representative of injury associated with the use of

inhalants alone. Publication in medical literature requires the

occurrence of a clearly identified injury within reasonable temporal proximity of the use of inhalants. Consequently , medical

literature is weighed heavily toward the more dramatic clinical

manifestations that occur as an immediate or early effect of inhalant use. Chronic or delayed effects of inhalant use are not likely

to be recognized clinically as associated with inhalants, and

remote effects, by definition, require 10 to 30 years to be manifest. There exists no comprehensive data base emerging from the

careful, systematic investigation of inhalant users with regard to

their state of continuing health or disability. Much of the published literature on inhalant effects comes from inadvertant occupational exposure. While such exposure is assumed to be accidental, patients occasionally indicate the vapors inducing euphoria

55
are not actively avoided. Table 1 summarizes published reports

stating briefly the circumstances of exposure and the clinical

effects.*

n-Hexane

n-Hexane exposure by inhalation clearly is associated with polyneuropathy , which is predominantly motor. A latent period of 6

to 10 weeks is usually necessary but months to years may elapse

between initial exposure and clinical effects following lower levels

of exposure. The question of persistent cerebral dysfunction

following n-hexane polyneuropathy has not been addressed.

Injury to other organ systems has not been identified.

Toluene

Toluene (C6H5CH3; methylbenzene, toluol, phenylmethane) is a

substance preferred by many inhalant users. Commercial products containing toluene are sought after and used for long periods of’ time. Since commercial products containing toluene usually

contain a wide variety of other volatile organics, generalizations

from single case reports have precarious validity. In contrast

with n-hexane there is no single predominating target organ

system that shows a response to toluene. The diversity of responses associated with toluene suggests that other substances,

either alone or in combination, are the primary toxic agents.

Toluene users who do not develop significant injury are grossly

underrepresented in the literature. Selected case reports are

summarized in Table 1. Central and peripheral nervous system,

liver, and kidney injury have occurred in association with toluene

use.

Gasoline

Gasoline (petrol) vapor inhalation occurs primarily among younger

children or in isolated cultures where a very limited variety of

volatile substances is available. Various gasoline additives present special hazards. Triorthocresyl phosphate (TCP) is an

established cause of both upper and lower motor neuronal degeneration with spastic muscle wasting disorders. Benzene, a common ingredient, is an established cause of subacute and chronic

disorders of the hematopoietic system, including various combinations of cytopenia and delayed occurrence of leukemia. Organic

lead additives may cause acute and chronic lead encephalopathy.

The diversity of clinical effects reported in gasoline inhalers is

consistent with the effects of these various additives.

*Although the inhalants described in the following paragraphs and in Table 1 are listed by categories of major or identified constituent, the physiological effects may not be associated

solely with this agent or may be due to an action of this and

other agents present in the commercial mixture.

56
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTEO CASES FROM THE LITERATURE*

Neurologic CNS Effects

Chemical Compound/Product Clinical Effects

NHEXANE PRODUCTS

Yamamura, 1969:

Author presents a study

checking 1,667 workers in

Japanese industries with

exposure to n-hexane

Herskowitz et al., 1971:

A report of 3 cabinet workers

who developed neuropathy

while exposed to n-hexane

Gonzalez and Downey, 1972:

Case history of 20-year-old

male with 15-month history

of glue sniffing (80% n-hexane)

who presented with progressive

polyneuropathy. Improvement

occurred after 2-6 months of

admission

Goto et al., 1974:

Report of 4 cases primarily

motor polyneuropathy caused

by inhalation of an adhesive

agent. Weakness and sensory

impairment developed in 7-30

months with symptom

progression noted after

cessation of activity. Glue

also contained toluene

Shirabe et al., 1974:

Report of 2 patients involved

in glue sniffing: one for a

3-year period, one for 2 years

plus. Glue first used contained

small amounts of n-hexane (0-30%

n-hexane. 70-100% toluene)

Quadriplegia,

muscle weakness,

dysesthesia, muscle

atrophy, hypesthesia

Muscle weakness, Neuropathy, increased

hypesthesia, number of neurofilaments,

areflexia axonal degeneration

Muscle weakness,

hypesthesia,

paresthesia,

muscle atrophy

Muscle weakness,

muscular atrophy,

flaccid quadriplegia,

hypesthesia,

areflexia, foot and

wrist drop

Paresthesia, flaccid

paralysis of extremities, muscular

atrophy, hypesthesia

Diagnostic/Pathologic

Findings Other Effects

Polyneuropathy.

axonal degeneration

Polyneuropathy,

neurogenic atrophy

Polyneuropathy, axonal

degeneration, neurogenic

atrophy. decreased nerve

conduction rates

Polyneuropathy,

axonal degeneration,

denervation atrophy

*Although the inhalants described in Table 1 are listed by categories of major or Identified constituent, the

physilogical effects may not be associated solely with this agent or may be due to an action of this and other

agents present in the commercial mixture.

57
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTEO CASES FROM THE LITERATURE (con.)

Neurologic- CNS Effects

Chemical Compound/Product Clinical Effects

Diagnostic/Pathologic

Findings Other Effects

N-HEXANE PRODUCTS (con.)

Korobkin et al., 1975:

Case report of 29-year-old

male with 5-year history of

contact cement inhalation.

Several months prior to

symptom onset, patient

changed to brand containing

n-hexane. Improvement followed

avoidance of n-hexane exposure

Paulson and Waylonis. 1976:

Authors review situation in

a small plant using n-hexane

in which at least 8 of 50

employees (in 25-year period)

developed mild neuropathy.

Four patient summaries are

presented.

Towfighi et al., 1976:

Report of 2 cases exhibiting

chronic glue sniffing behavior.

Both patients initially used

glues containing no n-hexane

(pt. 1, 5 yr. hx., pt. 2, 10 yr. hx.)

and experienced good health.

Both changed to brand containing n-hexane with onset

of symptoms appearing in

1-2 months.

TOLUENE PRODUCTS

Grabski, 1961:

Author presents case of

irreversible cerebellar

degeneration following

continuous pattern of

toluene sniffing lasting

several years.

Muscle weakness,

paresthesia, muscle

atrophy of distal

extremities

Muscle weakness,

hyporeflexia

Paresthesia, muscle

weakness, atrophy

of distal extremities,

arefiexia

Peripheral neuropathy,

axonal abnormalities,

decreased nerve

conduction rates

Polyneuropathy

Neuropathy,

neurogenic-atrophy,

axonal swelling,

decreased nerve

conduction rate

Ataxia, intention

tremor posterior

column signs

adiadochokinesis

Cerebellar

degeneration

Hepatomegaly

58
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Neurologic - CNS Effects

Chemical Compound/Product Clinical Effects

Diagnostic/Pathologic

Findings Other Effects

TOLUENE PRODUCTS (con.)

Massangale et al., 1963:

Summary of 27 children

chronically habituated to

inhalation of cement vapors.

Toluene was major component

of glue used. Two detailed case

histories are presented.

Satean and Dodson, 1963:

Summary of patient presenting

with 10-year history of toluene

inhalation who presented because

of loss of consciousness. No

systemic abnormalities were

found.

Knox and Nelson, 1966:

This paper discusses the report

and conclusion of Grabski,

1961.

O’Brien et al., 1971:

Case history of 18-year-old

male with 6-year history of

glue sniffing. Presentation

followed 6-hour sniffing of

a liquid cleaner.

Taher et al., 1974:

Two case histories are

presented, one patient with

a 3-year history of glue

sniffing, with a 1-year history

of toluene sniffing, other

patient with 5-6 day history

of sniffing paint (60.4%

toluene)

Microscopic

hematuria

Ataxia, nystagmus

tremor, diffuse EEG,

Babinski’s reflex

Permanent encephalopathy, corticobulbar

damage, diffuse cerebral

atrophy, corticospinal

damage

Muscle weakness,

flaccid quadriplegia,

areflexia

Jaundice, hepatocellular damage;

anuria. hematuria,

proteinuria

Renal tubular

acidosis

59
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Neurologic - CNS Effects

Chemical Compound/Product

TOLUENE PRODUCTS (con.)

Kelly, 1975:

Presentation of case history

of 19-year-old female with

1-year history of paint

sniffing. Toluene was common

in all brands she sniffed.

GLUE SNIFFING GENERAL

Clinical Effects

Intention tremors,

impossible tandem

gait, ataxia

Diagnostic/Pathologic

Findings

Cerebellardysfunction

Other Effects

Glaser and Massengale, 1962:

An overview of glue sniffing

among children. The authors

note that in a 2-year period

in Denver, 130 (average age

13) were arrested for glue

sniffing. Six detailed case

histories are presented.

Merry Zachariadis, 1962:

Case history of 20-year-old

man presenting with an 18-

month history of glue sniffing. Presentation was

precipitated by the inhalation of 6 tubes of cement

glue which resulted in a

semi-comatose state.

Powars, 1965:

Paper describes 5 adolescents (all with sickle cell

disease) who developed

hematologic disorders

associated with glue

sniffing.

GASOLINE PRODUCTS

Easson, 1962:

Two cases of gasoline inhalation in children (ages 11 and

14) are presented in which a

degree of physical tolerance

is indicated.

Tetany

Wallerian degeneration,

neuronal death

“Borderline EEG”

Septicemia;

Apiastic anemia,

reticulocytopenia,

hypoplasia.

pancytopenia

60
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Chemical Compound/Product

Neurologic - CNS Effects

Diagnostic/Pathologic

Clinical Effects Findings Other Effects

GASOLINE PRODUCTS (con)

Tolan and Lingl, 1964:

Two cases of adolescents

with history of gasoline

inhalation are presented.

Karani, 1966:

A case report of a 20-year-old

mechanic with a 3-year history

of gasoline consumption and

inhalation. Author attributes

diagnosis to Triorthocresyl

phosphate component of

gasoline.

Law and Nelson, 1968:

Report of a 41-year-old

female presenting with

8-month history of leaded

gasoline sniffing (3-4 hr/day)

exhibiting a chronic psychosis.

Carroll and Abel, 1973:

Case report of chronic

gasoline inhalation (6 years)

in a 14.year-old male.

AEROSOL PRODUCTS

Bass, 1970:

The author discusses the

incidence of sudden sniffing

deaths (without plastic bag

suffocation) in the 1960’s.

Details of 5 case histories

are presented. In 4 of the 5

cases autopsies were performed which showed no

anatomical cause of death.

Death occurred after sniffing

followed by some stressful

situation, i.e., exercise.

“Model psychosis”

Muscle weakness,

moderate-severe

areflexia, bilateral

foot drop, bilateral

claw deformity,

muscle atrophy,

paresthesia

Ataxia, tremor,

psychotic behavior,

recent memory

impairment

Choreiform movements, diffuse EEG

delerium

Peripheral neuritis,

neurogenic muscular

atrophy

Lead

encephalopathy

Diffuse Mild liver

encephalopathy congestion

Anemia

61
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Neurologic - CNS Effects

Chemical Compound/Product Clinical Effects

Diagnostic/Pathologic

Findings 0ther Effects

AEROSOL PRODUCTS (con.)

Traffert, 1974:

The author discusses sudden

sniffing death problem and

the mechanism of death.

Wenzl et al., 1974:

Discussion of 4 teenagers

who sniffed PAM.

Kamm, 1975:

Report of a 18-year-old

male who inhaled Arid

Extra Dry deodorant.

Death followed immediately after inhalation.

Poklis, 1975:

Report of case history of

adolescent death due to

aerosol propellant

inhalation.

Standefer, 1975:

Case history of 13-year-old

male who died following

inhalation of fluorocarbons

F11 and F12 in cooking spray.

Wilde, 1975:

Discussion of inhalation of

spray paints with particular

reference to those which

contain metals, i.e., zinc

and copper.

Carlton, 1976:

Discussion of 12 cases of

death due to fluorocarbon

inhalation from 1971-1975

Postmortems am nonspecific,

excitation precedes death.

Cerebral edema

Stepping gait

Anesthetic

Hypercapnia; sever

cardiac arrhythmia,

ventricular fibrillation

Acute renal tubular

necrosis, proteinuria, uremia;

azotemia

Pulmonary edema,

mild to moderate

pulmonary vascular

congestion; ventricular fibrillation

Pulmonary and

laryngeal edema

at autopsy

Lung congestion;

cardiac arrhythmia

Systemic absorption of metal:

62
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Neurologic - CNS Effects

Diagnostic/Pathologic

Chemical Compound/Product Clinical Effects Findings Other Effects

AEROSOL PRODUCTS Icon.)

Crawford, 1976:

Report of the death of en

adolescent following

inhalation of fluorocarbons.

LACQUER THINNER

Prockop et al., 1974:

Seven cases of severe peripheral neuropathy are reported

as seen in 7 males (ages 17-22

years) with history of chronic

inhalation of lacquer thinner.

Syndrome progression was

predominately motor.

Oh and Kim, 1976:

Summary of findings in case

of 20-year-old male with 2-

year history of “huffing”

lacquer thinner.

LIGHTER FLUID

Ackerly and Gibson, 1984:

Summary of 12 cases of

lighter fluid inhalation among

children in the San Antonio,

Texas, area. Duration of

involvement ranged from

limited to continuously for

3 years.

CHLOROFORM

Storms, 1973:

Case report of a 10-year-old

male who participated in a

“chloroform party” in which

large amounts of chloroform

were inhaled.

Cardiac

arrhythmia

Muscle weakness, “Huffer's" neuropathy.

hypalgesia, hypesthesia, neurogenic muscular

decreased nerve con- atrophy, corticobulbar

duction, acute denerva- neuropathy

tion paralysis,

paresthesia

Respiratory

distress,

diminished

vital capacity

Muscle weakness, Peripheral neuropathy,

hyperesthesia, moder- giant axonal swelling

ate areflexia, decreased

nerve conduction

Minimal EEG Convulsive

abnormality disorder

Coma Severe

hepatic

damage

63
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con)

Neurologic - CNS Effects

Chemical Compound/Product Clinical Effects

Diagnostic/Pathologic

Findings Other Effects

TRICHLOROETHYLENE

Mitchell and Parson-Smith, 1969:

Case description of 33-year-old

male who worked as a metal

degreaser in which ha lowered

a basket containing metal into

warm trichloroethylene.

Seage and Burns, 1971:

Loss of taste,

vertigo, analgesia

in all divisions of

RT. Trigeminal

nerve

Neuropathy

Report of male with history

of cardiac disease who drank

alcohol following inhalation

of trichloroethylene.

Hayden et al., 1976:

The authors cite three

sources of inhalation of

cleaning fluids which

contain trichloroethylene.

Vertigo, trigeminal

analgesic, decreased

visual field.

Neuropathy

TRICHLOROETHANE

Travers, 1974:

Case report of an 16-year-old

male seaman who collapsed on

ship; 24 hr later death occurred.

Evidence in his bunk indicated

he had been sniffing the

substance.

Cerebral edema

Guberan et al., 1976:

Case report of a 20-year-old

mechanic who inhaled trichloroethane in en episode

which led to his death.

Autopsy showed no

anatomical cause of death.

Pulmonary

edema

Jaundice, centrilobular necrosis,

hepatomegaly;

anuria, hematuria,

oliguria, proteinuria (tubular

necrosis)

Hematuria;

ventricular fibrillation, tachycardia,

cardiac arrest

Ventricular

fibrillation

64
TABLE 1

SUMMARY OF CLINICAL SYNDROMES OF SELECTED CASES FROM THE LITERATURE (con.)

Neurologic - CNS Effects

Chemical Compound/Product Clinical Effects

Diagnostic/Pathologic

Findings Other Effects

BENZENE

Vigliani and Saita, 1964:

A review of the history of

benzene exposure resulting in

leukemia. Plus 6 case reports

from personal observation in

which all worked with benzene.

Forni and Moreo, 1967:

Case report of a 38-year-old

female who worked for 22

years as a cable cleaner using

solvents containing benzene.

Winek and Collom, 1971:

Case report of 16-year-old

male who died following

inhalation of reagent grade

benzene. Boy’s head was

found inside a plastic bag.

Aksoy et al., 1972:

Four case histories are reported

in which shoemakers using

benzene-containing adhesives

developed acute leukemia.

Aksoy et al., 1974:

Two case reports of leukemia

following exposure to benzene

are discussed with particular

reference to the familial

factors in this case.

Hayden et al., 1976:

The authors enumerate Erythroleukemia,

several sources of pancytopenia,

principally industrial thrombocytopenia,

exposure resulting myeloid

in hematologic metoplasia.

damage. apiastic anemia

Epistaxis, hemocytoblastic

leukemia;

mucosanguineous

diarrhea

Hyporegenenerative

anemia, leukemia

Cerebral edema

Pancytopenia;

apiastic anemia,

acute myeloblastic

leukemia, thrombocythemia

Acute lymphoblastic leukemia,

acute myeloblastic

leukemia

65
Aerosols

Abuse of freon-pressurized aerosol products is common. (Not all

aerosols contain freons and many contain solvents other than

freon.) The great variety of clinical manifestations attributed to

these products is not surprising because of the diversity of

contents. The consistently recognized syndrome is sudden death

associated with vigorous exertion immediately after inhaling freon.

Myocardial sensitization to endogenous epinephrine with ventricular fibrillation is one accepted mechanism. A number of case

reports and reviews of freon use appear in the current literature

(Carlton, 1976; Crawford, 1976; Kamm, 1975; Poklis , 1975;

Standefer, 1975; Treffert, 1974; Wenzl et al, 19’74; Wilde, 1975).

Chlorinated Hydrocarbons

Among the chlorinated hydrocarbon solvents there is a potential

for injury of various organ systems especially neuropathy and

liver and kidney injury. These substances also sensitize the

myocardium to epinephrine-induced dysrhythmia.

SURVEY OF MEDICAL EFFECTS OF INHALANT ABUSE

During the 2 years of existence of the Houston Polydrug Abuse

Research and Treatment Program, 22 patients among 241 admissions were identified as having sustained intense and long-term

exposure to inhalants. Among these 22 patients, 8 patients were

identified as primarily inhalant users with minimal and sporadic

involvement with other drugs. The patients were admitted primarily for drug abuse sufficient to be significantly disruptive of

their life style and not selected on medical criteria. This population provides an opportunity to assess the health status of heavy

and long-term inhalant users.

All patients in this data base had been using inhalants up to and

including the day prior to admission. Seven of the eight patients

presented with an acute organic brain syndrome as the predominant finding on the day of admission. Several days were required for the acute organic brain syndrome to clear, and it is

assumed that this represents the time required to clear accumulated residual lipophilic vapors from fat depots in the body.*

Completion of any examination dependent on subjective data was

difficult during the initial 2 to 3 days of admission because of the

confusion, disorientation, and general lethargy manifested by the

patients. Neurologic examinations during the initial stages of

admission also are unreliable, particularly with regard to ataxia

and dysmetria, characteristic findings in acute organic brain

syndrome which clear after several days of inhalant-free living.

*Editor’s note: Further work needs to be done to assess

whether the amount persisting in tissues can cause these symptoms or whether this is a metabolic: process of regeneration or reorganization.

66
CASE ABSTRACTS

Patient #9238

The patient is an 18-year-old white male who presently

is on probation. Drug history includes marihuana three

to four times a week, methaqualone once a week for one

month and spray paint inhalation for more than 5 years

with use occasionally as much as 12 hours per day.

The patient dropped out of school after the tenth grade

and presently is living with his family. He had been

employed intermittently. Psychiatric diagnosis: Acute

organic brain syndrome. The patient was released to

his parents against medical advice after 5 days in the

inpatient treatment program. Past history reveals a

suicide attempt with drugs.

Patient #9258

The patient is a 23-year-old white female with a 10-year

history of drug abuse who considers herself to be

physically dependent on Plasticoat aerosol spray. Over

the past 2 years she has used Plasticoat, plastic enamels , and toluene from paint thinner. She estimates

daily use up to 5 hours. The patient completed the

twelfth grade. She has made two suicide attempts with

drugs. The patient is married but separated from her

husband whose location is unknown. The patient’s

parents are divorced and the patient has lived in at

least five households since the divorce. Both parents

are alcoholics. The patient has had approximately 30

arrests with charges currently pending for assaulting a

police officer. In 1969 she was hospitalized for 5-1/2

months at the Austin State Hospital. Admission diagnosis: Acute organic brain syndrome. The patient was

discharged after 16 days on an inpatient program. Her

typical pattern of abuse was to inhale the toluene-based

acrylic spray paint for up to 5 hours a day. She

managed to remain almost continuously intoxicated

during this period by saturating a cloth with the spray

paint, placing the cloth in her mouth, and inhaling the

vapors through her mouth. Routine physical examination revealed no neurological deficit in either motor

sensdry function; however, the patient complained of

continual muscle pain and loss of sensation distally in

her extremities. With the exception of a slightly elevated alkaline phosphatase, her laboratory values were

all within normal limits. A routine toxicology screen

failed to detect the presence of any common ‘drugs of

abuse in her blood or urine. Electromyography and

nerve conduction tests failed to indicate evidence of

67
either peripheral neuropathy or myoneural transmission

defects; however, borderline myopathic changes consistent with a low-grade myopathy were observed. A

deltoid muscle biopsy was performed and microscopic

examination of the muscle specimen indicated the presence of minor pathological changes including isolated

rare atrophic skeletal muscle cells with increased sarcolemma cell activity. In general, however, there was no

evidence of gross changes that would account for the

patient’s symptomatology.

Patient #9279

The patient is a 15-year-old Mexican-American male who

has used clear plastic acrylic sprays, Texas Shoeshine,

and other aerosols three times a week for approximately

1 year. The patient completed the ninth grade and is

not in school presently. There were several suspensions for fighting and he has been arrested more than

ten times having spent 7 months in Gatesville Prison for

automobile theft. The patient’s father is an alcoholic

who is frequently drunk and belligerent. The patient

has never been employed. Psychiatric diagnosis:

Acute organic brain syndrome. The patient remained 13

days in the inpatient treatment program.

Patient #9281

The patient is a 21-year-old white male who has been

using inhalants for 4 years and now considers himself

to be psychologically dependent. Substances used

include Texas Shoeshine, clear acrylic spray, and

toluene The patient completed the twelfth grade and

currently is on probation by both the county and the

state. There have been six arrests with a total of 67

days in Harris County jail. The patient entered the

program as an alternative to incarceration. Family

background reveals parents divorced and the parents

state that they have "given up on him." The patient

has had four jobs with 4 months being the longest at

any one job. He states his present occupation is "getting high." There have been two previous psychiatric

admissions with a tentative diagnosis of paranoid schizophrenia. Psychiatric diagnosis: Acute organic brain

syndrome. Duration of hospital stay was 17 days.

Patient #9285

The patient is a 13-year-old Mexican-American male who

has been using gold spray paint and Texas Shoeshine

every other day for approximately 4 months. The

patient was abandoned at birth and reared in foster

68
homes. Presently he is in the seventh grade and has

been suspended from school for disciplinary problems

and truancy. There have been two drug-related arrests. Psychiatric diagnosis: Adolescent adjustment

reaction and depression neurosis. The patient remained

in the inpatient treatment program for 22 days.

Patient #9289

The patient is a 2l-year-old Mexican-American male with

a history of using glue, paint thinner, and Texas

Shoeshine over the past 11 years, three or more times

daily. The patient states that he is dependent upon

these substances. The patient completed the seventh

grade of school and was suspended and has not. returned to school. Presently he is unemployed but has

been employed intermittently over the past 4 years.

The patient has had nine juvenile arrests and four

adult arrests with no charges pending currently.

Parents are separated. Psychiatric diagnosis: Acute

organic brain syndrome with mild retardation. The

patient remained in the treatment program for 16 days.

Patient #9308

The patient is a 16-year-old white male who has been

using paint thinner and clear acrylic plastic sprays on

a daily basis for 2 years. The patient completed the

ninth grade and was suspended for poor attendance,

inattentiveness, and truancy. The patient has held one

job for 14 months and has no arrest record. Both

natural parents are dead. Presently being reared by a

stepmother and maternal grandparents. Psychiatric

diagnosis: Organic brain syndrome. Patient remained

in the program 14 days.

Patient #9312

The patient is a 17-year-old white male who has been

using clear acrylic paints several times a week for 3

years. The patient completed the eleventh grade and

dropped out of school. He has been arrested twice for

driving while under the influence of drugs and currently has charges pending for the possession of marihuana. The patient has been in jail on three different

occasions. Both parents are alive. Mother is an alcoholic who has had psychiatric hospitalization twice.

Father is an epileptic with asthma. Psychiatric diagnosis: Acute organic brain syndrome. Patient remained

in the treatment program 14 days.

69
DATA SUMMARY

Table 2 summarizes the history of inhalant use for these patients.

Table 3 presents positive responses to questions in the review of

systems for six of these primary inhalant-using patients. (Case

#9238 was excluded becausce of other drug involvement; data for

case #9279 are missing.) Their responses are compared with

those of 95 non-inhalant polydrug abuse patients admitted to the

Houston Polydrug Abuse Research and Treatment Program.

Serum chemistries included: total protein, albumen, calcium,

cholesterol, glucose, blood urea nitrogen, uric acid, creatinine,

total bilirubin, alkaline, phosphatase, lactic dehydrogenase, glutamic-oxaloacetic transaminase, and glutamic-pyruvic transaminase.

These were found to be within normal limits, Other admission

evaluation included physical examination, EKG, chest X-ray,

complete blood count, and urinalysis. None of these procedures

yielded clinically significant findings.

DISCUSSION

The clinical assessment of the eight inhalant-abusing patients on

whom data are presented was not designed prospectively specifically for evaluation of inhalant users, but was the routine clinical

assessment performed on all Polydrug patients. The data illustrate that no abnormalities of clinical significance were detected

by the approaches used for medical assessment. The only exception is the acute organic brain syndrome which was manifest

characteristically by a vast majority of inhalant-using patients on

their admission to the unit. This was manifest by varying

degrees of ataxia, lethargy, irritability, confusion, and in some

cases disorientation and impaired short-term memory. The acute

organic brain syndrome characteristically disappeared in a time

frame consistent with the metabolism and/or excretion of accumulated lipid soluble psychoactive volatiles.

These data are remarkable for the absence of abnormalities. In

this population selected for heavy and prolonged inhalant use,

there was no evidence of neuropathies, liver injury, kidney

injury, anatomical lung changes, or hematopoietic abnormalities.

The opinion that frequent and prolonged inhalant use does not

commonly result in significant tissue injury is supported by this

investigation. These data do not address the issue of more

subtle abnormalities detectable by neuropsychological testing and

their etiology. Neither do they address the problem of delayed

increase in incidence of neoplastic disease requiring 10 to 30 years

to be manifest. They also comprise a small sample and may not

be very representative of the inhalant pollulation.

MEDICAL EVALUATION OF INHALANT USERS

Medical evaluation of inhalant users may have to be performed in

several stages or repeated several days after the patients have

70
TABLE 2

INHALANT USE HISTORY OF SELECTED CASES*

Case No.

Age, Ethnicity

and Sex Substance Duration Frequency

9238 18 WM Spray paint >5 yr Daily up to 12 hr

9258 23 WF Acrylic spray

Enamel spray

Toluene

2 yr Daily X3 up to 5 hr

9279 15 M-AM Acrylic spray

Texas Shoe Shine

1 yr Weekly X3

9291 21 WM Acrylic spray

Lacquer

Toluene

4yr Daily X3

9285 13 M-AM Gold spray paint

Texas Shoe Shine

4 mo Weekly X 3-4

9289 21 M-AM Glue

Paint thinner

Texas Shoe Shine

11 yr Daily X3+

9308 16WM Acrylic spray

Paint thinner

2 yr Daily

9312 17 WM Acrylic spray 3 yr Weekly

*Age, ethnicity, sex, substances used, duration of use, and frequency of use for eight patients (selected from

241 polydrug admissions) for primary solvent abuse without significant simultaneous abuse of other substances.

WF = White female.

WM = White female.

M-AM = Mexican-American male.

71
TABLE 3

REVIEW OF SYSTEMS OF SELECTED CASES*

95 Drug abuse

No. % admissions,

9258 9281 9285 9289 9308 9312 Positive Positive % positive

Ear disease

Nose, sinus, throat

Fainting spells

Loss consciousness

Convulsions

Paralysis

Dizziness

Frequent severe headaches

Depression, anxiety

Difficulty concentrating

Memory problems

Enlarged glands

Skin disease

Chronic or frequent cough

Chest pain or angina

Cough blood

Night sweats

Shortness of breath

Palpitations, heart fluttering

Swelling hands or feet

Back, arm, or leg problems

Varicose veins

Extreme tiredness or weakness

Kidney disease

Bladder disease

Urine albumin, sugar

Urine pus or blood

Difficulty urinating

Abnormal thirst

Stomach trouble, ulcer

Indigestion

Appendicitis

Liver-gall bladder disease

Colitis or bowel disease

Hemorrhoids-rectal bleeding

Constipation or diarrhea

2 33

1 16

4 66

3 50

2 33

2 33

2

1

2

4 66

3 50

3 50

1 16

2 33

50

33

16

33

20

49

27

32

17

5

63

66

76

46

69

16

10

29

29

20

37

55

28

27

23

8

57

22

4

2

4

19

27

38

42

15

5

7

18

42

*Review of systems on six primary solvent abuse patients showing number and percent of positive responses;

percent of positive responses on 95 drug abuse patients not primarily solvent users (Case 9238 was excluded

because of other drug involvement; data for case 9279 are missing).

72
been free of inhalant use. This is necessary in order to differentiate effects due to the influence of volatile substances in the

body in contrast with residual effects present after the substances have been cleared from the body. Aspects of the examination which require responsiveness from the patient or subjective

assessment may vary substantially from the first day of admission

to a drug-free program as compared with similar assessment after

3 to 4 days.

Clinical Assessment

Chief Complaints

The chief complaint should review in brief form the principle

immediate health concerns of the patient along with a statement of

the duration of each health concern. For example, a usual complaint would be headache. A brief simple statement should indicate the location, the quality, the frequency, and duration of

headaches experienced by the patient. Other chief complaints

may be dizziness, loss of memory, inability to think, cough, easy

bruising or easy bleeding, abdominal pains, menstrual disorders,

urinary pain, muscle cramps, weakness in extremities, numbness

or tingling in the extremities, or spotty paralysis. These are

examples of typical chief complaints and not an exhaustive enumeration. Each statement of a chief complaint should give the location , the duration, the frequency, and the quality of the health

concern involved.

A patient experiencing an acute organic brain syndrome secondary

to the immediate effects of inhaled substances may not have a

chief complaint upon his admission to a treating program. Several

days may be required before the confusion clears.

Present Illness

The present illness consists of a careful, detailed chronological

development of circumstances leading to the illness enumerated in

the present illness. In the case of inhalant users, the present

illness should include a statement as to first involvement with

inhalants, the types of inhalants used and the manner in which

they were used; for example, head in a plastic bag, inhaled

through a saturated cloth, inhalation from a rigid container. A

description of the present illness may well be developed from

exploring with the patient the most recent time that he felt himself to be normal or well. The time of onset of all symptoms

should be recorded and the chronological development of symptoms

explored. The present illness should include detailed description

of therapeutic intervention undertaken during the course of the

present illness. This should include doctors or other health care

persons visited and nature of therapy undertaken, particularly

the use of prescription drugs. Attempts at self-treatment should

be explored and enumerated, especially with reference to use of

73
over-the-counter drugs or use of other home remedies. The

present illness should consist of the patient’s description of the

chronological development of his current clinical status. Examiner

should avoid extensive probing in a manner such as to be suggestive of manifestations which the observer injects into the

patient’s account of his illness. When a patient complains of such

symptoms as chills, fever, headache, gastrointestinal disturbances, cough, regional pain, or any other general or local symptoms, then these should be documented with respect to their time

of first onset and changes in the quality and duration of these

symptoms as the present illness has progressed. The relationship

of any complaint to the pattern of use of inhalants should be

documented since the use of inhalants is intermittent and cyclic.

Some disabilities may occur only while under the influence of

volatile substances while others persist through the non-use

period.

Review of Systems

In order to determine the presence or absence of specific significant manifestations, a review of systems as detailed in any standard text on internal medicine should be documented.

Past Medical History

Inquiry into past medical history should include documentation of

physician visits wherever possible, with identification of the name

and address of the physician to facilitate obtaining past records.

Any hospitalization should be identified as to date, duration,

principle reason for admission, and name of the attending physicians so as to facilitate obtaining hospital records. Consent forms

for obtaining past medical records should be signed by the

patient at this time. Inquiry should be made as to childhood

diseases, acute or chronic infections with description as to

nature, duration, treatment, and complications. Any injuries

sustained should be documented, described, and resulting disabilities enumerated.

Employment History

Any jobs held by the patient should be documented as to time the

job began, duration of employment, nature of work with special

regard to potential for exposure to occupationally related toxic

substances, especially solvents and metals. Reasons for discontinuing each job should be documented.

Personal and Social History

A complete social and personal history should be documented.

74
General

At this point in the clinical assessment, there is a 70 to 80 percent chance of identifying probable areas of disability associated

with inhalant use. The remainder of’ the examination should be

guided by the findings evoked in the preceding assessment. The

remainder of the examination is predominantly confirmatory although an additional 20 percent of existing disability may remain

to be discovered by subsequent procedures.

Physical Examination

Physical examination must be performed by meticulous, consistent

adherence to predetermined protocol. The general physical examination may lead to areas of special concern requiring more elaborate diagnostic procedures to investigate variation from normal.

Physical examinations must be performed in a compassionate and

considerate manner; a cursory lo-minute physical examination is

totally unsatisfactory. Although reasonable consideration of the

patient’s modesty must be observed, a complete physical examination cannot be performed on a partially clothed patient. The

physical examination should be quantitative not qualitative; for

example, descent of the liver edge below the costal margin should

be stated in centimeters not finger breadths. Identified masses

should be measured rather than described in qualitative terms.

Pupillary size should be measured in millimeters. Data recovered

from physical examination should be objective and stated without

interpretation. For example, the identification of the left upper

quadrant mass should be indicated as to size, consistency, mobility, and not necessarily construed as splenomegaly, since it may

well be another abnormal intra-abdominal mass. Assessment of

liver size must not be performed exclusively on the basis of

palpation of the liver edge below the costal margin since a patient

with chronic emphysema may have enlarged chest capacity, depressed diaphragm, and abnormal liver position rather than an

actually increased liver size. The physical examination, however,

must not be rigid to the extent of exclusion of diversion for more

comprehensive assessment of particular findings. The alert

physician will pursue, in depth, abnormalities presented in the

routine physical examination. For example, discovery of a dusky

or bluish discoloration of the skin and nails may lead to a false

assumption of representing hypoxemia secondary to lung pathology, whereas in fact the discoloration may be secondary to methemoglobinemia induced by inhalation of aromatic substances in

patients with a glucose-6-phosphate dehydrogenase deficiency

which impairs ability to correct methemoglobinemia. The discovery

of an abnormal heart sound should lead to examination at rest,

after exercise, and in varying positions in order to complete its

assessment.

Before the performance of hands-on examinations, basic data on

the patient should be obtained by observation of his activity.

75
The patient is asked to stand, to walk toward and away from the

observer and to sit on the edge of the examining table. This

permits recognition of characteristic abnormalities in body posture, gait, associated movement, ataxia, gross defects in motor

neurologic control, gross limitations of motion as well as assessment of the patient’s mood and cooperativeness,. and assists in

development of initial rapport with the physician. A hasty,

inconsiderate attitude on the part of the physician will lead to an

irritable, uncooperative patient preventing the performance of an

effective, maximally informative physical examination.

Neurological examination. The neurological examination of the

inhalant-abusing patient is probably the most difficult part of the

physical examination. If performed in a cursory manner, many

abnormalities will be missed. Because of the frequency with

which subtle neurological abnormalities are associated with the

commonly inhaled substances, neurologic assessment must be

comprehensive. Suitable outlines for further neurologic examination occur in most text books of neurology. The neurologic

assessment of these patients is addressed in the following chapter

of this volume.

Genetic defects. Certain preexisting genetic defects are known to

influence to toxic substances, many of which appear

among the volatiles to which inhalant abusers are exposed. The

best example is the occurrence of a glucose-6-phosphate dehydrogenase deficiency, especially common among the non-Caucasian

races. The presence of this deficiency increases the sensitivity

to lead poisoning, increases sensitivity to intravascular hemolysis

induced by aromatic solvents in drugs and increases sensitivity to

methemoglobinemia induced by a number of toxic substances.

Other genetic abnormalities influencing response to toxic substances include the hemoglobinopathies. Presence of sickle cell

and thalassemia hemoglobin may significantly influence response to

commonly inhaled vapors (Powars, 1965) The area of genetic

predisposition to toxicologic injury is still in an investigational

stage and future research is sure to yield additional examples.

Extended clinical examinations. ‘The medical workup of inhalant

abusing patients should include chest X-ray. EKG. EEG, and

EMG. A screening electromyographic assessment, particularly in

the lower extremities. should be an essential component of all

clinical assessment of inhalant-abusing patients. It is equally as

important to document normal nerve conduction and normal EMG as

it is to document an abnormal result. Data are not sufficient at

this time to permit a logical decision upon which to base the need

for electromyographic assessment. If in the course of physical

examination obvious abnormalities in motor function, deep tendon

reflexes, or peripheral sensory perception are identified, there is

no doubt that an EMG should follow. However, accumulated

clinical experience is not yet sufficient to determine whether

electromyographic abnormalities might be present in the absence

of clinical detectable abnormalities.

76
Laboratory examinations. Clinical laboratory examination of the

inhalant-abusing patient should include a CBC, serum iron, iron

binding capacity, and a bone marrow in the event peripheral

hematologic abnormalities are identified A routine urinalysis is

required and this examination should include a careful microscopic

assessment of sediment performed within a few hours of collection

in order to assure reliable identification of formed elements in

the sediment. Serum chemistry should include the usual SMA 12

battery on serum collected while the patient is in the fasting

state, and minimally should include a total protein, albumin,

cholesterol, glucose, blood urea nitrogen (BUN), uric acid,

creatinine, bilirubin, alkaline phosphatase, lactic dehydrogenase

(LDH), glutamic-oxaloacetic transaminase (SGOT), glutamic

pyruvic transaminase (SGPT), and should be supplemented with

creatinine phosphokinase. A glucose-6-phosphate dehydrogenase

activity of red blood cells should be determined on non-Caucasian

patients minimally, Laboratory assessment also is valuable to

determine the chemical nature of the substances the patient has

been using. In order to achieve this, exhaled air, blood, or

urine is suitable for examination of particular substances. Almost

all commonly used inhalants can be identified by one or more of

these specimens if they are collected within 24 hours of the last

inhaling episode, In some instances volatiles may be identified as

long as a week or more after their last use.

CONCLUSIONS

The literature documents numerous episodes of individual and/or

sporadic outbreaks of significant injury associated with the abuse

of inhalant substances. Clinical assessment of chronic inhalant

users not presenting with primary medical complaints has revealed

remarkably little in the way of objectively documentable impairment. The overall health significance of inhalant abuse can be

assessed only by elaborate and detailed examination of a cross

section of long-term inhalant users. Only this type of research

will determine whether inhalant abuse constitutes a general hazard

to health as opposed to sporadic outbreaks of significant injury

secondary to an unusually toxic component in a particular product .

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Ackerly, W., and G. Gibson. Lighter fluid "sniffing." Psychiatry, 120:1056-61, 1964.

Aksoy, M., K. Dincol, S. Erdem, and G. Dincol. Acute leukemia

due to chronic exposure to benzene. Am J Med, 52:160-5, 1972.

Aksoy, M., S. Erdem, G. Erdogan, and G. Dincol. Acute leukaemia in two generations following chronic exposure to benzene.

Hum Hered, 2 4:70-4, 1974.

77
Bass, M. Sudden sniffing death. JAMA, 212:2075-9, June 1970.

Carlton, R. Fluorocarbon toxicity: Aerosol deaths and anaesthetic reactions. Ann Clin Lab Sci, 6:411-4, September-October

1976.

Carroll, H., and G. Abel. Chronic gasoline inhalation. South

Med J, 66:1429-30, 1973.

Crawford, W. Death due to fluorocarbon inhalation. South

Med J, 69:506-7, April 1976.

Easson, W. Gasoline addiction in children. Pediatrics, 29:250-4,

1962.

Forni, A., and L. Moreo. Cytogenetic studies in a case of benzene leukaemia. Eur J Cancer, 3:251-5, 1967.

Glaser, H., and O. Massengale. Glue sniffing in children.

JAMA, 181:300-3, 1962.

Gonzalez, E., and J. Downey Polyneuropathy in a glue-sniffer.

Arch Phys Med Rehabil, 53:333-7, 1972.

Goto, I., M. Matsumura, N. Inoue, Y. Murai, K. Shida, T.

Santa, and Y. Kuroiwa. Toxic polyneuropathy due to glue sniffing. J Neurol Neurosurg Psychiatry, 37:848-53, 1974.

Grabski, D. Toluene sniffing producing cerebellar degeneration.

Am J Psychiatry, 118:461-2, 1961.

Guberan, E., O. Fryo, and M. Robert. Sudden death from

ventricular fibrillation after voluntary inhalation of chlorothene in

a mechanics apprentice. Schweiz Med Wochenschr, 106:119-21,

January 1976.

Hayden, J., E. Comstock, and B. Comstock. The clinical toxicology of solvent abuse. Clinical Toxicology, 9:169-84, 1976.

Herskowitz, A., N. Ishii and H. Schaumburg. n-Hexane neuropathy. New Engl J Med, 285:82-5, 1971.

Kamm, R. Fatal arrhythmia following deodorant inhalation: Case

report. Forensic Sci, 5:91-3, 1975.

Karani, V. Peripheral neuritis after addiction to petrol. Br Med

J , 2:216, 1966.

Kelly, T. Prolonged cerebellar dysfunction associated with paintsniffing. Pediatrics, 56:605-6, 1975.

78
Knox, J., and J. Nelson. Permanent encephalopathy from toluene

inhalation. N Engl J Med, 275:1494-6, 1966.

Korobkin, R., A. Asbury, A. Sumner, and S. Nielsen. Gluesniffing neuropathy Arch Neurol, 32:158-62, 1975.

Kramer, N. Availability of volatile nitrites. JAMA, 237:1693,

1977. 

Law, W., and E. Nelson. Gasoline-sniffing by an adult. JAMA,

204:1002-4, 1968.

Massengale, O., H. Glaser, R. LeLievre, J. Dodds, and M.

Klock . Physical and psychologic factors in glue sniffing. N Engl

J Med, 269:1340-4, 1963.

Merry, J., and N. Zachariadis. Addiction to glue sniffing.

Br J Med, 2:1448, 1962.

Mitchell, A., and B. Parsons-Smith. Trichloroethylene neuropathy. Br Med J, 1:422-3, 1969.

O’Brien, E., W. Yeoman, and J. Hobby. Hepatorenal damage

from toluene in a “glue-sniffer.” Br Med J, 2:20-30, 1971.

Oh, S., and J. Kim. Giant axonal swelling in "buffer's" neuropathy. Arch Neural, 33:583-6, 1976.

Paulson, G. , and G. Waylonis. Polyneuropathy due to n-hexane.

Arch Intern Med, 136:880-2, 1976.

Poklis , A. Determination of fluorocarbon 11 and fluorocarbon 12 in

post mortem tissues: A case report. Forensic Sci, 5:53-9, 1975.

Powars, D. Aplastic anemia secondary to glue sniffing. N Engl

J Med, 273:700-2, 1965.

Prockop, L., M. Alt, and J. Tison. "Huffer's" neuropathy.

JAMA, 229:1083-4, 1974.

Satran, R. , and V. Dodson. Toluene habituation. N Engl J

Med, 268:719-21, 1963.

Seage, A., and M. Burns. Pulmonary oedema following exposure

to trichloroethylene. Med J Aust, 2:484-6, 1971.

Shirabe, T., T. Tsuda, A. Terao, and S. Araki. Toxic polyneuropathy due to glue-sniffing. J Neurol Sci, 21:101-13, 1974.

Standefer, J. Death associated with fluorocarbon inhalation.

Report of a case. J Forensic Sci, 20(3):548-51, July 1975.

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Storms, W. Chloroform parties. JAMA, 225:160, 1973.

Taher, S., R. Anderson, R. McCartney, M. Popovtzer, and R.

Schrier. Renal tubular acidosis associated with toluene "sniffing." N Engl J Med, 290:765-8, 1974.

Tolan, E., and F. Lingl. "Model psychosis" produced by inhalation of gasoline fumes. Am J Psychiatry, 120:757-61, 1964.

Towfighi, J., N. Gonatas, D. Pleasure, H. Cooper, and L.

McCree. Glue sniffer's neuropathy Neurology, 26:238-43, 1976.

Travers, H. Death from 1,1,1 trichloroethane abuse: Case report. Milit Med, 139:889-90, 1974.

Treffert, D. Spray-can roulette. Wis Med J, 73:525-7, 1974.

Vigliani, E., and G. Saita. Benzene and leukemia. N Engl J

Med, 271:872-6, 1964.

Wenzl, J., F. Jordan, J. Frazier, and C. Howard. Acute renal

tubular necrosis associated with drug abuse inhalation of a freon

propellant spray. Clin Res, 22:98A, 1974.

Wilde, C. Aerosol metallic paints: Deliberate inhalation. A

study of inhalation and/or ingestion of copper and zinc particles.

Int J Addict, 10:127-34, 1975.

Winek, C., and W. Collom. Benzene and toluene fatalities.

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80
Chapter 5

SPECIFIC NEUROLOGICAL EVALUATION OF

INHALANT ABUSERS: CLINICAL AND LABORATORY

Leon Prockop

INTRODUCTION

Volatile hydrocarbons are inhaled in the abuse situation in order

to produce an altered mental state, which may be an elevation of

mood (euphoria) or may be an escape from depression, anxiety,

or other unpleasant or distressing emotional states. In any case,

an alteration of cerebral or central nervous system (CNS) function is desired. In addition to the positive effect which the

abuser seeks, a variety of other effects may also occur. These

include: dizziness; malaise; tearing, conjunctival injection, diplopia, or other visual symptoms; altered hearing; rhinorrhea ,

altered smell, and other nasal symptoms; symptoms referable to

the oral mucosa and facial skin; gastrointestinal symptoms such as

nausea and vomiting; and cardiopulmonary symptoms such as

tachycardia and cough. In most instances these symptoms,

whether desirable or undesirable, are transient in nature. The

CNS effects, in particular, are usually a temporary alteration of

CNS function. However, as is the case with virtually all exogenous agents which alter general systems and/or CNS function

temporarily, permanent functional alteration may occur. This

leads to a pathophysiological or diseased state of CNS function.

In fact, death can be a direct result of solvent inhalation (Alha

et al., 1973; Press and Done, 1976). Although adverse effects to

other organ systems have been reported rarely, e.g., cardiac

arrhythmia (Reinhardt et al., 1971) and renal tubular acidosis

81
(Taher et al., 1974), permanent adverse effects to both the

central and peripheral nervous systems after inhalation of volatile

hydrocarbons is not uncommon. This occurs in both the abuse

situation (Shirabe et al., 1974; Korobkin et al., 1975; Prockop et

al., 1974; Grabski, 1961; Oh and Kim, 1976) and after “normal

use,” such as in the occupational setting (Billmaier et al., 1974;

Prockop, 1977; Mendell et al., 1974; Davenport et al., 1976).

Other sections of this monograph provide reference to a variety

of these toxic effects to the nervous system including “glue

sniffer’s neuropathy” (Shirabe et al. , 1974; Korobkin et al.,

1975)) “huffer’s neuropathy” (Prockop et al., 1974; Oh and Kim,

1976; Means et al., 1976), optic nerve damage (Prockop, 1977;

Benton et al. , 1953; Berg, 1971), cerebellar involvement (Grabski,

1961; Prockop, 1977), cranial nerve damage (Prockop, 1977; Feldman et al., 1970), and encephalopathy (Prockop, 1977; Knox and

Nelson, 1966). Furthermore, data derived from animal experiments involving inhalant exposure are beginning to accumulate

(Schaumberg and Spencer, 1976; Saida et al., 1976). They indicate that a CNS dysfunction, measured by a variety of parameters, can be documented. Some of these experimental data were

reported at the First International Symposium on the Voluntary

Inhalation of Industrial Solvents held in Mexico City, June, 1976.

NEUROLOGICAL EVALUATION

General Comments

Because inhalant abuse may lead to temporary and/or permanent

alteration of the function of both the central and peripheral

nervous systems, special attention must be paid to the neurological evaluation of inhalant abusers. In fact, proper neurological

evaluation may disclose more evidence of disease than the remainder of the medical evaluation.* The neurological dysfunction

suffered by the inhalant abuser may lead to further psychiatric

problems as well as medical, social, economic, and legal problems.

For example, an individual suffering from a peripheral neuropathy

secondary to inhalant abuse may become depressed because of the

physical disabilities and the inability to obtain employment because

of this disability. Therefore, further inhalant abuse as well as

other drug abuse may occur.

* A footnote is used here to emphasize a factor common in

the medical and/or psychiatric evaluation of inhalant abusers and

others in contact with potential toxins, whether drugs or otherwise. Organically caused neurological deficits such as ataxia and

weakness are often ascribed to sloppiness, laziness, or hysteria.

Signs of dementia or an organic mental syndrome are often

ascribed to a lack of cooperation or other psychological factors or

to psychomotor retardiation, i.e., a heredito-familial cause for

poor performance on mental status testing.

82
Neurological Physical Examination

The neurological evaluation form attached as an appendix to this

chapter is useful to document the neurological status of the

inhalant abuser. In some cases an initial evaluation should be

performed followed by serial evaluation over the course of time.

Futhermore, the dysfunction documented on this form may lead

the clinician to obtain laboratory and other diagnostic studies

which may further quantitate and delineate the dysfunction

suffered. It should be stated that this neurological evaluation

should follow the general medical evaluation as described in the

preceding section. The neurological history and examination

forms are self-explanatory. At their conclusion an assessment

and plan should be formulated by the clinician. The assessment

should consist of a summary of the history and the positive

neurological findings as well as a diagnostic formulation followed

by a treatment and/or management plan which would include any

further diagnostic tests indicated.

Diagnostic Assessment

In the diagnostic formulation, specific consideration must be given

to the disease categories of: peripheral neuropathy , cranial

nerve neuropathy, cerebellar degeneration, and cerebral degeneration or encephalopathy . Because these disease categories may

have etiologies other than that of inhalant abuse, specific consideration must be given to other pathophysiological mechanisms.

It is not possible to detail all of these sometimes rare diseases in

this section. The reader is referred to standard neurological

textbooks (Merritt, 1973; Gilroy and Meyer, 1975; Walton, 197’7).

Some common entities which might be seen in the inhalant abuser

and might be a causative or contributory factor to their neurological dysfunction, should be enumerated. When peripheral neuropathy is documented clinically, special consideration is given to the

possibility of diabetes mellitus and alcohol abuse with nutritional

deprivation as etiological factors. If an inhalant abuser is weak

without clearly demonstrable signs of peripheral neuropathy,

consideration must be given to primary muscle disease or disease

of the myoneural junction. Therefore. consideration must be

given to polymyositis, myasthenia gravis, muscular dystrophy,

and periodic paralysis. Special laboratory tests may be required

to evaluate these possibilities (e.g., a Tensilon Test). When a

cerebellar dysfunction is documented, the toxic effects of a variety of heredito-familial diseases must be considered. When

encephalopathy is documented, a variety of considerations must be

made. Most prominent is the potential effect of hypoxia or anoxia

on the brain. During the course of inhalant abuse the individual

participating in the activity is inhaling a gaseous mixture low in

oxygen, particularly if the abuser uses a paper or plastic bag

during the course of the procedure (Alha et al., 1973, Press and

Done, 1976) . Since death from asphyxia can occur if the abuser

inserts his head in a plastic bag and then becomes unconscious

83
during the course of the inhalation, the possibility of less catastrophic, but nonetheless serious, brain damage due to oxygen

deprivation must be considered. Practically speaking, it may be

impossible to separate the effects of potential hypoxia from the

direct toxic effects of the volatile solvents being used by the

inhalant abuser. When a multifocal neurological deficit is documented, e.g., multiple cranial nerve deficits including optic nerve

damage, the possibility of a demyelinating disorder such as

multiple sclerosis must be considered.

The possibility that the inhalant abuser is suffering the effects of

more than one toxin within a mixture being inhaled must be

considered. For example, leaded gasoline may be inhaled. Lead

itself causes peripheral neuropathy and also encephalopathy , alone

or together. Appropriate laboratory analysis for such neurotoxins must be conducted.

ANCILLARY TESTS FOR FURTHER NEUROLOGIC EVALUATION

It is not within the scope of this section to discuss in detail the

neurologically pertinent laboratory diagnostic tests which may be

indicated in a particular patient. However, they will be discussed briefly with reference to relevant, more detailed publications (De Jong, 1967; Toole, 1969; Kiloh and Osselton, 1976;

Ramsey, 1977; Lenmon and Pitchie, 1973).

Mental Status Evaluation

The mental status examination frequently requires significantly

more detail than called for in the neurological examination form.

Richard L. Strub and F. William Black, in their book, The Mental

Status Examination in Neurology, provide a recent and relevant

approach to this problem. In addition to the aspects of mental

status outlined in the attached examination form, they stress the

following: constructional ability. higher cognitive function, and

related cortical function. Criteria for further neuropsychological

evaluation including speech and language evaluation and psychiatric consultation are delineated. An appendix to the book outlines the standard psychological tests available for the assessment

of: intelligence; memory; constructional ability and perception;

aphasia batteries; auditory perceptions; other tests of cognitive

dysfunction; achievement; and personality. A second appendix

provides a “Composite Mental Status Examination” arranged as a

form which could be completed by any clinician in his evaluation

of an inhalant abuser.

Several other laboratory techniques for quantitation of neurological dysfunction will be pertinent to the inhalant abuser in selected circumstances as indicated by the assessment and plan formulated. These include: electroencephalography (EEG); electromyography (EMG); nerve conduction velocity studies (NCV); lumbar

puncture; and computerized axial tomography (CAT or EMI scan).

84
Other neurologically oriented diagnostic procedures such as plain

X-ray studies, angiography, pneumoencephlography, myelography, echoencephalography , and isotope brain scan will be of

little use in the evaluation of the inhalant abuser.

Electroencephalography

The EEG records the amplified voltage difference between two

points on the head. The brain normally has continuous electrical

activity which can be analyzed by EEG. In the case of the

inhalant abuser it can be used to determine whether there is a

local or generalized slowing or disorganization of electrical activity

or whether there are local or generalized spontaneous epleptiform

discharges (Kiloh and Osselton, 1972).

Electromyography and Nerve Conduction

Velocity Studies

The EMG is the amplification of electrical discharges from the

muscles. A needle electrode is inserted into the muscle; abnormal

muscle discharges at rest and during activity can thus best be

detected by audio and visual display. This technique is useful

for the determination of diseases of the muscles, nerves, and

anterior horn cells, all of which may be impaired secondary to

inhalant abuse. NCV is determined by measuring. the length of

time it takes a stimulus applied at one point on a nerve to travel

to another point on the same nerve. This technique is particularly useful in the evaluation of the peripheral neuropathy which

may occur as a result of inhalant abuse (Lenmon anti Pitchie,

1973).

Lumbar Puncture

The lumbar puncture performed in the inhalant abuser may indicate an increased pressure which may be related to cerebral

edema or an elevated protein content which may indicate CNS

degeneration. Various other special analyses may be performed

on the cerebrospinal fluid obtained at the lumbar puncture

(Toole, 1969).

Computerized Axial Tomography

The CAT involves small-dose X-ray penetration of the head in

multiple directions with quantitations of the uptake. Through a

process of triangulation with beams from other angles, the exact

density or hindrance of the X-ray beam for each point is obtained. By computer, an entire cross section of the brain can

thus be mapped with clear differentiation of density in all areas.

This technique will show differences in density between skin,

skull, dura, spinal fluid, gray matter, white matter, and vrntricles, and is useful in detecting tumors, infarcts, hemorrhages,

and ventricular abnormalities (Ramsey, 1977). In the inhalant

85
abuser, particular attention would be placed upon the ventricular

size and the size of the subarachnoid space over the cortical

mantle in an attempt to assess whether any disturbances in the

mental status as determined clinically can be correlated to

cerebral atrophy.

Nerve Biopsy

Under special circumstances muscle and peripheral nerve biopsy

may be performed. Nerve biopsy, in particular, may provide

valuable information to document the etiology of the peripheral

neuropathy which had been disagnosed clinically. The characteristics of peripheral neuropathy caused by volatile hydrocarbons

has been well documented by light and electron microscopic

studies (Shirabe et al. 1974; Oh and Kim, 1976; Mendell et al.,

1976; Means et al., 1976; Saida et al., 1976; Kaeser , 1970).

Therefore, this study would not be performed routinely but only

if it is essential to verify a clinical diagnosis or as part of an

investigative effort of potential benefit to the patient involved.

In that case the studies should be performed only at a medical

facility equipped to use the proper techniques and appropriate

processing and analysis of biopsy material obtained (Dyck and

Lofgren, 1968).

REFERENCES

Alha, A., T. Korte, and M. Tenhu. Solvent sniffing death.

Z Rechtsmedizin, 72:299-305, 1973.

Benton, C., Jr., and F. Calhoun, Jr. Ocular effects of methyl

alcohol poisoning: Report of catastrophe involving 320 persons.

Am J Ophthalmol, 36:1677-85, December 1953.

Berg, E. Retrobulbar neuritis. A case report of presumed solvent toxicity. Ann Ophthalmol, 3:1351-3, December 1971.

Billmaier, D., N. Allen, B. Craft, et al. Peripheral neuropathy

in a coated fabrics plant. J Occup Med, 16:665-71, October 1974.

Davenport, J., D. Farrell, and S. Sumi. “Giant ax!onal neuropathy” carried by industrial chemicals. Neurology Minneap, 26:919

-23, October 1976.

De Jong, R. The neurological examination. New York: Harper

and Rowe, 1967.

Dyck, P., and F. Lofgren. Neure biopsy. Fed Cli N Amer, 52:

885-93, 1968.

Feldman, R., R. Mayer, and A. Taub. Evidence for peripheral

neurotoxic effect of trichlorethylene. Neurology, 20:599-606,

1970.

86
Gilroy, J., and J. Meyer. Medical neurology. New York:

Macmillan Publishing Co. , 1975.

Grabski, D. Toluene sniffing producing cerebellar degeneration.

Am J Psychiatry, 118:461-2, November 1961.

Kaeser, H. Nerve conduction velocity measurements. In:

Diseases of Nerves, ch. 5, pp. 116-96; part 1, vol. 7, Handbook

of Clinical Neurology, P. Vinken and G. Bruyn, eds. Amsterdam: North-Holland Publishing Co., 1970.

Kiloh, L., and J. Osselton. Clinical electroencephalography.

London: Butterworth and Co., 1972.

Knox, J., and J. Nelson. Permanent encephalopathy from toluene

inhalation. N Engl J Med, 275:1494-6, December 29, 1966.

Korobkin, R., A. Asbury, A. Sumner, et al. Glue sniffing

neuropathy. Arch Neurol, 32:158-62, March 1975.

Lenmon, J,, and A. Pitchie. Clinical electromyography. Philadelphia: J. B. Lippincott Co., 1973.

Means, E., L. Prockop, and G. Hooper. Pathology of lacquer

thinner induced neuropathy. Ann Clin Lab Sci, 6:240-50, MayJune 1976.

Mendell, J., K. Saida, M. Ganansi, et al. Toxic polyneuropathy

produced by methyl-N-butyl ketone, Science, 185:787-9, August

30, 1974.

Merritt, H. A textbook of neurology. Philadelphia: Lea and

Febiger, 1973,

Oh, S., and J. Kim. Giant axonal swelling in "huffers" neuropathy. Arch Neurol, 33:583-6, August 1976.

Press, E., and A. Done. Solvent sniffing: Physiologic effects

and community control measures for intoxication from the intentional inhalation of organic solvents I and II. Pediatrics, 39:451-

622, 1976.

Prockop , L . Multifocal nervous system damage from volatile

hydrocarbon inhalation. J Occup Med, 19:139-40, 1977.

Prockop, L., M. Alt, and J. Tison. "Huffer's" neuropathy.

JAMA, 229:1083-4, August 19, 1974.

Ramsey, R. Computed tomography of the brain. Philadelphia:

W. B. Saunders Co., 1977.

87
Reinhardt, C., A. Azar, M. Maxfield, et al. Cardiac arrhythmias

and aerosole “sniffing.” Arch Environ Health, 22:265-79, February 1971.

Saida, K., J. Mendell, and H. Weiss. Peripheral nerve changes

induced by methyl-n-butyl ketone and potentiation by methyl

ethyl ketone. J Neuropathol Exp Neurol, 35:207-29, May 1976.

Schaumburg, H., and P. Spencer. Degeneration in central and

peripheral nervous systems produced by pure n-hexane: An

experimental study. Brain, 99:183-92, June 1976.

Shirabe, T., T. Tsuda, A. Terao, et al. Toxic polyneuropathy

due to glue-sniffing. Report of two cases with a light and electron microscopic study of the peripheral nerves and muscles.

J Neurol Sci, 21:101-13, January 1974.

Taher, S., R. Anderson, R. McCartney, et al. Renal tubular

acidosis associated with toluene "sniffing." N Engl J Med, 290:

765-8, April 4, 1974.

Strub, R., and F. Black. The mental status examination in

neurology. Philadelphia: F. A. Davis Co., 1977.

Toole, J.. ed. Special techniques for neurological prognosis. In:

Contempory Neurology Series, F. Plum and F. McDowell, eds.

Philadelphia: F. A. Davis Co., 1969.

Walton, J. Brain’s diseases of the nervous system. London:

Oxford Universiy Press 1977.

88
APPENDIX

NEUROLOGICAL EVALUATION FORM

89
NEUROLOGICAL HISTORY

A. Record onset (sudden, gradual, insidious) and course

(acute, subacute, chronic, with exacerbation and remissions)

of problem(s) and/or symptoms(s) and whether they are

focal or generalized. This should be recorded for:

Pain

Weakness

(including swallowing and breathing)

Stiffness

(or other muscle complaints)

Numbness

(or other sensory symptoms)

Syncope or

Seizures

Visual Change

Hearing Change

Memory Loss

Personality Change

Incoordination

(including ataxia)

Abnormal movements

(e.g., tremor)

Automatic functions

(bowel, bladder, sexual)

90
B. Record significant elements of systems review (ROS)

C. Record significant past medical history, especially, surgery;

trauma; medications; systemic illness, e.g., diabetes

mellitus; hypertension; mental illness.

D. Record significant history of heredito-familial illness

E. Record significant social history, especially. dietary habits ;

alcohol; tobacco and drug use; education; environmental

emotional stresses; marital and family status.

F. Record vocational and avocational history, including. exposure to toxins.

91
NEUROLOGICAL EXAMINATION

(Items to be completed always are in capital letters. Items

in small letters are done when appropriate. Some items may

be completed as N1=Normal or Abn=Abnormal; others must be

defined.)

A. MENTAL STATE

STATE OF CONSCIOUSNESS

ORIENTATION

ATTENTION

BEHAVIOR

INTELLECTUAL PERFORMANCE (Rate as excellent,

good, fair, poor, absent)

PAST FACTUAL FUND

MEMORY

RECENT

CALCULATIONS DIGITAL RECALL

(e.g. SERIAL 7'S) (5 forward, 4 backward)

AFFECT AND MOOD: (Circle appropriate term and/or

add other designations)

APPROPRIATE INAPPROPRIATE DEPRESSED EUPHORIC FLAT

THOUGHT CONTENT : SPONTANEOUS THOUGHT - YES NO

SPEAKS IN APPROPRIATE SEQUENTIAL SENTENCES -

YES N O OTHER (e.g, paranoid, incoherent,

evasive, tangential, etc.)-

LANGUAGE (Including aphasia)-

B. CRANIAL NERVES

I. OLFACTORY (Record odors used)

92
II. OPTIC

GROSS VISUAL ACUITY - NORMAI, ABNORMAI,

RE

best visual acuity

LE:

FUNDUS EXAM

DISC : A/V Ratio =

VESSELS : CONFRONTATION FIELDS

III, IV, VI. OCULOMOTOR, ‘I’ROCHLEAR, ABDUCENS

PALPEBRAL FISSURES ORBIT lids, conjunctiva, iris, cornea

eye position at rest (diagram if abnormal)

EYE MOVEMENTS - INDIVIDUAL & CONJUGATE NYSTAGMUS

optokinetic

PUPILS SIZE (mm) & SHAPE DIRECT CON- ACCOMMOR

L

V. TRIGEMINAL

MOTOR (temporalis L R

masseters)

CORNEAL

SENSUAL, DATION

SENSORY (diagram if abnormal)

93
VII. FACIAL

MOTOR (VOLITIONAL, EMOTIONAL)

taste (note test materials) hyperacusis

lacrimation

VIII. ACOUSTIC

IX.,

XI.

XII.

C.

HEARING - AD AS

LATERALIZATION (WEBER)

AIR/BONE CONDUCTION (RINNE) RIGHT (B = A)

LEFT (B = A)

calories - cold water

warm water

X. GLOSSOPHARYNGEAL, VAGUS

GAG REFLEX SWALLOWING PHONATION

SPINAL ACCESSORY

HYPOGLOSSAL

REFLEXES: (0 = absent; 1 = trace; 2 = active;

3 = very active; 4 = unsustained clonus;

5 = sustained clonus)

R L R L R L R L

94
D. MOTOR :

GAIT -

COORDINATION - left right

finger to nose

heel to shin

rapid alternating movement

POSTURE -

INVOLUNTARY MOVEMENTS -

(tremor, chorea, athetosis , ballism)

MUSCLE EVALUATION - STRENGTH (100% = normal;

75% = full range of motion (ROM) vs. some resistance; 50% = full ROM vs. gravity; 25% = full ROM

without gravity; 10% = contraction; 0 = no contraction, no movement)

UPPER EXTREMITIES : LEFT RIGHT

PROXIMAL

DISTAL

LOWER EXTREMITIES :

PROXIMAL

DISTAL,

MUSCLE TONE:

(whether normal; decreased, e.g., flaccid;

increased, e.g., spasticity)

FASCICULATION:

(whether present and where)

ATROPHY:

(whether present and where)

MYONTONIA

TENDERNESS & INDURATION

95
E. SENSORY: Chart deficits in: Pain Touch Temperature

Vibration Position when present.

Describe the following when tested:

two point

stereognosis

traced figures

extinction

localization

F. ASSESSMENT AND PLAN: This should be a summary of

history, a summary of positive neurological findings,

and a diagnostic formulation and further diagnostic,

treatment and/or management plan (on separate sheet).

96
PRECLINICAL: PHARMACOLOGY AND TOXICOLOGY

97
Chapter 6

INTRODUCTION

Daniel Couri

This section will be devoted to the characterization of volatile

agents used as inhalants. Significant aspects of the physical and

chemical properties as well as the known biological effects will be

highlighted. It is important to recognize that each of these

agents will be described and discussed in proportion to the data

available. Since most materials of solvent abuse consist of mixtures of varying composition, the effects noted in studies of

single solvent vapor exposure may, at best, suggest likely target

organ specificity, or more so, minimal toxicity (Couri and AbdelRahman, 1977). Furthermore, most of the literature dealing with

volatile agents is derived from studies of single agent exposure

(or administration) aimed at providing safety data and hazard

evaluation for the work environment. Consequently, these often

describe results of either acute high dose mortality data (LD50,

LC5 0 ) or long-term (chronic) low concentration exposures. In

either case, the data obtained provide guidelines for establishing

relative hazard indices. Animal studies coupled with any known

human exposures at various safe (and sometimes lethal) levels of

chemical agents are compiled, evaluated, and used as a basis for

recommended maximal allowable concentrations (MAC) or the

Threshold Limit Value (TLV), i.e., an average exposure level a

worker can be exposed to for an 8-hour workday over an indefinite period of time without any hazard to health.

98
OCCURRENCES OF VOLATILE AGENTS

The volatile solvents are often used in combinations which are

arrived at based upon the most desirable properties of mixtures

to achieve an industrial or commercial purpose. Thus, a composition of paint thinners or brush cleaners or degreasing agents

will vary greatly from region to region and from manufacturer to

manufacturer. A selected group of mixtures of commonly available

compounds is depicted in Table 1 according to chemical class.

PHYSICAL AND CHEMICAL PROPERTIES

OF VOLATILE SOLVENTS

Most of these compounds are liquids at room temperature and

inhaled toxicity is dependent upon their physical properties. For

example, a compound which has a relatively high TLV can still be

hazardous if it readily vaporizes at room temperature. Table 2

includes physical and chemical properties of the compounds discussed in this section. The table includes vapor pressure, a

measurement of the partial pressure the solvent exerts at 25° C.

Vapor pressures which have higher numerical values are more

easily volatilized than those with lower values, e.g., acetone is

about twice as volatile as methyl ethyl ketone. The more volatile

substances will be more concentrated in inhaled fumes. The

absorption of these compounds through alveolar membranes and

into tissues is enhanced by their organic solubility and diminished, in general, by their water solubility. This may be an

oversimplification of these properties and many exceptions occur.

However, these data may be utilized in this manner to determine

the relative toxicity and absorption that would occur from humans

exposed to these vapors.

For further information on many of these compounds in relation to

their hazards, the reader is referred to the numerous Criteria

Documents on individual substances that are listed (under “C”) in

the Bibliography of this volume.

REFERENCE

Couri, D., and M. Abdel-Rahman. Toxicological evaluation of

intentionally inhaled industrial solvents. Presented at The First

International Symposium on Voluntary Inhalation of Industrial

Solvents, Mexico City, June 1976.

99
TABLE 1

OCCURRENCES OF VOLATILE SUBSTANCES

Adhesives

Wind- and Aero- Spray Room Foem

Anti- Gaso- Paint De- shield Rubber Model sol Shoe Odor- DisCompounds freeze line Thinner graesers Washers Cement Cements Sprays Polish ants pensers

Alcohols

Methanol X

Ethanol

lropropanol X

Esters

Ethyl acetate

n-Propyl

acetate

n-Botyl acetate

Ketones

Acetone

Methyl ethyl

ketone

Methyl butyl

ketone

Aromatic

Hydrocarbons

Benzene

Toluene

Xylene

Stryene

Naphthalene

Aliphatic

Hydrocarbons

n-Hexane

n-Heptane

Anesthetics

Methylene

chloride

Trichloroethylene

Tetrachloroethylene

Nitrous oxide

“Freons”

Aliphatic Nitrite

lsoamyl nitrite

100
TABLE 2

PROPERTIES OF VOLATILE SOLVENTS

Compound

Molecular Boiling Point

Weight °C, 760 mm Hg

Solubility*

g/100 ml

Water, 25 °C

Vapor Pressure

mm Hg, 25°C

Alcohols

Methanol

Ethanol

Isopropanol

Esters

Methyl acetate

Ethyl acetate

n-Propyl acetate

n-Butyl acetate

Methyl formata

Ethyl formats

Ketones

Acetone

Methyl ethyl ketone

Methyl propyl ketone

Methyl butyl ketone

Methyl hexyl ketone

Di-isobutyl ketone

Methyl amyl ketone

Aromatic Hydrocarbons

Benzene

Toluena

Xylenes

Stryene

Naphthalene

Aliphatic Hydrocarbons

n-Pentana

n-Hexane

n-Heptane

n-Octane

Aliphetic Nitrite

lsoamyl nitrite

Anesthetic Agents

Nitrous oxide

Chloroform

Di-ethyl ether

Halothane

Ethyl chloride

Trichlomethylene

32 65

46 78

60 82

160

50

44

74 57 32.0 235

88 77 8.6 100

102 102 1.9 35

116 125 1.0 1.5

60 32 30.0 600

74 54 11.8 200

58

72

86

100

56

80

86

128

173

142

114

226

100

16

3.8

1.2

2.4

1.6

25.6

5.5

1.6

0.1

vss

0.4

128

142

114

78

92

106

80 vss 76

111 vss 36.1

141 10

145 6.5

211 0.1

194

128

72

86

36

68

100

114

409

103

41

10.2

100

114

117 97-99 0.11

30 -89

119 61

74 35

197 50

67 12

131 87

N A

N A

Gas

200

439

240

Gas

77

*All compounds listed in this table are miscible at all proportions in organic solvents.

 = Miscible at all proportions.

VSS = Very slightly soluble.

I = Insoluble.

NA = Not applicable.

101
Chapter 7

ABUSE OF INHALATION ANESTHETIC DRUGS

M. B. Chenoweth

HISTORY

It is generally accepted that surgical anesthesia with all its blessings arose out of the abuse of the earliest materials available,

diethyl ether and nitrous oxide. “Ether frolics” and “laughing

gas demonstrations” were common events and the absence of reactions to painful injuries noted during the effect of these substances led directly to their use in surgery. Yet not five years

after his introduction of nitrous oxide in 1844 to dentistry and

surgery, Dr. Horace Wells died, a victim of chloroform abuse

(Brown, 1967.) The literature on abuse of anesthetic vapors begins at about that time and is largely anecdotal.

Although there is no way other than inhalation to obtain the

effects of nitrous oxide diethyl ether is sufficiently liquid at cool

room temperatures to be drunk. Such use of ether progressed

concomitantly with its surgical uses, especially in certain geographical regions (Connell, 1965). It seems that ether was used

both as an alternative to the more expensive alcohol and as a

drink with its own special “desirable” properties. The waning of

its usage warrants more study of the mechanisms used to discourage ether drinking in Ireland. A combinaition of control of

sales and social pressure: seems to have been responsible, but

these forces seem not to help much in the United States today in

attacking the drug abuse problem in general

102
AGENTS AND ACTIONS

The inhalation anesthetics available in the United States are now

numerous and may be classified in numerous ways; for example,

by usefulness or popularity among anesthesiologists, or by price,

availability, color, boiling point, etc., etc. Perhaps a useful

categorization is between gases and liquids as it at least distinguishes the containers and the portability of the system. Some

features are gathered in Table 1 which are particularly relevant to

the problem of abuse.

The inhalation anesthetics as a class are presented to the legitimate user as extraordinarily pure and powerful drugs. They are

singularly low in organ toxicity and generally safe when used

properly. Much is known of their pharmacology and/or toxicology

and the desirable and undesirable features of each are massively

documented and updated in texts, treatises, and periodical scientific literature. Table 2 summarizes the pharmacological characteristics of some standard materials. Table 3 contains some chemical

information. A synopsis of anesthestic drug action may be of

value to readers not familiar with it.

ANESTHESIA AND ITS PROBLEM

With the exception of ethylene and nitrous oxide, the materials

listed in Table 3 are “complete anesthetics.” That is, they will

produce complete narcosis characterized by complete unconsciousness, total muscular relaxation, and respiratory and/or cardiac

arrest. This cannot be accomplished with 80 percent nitrous

oxide or ethylene in oxygen, the maximum concentration that can

be used safely.

The induction of anesthesia progresses in four stages classically

demonstrated by use of ethyl ether. Stage II is of importance to

the abuse problem for in this stage excitement, struggling, and

vomiting often occur. Stage III, divided into four planes, is that

of general anesthesia and in this stage reflexes become increasingly obtunded, ending with Stage IV--cessation of everything. A

special hazard to the abuser is the extreme relaxation of the

throat which occurs, occluding the respiratory passages. The

combination of vomitus, relaxed tongue and throat muscles, and

feeble breathing efforts is a likely cause of death in many

abusers.

TOXICITY OF ANESTHETICS

Although possibly less toxic in terms of organ damage potential

than most commercially employed solvents, the anesthetics are not

free of unwanted effects. Sensitization of the myocardium to the

catecholamines can lead to abruptly fatal ventricular fibrillation,

and hepatic damage is reported in abusers as well as patients.

Although nitrous oxide is known to produce leukopenia, this has

103
TABLE 1

FEATURES OF ANESTHETIC RELEVANT TO ABUSE

Name

GASES

Nitrous Oxide

Ethylene

Cyclopropane

Source

(See Footnote)

1,2,3

1,2,5

1,2,5

Comment

Great volumes used in anesthesia Abuse increasing.

Unpleasant odor. Explosive. Weakly active. No record of abuse.

Explosive. Costly. No record of abuse.

VOLATILE LIQUIDS

Chloroform 1,2,4,5

Diethyl Ether 1,2,3

Halothane 1

Ethyl Chloride 1,2,5

Methoxyflurane 1

Enflurane 1

Fluroxene 1

Divinyl Ether 1,2,5

Trichloroethylene 1,2,3,5

Explosive, irritating.

Very dangerous to abuser.

Unusual for abuse.

Notable odor. Slow acting. Rarely abused.

Excitatory properties may influence ebuse.

No longer marketed. Explosive. No record of abuse.

No record of abuse.

Special interaction with ethanol to cause flushing.

1Pharmaceutical channels.

2Commercially available.

3

Found in consumer products.

4

Specifically excluded from consumer products.

5Can be had in anesthetic grade but is used in anesthesiology in the United States very rarely, if at all in 1977.
TABLE 2

CHARACTERISTICS OF SOME STANDARD GENERAL ANESTHETICS

Anesthetic Flammable

Rate of

Induction

Rata of

Emergence Analgesia Respiration

Cardiovascular

System

Liver

Function

Postop.

Kidney Nausea &

Function Vomiting

Cyclopropane Yes Rapid

Ether Yes Slow

Methoxyflourine NO Slow

Halothane No Moderately

rapid

Nitrous Oxide No Rapid

Moderately

rapid

Good Depressed

Slow Good Light-not

depressed

Deep-depressed

Slow Good Depressed

Depends on

duration

Poor Depressed Depressed

Rapid Good Not affected

Supported Depressed

mildly

Depressed Moderate

Moderately well

supported

Depressed Depressed Moderate

mildly

Depressed Depressed Depressed Moderate

mildly

Depressed Depressed Mild

mildly

Not affected Not Not Minimal

affected affected
TABLE 3

CHEMICAL DATA ON ANESTHETICS

Generic Name Trade

Nitrous Oxide None

Ethylene Nom

Cyclopropane None

Chloroform None

Chemical

Structure

N2O

CH2=CH2

CHCl 3

Boiling

Point

-88.46 °C.

-102.4 °C.

-34.5 °C.

61.0 °C

Flammability

None (supports combustion

however)

Explosive limits in air,

3.02-34%

Explosive limits in air,

2.41-0.3%

Nom

Miscellaneous

Blue tanks

Violet tanks

Orange tanks

Diethyl Ether None CH3CH2OCH2CH3 35.0 °C. Explosive limits in air.

1.85-100%

Halothane “Fluothane” CF3CBrCIH 50.0 °C. None

Ethyl Chloride Several* CH3CH2Cl 12.3 °C. Burns. Explosive limits in Pressurized glass

air, 3.6-14.8% containers

Methoxyflurane “Penthrane” CH3OCF2CCL2H 104.6 °C. Lower explosive limits in

oxygen 5.4%, usually

unreachable in clinic

Enflurane

Fluroxane

“Ethrane”

“Fluoromar”

F2CHOCF2CClFH

F3CCH2OCH=CH2

Divinyl Ether “Vinethene” H2C=CH-OCH-CH2

56.5 °C.

42.5 °C.

30.0 °C.

Nom

Explosive Lower limit in

oxygen, 4.0%

Explosive. Slightly less so than

diethyl ether

Contains 4% ethanol

TrichloroMhylsne "Trilene"*

*See Merck Index 3713,9319, 9th Ed.

Cl 2H=CHIH 86.7 °C. None.
not been a feature of abuse. Malignant hyperthermia is potentially a serious threat to abusers who possess the genetic requirements for this oft-fatal phenomenon.

Although the acute effects of anesthetic vapors have been very

extensively studied, the effects to be expected from long-term low

level inhalation are only now under study (Chang and Katz,

1976). Furthermore, as with all the abused materials, next to

nothing is known about the long-term results of repeated, brief

sub-anesthetic self-dosing. The self-dosing aspect is important

because of the risks of partial anoxia and occasional overdosage.

The details will be difficult enough to ascertain for the cases of

single drug abuse, but there are probably far more persons who

abuse two or more drugs simultaneously.

SOURCES OF ANESTHETIC CHEMICALS

Some compounds are available in commerce as general chemicals,

but for others the system of distribution is almost entirely that of

prescription drugs (Table 2). Indeed, because almost all inhalation anesthesia is carried out in hospitals, the disbribution pattern is even more narrowed. A practicing physician wishing, for

whatever strange but legitimate reason, to keep inhalation anesthetics in his offices must be quite insistent to obtain a supply.

Dentists, however, make use of nitrous oxide as an analgesic and

often they are equipped to use it regularly.

The veterinarian makes considerable use of these drugs and may

have a sizeable supply. Biological and chemical laboratories often

have large supplies of these drugs.

Fortunately, even the cheapest of the chemicals is costly and the

best are downright dear, so storage generally tends to be more

secure than casual. Several are flammable and this, too, limits

the carelessness with which they are stored.

In short, the abuser must have legitimate access to these drugs

or he must be a thief. Roth occur.

ADDICTION AND ABUSE OF ANESTHETICS

Some case reports showing the details of usage by addicted anesthesiologists and by inexpert thieves are instructive (see annotated bibiography) As a generality, the anesthesiologist addicted to anesthetic “sniffing” is careful not to exceed the social

tolerance of his peers, but as with ethanol, excess occurs. He

is, then, in the position of the alcoholic physician and may end in

disgrace or in another area of work. The inexperienced thief

frequently ends on a slab in the morgue. These latter cases

often appear in the medical literature; the former do not.

107
INCIDENCE AND CONTROL OF ANESTHETIC ABUSE

It is difficult to get a grasp on the incidence of anesthetic abuse

by professionals. The old practice of testing the anesthetic

mixture upon oneself is fading due to better instrumentation of

anesthesia machinery but it is not gone. The bottles of halothane, methoxyflurane, or enflurane are small and easily secreted. In a busy hospital only the administrator really worries

about the cost and numbers of such bottles which must be at

hand at all times. Some operations use more, some less, and the

anesthesiologist is buried at the end of the table alone behind the

drapes. “Sniffing” may go undetected. With most eyes riveted

to the table, it is easy for an intern, a circulating nurse, or an

orderly to drop a bottle for future use into a pocket or cache.

The National Institute for Occupational Safety and Health (NIOSH)

estimates 214,000 workers are exposed to anesthetic vapors in

1977. In addition, total strangers in white coats, grabbed from a

handy coat room, can walk boldly into the drug room, as often

hospitals have little in the way of security measures.

A “bottle count” similar to the classical sponge count at the end

of the operation could discourage hospital staff thefts or at least

increase their chances of being detected.

Why does a professional turn to inhalation anesthetics as a drug

of abuse? It is speculated that perhaps they are already alcoholic

in that they drink to excess while off duty and the anesthetic

“sniffed” in the operating room merely tides them over until they

can get to a bottle. Later, the balance swings more to the anesthetic than to alcohol. However, there are “pure” anesthetic

addicts who do not use alcohol. Perhaps they rationalize that the

anesthetic is less toxic and in any case, they “are not alcoholics.”

The rapid move to regard the surgical suite as a “workplace” in

the meaning of the Occupational Safety and Health Act, together

with the previous findings of hazard to the workers in such

places (Van Stee, 1976), is leading to air monitoring and a profound decrease in the ambient vapor concentrations. NIOSH, in a

recent Criteria Document, proposes a 2 parts per million (ppm)

limit on halogenated anesthetic vapors in the workplace and 25

ppm for nitrous oxide. This can only be generally salutory.

Furthermore, a sudden rise in concentration may then reveal

“on-the-job” abuse to some extent. Theoretically, the absence of

clouds of vapors may also decrease the number of persons experiencing an effect which might later lead to deliberate abuse.

A recent popular magazine article put the proportion of alcoholic

physicians at about 12 percent of the total (Robinson, 1977).

Therefore, it is perhaps fair to guess the proportion of 214,000

persons who abuse anesthetic vapors at around 1 in 10, a frightening figure the author hopes is wildly erroneous. Several dis108
tinguished anesthesiologists have assured the author that the

incidence among anesthesiologists is less than 1 or 2 percent, but

they fear it may be higher among other groups having access to

these substances. Thievery can be reduced by commonplace

measures but the old problem remains, “nam quis custodiet ipsos

custodes?”

SUMMARY

Abuse of inhalational drugs used to produce anesthesia has progressed pari passu with their evolvement and may exist far into

the future. It occurs among both professional and lay people and

is fraught with toxicological and sociological hazard in excess of

many other forms of substance abuse.

REFERENCES

Brown, C. The agony of Dr. Wells. Mil Med 132:101-2, 1967.

Chang, L., and J. Katz. Pathologic effects of chronic halothane

inhalation. Anesthesiology, 45:640-53, 1976.

Connell, K. Ether drinking in Ulster. Q J Stud Alc, 2:629-53,

3965. Examination of the sociologic events surrounding the last

century’s epidemic of ether abuse.

Robinson, D. The menace of drunken doctors. Ladies Home

Journal, 94 (4):94, 215-6, 1977.

Van Stee, E. Toxicology of inhalation anesthetics and metabolites. Annu Rev Pharmacol, 16:67-79, 1976.

ANNOTATED BIBLIOGRAPHY

Chloroform

Storms, w. Chloroform parties. JAMA, 225(2):160, July 1973.

Calls attention to current abuse of this material by describing a

case of orally ingested chloroform overdose. Depression was

severe but recovery was complete.

Weinraub, M. , P. Grace, and M. Karno. Chloroformism - a new

case of a bad old habit. Calif Med, 117:63-5, 1972. Male, 24

hrs . Peaked at a gallon per week. Mild withdrawal symptoms

and no organ damage.

Ether

Bartholomew, A. Two cases of ether addiction/habituation.

Med J Aust, 49:550-3, 1962. Both sniffing and drinking.

109
Deniker, P., M. Cottereau, H. Lôo, and L. Colonna. L’usage de

l’ether dans les toxicomanies actuelles. Ann Med Psych (Paris),

1:674-81, 1972. Describes both the intravenous and intramuscular

routes of administration for ether abuse.

Kerr, N. Ether inebriety. JAMA, 17:791-4, 1891. General

review in late Victorian style. Mentions considerable abuse by

inhalation as well as drinking. One subject inhaled a pint a day.

Halothane

Spencer, J., F. Raasch, and F. Trefny. Halothane abuse in

hospital personnel. Three young male JAMA, 235:1034-5, 1976.

hospital technicians overdosed fatally on stolen halothane.

Tucker, S., and T. Patteson. Hepatitis and halothane sniffing.

Ann Int Med, 80:667-8, 1974. The small amount of stolen halothane available to this prisoner cannot be specifically indicted as

the cause of his icterus.

Nitrous Oxide

Brilliant, L. Nitrous oxide as a psychedelic drug. N Engl J

Med, 283:1522, 1970. Mentions two asphyxial deaths.

Brodsky, L., and J. Zuniga. Nitrous oxide: A psychotogenic

agent. Compr Psychiatry, 16:185-8, 1975.

developed

A 32-year-old man

psychotic and toxic-organic features after 6 months of

almost daily inhalation of nitrous oxide.

Dillon, J. Nitrous oxide inhalation as a fad. Calif Med, 106:444-

6, 1967. Of sociologic interest primarily.

Helisten, C. Nitrous oxide is a gas. Pharm Chem Newslett,

4(5):1-2, 1975. General review of nitrous oxide use and abuse.

Lynn, E., M. James, R. Dendy, L. Harris, and R. Walter.

Non-medical use of nitrous oxide: A preliminary report. Mich

Med: 203-4, 1971. Surveys a local scene and presents some

experimental data on human volunteers breathing pure N2O from a

balloon. Effects are very transient and anoxia is not a problem

with a one- or two-breath balloon.

Miscellaneous

Anonymous. Limit of 2 ppm on exposure to halogenated anesthetics recommended. Occup Health Saf Letter, 7:7-8, 22 March

1977.

Carver, A. Paraldehyde addiction.

and Drug Addiction), 31:73-97, 1934. Paraldehyde addiction was

Br J Inebriety (Alcoholism

common as the era of barbiturates began. It may still be found

in remote corners of the world.

110
De Francisco, C. Pentrane (sic) dependence: A case report.

Br J Psychiatry 119:609-10, 1971. Male, 31-year-old anesthesiologist of unstable character abuses methoxyflurane in Mexico.

Author cites knowledge of four other abusing anesthesiologists.

De Francisco, C. Drogaddicion por inhalantes. Rev Lat Am

Psicol 5:41-7, 1973. A young female subject abusing ethyl

chloride is described.

TEXTS AND TREATISES

Chenoweth, M., ed. Modern inhalation anesthetics. New York:

Springer-Verlag

Di Palma, J., ed. Drill’s pharmacology in medicine. New York:

McGraw Hill.

Goodman, L., and A. Gilman, eds. The pharmacological basis of

therapeutics. New York: Macmillan,

111
Chapter 8

TOXlCOLOGY OF ALCOHOLS,

KETONES AND ESTERS--INHALATION

Daniel Couri and J. P. Nachtman

ALCOHOLS

Although alcohols as solvents are not generally inhaled, their

occurrence in solvent mixtures makes it important to describe

their known toxicities. Oftentimes, when alcohols occur in these

mixtures, the cautionary label on the product refers to symptoms

of ocular damage especially referable to methanol.

Alcohols are synthesized from natural gas, wood and grain distillation, and petroleum distillates. Most water soluble of the organic solvents, they are poorly eliminated from the lungs, are metabolized to acetate and/or excreted by the kidney. Much is known

about alcohol metabolism because of its ingestion toxicity and

addiction.

The general metabolic pathway for alcohols is outlined below.

(A) Alcohol and corresponding metabolites

R Compound Metebolite-1 Metabolite-2

H- Methanol

CH3 Ethanol

CH3CH2 n-Propanol

Formaldehyde

Acetaldehyde

Proprionaldehyde

Formic acid

Acetic acid

Proprionic acid

112
Methanol

Symptoms of Exposure

Methanol (CH3OH) is used as a solvent for paints and varnishes,

resins, films, antifreeze and inorganic synthesis and extraction.

High concentrtrations occur during beer vat cleaning, varnishing of

ship engine rooms, shellacking, and dye preparations, often

causing fatalities Thus, inhalation of methanol can be lethal

similar to that following oral intoxication.

Early symptoms of methanol poisoning are headache, weakness,

vertigo, and occasionally nausea, vomiting, and abdominal pain.

Symptoms due lo acidosis (formic acid metabolite) can be treated

with bicarbonate.

Delayed symptoms occur in the visual system: blurred vision,

loss of acuity (spots or gray mist seen), photophobia, and eye

tenderness. Pupils dilate and lose their reflexes. The high rate

of oxidative metabolism of the retina is thought to produce formaldehyde in situ with resulting edema, blurring of the optic disk,

and permanent damage to ganglion cells. Infused formaldehyde

cannot produce this injury, which appears from 6 to 30 hours

after exposure to methanol.

Delayed retinal toxicity can be treated by infusion of ethanol until

plasma ethanol levels reach about 0.1 g% (grams per 100 ml blood).

Ethanol is a better substrate than methanol for alcohol dehydrogenase, thereby preventing the formation of formaldehyde; methanol

is excreted unchanged by the kidney.

Retinal and Central Nervous System Toxicity

Methanol intoxication has been studied in primates (Potts and

Gonasun, 1975), since they are the only species showing this

retinal and central nervous syte (CNS) toxicity. Potts et al

(1955) showed three disease processes in primates given a 90

percent fatal dose of methanol:

1. Organic solvent poisoning,

2. Systemic acidosis (cause of fatalities due to methanol),

and

3. CNS and eye toxicity.

113
The time course of effects shows a minimal initial solvent depressant effect followed by a lucid interval. This reversal was transient as systemic acidosis would be fatal if base (sodium bicarbonate) were not infused. CNS effects, primarily in the

putamen, were noted in animals who survived the first two

stages, only to die from the CNS toxicity of methanol.

To determine whether methanol, a metabolite, or acidosis is responsible for these effects, Potts et al. (1955) administered methanol, formaldehyde, or formate to rhesus monkeys. Control

monkeys were given ammonium chloride by stomach tube to serve

as acidotic controls. All the animals given methanol died despite

reversal of acidosis by sodium bicarbonate. At autopsy, only one

animal showed retinal changes of any kind. This exception survived the longest (9 days vs. 23 hours) and had fixed, dilated

pupils with apparent blindness but no retinal edema at the time of

death.

Examination of the brains of methanol-treated animals showed the

caudate nucleus and putamen with hemorrhagic infiltration and

necrosis. Controls treated with ammonium chloride, formate, or

formaldehyde showed no such lesions.

Electroretinograms (ERG) showed the absence of ß wave and

accentuated wave in methanol animals with comparable results

for formate- and formaldehyde-infused monkeys. The methanoltreated group showed symptoms and ERG changes 20 to 30 hours

after administration, while formate and formaldehyde produced

effects at 45 and 90 minutes, respectively.

Similar effects have also been observed in humans, including the

basal ganglion disease. These ERG changes have been observed

in man, suggesting ERG would be of diagnostic value in measuring the severity of methanol poisoning.

Metabolism

Inhalational toxicity data in humans arc inadequate, yet lethal

levels of methanol and formic acid ingestions in humans are as

follows:*

Methanol Formic Acid

mg% mg%

Bood 74-110 9-68

Urine 140- 240 216- 785

Liver 106 60-99

Urine methanol is approximately twice blood levels.

*A principal source of these data is Lund (1948).

114
Ethanol

Symptoms of Exposure

Inhalation of ethanol (CH3CH2OH) will produce irritation of

mucous membranes and upper respiratory tract, headache, nervousness, and narcosis. Asthma patients inhaling an ethanol mist

to control bronchospasm do not show ethanol toxicity. About 90

percent of inhaled ethanol is metabolized to acetaldehyde, acetate,

and ultimately CO2. Concentrations that produce drowsiness in

humans range from 6,000-9,000 parts per million (ppm) (Loewy

and Von Der Heide, 1918) and are accompanied by an intense odor

which would normally cause an individual to escape.

Metabolism

The rate of metabolism of ethanol is about 1/3 oz. of 200 proof

per hour.

A lethal level of ethanol in blood (by ingestion) is around 0.4 g%.

Exposure to 8,000 ppm for 6 hours produced only 0.05 g% in

blood, indicating how difficult it is to inhale a lethal dose of

ethanol (Lester and Greenberg, 1951).

Ethanol also will induce tolerance. Also, chronic ingestion will

increase the activity of drug-metabolizing enzymes in liver

microsomes (Rubin and Lieber, 1971).

Isopropanol

Isopropyl alcohol (CH3CHOHCH3) is synthesized from propylene, a

product of petroleum cracking. Like methanol, it is found in

many formulations including perfumes, lacquers, preserving

solutions, and rubbing alcohol.

Symptoms of Exposure

Isopropanol becomes irritating to the eye and nose at concentrations of 800 ppm, well below that of lethal effects. Isopropanol

produces narcosis and death in high concentrations (12,000 ppm

for 4 hours). Hemodialysis is recommended for acute intoxication.

Metabolism

Isopropanol is metabolized to acetone which has been found in

urine. Acetone is more readily excreted in expired air (10:1 over

isopropanol).

Acute Toxicity of Alcohols

Data are available on the effects of alcohol vapor exposure in a

variety of species; a principle source of the data in Table 1 is

Patty (1963).

115
TABLE 1

ACUTE TOXICITY OF ALCOHOLS

TLV (ppm) Compound ppm/Duration Effect Species

200 Methanol 31.600/18-21 hr

22.500/8 hr

8,800/8 hr

1,000 Ethanol 32,000/8 hr

22,000/8 hr

6,400/8 hr

400 lsopropanol 12,000/8 hr

12,000/4 hr

Lethal 100%

Narcosis

Lethargy

Some deaths

Deep narcosis

Lethargy

Lethal 50%

Narcosis

Rat

Rat

Rat

Rat

Rat

Rat

Rat

Rat

ESTERS

General Features of Toxic Exposure

Esters are synthesized from organic acids and alcohols as follows:

The loss of polarity evidenced by this reaction causes the ester

to have a higher lipid solubility, liquid phase at. room temperature, and lower boiling point than the alcohols. Because esters

are liquids and have high nonpolar solubility they can be used as

plasticizers and lacquer solvents.

As with the ketones, esters are capable of producing eye, skin,

and mucous membrane irritation. In this, the lower molecular

weight esters are more potent than the corresponding alcohols.

For example, ethyl acetate is more irritating than ethanol. However, chronic exposure does not produce observable eye disease.

Halide esters are the most potent eye and skin irritating compounds of this class. It is thought that these halide esters bind

sulfhydryl groups,

Central nervous system depression is the primary effect of volatile esters. esters of highest molecular weight having the greatest

anesthetic. effect Because esters have higher solubility than

ketones, they are not excreted as readily through the lungs.

Metabolism

Esters are converted in the body to the original alcohol and acid.

Whole blood can metabolize ethyl acetate to ethanol and acetate.

116
However, the biological half-life of ethyl acetate in rat whole

blood in vitro is 65 minutes versus only 5 minutes in vivo. The

pseudo-cholinesterase of blood is thought to be responsible for

the whole blood breakdown of ethyl acetate, whereas the liver is

thought to contribute to the short in vivo half-life. Inhalation of

20,000 ppm and above causes increased ethylacetate over ethanol,

suggesting saturated biotransformation.

Acute Toxicity of Esters

Data are available on the effects of exposure to esters in a variety of species; a principle source of the data in Table 2 is Patty

(1963).

TABLE 2

ACUTE TOXICITY OF ESTERS

TLV (ppm) Compound ppm/Duration Effect Species

200 Methyl acetate

400 Ethyl acetate

22,000/2-1/2 hr

10,000/22 hr

12,000/5 hr

20,000/3/4 hr

200 n-Propyl acetate

150 n-Butyl acetate

24,500/1/2 hr

17,500/1/2 hr

100 Methyl formats

100 Ethyl formate

50,000/l/2 hr

10,000/80 min

Lethal 100% Cat

Lowest

narcotic

concentration

Oeep narcosis

(recovered)

Narcosis/death

Narcosis

some lethal

Lethal 100%

Narcotic and

lethal 100%

Cat

Cat

Cat

Cat

G. Pig

Cat

KETONES

General Features of Source and Exposure

Ketones are largely produced from petrochemicals by dehydrogenation of a secondary alcohol. Their use ranges from solvents for

inks, paints, and resins, to intermediates in organic synthesis, to

specialty products such as perfumes.

The current threshold limit value for aliphatic ketones is based

primarily on an irritation threshold. Subnarcotic levels of

ketones produce eye, nose, and mucous membrane irritation

sufficient to prevent acute overexposure.

117
Industrial exposure to ketones occurs in painting, printing,

cleaning, and plastic processing operations. The extreme flammability of ketones has caused their replacement by higher flash

“Safety Solvents” and thus has tended to reduce defatting

injuries to the skin. Eye irritation is a common complaint in

situations where high concentrations are volatilized.

Generally, narcotic effects occur in animals exposed to high

concentrations of ketones with death due to respiratory depression. Animals will recover from otherwise lethal concentrations if

they are removed to fresh air, indicating that excretion of the

inhaled solvent is mostly through the lungs.

Acute Toxicity of Ketones

Data are available on the effects of exposure to ketones in a

variety of species; a principle source of the data in Table 3 is

Patty (1963).

TABLE 3

ACUTE TOXICITY OF KETONES

TLV (ppm) Compound ppm/Duration Effect Species

1,000

200

200

25

75-100

(range)

50

100

Acetone

Methyl ethyl ketone

Methyl propyl ketone

Methyl n-butyl ketone

Methyl hexyl ketone

46,000/1 hr Lethal 100%

20,256/1-1/2 hr Narcotic

3,000/2 hr Lethal 50%

30.000/3/4 hr Lethal 100%

5,000/3/4 hr Lethal 100%

1,300/1 hr Narcotic

Di-isobutyl ketone

Methyl amyl ketone

2,000/8 hr

4,800/4-8 hr

Lethal 100% Rat

Narcosis/death G. Pig

Mouse

Mouse

Rat

G. Pig

G. Pig

G. Pig

Methyl Ethyl Ketone

Methyl ethyl ketone (MEK; CH3COCH2CH3) is used as a solvent

for cellulose products in the plastics industry and in paints and

lacquers. It is a CNS depressant and causes irritation of the

mucous membranes. Nelson et al. (1953) reported slight nose and

throat irritation at 100 ppm and mild eye irritation at 200 ppm.

Their recommendation for exposure limit was 200 ppm based on

these irritant properties.

118
Acute toxicity of MEK vapors is low: Guinea pigs survived

l-minute exposures to 100,000 ppm and l-hour exposures to 10,000

ppm. The latter produced irritation of the eyes and nose soon

after the start of exposure with narcosis after 4 to 5 hours.

In high concentrations MEK produces CNS depression, emphysema

in lungs, and congestion of the liver and kidneys. Since MEK is

less soluble in water than acetone, it is more rapidly eliminated in

the lungs.

Little serious injury to humans from MEK exposure has been

documented. Skin exposed to a solution of MEK or its vapors has

developed dermatitis, and fainting occurred due to MEK exposure

(300-500 ppm exposure) (Smith and Mayers, 1944). These authors

also report a numbness of fingers and arms in workers exposed to

MEK vapor and liquid.

Acetone

Acetone (CH3COCH3) is a common industrial solvent for resins,

lacquers, oils, paints, acetylene, and fats. It is the most volatile

of the aliphatic ketones and easily produces dermatitis by defatting the skin. Acetone is highly flammable and has a flashpoint

of 0° F (-17.8° C).

Acetone is rapidly taken up by inhalation. Kagan (1924) found

that 71 percent of inhaled acetone (9,300 ppm) is absorbed in a

5-minute exposure. Human exposures have shown acetone to be

irritating to the eye, nose, and throat at 500 ppm. Exposure to

700 ppm produced severe irritation initially but shortly after

initial contact, 700 ppm was undetectable by odor or irritation.

After acclimation, 2,500-3,000 ppm caused only slight eye and

nose irritation.

Acetone has a very high solubility in water. The distribution

between alveolar air and blood (water) is 1:333 (Briggs and

Shaffer, 1921), indicating a large amount of inhaled acetone would

be retained. Since physiological dead space is 24 percent, the

predicted retention of acetone would be 76 percent; this agrees

well with Kagan’s aforementioned 71 percent retention.

Once inhaled, acetone is largely excreted unchanged by the lungs

with no reduction. Small (1.7 mg/kg) oral doses are found to be

oxidized almost completely (Price and Rittenberg, 1950). 14Cmethyl-acetone has been found in choline, methionine, and the 1,6

positions of glycogen, suggesting that acetone can be cleaved to

acetate and formate. Formate then enters one carbon pool to

reappear in choline, methionine, and glycogen; 14C-methyl-acetate

appears in acetylated compounds and the 2,5 positions of

glycogen.

119
Despite widespread use of acetone in commercial and industrial

products. few cases of industrial poisoning have been reported.

The most common effect is dizziness due to anesthetic concentralions and irritation to mucous membranes at lower concentrations.

Lacrimation, salivation, and giddiness follow exposure to acetone.

A threshold limit value of 1,000 ppm is set for acetone.

Methyl n-Butyl Ketone and

Ketones Derived from Hydrocarbons

Methyl n-butyl ketone (MBK; CH3CO(CH2

)3CH3) has also been

shown to cause peripheral neuropathy in man (Allen et al., 1975).

In a study of 86 cases of peripheral neuropathy from a plastic

coatin operation. 11 were severe with both motor and sensory

involvement, 38 were mild, primarily showing sensory impairment,

and 37 were virtually asymptomatic with characteristic electromyographic changes.

Incidence of these cases was highest for members of the printing

shop (21.5 percent of employees there). Printing operators, with

greatest contact with the printing inks and solvents, had an

incidence rate of 36.1 percent, followed by pan washers (28.6

percent). No symptoms were noted before December 1972, indicating that the disease was of recent origin. In August 1972,

MBK had replaced methyl isobutyl ketone as a printing ink solvent.

Airborne concentrations inhaled by printers averaged about 9 ppm

MBK and 331 ppm MEK. Other plants which produced similar

products using solvents other than MBK showed no neurotoxicity.

(Chief clinical signs are as follows: gradual onset of sensory loss,

predominately distal proceeding to proximal regions. In more

severe cases, motor invovement occurs with sparing of proprioception and reflexes (large fibers spared). Progression of symptoms persists in spite of cessation of exposure, but gradual

recovery follows.

Electron microscopic examination of single teased nerves shows a

paranodal denudation of myelin with focal internodal myelin loss.

Axonal swelling with increased numbers of microfilaments appear,

Schwann cells remaining intact.

Hexane is also described here since recent evidence indicates that

hexane is biotrunsformed to hexanol and 2,5 hexanedione. The

latter ketone can cause neurotoxicity similar, if not identical, to

that of n-hexane. Yamamura (1969) found hexane to be neurotoxic to workers. Two workers using hexane as a glue solvent in

the manufacture: of sandals became quadriplegic. Survey of other

employees revealed 93 cases of polyneuropathy, all of whom were

involved in gluing sandals in their own homes. Gas chromato120
graphic analysis of the rubber paste solvent revealed 70 percent

n-hexane with a small amount of toluenc. Environmental concentrations of hexane varied widely, from 500 to 2,500 ppm.

Of the 93 workers in Yamamura’s study, 53 experienced sensory

polyneuropathy and 32 had sensorimotor polyneuropathy; 8

showed muscle atrophy upon examination.

Yamada (1927) found two plants where hexane was used and noted

17 workers showing evidences of polyneuropathy: fatigue and

loss of appetite initially, followed by distal sensory paresthesia

and difficulty in walking. Three months after cessation of exposure, the progression of disease was stopped with gradual recovery over the next 2 years.

Herskowitz (1971) investigated a polyneuropathy outbreak in

cabinet-finishing workers. Air analysis revealed an average

concentration of 650 ppm hexane with peak excursions of 1,300

ppm. Electron microscopy of muscle anterior tibialis showed two

types of axonal changes:

1. Increased neurofibrils and abnormal membranous structures, and

2. Clumping and degeneration of mitochondria within the

axon with many onion bulb structures.

These workers applied the solvent. in a small, poorly ventilated

room (3.6 m by 3.6 m), taking the hexane from an open 189-liter

drum. The dipping of rags into the drum and wiping of excess

glue from finished cabinets also led to cutaneous exposure.

Swann et al. (1974) exposed mice to 64,000 ppm n-hexane and

found respiratory arrest occurring within 2-1/2 to 4-1/2 minutes.

These authors found that 32,000 ppm produced deep anesthesia

(in mice) but 16,000 was not anesthetic. Truhaut et al. (1973)

exposed Wistar rats to hexane (2,000 ppm) and heptane (1,500

ppm) for 1 to 6 months. These exposures reflected occupational

contact 5 hours/day, 5 days/week. Technical grade hexane was

used and consisted of only 15 percent n-hexane. Sciatic anti

saphenous nerves were excised and removed after 1, 2, and 5

months of exposure. Electrophysiological analysis showed a

decreased nerve conduction velocity and excitability with an

increased refractory period.

SOLVENT MIXTURES

Most inhalation toxicity tests have been done with reagent grade

(pure) substances. Little is known about the uptake, distribution, and retention of solvents when inhaled as mixtures.

121
It has been shown that methyl ethyl ketone will increase both

plasma levels and toxicity of methyl butyl ketone.

Since no commercial or industrial preparations are so pure, inhalation will be of solvent mixtures. Therefore, attention should be

paid to possible potentiation of toxicity of one solvent by mixtures

(Couri and Abdel-Rahman, 1977).

REFERENCES

Allen, N., J. Mendell, D. Billmaier, R. Fontaine, and J. O’Neill.

Toxic polyneuropathy due to methyl n-butyl ketone. Arch

Neurol, 32:209-11, 1975.

Briggs, A. , and P. Shaffer. The excretion of acetone from the

lungs. J Biol Chem, 48:413, 1921.

Couri, D., and M. Abdel-Rahman. Toxicological evaluation of

intentionally inhaled industrial solvents. Presented at the First

International Symposium on Voluntary Inhalation of Industrial

Solvents, Mexico City, June 1976.

Herskowitz, A., N. Ishii, and H. Schaumburg. N-Hexane

neuropathy. N Engl J Med, 285:82-5, 1971.

Kagan, E. Experimentelle studien uber den einsluss technisch

und hygienish wichtiger Gase und Dampse auf den organismus.

Arch Hyg, 94:41, 1924.

Lester, D., and L. Greenberg. Inhalation of alcohol. Quart J

Stud Alc, 12:167, 1951.

Loewy, A., and R. Von Der Heide. Taking up of ethanol by the

lungs. Biochem Z, 86:125, 1918.

Lund, A. Rational treatment of formaldehyde poisoning. Acta

Pharmakol, 4:208, 1948.

Nelson, K., J. Ege, Jr., M. Ross, J. Woodman, L. Silverman.

Sensory response to certain industrial solvent vapors. Ind Hyg

Toxicol, 25:252, 1953.

Potts, A., and L. Gonasun. In: Toxicolology: The Basic Science

of Poisons, L. Casarett and J. Doull, eds., p. 299. Macmillan

Publishing Company, Inc., 1975.

Potts, A., J. Praglin, I.

Studies on the visual

40 :76-82, 1955.

Farkas, L. Orbison, and D. Chickering.

toxicity of methanol. Am J Ophthalmol,

122
Price, T., and D. Rittenberg. Metabolism of acetone. I. Catabolism and excretion. J Biol Chem, 185:449, 1950.

Rowe, V., and M. Wolf. Ketones.

Toxicology,

In: Industrial Hygiene and

volume II, F. Patty, ed., pp. 1719-50. Wiley-Interscience, 1963.

Rubin, E., and C. Lieber. Alcoholism, alcohol, and drugs,

1971. Science, 172 : : 1097, 1971.

Smith, A., and M. Mayers. Poisoning and fire hazard of

butanone and acetone. Ind Bull, NY State Dept Labor, 23:194,

1944.

Swann, H., B. Kwon, G. Hogan, and W. Snelling. Acute inhalation toxicology of volatile hydrocarbons. Am Ind Hyg Assoc J,

35:511-8, 1974.

Truhaut, R., P. Laget, G. Piat, P. Nguyen, H. DutertreCattella, and V. Huyen. First electrophysiological results after

experimental intoxication of the albino rat with technical hexane

and heptane. Prof Med Trav Secur Soc, 34:417-26, 1973,

Yamada, S. Polyneuritis in workers exposed to n-hexane, its

cause and symptoms. (Jpn) J Ind Health, 9:651-9, 1972.

Yamamura, Y. n-Hexane polyneuropathy

(Jpn), 23:45-57, 1969.

Folia Psychiatr Neural

123
Chapter 9

TOXICOLOGY OF ALIPHATIC AND

AROMATIC HYDROCARBONS

James V. Bruckner and Richard G. Peterson

AROMATIC HYDROCARBONS

The aromatic hydrocarbons are a series of cyclic compounds which

are based upon benzene as the parent compound. They may be

monocyclic or polycyclic and differ from one another not only in

the number of rings, but degree and placement of alkyl substitution on the ring(s). Coal and petroleum are the chief sources

of aromatic hydrocarbons. Various methods of catalytic reforming

or fractional distillation are employed to obtain them from the

crude products. Aromatic hydrocarbons are mostly insoluble in

water, but freely miscible in other organic solvents. The aromatics are used individually as solvents and as synthetic substrates. A number of aromatics are also major components of

common hydrocarbon mixtures.

Benzene

Benzene (C6H6 ; benzol, phenyl hydride, cyclohexatriene) is a

volatile, highly flammable liquid with a characteristic odor. It is

only slightly soluble in water, but freely soluble in alcohols and

other organic solvents. Benzene is obtained as a byproduct from

petroleum and coke oven emissions. Benzene is used as a substrate in the manufacture of many aromatic compounds, and as a

solvent for waxes, resins, plastics, lacquers, varnishes, and

paints. The use of benzene as a solvent has been more limited in

124
recent years, due to its recognized myelotosic potential. Benzene

is nevertheless often present in varying quantities in hydrocarbon

solvent mixtures, including gasoline (Parkinson, 1971; Runion,

1975) and assorted thinners and solvents (Carpenter et al.,

1975-1976).

Absorption and Distribution

Inhaled benzene is rapidly absorbed into the blood and distributed throughout the body (Schrenk et al., 1941). In studies

involving exposure to relatively low vapor levels (25-100 ppm),

humans quickly approach a steady-state or equilibrium between

inhaled and exhaled vapor concentrations (Srbova et al., 1950;

Hunter, 1966). This equilibrium is largely governed by the

solubility of benzene in the blood, as data discussed by Patty

(1958) show rapid saturation of the blood in such circumstances.

Approximately 50 percent. of inhaled benzene is retained in subjects in these studies, although individual variability is pronounced Because of its lipophilicity, benzene is distributed to

tissues according to their fat content.. The highly perfused

lipoidal tissues, including the brain. are anticipated to most

rapidly accumulate benzene. This phenomenon would account. for

the rapid onset of narcosis upon exposure to concentrated organic

solvent vapors. The bone marrow possesses a quite high tissue/

blood partition coefficient for benzene, due to a high neutral fat

content (Sato et al., 1974). This is undoubtedly an important

factor in consideration of benzene’s myelotoxicity

Upon cessation of solvent exposure, benzene is eliminated from

the body at a rate dictated by a number of interdependent factars, including alveolar ventilation, blood/tissue partition coefficients, blood/air partition coefficient, and metabolism. Benzene

levels in the blood and exhaled air fall quickly during desaturation (Hunter, 1966; Sato et al. , 1974). The human studies of

Srbova et al. (1950) and Sato et al. (1974) indicate that roughly

30-50 percent of systemically absorbed benzene is exhaled, which

agrees with findings of Parke and Williams (1953) in orally dosed

rabbits. Those tissues with greater blood perfusion and lower

lipid content will lose benzene most rapidly, while the poorly

perfused adipose tissue will most slowly release benzene. This

concept is supported by findings of Hunter and Blair (1972) that

more obese persons excrete larger proportions of inhaled benzene

as urinary metabolites than do their “slimmer” counterparts.

Adipose tissue apparently acts as a depot from which benzene is

gradually released and subject to metabolism.

Metabolism

The majority of benzene which is not exhaled is metabolized in the

liver to phenolic derivatives. These are excreted principally as

urinary sulfates and glucuronides. In an early study with

rabbits, Parke and Williams (1953) recovered approximately 35

125
percent of an oral dose of benzene as urinary metabolites within 2

days of dosing. Conjugates of phenol comprised the majority of

these metabolites, while less significant quantities of catechol,

quinol, hydroxyquinol, trans- trans-muconic acid, and phenylmercapturic acid were present. Cornish and Ryan (1965) found

that 23 percent of an intraperitoneal (i.p.) dose of benzene was

excreted within 24 hours by rats as free or conjugated phenols.

Some variance in the metabolic fate of phenol in 19 species of

animals including man has been demonstrated, with the major

difference being in the preponderance of ethereal sulfate or

glucuronide conjugates (Capel et al., 1972). The quantity of

urinary phenols (Walkley et al., 1961; Hunter and Blair, 1972) and

the urinary inorganic/organic sulfate ratio (Elkins, 1959; Gerarde

and Ahlstrom, 1966) have been advocated as indices of industrial

exposure to benzene. The in vitro metabolism of benzene by the

microsomal mixed function oxidase system has been reviewed in

detail by Snyder and Kocsis (1975).

Acute Toxicity

The acute toxicity of benzene resembles that of other hydrocarbon

solvents. Exposure to high concentrations of benzene vapors may

produce irritation of the eyes, nose, and respiratory tract. The

nature and severity of symptoms depend upon the time and level

of exposure. Effects seen in man (Gerarde, 1960) range from

exhilaration, dizziness, and headache to fatigue, vertigo,

dyspnea, and collapse. Svirbely et al. (1943) report a 7-hour

LC50 for benzene in mice of about 10,000 ppm, while Drew and

Fouts (1974) find the 4-hour LC50 in rats to be 13,700 ppm.

Rabbits subjected to levels as high as 35,000 to 45,000 ppm live

an average of 36 minutes before succumbing to benzene narcosis

(Carpenter et al., 1944).

Marked individual variation in susceptibility to the acute lethal

effect of benzene suggests that the solvent cannot only produce

respiratory arrest in deeply anesthetized persons, but may predispose to cardiac failure. Early studies utilizing the cat and

monkey (Nahum and Hoff, 1934) and the dog (Chenoweth, 1946)

indicate that inhaled benzene sensitizes the myocardium to

epinephrine, resulting in ventricular arrhythmias. This mechanism is implicated in numerous human fatalities in both occupational

settings (Browning, 1965; Tauber , 1970) and in instances of

solvent abuse (Winek et al. , 1967; Bass, 1970; Winek and Collom,

1971). Physical exertion and/or emotional excitement often associated with these fatal cases may contribute to the victim’s demise

by liberating epinephrine.

Organ Toxicity

General. Direct organ damage, other than myelotoxicity, has only

rarely been attributed to acute or chronic benzene exposure in

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humans and experimental animals (Browning, 1965; Snyder and

Kocsis, 1975). Modest, variable effects on body weight gain,

organ weight, and histology of the liver, kidney, spleen, and

testes were occasionally seen in rats, guinea pigs, and rabbits

subjected for 7 hours daily to benzene vapors for as long as 11

months (Wolf et al., 1956). Determinations of levels of various

serum enzymes have failed to reveal significant organ damage

upon chronic exposure of rats, guinea pigs, monkeys, and dogs

(Jenkins et al., 1970), and upon acute exposure of rats

(Wirtschafter and Cronyn, 1964) and guinea pigs (DiVincenzo and

Krasavage, 1974) to benzene.

Myelotoxicity. The most significant toxic action of benzene is

upon the blood-forming elements of the body. This toxic effect is

thought to be unique, in that simple alkyl substitution of the

benzene ring apparently negates myelotoxicity. Although susceptibility and hematologic findings vary markedly among individuals , classic benzene-induced abnormalities include anemia, leukopenia, and thrombocytopenia. These alterations in the circulating

blood may also be elicited in a variety of animals, although leukopenia appears here to be the most sensitive and consistent manifestation of benzene exposure. Benzene is believed to produce

chromosomal abnormalities in humans and animals, as well as

induce leukemias in humans (Vigliani and Forni, 1976). It is

beyond the scope of the present. discussion to relate in detail the

majority of topics pertaining to benzene myelotoxicity . This

subject matter is reviewed in detail in a Criteria Document (1974)

and Snyder and Kocsis (1975).

A variety of factors have been considered as potentially important

in benzene myelotoxicity Shils and Goldwater (1949) found that

inadequate dietary protein intake by dogs and rats predisposed to

benzene-induced blood dyscrasias, raising the possibility of

altered formation, intracellular binding, and conjugation of toxic

metabolites. Although a history of infection preceding symptoms

of benzene poisoning has been recorded on occasion, it appears

more likely that. increased susceptibility to infection will result

from benzene-induced leukopenia. It has been widely held that

women are more prone to chronic benzene poisoning than are men,

and that. the young are more susceptible than adults. Animal

studies have been conducted which support this concept

(Hirokawa and Nomiyama, 1962; Ikeda, 1964; Nomiyama et al.,

1965). These age and sex differences in experimental animals

have generally been linked to differences in benzene metabolism.

The relationship of animal studies to man is quite tenuous, however, since marked sex differences in chemical metabolism seen in

animals (e.g., rats) likely (10 not occur in humans. Although

certain epidemiologic studies and individual case reports have

supported the belief that sex and/or age are predisposing factors

in benzene myelotoxicity, sufficient numbers of findings to the

contrary have largely discounted this concept at present (Criteria

Document, 1974; Snyder and Kocsis, 1975). Nevertheless, marked

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individuality in resistancce to benzene poisoning cannot be overlooked. Factors including genetic variation, differences in degree

and duration of exposure. concomitant exposure to additional

chemicals and drugs, nutrition. general state of health , smoking

and drinking habits, age, sex, metabolic capability each may

contribute to the final outcome of benzene exposure.

Metabolites of benzene are believed to play an important role in

development of blood dyscrasias. Although the precise mechanism

of toxicity is unknown, it is widely held that metabolites must

interact with cellular constituents. Covalent binding of metabolites to DNA is advanced as a plausible explanation for such

findings in the bone marrow as inhibition of RNA and DNA synthesis (Moeschlin and Speck. 1967) , chromosomal abberations

(Kissling and Speck, 1969; Forni et al., 1971 a,b), abnormalities

and decreases in mitotic figures (Pollini et al., 1965), and diminished incorporation of radiolabeled iron into hemoglobin (Lee et

al., 1974). Lee and coworkers use this latter technique to demonstrate potentiation of benzene toxicity in phenobarbital-pretreated

mice, and protection from benzene toxicity in mice concomitantly

administered benzene and toluene. Under, these conditions phenobarbital is known to stimulate and toluene to competitively inhibit

benzene metabolism (Ikeda et al., 1972; Snyder., 1971). Interestingly, Ikeda and Ohtsuji (1971) and Mitchell (1971) report that

while phenobarbital stimulates metabolism of’ benzene in rats, the

rats are apparently protected against myelotoxicity. Mitchell

(1971) also notes that piperonyl butoxide, a microsomal enzyme

inhibitor, protects against benzene myelotoxicity.

Phenobarbital stimulates not only oxidation of benzene, but conjugation and excretion of benzene metabolites as well, thereby

likely affording the bone marrow protection from metabolites

formed in the liver. The metabolic changes measured by Ikeda

and Ohtsuji (1971) and Mitchell (1971) reflect largely handling of

benzene by the liver. Event:, occuring in the bone marrow,

however. would appear to dictate whether myelotoxicity develops

upon benzene exposure. Since large quantities of benzene accumulate in the marrow, it seems reasonable that highly reactive

metabolites formed in situ may simply bind to marrow elements and

exert a direct toxic effect. Parmentier (1953) did see abnormal

mitoses and chromosomal aberrations in the bone marrow of hamsters within 6 hours of intraperitoneal injection elf hydroquinone,

followed by appearance of pyknotic nuclei anti diminished numbers

of leukocyte mitoses within 24 hours. Harrison and Randoll (1948)

report that benzene is not toxic to cultures of bone marrow cells,

while phenol and pyrogallol are moderately toxic and catechol and

hydroquinone are very toxic. Nomiyama (1965) observes catechol

to be the most myelotoxic of a series of metabolic given rats by

subcutaneous injection. Findings of Mitchell (1971), that the major

benzene metabolites are largely nontoxic to the marrow when

given in vivo. suggest that these highly reactive and unstable

agents may not reach the marrow before being inactivated and/or

128
excreted. In order to clarify this phenomenon, the techniques of

Mitchell and Jollows (1975) might be employed to correlate covalent

binding of benzene metabolites with toxicity in the bone marrow.

Development of myelotoxicity upon benzene exposure has been

demonstrated to be both time and concentration dependent.

Although it has been difficult. to accurately correlate clinical

findings in victims with length and level of exposure, hematologic

abnormalities have been noted in workers breathing vapor concentrations as low as 40 to 80 ppm (Hardy and Elkins, 1948) and 30

to 150 ppm (Juzwiak et al., 1969). The period of benzene exposure prior to onset of symptoms may vary from months to years

(Hunter, 1939; Hardy and Elkins, 1948). Studies utilizing relatively high benzene vapor levels (600 to 1,000 ppm) have revealed

leukopenia in rats after approximately 1 week (Deichmann et al.,

1963; Nau et al., 1966; Ikeda and Ohtsuji, 1971). Deichmann et

al. (1963) found 47 ppm to be the minimum toxic concentration,

with 15 and 30 ppm exerting no leukopenic action within exposure

periods of 90 and 215 days, respectively. Evaluations of more

sensitive histological and biochemical parameters have revealed

adverse effects within hours of administration of relatively high

doses of benzene or its metabolites to animals (Parmentier, 1953;

Wirtschafter and Bischel, 1960; Lee et al., 1974). Gerarde (1960)

has stated that a single, high-level exposure to benzene may

result in development of myelotoxicity, although concrete evidence

appears to be lacking. Based on the foregoing evidence, the

current standard for occupational benzene exposure was set at 10

ppm (Criteria Document, 1974), however, an emergency standard

of 1 ppm has recently been implemented.

Potential Health Risks

Gasoline. Individuals who abuse solvents containing substantial

quantities of benzene would appear to face the potential risk of

myelotoxicity Many commercial solvent mixtures contain benzene

in varying amounts, ranging from a trace to as high as 50 percent by volume (v/v). There are no present restrictions on the

sale or use of commercial products or fuels containing benzene,

other than precautionary labeling of household products. Benzene exposure is of particular concern in the gasoline industry,

such that exposure standards for gasoline in the United States

are now based upon benzene content. A recent study (Runion,

1975) relates that representative United States gasolines contain

an average of about 1% (v/v) benzene, while European gasolines

contain an average of 5% (v/v) or more. Runlon (1975). and

others (Parkinson, 1971; Sherwood, 1972) conclude that it is

unlikely industrial workers handling gasoline are at risk under

properly controlled conditions. The gasoline abuser, however,

may readily exceed the benzene threshold limit value, since he

subjects himself to such high vapor concentrations. Based on

responses seen in early human studies of Fieldner et al. (1921)

and Drinker et al. (1943), the gasoline abuser could be expected

129
to intoxicate himself within 1 to 3 minutes by inhaling 20,000 to

30,000 ppm of gasoline. The degree of benzene exposure would

of course depend upon a number of variables, including among

others benzene content of the gasoline, inhalation time, and

interval elapsed between inhalation periods and sessions.

Other mixtures. Myelotoxicity should also be considered a hazard

upon abuse of benzene-contaminated solvents other than gasoline.

Deichmann et al. (1963) exposed rats to vapors of a solvent

containing 7% benzene in hexane and noted leukopenia within 3

weeks. Mean benzene vapor levels were found to be approximately 60 ppm. It should be recalled here that the majority of

occupational cases of benzene-induced blood dyscrasias involved

solvent mixtures. The role of other solvents in benzene myelotoxicity has yet to be elucidated.

Blood dyscrasias are observed in individuals who abuse solvents,

although such findings are not commonplace in this population.

Commercial products which have been associated with blood

dyscrasias include plastic cements, glues, rubber cements, gasoline, and paint thinners. Hematologic abnormalities reported

include eosinophilia (Massengale et al., 1963; Sokol and Robinson,

1963; Press and Done, 1967), lymphocytosis (Massengale et al.,

1963), anemia (Edwards, 1960; Powars, 1965), hemoglobin reduction

(Lawton and Malmquist, 1961; Powars, 1965), basophilic stippling

of erythrocytes (Christiansson and Karlsson, 1957; Sokol and

Robinson, 1963), and hypoplastic bone marrow (Christiansson and

Karlsson, 1957; Powars, 1965). Individual responses to solvent

exposure within groups of patients in each study are quite variable. Some patients demonstrate no hematologic abnormalities,

while others show alterations of varying magnitude in one or more

parameters. Such discrepant findings are typical of occupational

exposure to benzene-contaminated gasoline (Amorati et al., 1952;

McLean, 1960; Verwilghen et al. , 1975) and likely reflect not only

individual susceptibility to benzene, but the length and pattern of

solvent abuse and the composition of abused solvent(s). Benzene

is generally considered to be responsible for blood dyscrasias in

solvent abuse cases, although neither benzene content nor vapor

levels have been accurately determined for commonly abused

products under conditions approximating self-intoxication.

Because benzene myelotoxicity is so variable and insidious, the

condition may go largely unrecognized and undiagnosed in the

solvent abuser. There is an obvious need not only for control

and recognition of benzene content of commercial products, but

for delineation of the nature and conditions under which myelotoxicity can result from abuse of benzene-contaminated solvents.

Toluene

Toluene (C6H5CH3; methylbenzene, toluol, phenylmethane) is a

volatile, flammable liquid at room temperature, with a benzene-like

odor. It is very slightly soluble in water, but freely soluble in

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alcohol, acetone, chloroform, and other organic solvents. Toluene

is used as a starting material in the manufacture of a variety of

organic compounds. It is also commonly employed as a solvent or

thinner for paints, varnishes, enamels, lacquers, gums, fats, and

resins.

Absorption and Distribution

Toluene is rapidly absorbed upon inhalation and distributed

throughout the body, with lipids in the various tissues acting as

an extensive reservoir (Sato et al., 1974). Despite inhalation of

as high a vapor concentration as 4,000 ppm for 3 hours, saturation in the liver and brain of the mouse is not reached (Peterson

and Bruckner, 1976a). Toluene that is not exhaled is largely

metabolized by the liver to hippuric acid and excreted by the

kidneys. The measurement of urinary hippuric acid is used as an

index of human exposure to toluene in industrial settings (Ikeda

and Ohtsuji, 1969; Ogata et al., 1971).

Acute Toxicity

Relatively little animal experimentation has been conducted to

delineate the toxicologic properties of toluene. Svirbely et al.

(1943) report that the LC50 for a 7-hour inhalation exposure of

mice to toluene is 5,300 ppm, while Kimura et al. (1971) report the

oral LD50 for adult rats to range from 6.4 to 7.4 ml/kg. Toluene, like other hydrocarbon solvents, acts acutely as a narcotic.

The degree of central nervous system (CNS) depression produced

by toluene inhalation is, of course, both time- and concentrationdependent. The onset of toluene-induced narcosis is quite rapid

upon inhalation of high vapor concentrations. CNS depression in

mice, as evidenced by loss of coordination, is manifest within 5

minutes of inhalation of 10,600 ppm toluene (Peterson and

Bruckner, 1976b). Kojima and Kobayashi (1973) report that rats

exposed to 20,000 ppm of toluene die within 30-50 minutes. The

average toluene level in the brain of the animals at death is 0.89

mg/g of tissue.

Inhalation of toluene by humans is reported to elicit a variety of

manifestations of narcosis, ranging from diminished psychomotor

performance and fatigue upon low-level exposure (Von Oettingen

et al., 1942; Gamberale and Hultengren, 1972) to intoxication and

unconsciousness upon high-level exposure (Lurie, 1949; Longley

et al., 1967). Although it was felt that the current threshold

limit value of 100 ppm for toluene (Criteria Document, 1973) would

protect workers from any depressant effects, studies by Astrand

(1975) have demonstrated that exercise may enhance total uptake

of a variety of solvents sufficiently to impair certain mental

functions in human subjects (Soderlund, 1975).

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Organ Toxicity

Animal. Toxicity studies of animals subjected to prolonged toluene inhalation have revealed little evidence that toluene exerts a

biologically significant toxic action on any organ system. Early

reports of toluene-induced myelotoxicity have been discounted in

that toluene was then likely contaminated by benzene. High

concentrations of toluene have been reported to have a limited

irritant effect on the lungs, liver, and kidneys in several species

of animals (Svirbely et al., 1943; Fabre et al., 1955). This

histopathologic manifestation was apparently of minor consequence,

in that no evidence of cumulative injury on repeated toluene

exposure was noted. In a later study of several species of

animals, 30 daily sessions of exposure to 1,085 ppm toluene over a

6-week period failed to alter body weight gain, hematologic parameters, or organ histopathology (Jenkins et al., 1970). Bruckner

and Peterson (1976), utilizing the mouse as an animal model of

human solvent abuse, failed to detect lung, liver, or kidney

injury in animals subjected for 3 hours for 5 of 7 days at 4,000

ppm of toluene vapor for up to 8 weeks.

Inhalant abuse subjects. Liver and kidney injury have occasionally been noted in persons who have abused toluene (Grabski,

1961; Massengale et al., 1963; Sokol and Robison, 1963; Barman et

al., 1964; Press and Done, 1967; O’Brien et al., 1971; Pinkhas et

al., 1972; Taher et al., 1974). Those investigators who did see

evidence of hepatorenal injury in certain patients generally found

the damage to be mild and transitory. The more severe cases of

injury commonly involved exposure to mixed solvents, or both

solvents and drugs.

There have been widely scattered reports of other forms of toxicity in persons who intentionally inhale vapors of products containing toluene. Grabski (1961) and Knox and Nelson (1966)

reported brain damage in an individual who regularly abused

toluene Cerebellar dysfunction was more recently reported in

another patient who had repeatedly sniffed toluene-based spray

paint (Kelly, 1975). Blood dyscrasias have been seen following

abuse of products containing toluene in combination with other

solvents (Powars, 1965; Pinkhas et al., 1972). A variety of

hydrocarbon solvents, including toluene, have been implicated in

“sudden sniffing death” (Winek et al., 1968; Bass, 1970; Winek

and Collom, 1971). Taylor and Harris (1970) found that toluene

produced electrocardiographic abnormalities and sensitized the

heart to asphyxia-induced atrioventricular block, thereby predisposing to ventricular fibrillation or arrest.

Potential Health Risks

Toluene has been shown to alter the metabolism of a number of

other solvents. The biotransformation of benzene and styrene

(Ikeda et al., 1972) and of trichloroethylene (Ikeda, 1974) are

132
inhibited upon coadministration of toluene. Ikeda and Ohtsuji

(1971) also observed that phenobarbital-pretreated rats were

tolerant to toluene narcosis, apparently as a result of an increased ability to metabolize toluene. Toluene, in combination

with certain chemicals, has been shown to the more actuely toxic

than would be predicted on the basis of simple additive toxicity

(Smyth et al., 1969).

With the exception of cardiac sensitization, there is little firm

evidence that toluene exerts a specific toxic effect on any organ

system in experimental animals or in man. Even repeated inhalation exposures to high levels of the solvent do not appear to

result in significant injury. There is firm evidence, however,

that toluene may markedly alter the metabolism of other solvents.

Since abused commercial products commonly contain mixtures of

solvents including substantial amounts of toluene, the role of

toluene in potentiation of toxicity of the other solvent. components

deserves thorough investigation.

Xylene

Xylene (C 6H 4(CH3) 2; xylol, dimethyl benzene) is a volatile,

flammable liquid at room temperature. It is practically insoluble

in water, but freely miscible with most organic liquids. Xylene

exists in three dimethyl isomeric forms: 1,2 (ortho); 1,3 (meta);

1,4 (para). Xylene is produced from both petroleum and coal tar,

and is used as a solvent or filler in a myriad of commercial products including paints, lacquers, varnishes, dyes, inks, cements,

cleaning fluids, gums and resins, oils, rubber, and gasoline.

Xylene is also used in the chemical industry as a synthetic intermediate. Because of such widespread use and availability, there

is a potential for abuse of xylene.

Acute Toxicity

Like other organic solvents, xylene has both direct irritant and

CNS depressant actions upon inhalation. Based on subjective

responses of humans, 200 ppm of xylene was reported to be

slightly irritating to the eyes, nose, and throat, but to have

little recognizable depressant effect (Nelson et. al. , 1943;

Carpenter et al., 1975). Eye irritation was seen in the latter

study in rats exposed to levels of mixed xylenes as low as 1,300

ppm. Mild, reversible corneal damage was reported in German

industrial workers (Schmid, 1956; Matthaus, 1964) and in rabbits

(Wolf et al., 1956) exposed to xylene. Respiratory irritation

occurred in some rats subjected acutely to levels exceeding 1,000

ppm (Carpenter et al., 1975). Pulmonary edema and hemorrhage

were seen at autopsy in one of three painters who died after

being overcome by vapors of a solvent containing 90% xylene

(Morley et al., 1970). Subjective symptoms of narcosis such as

“lightheadedness” and “giddiness” have been reported in other

industrial exposure cases involving xylene (Goldie, 1960; Glass,

133
1961). The threshold limit value for industrial exposures in the

United States was set at 100 ppm (Criteria Document, 1975). It

was felt that this standard would protect against minimal irritation

or depressant effects which might impair attention, judgment, or

perception.

Results of inhalation studies of the relative acute toxicity of the

isomers of xylene and related solvents, such as toluene and

benzene) are conflicting. Consideration of the reports leads one

to conclude, however, that each is of the same order of acute

toxicity. Individual isomers (Cameron et al., 1938) are seemingly

equivalent in narcotic potency/acute toxicity with mixed xylene

vapors (Carpenter et al., 1975). Carpenter and coworkers report

the 4-hour LC50 for rats to be 6,700 ppm, and the LT50 at 11,000

ppm to he 92 minutes. Prostration of the animals was Seen within

20 minutes at the 11,000 ppm level.

Metabolism

Upon systemic absorption, xylene is metabolized primarily to toluic

acid. Bray et al. (1949) demonstrated in rabbits that from 60 to

88 percent of the three isomers were oxidized to their corresponding toluic acids, with formation of xylenols a relatively minor

pathway. These findings are confirmed in later studies in

rabbits, rats, and guinea pigs (Fabre et al., 1960; Bakke and

Scheline, 1970) and in humans (Ogata et al., 1970). Ogata and

coworkers state that m- and p-xylene are metabolized in man

principally to m- and p-hippuric. acid, which can be readily

quantitated in the urine. The rapidity of formation and excretion

of these relatively nontoxic metabolites, coupled with the small

amounts of phenolics produced, is believed responsible for the low

degree of systemic toxicity usually seen upon xylene exposure.

Organ Toxicity

Systemic toxicity has been attributed on occasion to xylene inhalation Although early investigators believed that xylene shared

myelotoxic properties with benzene, more recent studies (Speck

and Moeschlin, 1968; Jenkins et al., 1970; Carpenter et al., 1975)

indicate that xylene uncontaminated with benzene does not exert

myelotoxicity Toxicity to the cardiovascular (Hirsch, 1932;

Sikora and Gala, 1957), female reproductive (Michon, 1965), and

skeletal (Kucera, 1968) systems has been reported in humans, but

not substantiated. Liver and/or kidney damage was diagnosed in

workers exposed to xylene (Ghislandi and Fabiani, 1957; Joyner

and Pegues, 1961; Morley et al., 1970). Fabre et al. (1960) saw

histopathologic evidence of renal injury in rats and rabbits subjected to mixed xylene vapors for up to 130 days, though Jenkins

et al. (1970) and Carpenter et al. (1975) could not detect

hepatorenal damage in several species of animals tested comparably. The absence of toxicity in these latter two studies may be

attributahle to an insufficient xylene exposure level. DiVincenzo

134
and Krasavage (1974) confirmed that xylene can cause liver injury, as demonstrated in guinea pigs by elevation of serum

ornithine-carbamyl transferase activity and liver lipids following

intraperitoneal injection of xylene. Whether xylene-induced

hepatorenal injury may occur under circumstances of solvent

abuse remains to be determined. As it has been proposed that

phenolic metabolites of xylene may be potent toxicants, concomitant exposure to agents which enhance xylenol formation may

potentiate xylene toxicity. Potential interactions of xylene with

drugs and with other solvents would therefore be worthy of

investigation.

Styrene

Styrene (C6H5CHCH2; vinylbenzene, phenylethylene) is a colorless, oily liquid with a penetrating, pungent odor. It is only

sparingly soluble in water, but quite soluble in organic solvents.

Styrene is used primarily as a solvent and substrate for synthetic

rubber and plastics.

Absorption and Acute Toxicity

Systemic absorption occurs readily upon inhalation of styrene

(Astrand, 1975), with systemic distribution largely dependent

upon lipid content of tissues. As with other organic solvents,

the highest styrene levels following inhalation are seen in adipose

tissue (Shugaev, 1969). Acute vapor exposure is characterized

by narcosis and by irritation of the nose, eyes, and throat.

Carpenter et al. (1944) report that humans exposed to 800 ppm of

styrene experience immediate irritation of mucous membranes,

followed by signs of significant CNS depression. Stewart et al.

(1968), in testing human subjects exposed to styrene vapor concentrations of approximately 50, 100, 200, and 375 ppm, report

both objective and subjective signs of irritation and narcosis only

at the highest solvent level. This finding is confirmed by recent

studies of Gamberale and Hultengren (1974). The current threshold limit value of 100 ppm is thus felt to protect the worker from

any distress. Shugaev (1969) observes a positive correlation

between concentration of styrene in the rat brain and degree of

styrene-induced narcosis. The 4-hour LC50 for styrene in the

rat is reported by Shugaev to be approximately 3,000 ppm, while

the 2-hour LC50 in the mouse is about 5,000 ppm.

Metabolism

Although a portion of systemically absorbed styrene is eliminated

via the lungs, the majority is apparently metabolized. Stewart et

al. (1968) estimate in humans that from 0.7 to 1.2 percent of the

total quantity of styrene absorbed upon inhalation is exhaled in

the first several hours postexposure. Danishefsky and Willhite

(1954) find that the rat rapidly metabolizes styrene, eliminating

over 85 percent of a subcutaneous dose within 24 hours. Approx135
imately 3 percent of the styrene is exhaled unchanged, 12 percent

exhaled as CO2, 71 percent excreted in the urine, and 3 percent

excreted in the feces. The pathways of metabolism of sytrene are

reviewed by Leibman (1975). The majority of styrene is believed

to undergo microsomal oxidation to styrene oxide, which is in

turn hydrated to form phenylethylene glycol. This intermediate

may be decarboxylated to produce benzoic acid and ultimately

hippuric acid, or oxidized to mandelic acid and phenylglyoxylic

acid. Although hippuric acid is a major metabolite in rodents

(Ohtsuji and Ikeda, 1971), styrene exposure does not lead to a

significant elevation of urinary hippuric acid in man (Stewart et

al., 1958; Ikeda et al., 1974). Rather, mandelic and phenylglyoxylic acids predominate and are used as indices of human

exposure to styrene. Pretreatment of rats with phenobarbital is

known to enhance formation of styrene metabolites, while coadministration of toluene or SKF 525-A inhibits styrene metabolism

(Ohtsuji and Ikeda, 1971; Ikeda et al., 1972).

Organ Toxicity

The acute toxic effects of styrene would appear to be due to the

parent compound, although metabolites may play a role in subsequent manifestations of injury. Ohtsuji and Ikeda (1971) find

styrene oxide to be four times as acutely toxic as styrene, although styrene glycol, mandelic acid, and phenylglyoxylic acid

are reported to be equally or less toxic than styrene (Vera and

Madlo, 1966). Reports of styrene-induced organ toxicity are quite

rare. Although two accounts of hepatotoxicity in workers exposed to styrene appear in the Russian literature (Kats, 1962;

Orlova and Solovera, 1962), the etiology of these injuries remains

unproven. Histopathological and hematological studies of several

species of laboratory animals, exposed to 1,300 ppm and 2,000

ppm of styrene daily for 6 months, fail to reveal significant toxic

effects (Spencer et al., 1942; Wolf et al. (1956).

Potential Health Risks

Epoxides have been implicated in hepatotoxicity and carcinogenicity . Any circumstance which would enhance epoxide formation or

longevity might increase covalent binding and tissue injury due to

styrene oxide (Leibman, 1975). Also, it appears likely that

styrene may significantly alter the metabolism and bioactivity of

other organic chemicals.

Naphthalene

Naphthalene (C10H8; naphthalin, tar camphor) is a white, crystalline solid which volatilizes appreciably at room temperature. It is

obtained primarily from coal tar and petroleum. Naphthalene is

insoluble in water, but quite soluble in organic solvents. It is

used commercially as a substrate for synthesis of a number of

chemicals, as a moth repellent, as a toilet bowl deodorant, and as

136
a veterinary antiseptic and vermicide. Naphthalene is also a

common constituent of such hydrocarbon mixtures as gasolines,

thinners, and assorted organic solvents.

Acute Toxicity

Naphthalene is absorbed systemically upon inhalation of its

vapors, as indicated by toxic manifestations in exposed subjects.

A paucity of information exists, however, concerning most aspects

of the pharmacokinetics and acute toxicity of naphthalene.

Gerarde (1960) relates that time- and concentration-dependent eye

irritation, headache, nausea, vomiting, and perspiration may

occur upon vapor inhalation. The two principal dangers of naphthalene exposure are possible cataract formation and hemolytic

anemia.

Organ Toxicity

Hemolytic action. The literature contains numerous accounts of

acute hemolysis following oral ingestion of naphthalene, but relatively few reports of the malady in persons exposed by inhalation

(Gleason et al., 1976). The classic findings in those afflicted

include: marked decreases in hematocrit, hemoglobin, and erythracyte count; leukocytosis; erythrocytic fragmentation, Heinz

body formation, and anisocytosis; hyperbilirubinemia; hemoglobinuria and dysuria. Persons with a hereditary deficiency of erythrocytic glucose-6-phosphate dehydrogenase activity appear particularly susceptible to the hemolytic effects of not only naphthalene, but a variety of other chemicals. The severity of hemolysis is apparently dependent upon the degree of enzyme deficiency and upon the extent of naphthalene exposure, with heavy

exposures presumably capable of causing hemolysis in normal

individuals, In a study by Valaes et al. (1963) of 21 infants with

hemolytic anemia caused by naphthalene inhalation, glucose-6-phosphate dehydrogenase activity was normal in 9 of the 21. It is

speculated here that a limited capability of the infants to conjugate and excrete naphthalene metabolites may have also been a

causative factor, in that naphthalene itself is not believed to

cause hemolysis. Mackell et al. (1951) report that naphthalene

acutely produces no hemolysis when incubated in vitro with suspensions of human erythrocytes, or when injected intravenously

(i.v.) into rabbits. Naphthol is a relatively potent hemolytic

agent under these experimental conditions, while ß-naphthol and

and ß-naphthoquinone are less active in vitro and inactive in

vivo.

Cataract induction. The ability of naphthalene to induce cataract

formation is reviewed in detail by Grant (1974). This toxic effect, like the hemolytic action, appears to be dependent upon

biotransformation of naphthalene to specific metabolites. Studies

of the metabolism of naphthalene are well summarized in a recent

paper by Rock et. al. (1976). Naphthalene may be converted via

137
several intermediates to 1,2-dihydroxynaphthalene, which in turn

is autoxidizable to 1,2-naphthoquinone. Van Heyningen and Pirie

(1967) present evidence that 1,2-naphthoquinone may indeed be

formed in the eye, where it may exert its toxic effects by reacting with a variety of intracellular cofactors, as well as with

structural and enzymatic proteins (Rees and Pirie, 1967). The

progression of lesions, as seen microscopically, is described by

Pirie (1968) in rabbits fed 1 gram of naphthalene daily. Principal

changes in the lens, in order of appearance, include: vacuolation

between epithelial cells; disarrangement of cells; inhibition of

mitosis; cellular destruction with inadequate cell reduplication.

Injury of retinal cells and deposition of oxalate crystals within the

retina and vitreous body are also described by Pirie (1968).

Accounts of ocular injury upon naphthalene inhalation in humans

are rare. Ghetti and Mariani (1956) described lens opacities in 8

of 21 workers exposed to naphthalene fumes.

Potential Health Risks

Very little toxicological information has been derived from studies

involving inhalation of naphthalene vapors. The current threshold limit value for occupational exposure has been set at 10 ppm,

in that eye irritation was said to occur at 15 ppm (Hygienic Guide

Series, 1967). Nau et al. (1966) reported cataracts in rats subjected repeatedly by inhalation to mixtures of C9

 - Cl 2 hydrocarbons containing naphthalene. It would appear that certain

individuals who abuse solvents ‘containing large quantities of

naphthalene might predispose themselves to hemolytic anemia

and/or cataract formation. Properly designed investigations of

this phenomenon should be conducted.

ALIPHATIC HYDROCARBONS

General Properties

The aliphatic hydrocarbons (paraffins) are a series of straightand branched-chain hydrocarbons, including: alkanes (saturated); alkenes (one double bond); alkadienes (two double bonds);

alkatrienes (three double bonds). Those aliphatics with at least

one double bond are also known as olefins. These hydrocarbons

occur naturally as mixtures in petroleum, from which they may be

separated by cracking processes and fractional distillation. For

purposes of the present paper, discussion will be limited largely

to the straight-chain alkanes of intermediate length. Alkanes

containing fewer than five carbon atoms are gases at room temperature, while pentane and the higher alkanes are volatile, flammable liquids. All are insoluble in water, but miscible in other

organic solvents. These aliphatics are used individually as solvents and are major constituents of such mixtures as petroleum

ether, gasoline, kerosene, and assorted thinners and solvents.

138
Acute Toxicity

Relatively little ‘emphasis has been placed on the toxicological

evaluation of the aliphatic hydrocarbons. Each may produce

narcosis and loss of consciousness if breathed in sufficiently high

concentrations. Narcotic potency has been demonstrated to vary

directly with the lipophilicity, or number of carbon atoms in the

molecule. Swann et al. (1974), upon cxposing mice for 5 minutes

to a series of vapor concentrations of n-pentane, n-hexane, and

iso-octane, noted increasing mucous -membrane irritation and

narcotic potency with increasing carbon chain length. According

to Spector (1956), lethal levels for mice were found to be as

follows: n-pentane--128,200 ppm; n-hexane--40,000 ppm; n-heptane--15,900 ppm. Shugaev (1969) noted an apparent increase in

the acute toxicity of 4-carbon aliphatics in mice with increasing

unsaturation and/or branching of molecular structure. He also

noted a positive correlation between hydrocarbon level in the

brain and depth of narcosis, ranging from deep anesthesia to

minimal disturbance in locomotion.

Cardiotoxicity

With the exception of respiratory irritation and CNS depression

manifest acutely upon exposure to high vapor concentrations, the

aliphatic hydrocarbons were regarded until recently as relatively

innocuous. A number of these solvents have been shown, however, to have the potential to induce ventricular fibrillation. In

an early study, Chenoweth (1946) found heptane to be quite

potent in eliciting arrhythmia in dogs challenged with epinephrine.

Much higher levels of methane and butane, in conjunction with

increased doses of epinephrine, were required to produce ventricular fibrillation. Other aliphatic hydrocarbons which have more

recently been shown to sensitize the heart included ethane,

acetylene, propane, propylene, isobutane , butene , and isopentane

(Krantz et al., 1948; Reinhardt et al., 1971).

Neurotoxicity

Another significant toxic effect ascribed to certain of the aliphatic

hydrocarbons has been induction of peripheral neuropathy. The

ability of n-hexane to produce nerve damage will be discussed

here under a separate heading. A report by Prockop et al.

(1974), of neuropathy in seven men who abused a lacquer thinner, suggested that n-heptane in combination with other solvents

might also be neurotoxic. The lacquer thinner was found to

consist of at least 11 components, including 0.5% n-hexane and

15.5% 2-heptanone (Prockop, 1976). n-Heptane is metabolized

primarily to 2-heptanol (Frommer et al., 1972), with subsequent

hydroxylation and/or oxidation likely. Since this metabolic sequence closely resembles that of n-hexane, an established neurotoxin, n-heptane may be neurotoxic as well. Studies are needed

to investigate this phenomenon.

139
n-Hexante

n-Hexane (CH3(CH2)4CH3) is a colorless, volatile liquid at room

temperature. It is insoluble in water, but miscible with organic

solvents. n-Hexane is used as a solvent, often in combination

with other aliphatic and aromatic hydrocarbons. Since n-hexane

is currently a principal component of many “over-the-counter”

glues and cements, individuals who abuse these products may

subject themselves to quite high vapor concentrations of n-hexane

(Korobkin et al.. 1975),

Absorption and Acute Toxicity

n-Hexane is readily absorbed via the lungs. Bohlen et al. (1973)

relate that the uptake of n-hexane, into the blood and tissues of

rats follows an exponential function, with tissue concentrations at

saturation directly proportional to lipid content of each tissue.

Swann et. al. (1974) report on the acute depressant effects of 5

minutes inhalation of a series concentrations of n-hexane in

mice, noting at: 8,000 ppm--no anesthesia; 16,000 ppm--light

anesthesia: 32,000 ppm- deep anesthesia; 64,000 ppm--respiratory

arrest within 4.5 minutes of exposure. In an acute toxicity

study, Kimura et al. (1971) found n-hexane, with an oral LD50 of

49.0 ml/kg, to be the least toxic of a number of organic solvents

tested in young rats. The occupational threshold limit value of

500 ppm for n-hexane is based on data derived from human

studies in which giddiness and dizziness are experienced at 5,000

pmm. while eye and throat discomfort headache, and nausea are

claimed by some subjects at about 1.500 ppm.

Organ Toxicity

Occupational toxicity. Neuropathy has been attributed to n-hexane inhalation in both occupational settings and in solvent-abuse

cases. The earliest reference to hexane as a possible cause of

neuropathy appeared in the 1960's in Japanese journals (Oishi et

al., 1964: Wada et al., 1965. Yamada, 1967; Sobue et al., 1968;

Yamamura, 1969). Each of the cases described in these publications was related to industrial exposure. In the comprehensive

clinical study of Yamamura (1969), 93 of 1,662 workers with potential exposure to n-hexane were found to exhibit nerve damage.

It was estimated that these individuals were exposed during

working hours to 500-2,500 ppm of n-hexane. The neuropathy

associated with these cases involved both the sensory and motor

systems, with sensory loss predominant. Histologic, electromyographic, and nerve conduction velocity studies revealed degenerative changes consistent with denervation including axonal swelling and loss of myelin. More recently, industrial cases of n-hexane-induced neuropathy have been observed in the United States

(Herskowitz et al., 1971; Paulson and Waylonis, 1976).

140
Inhalant abuse neuropathy. Neuropathy has been linked in

numerous instances with n-hexane in solvent abuse cases

(Gonzalez and Downey, 1972, Goto et al., 1974; Shirabe et al.,

1974; Korobkin et al., 1975; Towfighi et al., 1976). In some

instances the patients had intentionally inhaled volatiles without

n-hexane for years without apparent detrimental effect, but

developed crippling peripheral neuropathy within a matter of

months after switching to products containing n-hexane. In each

circumstance, however, n-hexane was only one component of a

solvent mixture. Clinical findings in these cases were analogous

to the industrial cases. Microscopic examinations revealed axonal

swelling, accumulation of neurofilaments in axons, myelin thinning

and denudation, and skeletal muscle changes characteristic of

neurogenic atrophy. Most patients in these studies exhibited

gradual functional improvement upon discontinuation of solvent

abuse.

Animal neuropathy. A limited number of studies utilizing experimental animals have been conducted to determine whether n-hexane is actually a neurotoxin. In an early study, Miyagaki (1967)

exposed mice 24 hours daily for 1 year to n-hexane at levels of

approximately 100, 250, 500, 1,000, and 2,000 ppm. Miyagaki saw

electrophysiological and histological evidence of nerve damage only

at the three highest concentrations, leading him to conclude that

the mouse was much less sensitive than man to neurotoxic effects

of n-hexane. The rat has been demonstrated to be more susceptible than the mouse (Kurita, 1967; Ishii et al., 1972), with

Schaumburg and Spencer (1976) seeing evidence of neuropathy

after 1 to 2 months in rats exposed continuously to air containing

400-600 ppm of n-hexane. Schaumburg and Spencer, on the basis

of their findings of both peripheral and central axonal degeneration , suggested that permanent CNS damage as well as peripheral

degeneration may also occur in humans.

n-Hexane and related compounds are metabolized by the microsomal enzyme system, possibly to metabolite(s) which actually are

neurotoxic . Frommer et al. (1974) observed with rat liver microsomes the formation of three isomeric alcohols from n-hexane, with

2-hexanol the predominant metabolite. Secondary hydroxylation

and alcoholic oxidation to form the corresponding ketones likely

occur to some degree, in that DiVincenzo et al. (1976) have

recently detected 5-hydroxy-2-hexanone and 2,5-hexanedione in

the serum of guinea pigs dosed with n-hexane. As discussed

elsewhere in this monograph, 2,5-hexanedione may well be the

metabolite responsible for apparent n-hexane-induced neuropathy

Since each of the aforementioned industrial and solvent abuse

cases involved exposure to mixed solvents, it is possible that

certain of the extraneous solvents may have modified the neurotoxicity of n-hexane. If 2,5-hexanedione is principally responsible for n-hexane neuropathy, chemicals which would enhance the

metabolism of n-hexane logically might increase its apparent neuro141
toxicity. Frommer et al. (1974) noted that phenobarbital pretreatment elicited a several-fold increase in 2-hexanol formation in rat

microsomes, while Abdel-Rahman and coworkers (1976) found that

phenobarbital hastened the elimination of 2-hexanone (methyl

n-butyl ketone) from the bloodstream of rats. Abdel-Rahman and

his colleagues observed that chronic phenobarbital treatment

seemed to protect rats dosed with 2-hexanone, but 2-butanone

(methyl ethyl ketone) potentiated neurotoxicity in such animals.

Since Traiger et al. (1975) have shown 2-butanone to be an

inducer of microsomal enzyme activity, it is possible that 2-

butanone may enhance 2,5-hexanedione production from 2-hexanone, or conversely may competitively inhibit glucuronidation and

excretion of 2,5-hexanedione. Suzuki et al. (1974) found that coadministration of toluene did not seemingly alter elimination of

n-hexane from the bloodstream, although levels of n-hexane

metabolites were not measured. The influence of other solvents,

drugs, and alcohol on n-hexane metabolism and neurotoxicity

remains subject to speculation.

Other organ pathology A paucity of information, other than that

relating to neurotoxicity, is available concerning the potential of

n-hexane to produce organ damage. Although hepatorenal injury

is usually not manifest in patients treated for n-hexane-induced

neuropathy, Paulson and Waylonis (1976) did see elevation of

certain serum enzymes indicative of liver injury in one such

patient. Nix et al. (1976) report morphologic evidence of injury

in mice exposed continually to 6,000 and 12,000 ppm of mixed

hexanes for 2 to 49 days. The severity of histopathologic change

in these mice varies directly with duration of exposure and solvent level. Bohlen et al. (1973) relate that n-hexane inhalation

may elicit hepatic lipid accumulation. This is confirmed in guinea

pigs by DiVincenzo and Krasavage (1974), who also find that

n-hexane produces an increase in serum ornithine-carbamyl transferase activity. Studies conducted under conditions approximating solvent abuse should be performed to assess the hepatorenal toxicity of n-hexane.

MIXED ALIPHATIC/AROMATIC HYDROCARBONS

Gasoline

Gasoline (petrol) is a mixture of C4 to C12 hydrocarbons, including paraffins, olefins, naphthenes, and aromatics. The relative

amounts of various constituents depend upon the origin of the

petroleum and the method of preparation. Gasoline is normally

obtained from crude petroleum by thermal or catalytic cracking

and by fractional distillation. Leaded gasolines contain approximately 3 ml of tetraethyl lead per gallon to prevent engine “knocking” (Lane, 1966). Gasoline is used primarily as a fuel, but

enjoys some industrial applications as a solvent or thinner.

142
Acute Toxicity

Inhalation of gasoline vapors may result in both mucous membrane

irritation and narcosis. In an early study of human subjects by

Drinker et al. (1943), exposure to approximately 1,000 ppm of

gasoline for 1 hour produced slight eye, nose, and throat irritation, but little evidence of narcosis. When Drinker et al. (1943)

exposed subjects to 2,600 ppm, slight dizziness accompanied the

eye irritation, while at 10,000 ppm marked intoxication was experienced after 4 to 5 minutes. A more recent study by Davis et al.

(1960) of three different unleaded gasolines revealed no manifestations of intoxication in humans subjected for 30 minutes to any of

the gasolines at concentrations of 200, 500, and 1,000 ppm. The

only significant effect noted was eye irritation at the 1,000 ppm

level. Little definitive animal experimentation has been reported

to date which has assessed the acute toxicity of commonly used

gasolines.

Deaths have been reported in persons who have inhaled concentrated gasoline vapors. Aidin (1958) measured gasoline levels

varying from 8,000 to 35,000 ppm under conditions approximating

those which resulted in a fatal intoxication. Wang and Irons

(1961) related circumstances surrounding the death of a man who

was overcome within 5 minutes after entering a tank estimated to

contain 5,000 to 16,000 ppm of gasoline vapor. More recently,

two fatal cases were reported in which the gasoline concentration

measured in the brain of one victim 30 hours after death was 0.3

to 0.4 mg/g of tissue, while that in the liver of the second victim

was 0.7 mg/g (Nelms et al., 1970). Gasoline was detected by gas

chromatography in the liver of an adolescent who died suddenly

upon deliberately sniffing gasoline fumes, although no attempt was

made at quantitation (Poklis, 1976).

It is difficult to establish, with any degree of certainty, vapor

and tissue concentrations of gasoline required to produce intoxication and death. The time elapsed between subject death and

analysis, as well as problems with analytical sensitivity and specificity in published reports, leave room for a good deal of conjecture. Quantitation is complicated by the large number of aliphatic

and aromatic hydrocarbons present in all gasolines. Should the

major components of a particular gasoline be ascertained, one is

faced with the problem of attributing narcosis to individual hydrocarbons or to combinations of hydrocarbons which may interact

with one another in vivo. The researcher is also faced with

great variability in gasoline composition.

Death upon acute exposure to gasoline fumes is generally attributed to severe CNS depression terminating in respiratory paralysis

(Machle, 1941). Autopsy reports in humans commonly include the

finding of pulmonary irritation, although the edema seen in the

respiratory tract does not appear severe enough to be fatal (Wang

and Irons, 1961; Nelms et al., 1970; Poklis, 1976), Poklis sug143
gests that death may result in some cases from sensitization of

the myocardium, since both gasoline (Chenoweth, 1946) and numerous constituents of gasoline are known to predispose to cardiac

arrhythmias (see discussion of individual solvents).

Inhalation Abuse

Intentional inhalation of gasoline fumes is widely reported in the

medical literature. One of the first reports is by Clinger and

Johnson in 1951, with subsequent accounts by Faucett and Jensen

(1952), Edwards (1960), Lawton and Malmquist (1961), Oldham

(1961), Easson (1962), Gold (1963), Bethell (1965), Durden and

Chipman (1967), Law and Nelson (1968), Carroll and Abel (1973),

and Poklis (1976). In most instances the subjects in these cases

relate that gasoline sniffing produces pleasant sensations, although frightening hallucinations are experienced by some individuals The subjects commonly sniff gasoline vapors from an

opened container for 2 to 5 minutes to attain a “high,” although

they may sniff for too long and lose consciousness. An abuse

episode may last for several hours, during which the person must

repeatedly inhale gasoline in order to maintain the high.

Organ Toxicity

Physical and neurological examinations of patients who abused

gasoline for as long as 11 years generally have failed to reveal

evidence of residual injury. The patients characteristically have

exhibited serious emotional problems which often improved upon

abstention from solvent inhalation. At least four cases involving

abnormal electroencephalograms have been reported in persons

who abused gasoline (Faucett and Jensen, 1952; Lawton and

Malmquist, 1961; Law and Nelson, 1968; Carroll and Abel, 1973).

In the latter two reports, elevated lead levels were measured in

the urine or blood, suggesting tetraethyl lead as the causative

agent . Chelation therapy resulted in a significant reduction in

blood lead levels and a marked symptomatic improvement in the

patient described by Law and Nelson (1968). Durden and Chipman (1967) related the history of a man who had inhaled gasoline

fumes for 7 years without apparent harm. but developed severe

hepatorenal injury upon drinking beer and inhaling vapor of a

solvent containing 60% carbon tetrachloride. Anemia has on

occasion been described in industrial workers exposed to benzenecontaminated gasoline (Machle, 1941; Amorati et al., 1952: McLean,

1960; Verwilghen et al. , 1975). Salamone (1961) observed aplastic

anemia in rabbits subjected 8 hours daily for 80 days to 60 mg/l

of gasoline vapors. The presence of benzene in varying amounts

in gasolines (Parkinson, 1971; Runion, 1975) raises the possibility

that myelotoxicity may be an unrecognized hazard of gasoline

abuse.

144
Miscellaneous Hydrocarbon Solvents

Vast quantities of hydrocarbon solvents are used annually in the

United States. The majority of these are not single chemicals,

but complex mixtures having boiling ranges varying from less

than 10o F to more than 100° F. These hydrocarbon solvents are

comprised of varying proportions of aliphatics (paraffins), benzene, alkylbenzenes, and mono- and dicycloparaffins. Solvent

mixtures are commonly used in paints and surface coatings as

thinners and fillers. Large volumes are also used in the dry

cleaning industry, for extraction of edible oils, as lighter fluid

and fuel, and as solvents for pesticides, inks, and rubber cement. Because of such widespread use and access, the potential

exists not only for occupational exposure during legitimate solvent

use, but for intentional inhalation for purposes of self-intoxication.

Acute Toxicity

Despite the common use of hydrocarbon solvent mixtures, there is

Little published information pertaining to their toxicity. Knowledge up to 1940 is compiled by Von Oettingen (1940), while information through the 1960’s is summarized by Gerarde (1960, 1963)

and by Browning (1965). The majority of reports suffer from

inadequate identification of physical properties and composition of

the solvent mixtures tested. Thus, comparison of results from

one study to another and application of a study’s findings to an

immediate solvent exposure situation are difficult.

With the advent of more definitive analytical techniques, better

characterization has been possible for hydrocarbon mixtures being

tested for their toxicity. Rector et al. (1966) found that samples

of mineral spirits contained a complex mixture of saturated and

unsaturated aliphatics (80-87 percent) and aromatics (13-19 percent), with a boiling range of 140°-190° C. Upon continuous

exposure of dogs, monkeys, rabbits, rats, and guinea pigs for as

long as 90 days to a range of concentrations of mineral spirits,

fatalities/toxicity were seen only in the guinea pig (Rector et al.,

1966). No biochemical or histopathologic explanation could be

found for the selective toxicity of mineral spirits in the guinea

pig. Nau et al. (1966), in an evaluation of the subacute inhalation toxicity of C9

- C12 fractions of petroleum distillates in rats

and monkeys, observed certain hematologic abnormalities, depression of body weight gain, and mucous membrane irritation in each

species. The C1 1 - C1 2 fraction was found to be more toxic than

the C9 - Cl0 fraction, leading Nau and his coworkers to recommend threshold limit concentrations of 50 and 25 ppm, respectively, for the C9

 - Cl 0 and C11 - C12 fractions. Hine and Zuidema

(1970) reported toxicological studies in rats of a number of hydrocarbon mixtures having relatively narrow boiling ranges (i.e.,

consisting of a limited number of components). Upon inhalation of

high vapor concentrations of these mixtures, the rats exhibited

145
incoordination, prostration, and convulsions before dying. Scrutiny of the data of Hine and Zuidema revealed: (1) aromatic

fractions were more acutely lethal than were corresponding aliphatics; (2) acute lethality was directly proportional to the number of carbon atoms or average molecular weight of components of

each hydrocarbon fraction.

To date, the most definitive reports on inhalation toxicology of

hydrocarbon mixtures have been published as a series of articles

by Carpenter et al. (1975-1976). A standard protocol was followed

for 12 different solvent mixtures in evaluation of their “no-illeffect” level in rats and dogs, LT50 and LC50 in rats, central

nervous system effects in cats, subacute toxicity in rats and

dogs, respiratory irritation in mice, and odor and irritation

thresholds in humans. The LC50 values commonly ranged from

5,000 to 9,000 ppm, although values as low as 1,400 ppm and as

high as 15,000 ppm were measured, Some solvent mixtures such

as kerosene were so poorly volatile that lethal vapor levels could

not be achieved. Signs of narcosis preceding death on acute

exposure commonly included loss of coordination, ataxia, loss of

proprioception, salivation, unconsciousness, tremors, and convulsions Narcotic and irritant potency varied directly with the

carbon content and boiling range. Solvent concentrations, which

acutely elicited “no ill effect,” were used for subacute exposures

lasting up to 14 weeks. Toxicological parameters including hematology, serum enzyme measurements, urinalyses, histopathology,

body weight and organ weight monitoring, and electrocardiogram

recordings revealed little or no evidence of solvent-induced injury

within the 14-week study periods. These studies lend additional

support to the concept that the majority of aliphatic and aromatic

hydrocarbons appear to be relatively nontoxic, even when encountered as mixtures.

Potential Health Risks

A variety of maladies have been tentatively attributed to inhalation of hydrocarbon solvents, Beirne and Brennan (1972) and

Zimmerman et al. (1975) reported a number of cases of autoimmune

glomerulonephritis which appeared to be associated with prior

exposure to individual solvents or solvent mixtures. These

investigators advanced the theory that antibody production ensued following solvent-induced injury of lung or kidney membranes. Capurro (1976) suggested that hydrocarbon solvents

might , via a similar mechanism, alter the immune status of subjects and predispose them to certain forms of cancer. Finally,

recent studies have demonstrated inferior psychological performance (Lindstrom, 1973) and an increased incidence of nonspecific

neuropsychiatric disorders (Axelson et al. , 1976) in workers

including painters, varnishers, dry cleaning employees, and

printers. These findings may be important in light of psychological problems commonly manifested in individuals who abuse solvents.

146
The occasional variances from normal seen by Carpenter et al.

(1975-1976) for certain subacute toxicity parameters, coupled with

aforementioned finding of Nau et al. (1966), and others illustrate

the harmful nature of repeated high-level inhalation of mixed

solvent vapors. Few investigations have yet been conducted to

assess the toxicity of such solvent mixtures under conditions

approximating human solvent abuse.

ALIPHATIC NITRITES

The relatively low molecular weight aliphatic nitrites are very

volatile, highly flammable liquids. The most commonly used and

abused of these is amyl nitrite (C5Hl lNO2). Synonyms for this

compound are isoamyl nitrite and isopentyl nitrite. Aliphatic

nitrites have several medical applications. Among these are

treatment of angina pectoris (Aviado, 1972; Dewey et al., 1973),

cyanide poisoning (Aviado, 1972; Stine et al., 1976), and hydrogen sulfide poisoning (Stine et al., 1976). Amyl nitrite is also

occasionally used in the diagnosis of ventricular septal defects

(Aviado , 1972).

Abuse

Amyl nitrite NF (Vaparole) is supplied in crushable glass ampules

which contain 0.3 ml of the compound. In the drug culture these

are known as “poppers” or “snappers.” This drug has been

popular in the male homosexual population for a number of years

(Everett, 1972, 1975b; Gay et al., 1975; Gay and Sheppard, 1972,

1973; Hollister, 1975a, 1975b). More recently it has become popular in the heterosexual community (Everett, 1972; Everett, 1975b;

Gay and Sheppard, 1972 and 1973). Apparently, the most effective time to inhale the drug is just before orgasmic climax

(Everett, 1972 and 1975b; Gay et al., 1975; Gay and Sheppard,

1972, 1973; Hollister, 1975a; Pearlman and Adams, 1970). The

apparent effect is lengthening the time and intensity of the pleasurable feeling associated with climax (Everett, 1972 and 1975b;

Gay and Sheppard, 1972, 1973; Hollister, 1975a, 1975b; Knoepfler,

1977; Louria, 1970; Pearlman and Adams, 1970). Although this

drug has been used in intercourse by both sexes, it is much

more popular in the homo- and heterosexual male population

(Everett, 1972, 1975b). Some questionable increases in sexual

aggressiveness have also been associated with the use of this

drug (Everett, 1975a; Gay et al., 1975). These compounds are

apparently becoming increasingly popular in drug-oriented populations .

Toxicity

The use of amyl nitrite may be accompanied by medical complications . Limited toxicological data have been available. When given

to mice by i.p. injection, the LD50 was 130 mg/kg. When given

147
i.v. the LD50 was 51 mg/kg Dewey et. al., 1973). When dogs

were administered amyl nitrite i.v., low doses elicited tremors and

ataxia, while higher doses produced convulsions and death

(Dewey et al., 1973). When these same investigators exposed the

dogs to the drug by inhalation, one dog became quiet and another

ataxic for a short period. When they were subjected to repeated

inhalation doses of amyl nitrite at 20- to 90-second intervals for

up to 7 minutes. varying degrees of pharmacologic effects were

noted, ranging from no effect to ataxia, gagging, vomiting,

urination, defecation, and even brief convulsions. These effects

seemed to be somewhat related to the frequency of dose and the

number of doses. Other side effects have been noted in people

who have used or abused this drug, including dizziness, headache, tachycardia, hypotension, syncope, and increased intraocular pressure (Everett, 1972, 1975b); Gay and Sheppard, 1973;

Hollister, 1975a, 1975b; Louria, 1970; Pearlman and Adams, 1970).

Nitrites in general have also been associated with methemoglobinemia and rare sudden deaths (Louria, 1970). Amyl nitrite is

contraindicated in certain persons who have cardiovascular problems (Everett, 1975b; Hollister, 1975a, 1975b). If abuse of such

drugs continues to escalate medical complications may be seen

more frequently. Few if any investigations have been conducted

on the effects of butyl nitrites and related components contained

in over-the-counter products such as Locker Room or Rush.

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Chapter 10

PRECLINICAL PHARMACOLOGY AND TOXICOLOGY

OF HALOGENATED SOLVENTS AND PROPELLANTS

Domingo M. Aviado

INTRODUCTION

In recent years, there has been a considerable amount of investigation into the pharmacology and toxicology of halogenated solvents and propellants as they relate to the abuse of aerosol

products. The prevalent opinion is that the major hazard from

their abuse is death from cardiac arrest, However, since the

solvents and propellants contained in aerosol products are potentially toxic to the lungs, liver, and kidney, it will be necessary

to review briefly the extracardiac actions of the halogenated

inhalants. There is no reported case indicating that their abuse

exerts a permanent, irreversible damage to organs other than the

heart.

The pharmacologic features and toxicity of the halogenated solvents and propellants are presented by grouping them according

to the nature and the number of halogen in the chemical structure. Since there are review articles on the toxicity of the

halogenated compounds (Von Oettingen, 1955; Browning, 1965),

this chapter will emphasize the relative toxicities of the halogenated inhalants. The rating of toxicity is based on animal experiments performed by the author and his collaborators, as well as

information reported by other investigators.

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FLUORINATED HYDROCARBONS

At the time of writing this chapter several government agencies

were in the process of banning fluorinated propellants used in

aerosol products, The compelling reason is the suspected depletion of the ozone layer in the ionosphere, rather than to toxicities

identified through animal studies. In any event, it is important

to review the inhalational toxicity of fluorinated propellants to

provide a basis for any propellants now under consideration to

replace the fluorinated ones in current issue.

Cardiotoxicity of Fluorinated Propellants

The most harmful effects so far demonstrated during brief inhalation of fluorocarbons relate to the heart: cardiac arrhythmia,

depression of myocardial contractility, and reduction in cardiac

output. The lowest. concentration that influences the heart is

0.3% of trichlorofluoromethane (FC 11) which sensitizes the heart

to epinephrine-induced arrhythmia. It is the opinion of the

author that this concentration is reached when aerosols are

abused and that fatalities are caused by this mechanism. Comparative experiments indicate that FC 11 is more toxic than the

other two fluorocarbons (FC 12 and FC 114). For each of the

three propellants, the dog heart is more sensitive than the monkey heart (see Table 1).

Extracardiac Organs

There is no indication that fluorocarbons affect the liver and

kidneys (Jenkins et al., 1970). The effect on the airways varies

from species to species: Fluorocarbon 11 produces bronchospasm

in the rat and mouse but not in the dog and monkey, fluorocarbon 12 only in the mouse and monkey, and fluorocarbon 114 in

all four animal species, There is no comparative information in

man although aerosol hair-sprays produce temporary bronchospasm.

It has also been suspected that deaths of asthmatic patients who

misuse aerosol bronchodilators are the result of bronchospasm and

cardiac arrhythmia caused by the fluorocarbons (Aviado, 1975a).*

DICHLORINATED HYDROCARBONS

Although there are no reports in the literature of abuse with

dichlorinated solvents, it. is necessary to review their pharmacologic and toxicologic actions because they are likely to replace the

fluorinated propellants in aerosol products. At the time of this

writing, methylene chloride in combination with hydrocarbons has

been adopted by some manufacturers of aerosol products (Aviado

et al., 1977). Since other dichlorinated solvents have similar

*Editor’s Note: Isoproterenol was also present in high concentrations in these British preparations.

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TABLE 1

INHALATIONAL TOXlCITY OF

FLUORINATED HYDROCARBONS*

Minimal Effective Concentration

Trichloro- Dichloro- Dichlorofluoro- difluoro- tetrafluoromethane methane ethane

(CCl3F) (CCl2F2

) (CClF2CClF2)

FC 11 FC 12 FC 14

Cardiac Arrhythmia

Dog heart sensitized

to epinephrine 0.3%

Monkey heart spontaneous arrhythmia 2.5%

Monkey heart tachycardia 2.5%

Myocardial Contractility

Monkey heart depression 2.5%

Dog heart depression 0.5%

Hemodynamic parameters

Dog cardiac output

reduced 1.0%

Dog total systemic

vascular resistance

increased 2.5%

Airway resistance

Dog bronchospasm (absent)

Monkey bronchospasm (absent)

Rat bronchospasm 2.5%

Mouse bronchospasm 1.0%

5.0% 5.0%

10.0% 10.0%

10.0% 10.0%

10.0% 10.0%

10.0% 2.5%

10.0% 10.0%

20.0% 5.0%

(absent)

10.0%

(absent)

2.0%

10.0%

20.0%

15.0%

2.0%

*Adapted from Aviado 1975b.

effects on the central nervous system as the other abused solvents, three other dichlorinated hydrocarbons are included in the

following discussion.

At the outset, it should be stated that there is no published

comparison of the solvents under consideration. The author and

his colleagues have some unpublished results on the cardiotoxicity

of dichlorinated solvents when administered as a vapor by inhalation to anesthetized dogs. The minimal concentrations that depress myocardial contractility are as follows:

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methylene chloride 2.5%

acetylene dichloride 1.5%

ethylene dichloride 0.5%

propylene dichloride 0.25%.

There is a ten-fold difference between the most toxic and the

least toxic of the group. Compared to other chlorinated solvents,

such as methyl chloroform (0.25%) and trichloroethylene (0.05%),

methylene chloride stands out as the least cardiotoxic among the

di- and trichlorinated hydrocarbons.

Methylene Chloride

Methylene chloride (CH2Cl2)is one of the most widely used solvents for paint stripping. It is also used as a carrier in rapiddry paints and spray paints. A combination of methylene chloride

and hydrocarbons is under consideration as a replacement for the

fluorocarbons currently in use in aerosol products.

So far, there are no reports in the literature of the abuse of

methylene chloride. However, its introduction as a substitute for

fluorocarbons in aerosol products will raise questions of its toxicity in the event that aerosol products, in general, continue to be

abused. The few cases of occupational poisoning from methylene

chloride do not show pathologic lesions in the liver and kidneys.

However, sublethal amounts of methylene chloride produce hepatic

necrosis in animals (Criteria Document, 1976a). Additional investigation is needed to determine the potential effect of methylene

chloride on the liver, kidneys, and lungs following brief daily

exposure in animals.

The major concern regarding the safety of methylene chloride is

that it is metabolized to carbon monoxide in the liver. Stewart

and Hake (1976) have cautioned users of paint removers containing methylene chloride that the formation of carbon monoxide can

produce cardiovascular stress and even death. However, there

are no other known paint removers safer than methylene chloride,

so its benefit-to-risk ratio justifies its continued use provided

proper precautions (such as ventilation) are taken to minimize the

amount inhaled by the individual in the course of paint stripping.

The amount of methylene chloride contained in aerosol products is

limited in quantity compared to that needed for paint stripping.

Nevertheless, the cardiac effects of methylene chloride should be

analyzed, particularly because of its formation to carbon monoxide . The fundamental questions that need to be answered are as

follows: Does the formation of carbon monoxide increase the

cardiotoxicity of methylene chloride? Are the cardiac effects

exaggerated in the ischemic heart? Does methylene chloride

interfere with normalization of an elevated carboxyhemoglobin?

The following discussion reviews the effects of carbon monoxide,

methylene chloride, and interaction between both.

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There is no question that methylene chloride, per se, influences

the heart because experiments reported by Kiessling in 1921 and

by Joachimoglu in 1925 showed depression of the perfused heart

and excised vessel using artificial perfusates without hemoglobin.

In 1935 Hermann and Vial reported that the injection of epinephrine caused ventricular fibrillation in a dog that had been inhaling methylene chloride vapor. The concentration of methylene

chloride was not mentioned. However, the list of volatile solvents

that sensitized the heart to cardiac arrhythmia induced by epinephrine included the following: carbon tetrachloride, chloroform, and methyl chloride.

Cardiac Arrhythmia in Mice

The electrocardiogram was used to detect arrhythmia and conduction defect of the heart (Aviado and Belej, 1974). The minimum

concentrations of methylene chloride that produced abnormalities

in the electrocardiogram were as follows: 20% methylene chloride

in air with intravenous injection of 6 μg/kg of epinephrine and

40% without injection of epinephrine. The concentrations of

trichlorofluoromethane (FC 11) that produced arrhythmias were 5%

and 10%, respectively, indicating that methylene chloride is less

cardiotoxic than the fluorocarbon.

Cardiac Arrhythmia in Dogs

Reinhardt et al. (1971, 1973) and Clark and Tinston (1973) used

conscious dogs and recorded the electrocardiogram. The concentrations of methylene chloride and related compounds that sensitize the heart to epinephrine-induced arrhythmias were as follows:

Reinhardt et al. Clark and Tinston

methylene chloride 2.0% 2.4%

trichlorofluoromethane (FC 11) 0.5%-1.2% 1.25%

carbon tetrachloride 0.5%

Reinhardt et al. could not test greater than 2.0%, concentrations

of methylene chloride because the dog could not tolerate the

mixture. Clark and Tinston succeeded in administering up to

3.4% and reported a mean concentration of 2.4% to sensitize the

heart, which is two times that for trichlorofluoromethane (FC 11)

and almost five times higher than carbon tetrachloride.

Cardiac Arrhythmia in Carbon Monoxide Poisoning

In cases of human carbon monoxide poisoning, there are abnormalities in the electrocardiogram indicating myocardial ischemia.

These appear when carboxyhemoglobin levels exceed 50%, which is

high enough to produce loss of consciousness.

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In dogs, the threshold saturations that produce cardiac changes

were determined by Ehrich et al. (1944). There was depression

of the R-T segment and degenerative changes for a few hours at

40% carboxyhemoglobin. Heart block and myocardial hemorrhages

and necroses were observed only when the carboxyhemoglobin

level exceeded 75% for 1 hour or longer. In rats poisoned with

10,000 parts per million (ppm) carbon monoxide inhalation for 10

minutes, high enough to elevate carboxyhemoglobin to 65%, ultrastructural changes in the heart, consisting of intracellular edema,

swelling of mitochondria, and disruption of lysosomes, were reported. Suzuki (1969) concluded that the effects of carbon monoxide on the heart result not only from hypoxemia but also from

the direct toxic effects on the specific respiratory enzymes.

Twenty-four hours after the inhalation, the hearts of most rats

appeared essentially normal so that the toxic effect was reversible. From the foregoing experiments, cardiac arrhythmias appear

only if carboxyhemoglobinemia exceeds 40 percent, which is not

attained during ordinary use of methylene chloride.

Interaction Between Carboxyhemoglobin

and Solvents on the Heart

For completeness, it is necessary to discuss the question of

interaction between the direct cardiac effects of methylene chloride and the indirect cardiac consequence of carboxyhemoglobinemia resulting from metabolism of methylene chloride. Does carboxyhemoglobinemia increase the vulnerability of the heart to

epinephrine-induced arrhythmia? The answer was supplied in 1974

by Kaul et al. In dogs with elevated levels of carboxyhemoglobin

(to 35%) by inhalation of carbon monoxide, there was no increase

in vulnerability of the ventricles to arrhythmias provoked by

epinephrine and petroleum ether. There are no experiments

reported involving methylene chloride. However, it is safe to

conclude that carboxyhemoglobin, per se, does not increase the

sensitivity of the heart to hydrocarbon-epinephrine arrhythmias

and that although methylene chloride is converted to carbon

monoxide, this does not increase the vulnerability of the heart.

In other words, the arrhythmogenicity of methylene chloride is

not enhanced by the small amount of carbon monoxide produced

by its metabolism.

Myocardial Contractility

It was stated earlier that the threshold concentration that would

depress significantly myocardial contractility of the canine heart

is 2.5% methylene chloride. Since this was performed in an intact

animal, it was not possible to differentiate the effects of carbon

monoxide formation separately from the nonmetabolized solvent.

Experiments recently completed have succeeded in the identification of cardiac effects related and unrelated to carbon monoxide

(Juhasz-Nagy et al., 1977; Zakhari et al., 1977).

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In the canine heart-lung preparation, the inhalation of methylene

chloride was not accompanied by a rise in carboxyhemoglobin.

Thus, it was possible to identify the myocardial depressant action

of methylene chloride alone without formation of carbon monoxide.

In the dog with intact heart, the hemodynamic effects of methylene chloride alone were not exaggerated by the combined administration of carbon monoxide. This ischemic heart was no more

reactive to methylene chloride and to carbon monoxide compared

to the nonischemic heart. Furthermore, the initial elevation of

carboxyhemoglobin following the inhalation of carbon monoxide was

not influenced in its normalization pattern by the inhalation of

methylene chloride. These results indicate that the metabolic

conversion of methylene chloride to carbon monoxide does not

occur in the heart, does not influence the normalization of carboxyhemoglobinemia even in the presence of methylene chloride,

and that carboxyhemoglobinemia does not exaggerate the cardiac

effects of methylene chloride. As a matter of fact, the author

believes that conversion to carbon monoxide reduces the cardiac

depressant action of methylene chloride in as much as the same

concentration is more depressant in the heart-lung preparation

where there is no formation of carbon monoxide, compared to the

heart of an intact animal where metabolism is possible.

Acetylene Dichloride

Acetylene dichloride (CHClCHCl) is used as a solvent for waxes,

resins, acetyl cellulose, and rubber. It is contained in some

antiknock gasolines, fumigant mixtures, and in cleansing products. There is one reported fatality after inhalation of the acetylene dichloride vapor in a small enclosure (Hamilton, 1933).

Menshick (1957) reported four others and collected 27 instances of

occupational poisoning from the literature. There were pathological lesions in the liver and kidneys.

Ethylene Dichloride

Ethylene dichloride (CH2ClCH2Cl) is a constituent of rubber

cement , degreasing solvent mixtures, and leaded fuels. The

Criteria Document (1976b) reviews almost a hundred cases of

accidental poisoning and occupational inhalation of ethylene dichloride. Hepatic and renal lesions are the major lesions seen at

postmortem examination.

Propylene Dichloride

This solvent is a component of furniture finisher, paint remover,

and soil fumigants. A case of acute poisoning from oral ingestion

of propylene dichloride (CH2ClCHClCH2) was reported by Chiappino and Secchi (1968). Histologic studies of the liver biopsy

showed diffuse phenomena of turbid degeneration of the liver cells

and ultrastructural changes in Golgi apparatus, mitochondria, and

170
endoplasmic reticulum. Secchi et al. (1968) reported on seven

cases of acute poisoning from commercial solvents sold as trichloroethylene. Chemical analysis of solvents responsible for poisoning

revealed that severe liver toxicity occurred only in patients

poisoned by mixtures rich in propylene dichloride and 1,2-dichloroethane. In these patients, cytoplasmic and mitochondrial enzymes appeared in the serum, which indicates severe lesions in

the cytoplasmic and mitochondrial membranes.

Propylene dichloride brought about an increase in serum glutamicoxaloacetic transaminase and serum glutamic-pyruvic transaminase

activities in mice. The extent of hepatic damage is less than that

produced by chloroform (Osanai, 1967). Heppel et al. (1946)

found that weanling rats fed for several weeks with low-protein

choline-deficient diets were more susceptible to the toxic effects

of inhalation of propylene dichloride vapors (1,000 ppm for ‘7

hours) than the control group. Secchi and Alessio (1971) found

that humans poisoned with a mixture of commercial chlorinated

organic solvents containing propylene dichloride showed an increase in the activity of the following serum enzymes: sorbitol

dehydrogenase glutamic-pyruvic transaminase, glutamic-oxaloacetic

transaminase, lactic dehydrogenase, glutamate dehydrogenase,

RNase, ß-glucuronidase, and acid phosphatase.

The pathological changes resulting from daily exposures to propylene dichloride were described in detail by Highman and Heppel

(1946). In their study, guinea pigs and rats were exposed to

2,200 ppm of propylene dichloride for various intervals of time.

The most conspicuous changes were noticed in the adrenal glands

of guinea pigs which showed extensive coagulation and focal

hemorrhagic necrosis of the cortex, and congestion with hemorrhagic necrosis of the adrenal medulla. Both guinea pigs and

rats showed fatty degeneration of the liver and kidneys.

for the adrenal glands of guinea pigs,

Except

lesions and marked

necrosis noticed after the first few exposures to propylene dichloride underwent rapid resolution 3 or 4 days after the end of

the first exposure despite continuation of daily exposures.

TRICHLORINATED SOLVENTS

There was a time when methyl chloroform, trichloroethylene, and

chloroform were used as general inhalational anesthetics, but the

introduction of new anesthetics has made the trichlorinated solvents obsolete. However, all three trichlorinated hydrocarbons

are widely used as commercial solvents and have been abused by

inhalation. This section will not discuss chloroform because its

cardiotoxicity, hepatotoxicity,

known.

and nephrotoxicity are generally

Methyl Chloroform

Methyl chloroform (CH3CCl3)is used as a solvent primarily for

vapor degreasing and cold cleaning of metals and machinery. It

171
is used as a solvent in cosmetic and household aerosol products.

There are four reported cases in the literature of the abuse of a

cleanser containing methyl chloroform: One case of chemical

pneumonia and another of respiratory arrest were reported by

Hall and Nine (1966). The respective blood levels of methyl

chloroform were 13.0 and 72 mg/100 ml. The third case of nonindustrial poisoning was dcscribed by Stewart and Andrews (1966)

and consisted of accidental ingestion of 0.6 g/kg of methyl chloroform. There were signs of depression of the central nervous

system. The patient recovered after supportive treatment.

The fourth and most recent fatality from methyl chloroform was

reported in 1974 by Travers. An 18-year-old apprentice seaman

collapsed on the deck of his ship A bottle of methyl chloroform

was found in his bunk along with a rag soaked with the solvent.

After different supportive measures were taken, progressive

hypotension and bradycardia, unresponsive to isoproterenol and

norepinephrine infusions, and several episodes of cardiac arrest

eventuated in his death 24 hours after collapse. Autopsy showed

right atrial and ventricular dilation and circumferential left ventricular subendocardial hemorrhage. Microscopically, widespread

recent infarction was observed. Mild congestion of viscera,

cerebral edema, and Purkinje cell chromatolysis were also noted.

Postmortem analysis failed to detect methyl chloroform in the

liver, kidney, blood, or brain.

Absorption Metabolism, and Disposition

Morgan et al. (1970, 1972) used radioactive chlorine-38 labeled

methyl chloroform in human volunteers to study its absorption and

excretion in the lungs. The solvent was absorbed and excreted

more rapidly than the fluorocarbons described in the preceding

section. The urinary excretion of nonlabeled methyl chloroform

was examined by Tada et al. (1968). who exposed two male volunteers to methyl chloroform and reported an increase in urinary

excretion of trichloroacetic acid. as determined by the alkaline

pyridine method. However, the increase was not in proportion to

the concentration of the vapor and the duration of exposure, as

far as the exposures to 1.16 and 2.26 mg/l were concerned.

Monzani et al. (1969) reported that among 18 workers exposed to

1.0 mg/l, only one showed a detectable amount of trichloroacetic

acid (9.72 mg/l urine). Seki et al. (1975) examined the urine

samples collected from seven workers, and on the basis of excretion of trichloromethanol, estimated the biological half-life to be

8.7 hours for methyl chloroform

Cardiotoxicity

The proarrhythmic activity of methyl chloroform has been investigated in the dog. Rennick et al (1949) demonstrated sensitization of the heart to epinephrine induced arrhythmias after the inhalation of 0.33 to 0.53 g/kg (of methyl chloroform in dogs under

172
barbital anesthesia. They also concluded that ventricular arrhythimas could be more regularly induced with methyl chloroform

than with chloroform, but less than with cyclopropane. Reinhardt

et al. (1973) found the minimal concentration that causes sensitization in the dog to be 27.8 mg/l. The effective concentration50

(EC5 0 ) was 40.7 mg/l in another group of dogs examined by

Clark and Tinston (1973).

Somani and Lum (1965) and Lucchesi (1965) instilled 133.6 mg/kg

of methyl chloroform intratracheally and injected epinephrine (10

μg/kg) intravenously. This combination caused ventricular fibrillation except in dogs that were pretreated with beta-adrenergic

blocking agents.

In the absence of injection of epinephrine, the administration of

methyl chloroform produces alterations in the electrocardiographic

pattern as follows:

Humans nodal rhythm

(Dornette and Jones, 1960) premature ventricular

contractions

depression S-T segment

Monkeys flattened or inverted

(Krantz et al., 1959) T wave

Dogs flattened or inverted

(Krantz et al. , 1959) T wave

Mice 2nd degree block and

(Aviado and Belej, 1974) ventricular fibrillation

There is also a depression in contractility of the perfused frog

heart (Lazarew, 1929), the canine heart-lung preparation (Aviado

and Belej, 1975), and the primate heart in situ (Belej et al, 1974).

A depression of oxygen consumption also occurs in heart slices

obtained from rats anesthetized with methyl chloroform but not in

those from unanesthetized rats (Krantz et al, 1959). As a result

of myocardial depression, a fall in systemic blood pressure is

detected in the dog and the monkey when anesthetized with

methyl chloroform.

Herd et al. (1974) found that the peripheral vasodilation due to

methyl chloroform could be reversed by phenylephrine hydrochloride. Furthermore, injection of calcium ion ameliorated the

depression of myocardial contractility and hypotension induced by

methyl chloroform.

The hemodynamic effects of various inhaled concentrations of

methyl chloroform were investigated in the anesthetized intact dog

preparation (Aviado et al., 1976). A minimal effective concentration of 0.1% (5.42 mg/l) decreased peak left ventricular pressure,

173
mean aortic pressure, and mean pulmonary arterial flow by 3%,

3%, and 4%, respectively. A concentration of 0.25% (13.9 mg/l)

decreased peak left ventricular pressure, maximal rate of rise of

left ventricular pressure, dp/dt, mean aortic pressure, and mean

pulmonary arterial flow by 7%, 13%, 6%, and 6%, respectively. A

concentration of 0.5% (27.1 mg/l) exaggerated all previous

responses. A concentration of 1% (54.2 mg/l) decreased peak left

ventricular pressure, dp/dt, mean aortic pressure, mean pulmonary arterial flow, and systemic vascular resistance by 22%, 33%,

24%, 15%, and 11%, respectively, while it increased pulmonary

vascular resistance by 17%. It may be concluded from this study

that methyl chloroform is a general depressant of cardiovascular

function, effective in a minimal inhaled concentration of 0.1%. At

this concentration, the most sensitive indices of its cardiovascular

depressant effects are peak systolic pressure, mean aortic pressure, and cardiac output. With progressively increasing concentrations, the decrease in the maximal rate of rise of left ventricular pressure, dp/dt, occurs to the greatest extent, while the

decrease in mean aortic pressure and in peak left ventricular

pressure occupying an intermediate position. A mixture of 0.5%

FC 11 and 0.05% methyl chloroform exhibits no potentiative or

additive effects, probably implying differences in basic mechanisms by which each agent brings about its cardiovascular

depressant action. The effects demonstrated in these experiments

serve to explain death from poisoning with methyl chloroform.

Pneumotoxicity

In the monkey, inhalation of 138.8 to 277.5 mg/l of methyl chloroform causes depression of respiratory minute volume accompanied

by a decrease in airway resistance and an increase in pulmonary

compliance (Aviado and Smith, 1975). The pulmonary toxicity of

eight chlorinated solvents was studied in rabbits by the physiogram method. The overall toxicity of methyl chloroform was less

than the corresponding unsaturated compound trichloroethylene.

The presence of a double bond provoked a central depression

greater than that observed with the corresponding saturated

compounds (Truhaut et al. , 1972). No information is available on

pneumotoxicity in other animal species.

Hepatotoxicity

The effects of methyl chloroform were investigated in several

animal species. The mouse has been studied most extensively.

The intraperitoneal (i.p.) injection of 5.3 to 16.0 g/kg prolonged

the sleeping time induced by pentobarbital, an effect brought

about by interference with metabolizing enzymes in the liver; the

hepatotoxic effective dose 50 (ED50) was found to be 11.2 g/kg

(Plaa et al. , 1958). However, it is difficult to exclude the possibility that the prolongation of sleeping time is caused by the

addition of the hypnotic effects of pentobarbital and methyl chloroform, instead of the latter producing hepatic lesions.

174
Additional signs of hepatic dysfunction include retention of sulfobromophthalein and change in serum glutamic-pyruvic transaminase

(SGPT) activity following injection (Klaassen and Plaa, 1966) or

inhalation of methyl chloroform (Gehring, 1968). The doses of

methyl chloroform required to cause death and a significant SGPT

elevation in 50 percent of mice within 24 hours are as follows:

Route of

administration

Intraperitoneal

Intraperitoneal

Inhalation

SGPT

activity

SGPT potency

activity ratio

24-hr LD50 ED50 LD5 0 /EDs o

4.70 g/kg 2.91 g/kg 1.62

4.94 g/kg 3.34 g/kg 1.50

74.25 mg/l 74.25 mg/l <1.00

for 595 min for < 595 min -

MacEwen et al. (1974) exposed mice continuously for 100 days.

The concentration of 1.34 mg/l had no effect on the liver whereas

5.42 mg/l caused an increase in liver weight and elevation of liver

triglycerides. The minimal concentration tolerated continuously is

between the two levels tested.

In mice, the inhalation for 1 hour of 16.5 mg/l of methyl chloroform caused stimulation of the oxidative activity of microsomal

enzymes in the liver, manifested by shortening of sleeping time

induced by hexobarbital (Lal and Shah, 1970). These results

following inhalation are opposite to those described above for i.p.

injection and call into question the validity of using sleeping time

to indicate hepatic enzyme activity.

The hepatotoxicity has been investigated in rats following inhalation of methyl chloroform (13.75 to 16.5 mg/l) for 24 hours (Fuller

et al., 1970). It decreased the duration of action of hexobarbital,

meprobamate, and zoxazolamine. There was an in vitro increase

in the metabolism of these compounds by hepatic microsomal

enzymes under the influence of methyl chloroform. The carbon

monoxide-binding pigment (cytochrome p-450 reduced) and

nicotinamide adenine dinucleotide phosphate cytochrome reductase

activity of the hepatic microsomal fraction were increased. Pretreatment of rats with cycloheximide or actinomycin D prevented

the decrease in the hexobarbital narcosis and the increase in

hepatic drug metabolism induced by methyl chloroform. It is

noteworthy that, after 24 hours of methyl chloroform inhalation,

its concentration in the liver was markedly greater than that in

the blood.

The inhalation of methyl chloroform in a concentration of 54.28

mg/l for 4 or 6 hours has no effect on liver function of rats fed

with ethanol, although there was potentiation of hepatotoxicity of

carbon tetrachloride by the alcohol (Cornish and Adefuin, 1966).

175
Pretreatment of rats with phenobarbital sensitized the liver to the

hepatotoxicity of carbon tetrachloride but not to methyl chloroform

injected i.p. (Cornish et al., 1973). The i.p injection of methyl

chloroform (1 mg/kg) did not influence liver function in normal

rats but was hepatotoxic in alloxan-induced diabetic animals

(Hanasono et al., 1975). In the perfused rat liver, methyl

chloroform did not influence hepatic blood flow or the morphology

of the hepatic parenchymal cells to the same extent as carbon

tetrachloride (Rice et al.. 1967). However. there was an inhibition of respiration of liver mitochondrial preparation following the

addition of methyl chloroform (Herd and Martin, 1975).

Oral administration of 1.65 g/kg of methyl chloroform in liquid

paraffin to rats for 7 days caused an increase in both microsomal

and cell sap protein concentrations in the liver (Platt and

Cockrill, 1969). Intraperitoneal injection of methyl chloroform

(3.74 g/kg, i.e., 75% of the LD50) in male rats produced no

significant effect on the hepatic triglyceride level, nor was any

decrease in hepatic glucose-G-phosphatase activity detected

(Klaassen and Plaa, 1969). Disturbances in liver function have

been reported in dogs (Klaassen and Plaa, 1967) and in rabbits

(Truhaut et al., 1967). In all of these investigations, liver

function was readily influenced by the administration of methyl

chloroform.

Of the laboratory animals investigated, the guinea pig appears

most prone to liver injury. While Adams et al. (1950) reported no

organic injury after 3 months of repeated daily exposure to 8.20

mg/l for 7 hours per day, Torkelson et al. (1958) reported the

presence of slight lung and liver pathology in guinea pigs exposed repeatedly to 5.5 mg/l for 1.2 hours per day or 11 mg/l for

0.5 hour per day for 3 months. Methyl chloroform produced in

mice an enlargement of hepatocytes with cellular. infiltration and

vacuolation and with slight necrosis only in the lethal range

(Klaassen and Plaa, 1966).

Comparison of the hepatotoxic

hydrocarbons shows that this

the number of chlorine atoms

of some investigators such as

action is due to liberation of

-

action of the different chlorinated

increases within each series with

in each molecule. The assumption

Lucas (1928) that the hepatotoxic

hydrobromic or hydrochloric acid,

was not shared by Barrett et al. (1939). It appear’s questionable

whether the hepatotoxic action of chlorinated hydrocarbons should

be affiliated with the liberation of‘ hydrochloric acid or the formation of phosgene, but it is more likely that it is produced by the

molecule in toto and it is probably linked to the fat solubility of

the solvents (Van Oettingen, 1944).

Nephrotoxicity

The renal effects of methyl chloroform have been less extensively

studied. This solvent produces definite disturbances of renal

176
function in mice (Klaassen and Plaa. 1966; Plaa and Larson, 1965)

and in dogs (Klaassen and Plaa, 1967) as shown by phenolsulfonphthalein, glucose, and protein excretion data. The kidneys

are less vulnerable than the liver to toxic properties of methyl

chloroform. Little or no microscopic changes were observed

(Klaassen and Plaa, 1966).

Trichloroethylene

The detailed description of the pharmacologic and toxicologic

features of methyl chloroform is intended to serve as a comparison

with other chlorinated solvents. A monograph describing the

features of trichloroethylene (CHClCHCl2) can be consulted for

details. Briefly it can be stated that although methyl chloroform

and trichloroethylene have many similar uses in industry and in

consumer products. trichloroethylene contained in cleaning fluid,

glue, and aerosol products is more widely abused by teenagers.

The most frequent lesion encountered during postmortem examination of addicts who indulge in sniffing trichloroethylene is hepatic

necrosis and nephropathy. There are also cases of unusual

lesions in the brain including ecchymotic foci in the dentate

nucleus and cerebral vascular accident. The reports of sudden

death without pathological explanation indicate that cardiac arrest

is the probable cause. In animal experiments, the threshold

concentration that depresses the contractility of the canine heart

is as follows: 0.05% trichloroethylene, a concentration which is

five times more toxic than methyl chloroform. The hepatotoxicity

of trichloroethylene is 1.3 times greater than for methyl chloroform (see references cited by Aviado et al., 1976).

Acute Inhalation Toxicity of Chlorinated Hydrocarbons

The organ toxicity and related toxicology has been discussed in

the preceding paragraphs. Assembled in the table at the top of

the next page are representative values of the lethal effects on

small animals of several of the chlorinated hydrocarbons that have

been reported. Principal sources of these data are reviews by

Aviado and the Criteria Documents.

CONCLUDING REMARKS

The discussion on the pharmacologic. and toxicologic features of

chlorinated propellants and solvents has one common theme: almost

all of them are cardiotoxic, hepatotoxic, and nephrotoxic. This

generalization is based on observations of animal experiments and

human cases of accidental or occupational poisoning. There is no

information derived directly from individuals who abuse the aerosols and consumer products containing halogenated hydrocarbons.

However, it is safe to interpolate the pattern of toxicity in animals and humans from large doses of the halogenated compounds

to anticipate the dangers to individuals who abuse the solvents

and propellants.

177
ACUTE INHALATION TOXICITY OF CHLORINATED HYDROCARBONS

Compound

Dose

ppm x Hours Effect Species

FC 11

FC 12

Carbon tetrachloride

Methylene dichloride

100,000 x 0.5

800,000 x 4

9,500 x 8

26,700 x 0.33

14,500 x 2

Trichloroethylene 12,566 x 4

Methyl chloroform 16,400 x 4

Tetrachloroethylene 10,000 - 19,000 x 2

L C 5 0

L C L O

L C 5 0

L C 5 0

L C 5 0

L C 5 0

L C 5 0

L C 5 0

(Approx.)

Rat

Rat

Mouse

Mouse

Mouse

Rat

Rat

Rat

*LC50= Lethal concentration which kills 50 percent of the animals by a specified time.

Past experience with the fluorinated propellants indicates that

when abused, the primary concern is death from cardiac arrest,

cardiac arrhythmia, and depression of myocardial contractility.

In the event that the fluorinated propellants are banned, the

chlorinated compounds, together with the hydrocarbon gases, will

probably be accepted as substitutes. This chapter has covered

the potential cardiac effects in the event that chlorinated compounds replace the fluorinated compounds. From the standpoint

of cardiotoxicity, methylene chloride is the least potent as far as

animal studies are concerned. As soon as the new aerosol products containing methylene chloride become widely distributed, the

questions as to its abuse potential and cardiotoxicity in man will

undoubtedly be answered.

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184
Chapter 11

NERVOUS SYSTEM DAMAGE FROM

MIXED ORGANIC SOLVENTS

Leon Prockop and Daniel Couri

INTRODUCTION

General Comments

Epidemic inhalation of the vapors of intoxicating hydrocarbons has

been known only during the past quarter century. In a 1973

review, Cohen stated that the use of commercial solvents as a

means of achieving an intoxicated state probably started in California during the late 1950’s. Since then, inhalant abuse has

been quite widespread. For example, in an upper middle class

high school in California, 7 percent of the boys and 2.5 percent

of the girls have sniffed intoxicants. Other data derived from

high schools throughout the country are similar. A 1975 study

(Abelson and Atkinson) reported data on inhalant abuse gathered

by means of a nationwide probability sample designed to reach two

parts of the United States population: adults over 18 and youths

ages 12-17. Of the adults, 2.8 percent reported use of glue or

other inhalants on one or more occasions. In the youth experience, 8.5 percent were involved.

A wide variety of products are employed, including glues and

cements, gasoline, cleaning solutions, lighter fluid, and paint and

lacquer thinner (Hofmann and Hofmann, 1975). All of the products contain one or more organic substances that have a generalized depressant effect on the central nervous system (CNS)

similar to that of volatile general anesthetic agents. Other effects

185
include photophobia, irritation of the eyes, diplopia, tinnitus,

sneezing,. rhinitis, coughing, vomiting, diarrhea, chest pain, and

muscle-joint pains. As detailed in Chapter 4 of this monograph,

inhalant abuse can cause alteration of nervous system function.

Pathophysiological Considerations

Little is known about the pharmacology of the volatile solvents.

For example, relatively little is known about the biotransformation

of n-hexane, known to produce peripheral neuropathy in humans,

in mammalian systems. It is presumed that the lipid solubility of

volatile solvents causes CNS depression by impairing membrane

permeability and neural transmission. The exact mechanism(s)

whereby volatile solvents, whether alone or in mixtures, causes

permanent nervous damage, e.g., neuropathy, cerebellar dysfunction or encephalopathy, is not known. Pathological findings, to

be discussed below, include neuropathy which is primarily axonal

with subsequent demyelination. Perinodal axonal swellings with

neurofibrillary tangles have been described (Schaumberg and

Spencer, 1976), Experimentally, axoplasmic flow is impaired

(Spencer and Schaumberg, 1975). Referring to damage outside

the nervous system, Hofmann (1975) states that the toxic effects

of individual volatile solvents are numerous and include bone

marrow aplasia with benzene, hepatic cell dysfunction with trichloroethylene, and kidney damage with a variety of esters.

Information Derived From Accidental

or Occupational Exposure

Over the last few decades, great advances have been made in

establishing approximations of the safe or permissible limits of

accidental or occupational exposure for the protection of workers

engaged in processes involving exposure to these solvents. Such

exposure may be to either a single solvent or to mixed solvents.

In the case of single solvent exposure more than mixed solvent

exposure, information gathered from experimental studies with

laboratory animals along with the cumulative experiences of many

industries provided the data base for the estimations of relative

risk and potential health hazard associated with each of the most

commonly used volatile solvents (and other chemical agents). In

general, concern for occupational exposures restricted studies of

these safety evaluations to those time intervals and concentrations

of substances consistent with the usual working day conditions.

As a consequence, animal studies became increasingly formalized

to include exposure to a single agent for a duration of 5 to 7

hours/day, 5 days/week. Valuable information regarding lethality

and tissue or organ damage was obtained at very high concentrations of exposure, while chronic low level exposures yielded

subtle, less drastic alterations from normal. These kinds of

studies continue to serve as indices for potential hazards associated with human exposures.

186
EFFECTS OF MIXED SOLVEN’I’S

For the specific hazard invoIved in the inhalational misuse, i.e.,

inhalant abuse, of these volatile solvents, the pattern and conditions of exposure are markedly different from those of the work

environment. Literature reports of the intentional inhalation of

solvents commonly describe a typical pattern of tolerance development. Beginners usually inhale one or more days per week, and

quickly progress to a compulsive practice of multiple experiences

daily (Bass, 1970; Cohen, 1975; Massengale et al., 1963; Press and

Done, 1976). Those experiencted in volatile solvent inhalant usage

express a preference for one or more of the commercially available

solvents (or solvent mixtures) based upon the qualities of taste

and odor. Often the user will detect changes in the quality of

the product; in some cases these changes are accompanied by the

appearance of clinical symptoms in the user. Estimations of

inhaled solvent vapor concentrations are vague but are most likely

extraordinarily high and extremely variable. The high concentrations of solvent vapors inhaled repetitively for years result in a

chronic insult to the nervous system which cannot. readily be

evaluated or understood from any of the available systematic

studies in anesthesiology or from chronic low level safely evaluation studies. Fundamental studies directed towards understanding

this usage pattern are not yet. available. However, it is important to describe some basic principles of solvent vapor exposure

already gained from our experiences in: (A) general comments

and principles; (B) the area of clinical and pathological features

of nervous system damage secondary to inhalant abuse both in

humans and experimentally in rats and; (C) the area of industrial

exposure which is relevant to the inhalant abuse of volatile sol

vents. In addition, three other items will be briefly discussed:

(D) reports of increased toxicity from mixed solvent exposure

(E) reports of increased toxicity attributable to the inhalant

abuse of mixed solvents and (F) additional experimental data

related to the biological effects of mixed solvents.

General Comments and Principles

Before discussing the five specific related subjects, a number of

general statements are in order. Definition of the mechanism or

mechanisms whereby a single solvent causes impairment of organs

or organ systems is difficult. Little of a conclusive nature is

known. Obviously, the situation of mixed solvents, as encountered commonly with the inhalant abuser, provides problems of

even greater complexity.

in the mixture.

More than one toxic: substance may be

Each toxin may act alone to produce an additive

effect to that of another toxin(s) within the mixture. Alternatively, synergistic action may occur whereby the net toxic effect may

be more than simply additive. Furthermore, one toxin may alter

the metabolism so that another substance in the mixture. otherwise nontoxic, becomes toxic. A metabolite formed from one

solvent within a mixture may extend the toxic effect of its parent

187
compound or of another compound within the mixture. A parent

compound may be toxic in itself. Likewise , a metabolite of this

parent compound may exert an equal toxic effect. One solvent

within a mixture may enhance the toxic effect of another by

facilitating its entry into an organ or into organ systems or by

acting as a vehicle or carrier for its penetration into the extracellular or intracellular space, Thus, the carrier function served

by one of the solvents within a mixture may allow the penetration

of another solvent within the mixture (i.e., a more specific toxic

agent) into a specific site. Finally, biotransformation may occur

so that the toxicity of one solvent within the mixture may be

enhanced in the presence of other solvents.

Given these general principles, more specific consideration will be

given to the topics mentioned above.

Clinical and Pathological Features of “Huffer’s”

Neuropathy Secondary to Inhalant Abuse in Humans

and Experimentally in Rats

Clinical Data

Seven young men developed severe, diffuse, progressive, predominantly motor polyneuropathy after inhalant abuse involving a

commercially available lacquer thinner (Prockop et al., 1974).

Neurogenic muscular at atrophy was prominent. Three were completely paralyzed, including bulbar involvement and required

artificial respiration, and one died. Significant abnormal laboratory findings were: visual fields in two patients showed central

and paracentral scotomas; nerve conduction rates ranged from 0

to 30 m/sec (normal, 42 to 55) with electromyographic evidence of

acute denervation; electron microscopy of sural nerve in five

patients documented segmental paranodal axonal distention by

neurofilamentous masses; light microscopy of postmortem tissue

showed chromatolysis of anterior horn cells and axonal swellings

in the dorsal columns (Means et al., 1976). Examination of five

patients 1-1/2 years later defined residual neurological deficit in

all ranging from mild to severe (Prockop, unpublished data).

Toxicological Data

The seven men had been “huffing” the same brand of commercially

available lacquer thinner without adverse effect from 6 months to

2 years, although other organic solvents had been used by several individuals for as long as 10 years. Several weeks before

onset of symptoms, the patients noted a change in the odor of the

lacquer thinner. This odor change correlated with a solvent

formula change, apparently prompted by increased cost of previously used solvents. Gas chromatographic and mass spectrographic analysis of two different lacquer thinner mixtures both

marketed under the same label was performed by the Physical and

Chemical Analysis Branch of the National Institute of Occupational

188
Safety and Health. One mixture was identified by the patients as

“the good stuff” and was, according to them, inhaled regularly

for weeks or months without adverse effects. The second lacquer

thinner mixture was identified by the patients as the “bad stuff.”

They noted the malodorous change at the onset of its use. Clinical symptoms and signs developcd shortly thereafter. Components

of the commercial lacquer thinners samples #1 and #2) expressed

as volume percent are as follows:

#1

Toluene

Isobutyl acetate

Acetone

Methyl ethyl ketone

Xylene

Isopropyl alcohol

Isobutyl isobutyrate

Isobutyl alcohol

2-Heptanone

2-Nitropropane

Isopropyl acetate

n-Hexane

# 2

47

12.2

11.3

9.1

6.8

5.7

4.7

3.2

3.9

12.6

12.7

43.6

0.5

0.5

3.5

15.5

5.8

1.2

0.5

Data From In Vivo Animal Studies

In studies performed by Tison and Prockop (1977), SpragueDawley rats weighing from 250-300 grams were exposed to various

combinations of the organic solvents in the mixtures as identified

above. Animals were maintained in air-tight chambers which

allowed them to move about freely and to partake of food and

water ad libitum. This system was so constructed that the

“good” or “bad” solvents, whether used alone or in mixtures,

were vaporized by a dripping technique so that the concentration

of any solvent within the exposure chamber remained constant

during the entire exposure period. Concentrations of the vapors

to which the animals were exposed were analyzed daily by gas

chromatography to assure a constant exposure. The results of

these studies will be reported here in summary fashion and are

still of a preliminary nature. Further studies are in progress

and more conclusive presentation in print can be expected subsequent to their completion.

The mixture of chemicals comprising sample #1 was reconstituted

from reagent grade chemicals available commercially. The mixture

was vaporized in the manner described briefly above and vented

through the exposure chamber. Eight rats were exposed to this

vapor for 1,200 hours without clinical evidence of peripheral

neuropathy nor other ailments. The animals were sacrificed and

189
portions of the sciatic nerve were prepared in standard techniques and analyzed by light and electron microscopy.* No

abnormalities were noted. Another group of eight rats was exposed to the vapor of solvents reconstituted according to the

percentages tabulated under sample #2 for a total of 975 hours.

The average concentration of each solvent within the exposure

and their respective threshold limit values will he presented later.

The rats showed clinical signs of neurological damage characterized by difficulty in walking, inability to stand on their hind

legs, and difficulty with turning movements after 900 hours of

exposure. Two animals from this group were removed from the

exposure after 400 hours of exposure. There were no clinical

signs of neuropathy but light microscopy demonstrated the

following (Means and Tison, unpublished data): (1) teased fiber

preparations showed only “ruffled” myelin in a small percent of

fibers, (2) light microscopy showed intra-axonal aggregates of

Periodic Acid Schiff (PAS) positive material. In addition, rare

degenerating fibers were identified in transverse sections of

epon-embedded toluidine blue stained material; (3) electron microscopy demonstrated intra-axonal, membrane- bound aggregates of

glycogen Redundant axonal membrane containing Schwann cell

organelles were present in paranodal areas. Rare onion bulb

formations and denuded axons were also identified. Similar analysis of animals exposed for 900 hours demonstrated more prominent

pathological signs of neuropathy, predominantly of an axonal

variety.

Subsequent studies, some of which are still in progress or remain

to be done, were designed to determine which solvent or solvents

within the neurotoxic mixture (i.e., sample #2) were responsible

for the experimental findings and, therefore, for the toxicity in

the humans. Although it is not appropriate to present details of

the studies here, several of the findings can be reported. Ten

rats exposed to methyl amyl ketone for 2300 hours at a concentration of 1,300 mg/m3

 (three times the TLV) showed no clinical

signs of neurological impairment. No histological changes were

found in peripheral nerves. Likewise, rats exposed for 975 hours

to 400 mg/m3and 2-nitropropane at 350 mg/m3 of methyl amyl

ketone showed no clinical evidence of peripheral neuropathy.

Rats exposed to 10 mg/m3

of methyl ethyl ketone for 1,300 hours

appeared normal clinically. Animals exposed to the constituents

of sample #2, except for hexane, isopropyl alcohol, and isopropyl

acetate, for 1,000 hours were clinically well.

These data indicate that sample #1 is not a neurotoxic mixture but

sample #2 is a potent neurotoxin. The solvent or combination of

solvents within this mixture which exerts this action requires

further investigation, some of which is in progress. The remarks

*Light and electron microscopy analyses were performed and

are described here by Eugene Means, M.D., Tampa VA Hospital

Research Services, College of Medicine, University of South

Florida.

190
made in the general section above with respect to potential synergistic action of two or more solvents and potentiation of toxic

effects must be borne in mind in these and other studies investigating the effects of mixed solvents on the central and peripheral

nervous system.

The epidemiological data gathered in the “epidemic” of “huffer’s

neuropathy” in Tampa indicate that a third lacquer thinner mixture was used by one group of inhalant abusers and that it was

also responsible for neuropathy in the individuals involved. This

third lacquer thinner has a formula different from either sample #1

or sample #2 above. Toxicological and experimental data are, as

yet, too preliminary for discussion here.*

Industrial Exposure to Mixed Solvents

Relevant to Mixed Inhalant Abuse

Toxicologic studies involving the industrial solvents methyl nbutyl ketone (2-hexanone, MBK) and methyl ethyl ketone (2-

butanone, MEK) were initiated when 85 workers in a plastics

coating and printing plant were afflicted with a toxic peripheral

neuropathy of varying severity (Abdel-Rahman et al., 1976;

Abdel-Rahman and Couri, 1977; Couri, 1974; Couri et al., 1977b).

Investigations were directed towards isolating and identifying the

neurotoxic agent(s) responsible for the occurrence of these peripheral neuropathies .

The first objective was to determine whether the suspected solvent, MBK, had any neurotoxic potential. For this purpose,

several laboratory animal species were exposed to various vapor

concentrations of MBK, MEK, and MEK/MBK combinations. The

studies with MEK/MBK vapor mixtures involved those solvents in

ratios which corresponded to that of the factory setting. The

salient findings of these studies can be summarized as follows.

Chronic exposure of cats, rats and chickens to MBK vapors or

MEK/MBK combined vapors resulted in the development of peripheral neuropathies (Abdel-Rahman et al., 1976; Couri, 1974; Couri

et al., 1977b). Furthermore, electrodiagnostic techniques revealed

a slowing of nerve conduction velocity, positive waves, and fibrillations in cats at various times after solvent exposure. Also,

animals with clinical neuropathies showed histopathological and

ultrastructural changes in sciatic nerve preparations characterized

by paranodal axonal swelling, denudation of myelin, increased

number of neurofilaments, and a decrease in neurotubules.

Animals exposed to MEK vapors did not exhibit any neurotoxicity;

at very high levels slight to moderate narcosis occurred in

*Segments of the research work discussed in this section

were performed at the Research Service, Tampa VA Hospital.

191
chicken, cat, rat, and mouse. The ketone vapors alone, or in

combination, did not produce peripheral neuropathy in mice.

Significance of the MBK Study in Relationship

to the Inhalation Abuse of 1ndustrial Solvents

It is important that these studies demonstrated that after chronic

exposure to MBK vapors, chickens. cats, and rats (but not mice)

developed peripheral neuropathy It is significant that a more

severe toxicity was observed at a shortened time of exposure to

MEK/MBK combined vapors when compared to MBK alone. This

finding of increased toxicity with mixed solvent vapors may be of

paramount importance to the problem of inhalant abuse of industrial solvents. Because many of the industrial solvents used are

of technical grade quality or are used as mixtures of miscible

solvents, the possibility of producing an exaggerated adverse

effect is more likely if the MEK/MBK example can be generalized.

Reports of other solvent mixtures supporting this generalization

will be described below.

Enhanced Toxicity of MBK when Combined With MEK

In studies with three groups of six rats continuously exposed to

vapors of MEK, 1,500 parts per million (ppm); MBK, 400 ppm; or

MEK/MBK, 1,500/150 ppm, it was clear that MBK alone produced

severe neuropathies at 12 weeks; and that the MBK/MEK group all

developed severe neuropathies by the sixth week of exposure

(Couri, 1974). Similar data demonstrating the marked increase in

toxicity and a shortened time for onset were obtained with cats

and chickens. Animals exposed to MEK alone did not develop

neuropathy.

To investigate the possibility that the enhanced toxicity of the

mixed solvent vapors may be attributed to an alteration in MBK

or its metabolite(s), the kinetics of plasma MBK in rats exposed

to MBK alone and combined MBK/MEK vapors were determined

(Abdel-Rahman et al., 1976). The MBK content in tht: plasma of

rats exposed to MBK/MEK was not measured after a single

8-hour exposure, but did increase with continuous vapor exposure reaching 24 mg% (mg per 100 ml of’ blood) at 23 days. The

plasma MEK content showed an inverse relationship to that of

MBK. After 6 days of exposure, 2,5-hexanedione, an MBK metabolite, was detected in plasma. This metabolite is also capable of

producing peripheral neuropathies in experimental animals (AbdelRahman and Couri, 1977; Abdel-Rahman et al., 1977, Couri et al.,

1977a; Saida et al., 1976; Spencer and Schaumberg, 1976). In

contrast to the MBK/MEK data, the plasma of animals exposed to

MBK alone did not contain any measurable MBK (detection sensitivity 30 ng). It was observed that the MBK/MEK vapor exposure resulted in a prolonged and increased plasma titer of MBK

and its metabolite compared to MBK alone. Toxicity and mortality

occurred. The MBK/MEK exposure gropu all showed severe neu192
ropathies The experiment was limited to 23 days because of the

severity of the neuropathy The animals were removed from the

exposure chamber and held for recovery. One animal died on the

22nd day of exposure and the other five died within the next 10

days. In the MBK group two of six animals exhibited mild neuropathies and no fatalities occurred after 60 days of continuous

exposure. It is clear from this study that the animals exposed to

the combined MEK/MBK solvent vapors manifested markedly enhanced neurotoxicities with a shortened time to occurrence and a

dramatic increase in mortality.

Kinetics of Plasma MBK and MEK

After Exposure to Solvent Vapors

Animals exposed to MBK vapors always showed nondetectable

levels (<30 ng) of MBK in the orbital sinus blood samples (Couri,

1976). This was difficult to reconcile with the observed neurotoxicity after MBK exposure. In order to examine this further,

animals were prepared with jugular vein catheters exteriorized in

such a way that jugular blood samples could be obtained throughout the period of exposure to either MBK or MBK/MEK vapors.

There was a gradual increase in jugular blood MBK content

throughout the 150-minute (MBK, 500 ppm exposure) period studied. The animal was removed from the exposure chamber and a

retro-orbital blood sample was obtained as in the previous experiments. The data clearly indicate that in this 2-minute time interval 6.8 mg% MBK in blood rapidly diminished to a nondetectable

level. After an hour of rest (in air) this same animal was then

replaced in the exposure chamber containing MBK/MEK, 500/800

ppm. Throughout the 60-minute exposure to MBK/MEK, the MBK

content in blood was about twice that observed after MBK (500

ppm) alone, MEK content increased with time and no solvent

metabolites were detected. The presence of MEK vapors somehow

allowed a greater accumulation and a persistence of MBK in blood.

This was demonstrated in another set of two experiments where

animals were exposed to MBK/MEK 400/1,200 ppm for 150 minutes;

afterwards, postexposure blood samples were obtained simultaneously from the jugular and the orbital sinus. In both experiments, at 3 minutes postexposure the jugular vein and orbital

sinus blood content of MBK agreed very well. However, there

was a considerable loss of both MBK and MEK content in this time

interval. The striking features of the postexposure period at 13

(and 15) minutes is the persistence of both MBK and MEK in blood

which is about 90 percent of their concentrations seen 10 minutes

earlier (in air). Again, inhalation of MBK/MEK vapors resulted

in higher blood levels of each solvent for a longer period of time.

This, in part, can account for the increased toxicity and mortality of these combined vapors described above.*

*Segments of the research work discussed in this section

were performed at the College of Medicine, Division of Toxicology,

Ohio State University.

193
The combined solvents encountered in the inhalational abuse of

industrial solvents such as paint thinners., glues, adhesives,

lacquers, and paint solvents should be critically examined for

combinations which might produce much greater toxicity attributable to the presence of one or more of its components in the

mixture.

Reports of Increased Toxicity From

Mixed Solvent Vapor Exposures

There are several reports of industrial toxicities that involved the

presence of MEK in a mixture with other solvents(s); for example, with 10% 2-nitropropane/MEK, 500 ppm; acetone/MEK, each

300-500 ppm (Elkins, 1959); MEK and an unsaturated ketone

impurity (Smith and Mayers, 1944); in each of these cases workers presented symptoms which were of greater severity than could

be accounted for by any of the individual components. Similarly,

such events have been reported for ketones in combination with

butyl, ethyl, and amyl acetates, and other solvents (Heim DeBalzac

and Agasse-Lafone, 1922; Sessa and Troisi, 1947; both studies

cited in Browning, 1965). However, studies of Llewellyn, 1963;

Fasset, 1963; and Oglesby et al., 1949 (all cited in Browning,

1965) indicated that workers exposed to 1,000-2,000 ppm acetone

for years exhibited no permanent deficits but only a dull headache with temporary anorexia. Bone marrow injury related to

benzene exposure was considered to be a toxicity of toluene.

Later, the presence of benzene contamination in toluene was

established to be responsible for the myelotoxic events (Hamilton

and Hardy, 1974). This example of marrow toxicity caused by

very low levels of benzene in toluene can be looked upon as an

enhanced toxicity of low concentrations of benzene when combined

with toluene.

Reports of Increased Toxicity Attributable

to the Inhalant Abuse of Mixed Solvents

There are many case reports of toluene inhalant abuse in the

medical literature. Some of the histories indicate that toluene is

often a favorite solvent for inhalation. The two cases of Shirabe,

et al. (1974) illustrate this preference. These comrades inhaled a

glue containing principally toluene (70-100%) for more than 2

years; just prior to the onset of their toxic polyneuropathies they

switched to inhaling a glue composed of toluene 55% and n-hexane

45%. Evaluation of the clinical course by the authors led them to

conclude that the polyneuropathies were due to n-hexane and

possibly a contributory effect from toluene. Similarly, in the

case reported by Korobkin et al. (1975) the patient had been

inhaling contact cement vapors for about 5 years; when afflicted

with a polyneuropathy he still continued his habit; however, he

switched to a glue without n-hexane Three months later he was

unable to walk; subsequent hospitalization for approximately 1

year resulted in some degree of recovery. The case reported by

194
Knox and Nelson, 1966, described a patient who purchased “certified pure” gallons of toluene for his inhalation habit of 14 years

duration. He had permanent brain damage with diffuse cerebral

atrophy. Another use of “pure” toluene reported by Grabski,

1961, had a degenerative lesion of the lateral cerebellar lobes as a

result of years of inhalation of toluene vapors.

Spencer et al. (1975) reported minimal axonal degeneration with

giant axonal swelling in rats exposed to methy n-butyl ketone

(MBK), an isomer of methyl isobutyl ketone (MIBK). They stated

that minimal axonal degeneration due to MIBK may be related to

the presence of 3% MBK in the commercial grade of MIBK. Oh

and Kim (1976) reported giant axonal swelling in a case of

“huffer’s” neuropathy in a man who had “huffed” two kinds of

lacquer thinner--the first containing methyl ethyl ketone, methyl

isobutyl ketone, acetone, and toluene; the second containing

acetone, methanol, toluene, isopropyl alcohol, ethylene glycol,

and monoethyl ether acetate. Prockop (1977) documented the case

of a woman who developed peripheral neuropathy, bilateral optic

neuropathy, as well as evidence of cerebral and cerebellar damage

after chronic inhalation of volatile hydrocarbons in the course of

her work as a commercial artist utilizing a silk-screen process.

Additional Experimental Data Related to the

Biological Effects of Mixed Solvents

Couri and coworkers (1977c) have studied the influence of inhaled

ketone solvent vapors on hepatic microsomal biotransformation.

Young male Wistar rats were housed in environmental chambers

and exposed to solvent vapors (methyl n-butyl ketone, MBK, 225

ppm; methyl ethyl ketone, MEK, 750 ppm; MBK, 225 ppm/MEK,

750 ppm) . Hexobarbital sleep times were significantly reduced

following exposure to MBK/MEK or MEK, but MBK exposure did

not alter sleep time measurements. Aniline hydroxylase, aminopyrine demethylase, neoprontosil reductase, and p-nitrobenzoate

reductase activities were significantly enhanced two- to three-fold

in MBK/MEK and MEK exposure groups compared to controls.

Peripheral neuropathies caused by exposure to hexane and 2-hexanone (MBK) exhibit similar clinical and pathological features. In

both in vivo and in vitro studies Couri et al. (1977a) have determined that MBK and n-hexane undergo biotransformation to a

common metabolite, 2,5-hexanedione. In the in vitro studies,

hepatic reduction of MBK required the cytosolic enzyme to form

2-hexanol. The oxidation of MBK and hexane required microsomal

enzymes to form 2,5-hexanedione and 2-hexanol, respectively.

Although the pathophysiological mechanism(s) by which these compounds, i.e., hexane and MBK and their metabolite 2,5-hexanedione, produce neuropathy is unknown, Abdel-Rahman and

coworkers (1977) have demonstrated MBK and MBK metabolites

markedly decrease pupillary response and locomotor activity in

guinea pigs.

195
CONCLUDING REMARKS

Little is known about the mechanism(s) whereby single solvents

produce nervous system and other organ system damage. Even

less is known about the effects of mixed solvents. Unquestionably, further extensive laboratory investigation is urgently needed. This is especially true because further changes in the composition of organic solvents may produce human exposure, both

accidental and in the inhalant abuse situation, to dangerous

neurotoxins.

REFERENCES

Abdel-Rahman, M., and D. Couri. Toxicity of MBK metabolites.

Manuscript in preparation, 1977.

Abdel-Rahman, M., L. Hetland, and D. Couri. Toxicity and

metabolism of methyl n-butyl ketone. Am Ind Hyg Assoc J,

37:95-102, 1976.

Abdel-Rahman, M., J. Saladin, C. Bohman, and D. Couri. The

effect of 2-hexanone and 2-hexanone metabolite on pupillomotor

activity and growth. Am Ind Hyg Assoc J, in press, 1977.

Abelson, H., and R. Atkinson Public experience with psychoactive substances. Response Analysis Corporation, 1975.

Bass, M. Sudden sniffing death. JAMA, 212:2075-82, 1970

Browning, E. Toxicity and metabolism of industrial solvents. New

York:Elsevier, 1965.

Cohen, S. Glue sniffing. JAMA, 231:653-4, 1975.

Cohen, S. The volatile solvents. Public Health Rev, II, (2):85-

214, 1973.

Couri, D. Comments on a plastics industry neurotoxicity in

relationship to methyl hutyl ketone. Proceedings of the Fifth

Conference on Environmental Toxicology, AMRL-TR-74-125, 109-20,

1974.

Couri, D., and M. Abdel-Rahman. Toxicological evaluation of

intentionally inhaled solvents. Presented at the First International Symposium on Voluntary Inhalation of Industrial Solvents,

Mexico City, June 1976.

Couri, D., M. Abdel-Rahman, and L. Hetland. Biotransformation

of hexane and methyl n-butyl ketone. Am Ind Hyg Assoc J, in

press, 1977a.

196
Couri, D., M. Abdel-Rahmau, and L. Hetland. Metabolism and

toxicity of methyl butyl ketone and hexane. J Toxicol Appl

Pharm, in press, 1977b.

Couri, D., L. Hetland, M. Abdel-Rahman, and H. Weiss. The

influence of inhaled ketone solvent vapors on hepatic microsomal

biotransformation activities. J Toxicol Appl Pharm, 41:, September 1977c.

Elkins, H. The chemistry of industrial toxicology. New York:

John Wiley and Sons, 1959.

Grabski, D. Toluene sniffing producing cerebellar degeneration.

Am J Psychiatry, 118:461-2, 1961.

Hamilton, A., and H. Hardy. Industrial toxicology. Acton,

Massachusetts: Publishing Sciences Group, 1974.

Hofmann, F., and A. Hofmann. Handbook on drug and alcohol

abuse: the biochemical aspects. New York: Oxford University

Press, 1975.

Knox, J., and J. Nelson. Permanent encephalopathy from toluene

inhalation. N Engl Med, 275:1494-6, 1966.

Korobkin, R., A. Asbury, A. Sumner, and S. Nielsen. Glue

sniffing neuropa thy. Arch Neurol, 32:158-62, 1975.

Massengale, O., H. Glaser, R. LeLievre, J. Dodds, and M.

Klock. Physical and psychologic factors in glue sniffing. N Eng

J Med, 269:1340-4, 1963.

Means, E., L. Prockop, and G. Hooper. Pathology of lacquer

thinner induced neuropathy Ann Clin Lab Sci, 6:240-50, 1976.

Means, E., and J. Tison. Unpublished data.

Oh, S., and J. Kim. Giant axonal swelling in “huffer’s” neuropathy. Arch Neurol, 33:583-6, 1976.

Press, E., and A. Done. Physiologic effects and community

control measures for intoxication from intentional inhalation of

organic solvents. Pediatrics, 39:451-61, 611-22, 1976.

Prockop, L. Multifocal nervous system damage from inhalation of

volatile hydrocarbons. J Occ Med, 19:139-40, 1977.

Prockop, L. Unpublished data.

Prockop, L., M. Alt, and J. Tison. “Huffer’s” neuropathy.

JAMA, 299:1083-4, 1974.

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Saida. K, J. Mendell, and H. Weiss. Peripheral nerve changes

induced by methyl n-butyl ketone and potentiation by methyl

ethyl ketone. J Neuropathol Exp Neurol. 35:207-25, 1976.

Schaumberg, H., and P. Spencer. Degeneration in central and

peripheral nervous systems produced by pure n-hexane: An

experimental study. Brain, 99:183-92, 1976.

Shirabe, T., T. Tsuda, A. Terao, and S. Araki. Toxic polyneuropathy due to glue-sniffing. J Neurol Sci, 21:101-13, 1974.

Smith, A., and M. Mayers Poisoning and fire hazards of

butanone and acetone. Ind Bull NY State Dept Labor, 23:174-6,

1944 .

Spencer, P., and H. Schaumberg. Experimental neuropathy

produced by 2,5-hexanedione--A major metabolite of the neurotoxic industrial solvents methyl n-butyl ketone. J Neurol Neurosurg Psychiatry, 38:771-5, August 1975.

Spencer, P., and H. Schaumberg. Towards a molecular basis for

experimental giant axonal degeneration. Am Assoc Neuropathol:

349, June 1976.

Spencer, P., H. Schaumberg. R. Raleigh, et al. Nervous system

degeneration produced by the industrial solvent methyl n-butyl

ketone. Arch Neurol, 32:219-22, 1975.

Tison, J., and L. Prockop Manuscript in preparation, 1977.

198
PRECLINICAL BEHAVIORAL DYSFUNCTIONS

198
Chapter 12

PRECLINICAL BEHAVIORAL TOXICOLOGY

OF INHALANT SOLVENTS

Robert E. Bowman

TWO PROBLEMS: DEPENDENCY AND BEHAVIORAL TOXICITY

There are two broad and basically different classes of behavioral

questions which may be raised regarding inhalant solvents. The

first class revolves around the topic of the reinforcing properties of

inhalant substances and deals with the determinants of drug

dependency and dependency potential of the inhalant solvents. The

second class of questions relates to the alterations in nondrug

behavior induced by the inhalation of volatile solvents, or what may

broadly be termed the behavioral toxicity of the inhalant solvents.

These two main topics, dependency and toxicity, will each be

considered in turn in this chapter.

BEHAVIORAL ASPECTS OF DRUG DEPENDENCY

AND DRUG DEPENDENCY POTENTIAL.

Definitions of Terms

The term “drug dependence” was recommended in 1964 by the World

Health Organization (WHO) Expert Committee on AddictionProducing Drugs (cited by Fraser, 1974). Drug dependence was

operationally recognized as “...the repeated administration of a

drug on a periodic or continuous basis.” (Fraser, 1974). The

term included either psychic or physical dependence or both.

However, the term excluded any connotation regarding the degree

of risk to the subject or to the public from the drug dependence.

To fill this gap, Fraser (1974) proposed that the concept of risk

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from drug dependence be embodied in the term “drug abuse,"

defined as follows: “abuse of a drug exists if its use so harmfully

affects the individual and/or society as to require its control.”

Fraser’s proposal has some merit, since the term “drug abuse” is

not needed as a synonym for the more established term “drug

dependence,” and since the word “abuse” already stereotypically

carries the connotation of harm in its common usage. However, in

subsequently discussing “abuse potential” of drugs, Fraser (1974)

was exclusively concerned with dependency mechanisms, and

considered no factors relevant to assessing harm. Furthermore,

the term “drug abuse” appears frequently to be utilized by most

authors simply as a synonym for drug dependency.

The question of harm from drug use is a question of toxicity, in the

broadest sense of both physiopathological and behavioral toxicity,

and will be so treated here. In Fraser’s sense, the term “drug

abuse” is premature for many inhaled solvents, since the current

data are often insufficient regarding toxicity under the conditions

of human usage. Therefore, this chapter will in general avoid the

terms “drug abuse” and “abuse potential” in favor of “drug

dependency” and “dependency potential.”

Preclinical Models of Drug Dependency

Drug dependency occurs by definition if one repeatedly selfadministers the drug. The dependency may be maintained by either

physical dependence or behavioral (psychic) dependence on the

drug, or both. Physical dependence is recognized by the

appearance of a physiological syndrome upon withdrawal of the

drug, typically following high or prolonged dosage with the drug.

Behavioral dependence can be recognized through verbal reports of

subjective effects in humans, or by the appearance of drug

dependence in the absence of a physiological withdrawal syndrome.

Behavioral Dependence

The study of the determinants of drug dependency, and especially

of psychic dependency, is probably the central problem from the

standpoint of control or treatment of inhalant solvent abuse. Such

studies in the human must rely on clinical material and retrospective

assessments and are reviewed elsewhere in this monograph.

Experimental studies of solvent dependency can ethically only be

done in the animal. To perform such studies requires the

availability of animal models of inhalant dependency, and research

on such models is at an early stage.

By analogy with learning paradigms, one may distinguish two stages

in drug dependency, namely the acquisition of and then the

maintenance of the self-administration responses. The factors

determining acquisition and maintenance of drug dependency may

differ somewhat, so that both of these stages probably require

study.

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The squirrel monkey has been shown to acquire self-administration

of nitrous oxide (Wood et al., in press) delivered to a helmet encasing the head. The monkeys learned to press a lever to deliver

selected concentrations of nitrous oxide for a 15-second interval.

The lever rate declined when delivery of nitrous oxide was discontinued, and increased with increasing numbers of lever responses (a progressive fixed ratio schedule) required to deliver

a single reinforcer. At a fixed ratio set at 20 responses to

deliver nitrous oxide for each single reinforcement interval of

15-second duration, response rates increased with increasing

concentrations of nitrous oxide. Nitrous oxide was clearly a reinforcer and controlled the response rates for its delivery, but

appeared to be only a weak reinforcer.

Yanagita et al. (1970) had earlier reported toluene selfadministration in the monkey. Thus, Wood (1976) switched one of

the monkeys self-delivering nitrous oxide to toluene delivery. The

monkey readily transferred its lever responses to the delivery of

toluene, and indeed the data indicated toluene to be a more potent

reinforcer than was nitrous oxide. From the data of response rates

versus toluene concentrations, Wood proposed that one might be

able to determine a “self-administration limit value” below which the

solvent concentration would not act as a reinforcer. Wood’s

estimate of this parameter for toluene was 560 ppm. Wood

suggested that this might be a useful parameter in regulating

maximal permissible levels for occupational exposures, chosen to

preclude the possibility of workers’ adventitiously learning an

inhalation dependency through solvent exposures at their job.

Aside from this, no other data could currently be found on the

acquisition of solvent dependencies. It may be possible to train an

acquisition of dependency by eliminating the lever and letting the

monkey stick its head into a helmet with a solvent atmosphere (Ron

Wood, personal communication), thereby more directly mimicking the

response topology of the human with an inhalant dependency.

Rodents could also be trained in a two-chambered apparatus, with

free access to the solvent atmosphere maintained in one chamber.

Frequency of entries and duration of time in the solvent chamber

would reveal the development and maintenance of any solvent

dependency.

The potential usefulness of animal acquisition models of solvent

dependency is difficult to assess. With respect to alcohol

dependency, Freund (1975) stated his doubts that "...animal

experimentation can contribute significantly to the elucidation of the

complex human psychological and sociological factors that interact to

induce the initiation of excessive alcohol consumption." If this

point is true for alcohol dependency, it will also be true for solvent

dependency. It is perhaps premature to prejudge this issue. It

may well be that solvent dependency and excessive consumption

would be increased in animals which were socially separated or

malnourished, or reared in impoverished environments or stressed

with noxious stimuli. On the other hand, solvent dependency might

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be decreased by the addition of aversive solvents to the solvent

mixture. Such findings could offer valuable support to theoretical

formulations regarding the determinants of drug dependency in the

human. It is perhaps only the role of verbal or cultural factors in

human dependency, if any, which could not be assessed in the

animal model.

Physical Dependence

The determination of withdrawal syndromes (physical dependency)

is best done by experimenter-controlled administration of drugs to

the animal, and does not require self-administration by the animal.

Freund (1975) has reviewed a number of methods related to rodent

physical dependency syndromes following alcohol. Goldstein (1975)

utilized inhalant exposure to alcohol to obtain the prolonged,

continuous exposures necessary to produce physical dependency;

she further used behavioral measures (convulsions on handling) to

assess the severity of withdrawal symptoms over time following

cessation of alcohol delivery. Withdrawal syndromes peaked about

10 hours after termination of alcohol exposure and disappeared at

about 30 hours postexposure; physical dependence developed

progressively to a maximum at about 2 weeks of exposure.

Skoricová and Molcan (1972), among others, reported an abstinence

syndrome in patients who had been inhaling about 30 ml daily of

trichloroethylene for an average of a year prior to treatment.

However, the question of withdrawal syndromes to volatile solvents

appears generally undetermined.

Procedures similar to those reviewed by Freund (1975) could well be

useful in assessing the ability of a variety of solvents to induce

physical dependence. However, as Fraser (1974) points out with

respect to opiates, the occurrence of physical dependency does not

per se predict the dependency potential (“abuse potential”) for a

compound .

Aversive Properties of Solvents

One might suppose that aversive solvents would not sustain a

dependency. This is the obvious rationale for the adulteration of

glues with allyl-isothiocyanate. If so, then the measured

aversiveness of various solvents could be useful in assessing their

dependency potential. Unfortunately, it seems likely that “acquired

tastes” may occur with inhaled solvents, and that aversiveness

upon initial exposures might disappear later or be counteracted by

factors of positive reinforcement given prolonged exposures. For

example, thresholds for irritation of the eye or respiratory membranes have been reported for many of the volatilized solvents at

levels well below the concentrations reported inhaled in solvent

dependencies. Nevertheless, initial aversiveness, if sufficiently

strong, should serve as a first line of defense against the

development of dependency. Given a suitable animal model for the

self-acquisition of solvent dependency, then it will be possible to

study the role of volatile aversive additives on the acquisition of

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dependency. It may be possihle to identify solvents which produce

a “bad trip” (possibly through cholinergic effects) and which

could be used as adulterants in solvent mixtures to obviate the

attractive reinforcing properties of the mixture. Alternatively,

adulteration with solvents having noxious odors (such as the

mercaptans) or highly irritant properties might also prove beneficial

in avoiding not only solvent dependencies but also excessive

adventitious inhalation in the occupational use of solvents.

Unfortunately, this latter probably would not be well tolerated by

the occupational or legitimate users of solvent mixtures.

There are no systematic studies on the aversiveness of the inhalant

solvents . In humans, verbal report can be employed to assess the

pleasantness of solvents. For example, Rosenberg (1974) reported

that 44 percent of 110 women and 18 percent of 259 men found the

inhalation of nitrous oxide to be unpleasant. Aside from a few

solvents (such as the anesthetics) which are widely utilized as safe

with humans, work with humans would be limited for the most part

to low concentrations or to brief exposures.

There are a variety of procedures possible in animals for assessing

aversive properties. Vogel and Nathan (1975) utilized the taste

aversion paradigm in rats to measure the aversive properties of

certain barbiturates, nonbarbiturate hypnotics, and ethyl ether.

They administered the chosen drug immediately after the

consumption of 100 licks of sweetened condensed milk and then 7

days later they measured the time to complete 100 licks within a

maximum time limit of 600 seconds. Anesthetic doses of all of the

drugs tested induced subsequent aversion for the milk solution.

This procedure shows promise for application to solvent inhalation

in general, since ethyl ether in the above experiment exhibited

effects similar to those of injected anesthetics. A somewhat simpler

and perhaps more general procedure would be to measure the

latency of animals to exit from chambers containing a graded

concentration series of solvent vapors as the unconditioned

stimulus. However, aversive paradigms for inhalant solvents

remain to be established in detail, and with suitable controls.

Properties of the Dependency Potential

Human self-experimentation has already established a clinical

literature indicative of the dependency potential for a number of

volatile solvents. However, these data are in general not

quantitative and do not provide parametric or comparative

information about the potency of various volatiles for producing

dependencies.

General aspects of determining the dependency potential of opiatelike drugs have been discussed by Fraser (1974), who concluded

. . . that a comprehensive pharmacological profile of a drug is

essential in animals and man and that a battery of tests for

dependence may be necessary before an unknown drug can be

appropriately classified as to relative abuse.” However, it would

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appear that the main experimental technique for predicting the

dependency potential of a drug in man is to observe that the drug

will sustain self-administration in the monkey (and perhaps in other

species),

Other techniques may also be possible. For example, Colpaert et

al. (1976a, 1976b) have proposed a discriminative procedure which

does not rely upon an animal model of dependency. They trained

rats to select a particular one of two levers for food reward when

injected with an opiate (fentanyl) and the other lever when

injected with the carrier substance for their drugs. They then

tested a series of opiate-related drugs for their ability to induce

the rats, shortly after an injection, to select the drug lever over

the carrier lever. This paradigm relied upon the ability of the rat

to detect a distinctive perceptual internal state associated with the

presence of the drug in the body, and to respond accordingly when

that drug or similar drugs reproduced that state on successive

occasions (test for generalization). Colpaert referred to this as

producing the “narcotic cue,” and argued that drugs which

produced internal states discriminated as similar by the subject

would be drugs which would be alike with regard to dependency

potential. This is a reasonable position, and could be true for

many, if not all, drugs, but it remains to be definitively

established.

The above papers dealt with the problem of opiate dependency, and

their relevance to inhalant solvent dependencies is, of course, open

to question. It now appears that the opiates may owe their

dependency properties to their ability to stimulate the so-called

opiate receptor in the brain. Endogenous small polypeptides with

opioid properties have recently been discovered which are quite

potent in reducing pain. The extent to which inhalant solvents

might also affect the opiate receptor is unknown and probably

deserves investigation. There is a question whether inhalant

dependencies in man tend to lead to later dependencies on hard

drugs. If certain solvents stimulated the opiate receptor, this

would provide a common physiological basis for different

dependencies, and would imply a possible link between

dependencies on those inhalants in early life and other drug

dependencies in later life.

For a variety of reasons, it seems likely that solvent dependencies

will be based on diverse neural mechanisms. If so, then the

classification of solvents with common mechanisms could be

important. Such classification would have to rely on several lines

of evidence, including behavioral evidence. It would be pertinent,

for example, whether the use of a particular solvent was followed

by a physical dependency (withdrawal syndrome) or whether there

was a discriminative similarity between one solvent and another in a

test situation similar to that of Colpaert et al. (1976) or whether one

solvent might readily substitute for another in a self-administration

paradigm. The question of an abstinence syndrome in particular is

important for several reasons and should be assessed for a

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spectrum of solvents, for example, by procedures similar to those

discussed by Freund (1975) and demonstrated by Goldstein (1975) in

the case of ethanol dependence.

BEHAVIORAL TOXICITY OF SOLVENTS

Definitions of Intoxication, Persisting Toxicity,

Irreversible Toxicity, Remote Toxicity, Covert

Toxicity, and Tolerance

Given that subjects are exposed to solvent vapors for whatever

reason (self-administration, occupational exposure, or accident),

the question of the toxic effects from the exposure becomes

pertinent. In other words, the study of solvent toxicities does not

require animal models of solvent self-administration and may be

done during or after involuntary administration of the solvent

vapors to the subjects. The chronological characteristics of the

toxic manifestations lead to some important definitions with regard

to toxicities. Acute, transient, or reversible toxicity (intoxication)

occurs only when the solvent is present in the body and disappears

when the solvent is cleared from the body. Chronic, enduring, or

persisting toxicity represents damage to the subject which persists

long after the solvent has been cleared from the body, and which

results from long-lasting metabolic or morphological alterations that

the solvent produced while present in the body. Some of these

long-lasting alterations might be reversible, which would be

evidenced by eventual recovery, and some might be irreversible

within the life span of the animal. It is also possible to define a

“remote toxicity, " referring to a delayed damage which would not be

apparent during or soon after the solvent exposure, but which

would only manifest itself at some long time after the cessation of

exposure. Behaviorally, an example of remote toxicity would be a

subject who tested normal after solvent exposure, but who

eventually showed an earlier or more extensive failure of

neurobehavioral processes with aging.

With regard to the degree of toxicity, it also appears useful to

consider the concept of occult or covert toxicity, representing

damage not sufficient to be observed by the tests used. Such

damage might be unmasked by more sensitive tests, or by the

eventual appearance of remote toxicity with aging, or would be

implied for single solvent exposures if repeated solvent

administrations eventually produced a total loss sufficient to be

measurable.

Additionally, it is useful to define cumulative toxicity to refer to

the appearance of toxic signs only after repetitive or continuous

chronic exposure to toxins such as the inhalant solvents. The

phenomenon is well documented, and emphasizes that the toxic

profile for a drug cannot be established simply by a few exposures

of the animal. It is necessary to keep in mind, of course, that

chronic toxic exposure may produce symptoms secondary to the

drug action (e.g., symptoms mediated by malnutrition, sleep

disturbance, etc.)

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Finally, a common phenomenon with chronic intake of drugs or

toxins is the development of tolerance to the substance, so that

increased amounts of the substance are required to elicit a given

effect. It may be that the increased drug dosage which is selfadministered consequent upon the development of tolerance for

certain drug effects may eventuate in the appearance of new toxic

signs and hence account for some of what is here termed cumulative

toxicity. Whether indeed tolerance develops to the various inhaled

solvents is still open to question. It seems almost certain that

tolerance will be observed with at least some of the solvents, and

the clinical literature on inhalant solvents is suggestive of the

development of tolerance. However, experimental data on this point

are lacking.

Dose Response Curve, Dose Effect Curves,

and Threshold Limit Values

If one has chosen some biological (in this case, behavioral) endpoint

for toxicity, for example, locomotor activity, then one can plot the

proportion of subjects who show a stipulated degree of disturbance

in this endpoint versus the dose of the volatilized drug producing

this disturbance (a dose-response curve). Alternatively, one may

quantify the degree of alteration in the endpoint, measured in

individual subjects and averaged over the group, for groups of

subjects at different doses of the drug (a dose-effect curve). This

distinction between dose-response and dose-effect functions has

been proposed by the Subcommittee on the Toxicology of Metals

under the Permanent Commission and International Association of

Occupational Health in 19’74 (Nordberg, 1976).

For most behaviors, the dose-response and dose-effect curves can

be expected to exhibit no effects when assessed at sufficiently low

concentrations and exposure durations of a toxic volatile. This

could be because of a neural “reserve” in most neurobehavioral

systems, or because of neurobehavioral abilities to compensate for a

certain degree of neural damage, or because of compensation

through neural reorganization following central nervous system

(CNS) damage. It could also be that no organic neural damage is

produced by the drug up to some dose level. At and above some

concentration-duration, however, behavioral alterations will become

apparent, and will increase in magnitude as the concentrationduration of exposure continues to increase. The intersection of the

function of measurable behavioral effects versus drug dose with the

mean behavioral response of nonexposed (control) subjects can be

taken as a threshold limit value of the drug. This defines the

upper drug dose which is just short of producing measurable

toxicity.

Threshold Limit Values (TLV) as a term has been defined to refer

to safe levels of airborne contaminants; i.e., levels under which

“nearly all workers may be repeatedly exposed, 8 hours a day,

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without adverse effects. Threshold limit values refer to timeweighted concentrations for a 7- or 8-hour workday and 40-hour

workweeks” (Cornish, 1975). TLV’s may be set on the basis of

systemic toxicity, or on the basis of other factors such as irritation

of eye or respiratory membranes, narcosis, nuisance, etc. The

American Conference of Governmental Industrial Hygenists (ACGIH)

has published a yearly guide entitled “Threshold Limit Values of

Airborne Contaminants.”

In quantifying the dosage of volatile solvents, both the

concentration of the solvent and the duration of time for delivery

must be taken into account. Elkins (1959) discusses the limitations

of Habers’ law, which states that the concentration of drug times

the duration of the administration equals a constant in terms of the

potency of various dose-duration combinations for producing any

particular toxic endpoint. This law can only hold for time intervals

short enough to avoid significant drug metabolism, etc. For

repeated or chronic exposures over many days or weeks, it will

generally be necessary to study several selected dose-duration

combinations, rather than treating solvent concentration and

duration of exposure as variables which can be traded off according

to Habers’ formulation.

It is important to estimate threshold limit values as a succinct

statement of drug toxicity, permitting comparison of the toxicities

of different inhalant solvents and also providing for comparison of

the sensitivities of different behavioral endpoints for toxicity. It is

vital to note, however, that a threshold limit value does not imply

the absence of any toxicity, but only the absence of measured

toxicity for a given biological endpoint. There could well be covert

toxicity which would require particular conditions or procedures to

unmask.

Anesthetic Properties of Volatile Solvents

and Determination of Anesthetic Potency (MAC or AD50)

Most, if not all, of the inhalant solvents act as anesthetics. It is

possible that the dependency potential of solvents may be related

to their anesthetic properties. A characteristic of many anesthetics which is not emphasized enough is the production of an excitation stage that occurs at low doses of the anesthetic, or prior to

the onset of depressant effects at higher doses of the anesthetic.

It seems likely that neural inhibitory mechanisms are suppressed

by low doses of the anesthetic, thereby releasing excitatory

mechanisms normally held in check by the inhibitory systems. As

the dose of the anesthetic increases, then additionally the excitatory systems themselves are suppressed and the depression

stage of anesthesia then occurs (Bushnell et al., 1975). Various

psychological effects of the volatile solvents reported in the

human clinical literature imply an anesthetic spectrum which

includes excitation, loss of inhibitory controls, and depressant

actions.

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It is not clear whether solvents are inhaled for their excitant

effects or for their depressant effects, or both. Theories

concerning the psychological determinants of inhalant solvent

dependencies would obviously benefit from knowledge on this point.

One attraction of the inhalants may well be that the same substance

is both an “upper” and a “downer,” and the user need only titrate

his inhalation to obtain either excitation or depression, as his needs

dictate. The rapidity of absorption of inhalants, and the

consequent short latency for action on the CNS, indicates that such

a behavioral titration might readily be feasible.

In delineating the acute behavioral toxicity of the volatile solvents,

it therefore seems important to assess their anesthetic and analgesic

properties. The currently accepted measure of anesthetic potency

is the minimum alveolar anesthetic concentration, or MAC. The

statistical definition of MAC was recently emphasized by De Jong

and Eger (1975) as the dose which anesthetizes 50 percent of the

population (AD50). Other anesthetic doses can also be defined,

such as the AD50 or AD95, and De Jong and Eger (1975) described

the use of probit or logit analysis to aid in the calculation of any of

these parameters. Thus, MAC or anesthetic dose (AD) is simply a

variant of the concepts of effective dose (ED) and lethal dose (LD),

which are familiar parameters in pharmacology and toxicology

(Casarett and Doull, 1975).

There is a conflict between the acronym MAC as used in

anesthesiology and the same acronym as utilized earlier (Elkins,

1959) and as still utilized (Casarett, 1975) in industrial toxicology.

In toxicology, MAC has variously been reported to mean “maximum

allowable concentration,” “maximum acceptable concentration,” or

“maximum atmospheric concentration” (Elkins, 1959; Casarett, 1975).

Nuisance effects, as well as toxic effects, may be used in setting

the MAC value. The MAC is set so that “deleterious effects are

insignificant at exposure levels below the MAC for eight hours a

day, five days a week over a working lifetime” (cited by Casarett,

1975). As can be seen, the MAC and the TLV refer conceptually to

much the same value of the toxicant, namely, the highest

continuous or frequent exposure level which can be tolerated

without adverse or deleterious consequences. Guides on MAC

values for many substances, including the volatile solvents, have

been published as cited by Casarett (1975) and reprinted by Elkins

(1959).

An important feature of anesthetic potency, as measured by MAC or

by other response properties, was demonstrated by Shim and

Andersen (1972). They pointed out that MAC was defined in terms

of the loss of the motor response to a pinch or a cut. If other

behavioral or biological endpoints were utilized to determine

effective doses of the anesthetic, such as loss of the righting

reflex, loss of respiratory activity, or loss of cardiac activity, then

different AD50 values were generally obtained. Shim and Andersen

tested eight anesthetics. The righting reflex was generally

abolished at the lowest concentrations, MAC occurred next, then

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respiratory arrest at higher concentrations. Each endpoint

occurred at a very consistent value of a given anesthetic, but the

potencies and interrelationships between biological endpoints

differed for each anesthetic. For example, chloroform abolished the

righting reflex at a dose of 1 MAC, whereas trichloroethylene

abolished the righting reflex at a dose of 0.65 MAC. The six other

anesthetics fell between these extremes.

Most studies of anesthetics have concentrated on measures of the

depressant actions of the compound in question, using the above

techniques. From the standpoint of inhalant dependencies, it will

also be pertinent to determine effective doses or dose ranges for

excitatory effects and for loss of inhibitory functions. This can

readily be done within the framework of the above methodology

simply by utilizing behavioral endpoints characteristic of excitation

or loss of inhibitory function. For example, excitation can be

assessed in terms of lever rate for appetitive reinforcement under

the influence of the chosen anesthetic agents (Bushnell et al.,

1975). There are numerous ways to measure losses of inhibition, as

well as other approaches to the assessment of excitation, which will

suggest themselves to those trained in behavioral methods.

Behavioral Data on Intoxication (Acute Toxicity)

With Inhalant Solvents

The question of intoxication is almost exclusively a behavioral

question. Volatilized solvents will only be repeatedly inhaled if

they in fact produce an intoxication state which includes reinforcing

kinds of events or perceptual change. Most intoxications, however,

will not be specifically limited to reinforcing properties, but will

also include other behavioral changes, some of which may constitute

individual or social risks. Given the present frequency of inhalant

intoxications, there is an increasing need to define and document

any particular features of the acute toxicity which constitute risk.

Such documentation will allow recognition and control of any

unusually hazardous solvents, or will establish the basis for

sociolegal definitions of solvent intoxication. For example, with

specific reference to toluene and trichloroethylene, Bauer and

Molcan (1974) have briefly discussed the problem of volatile solvent

intoxication and traffic safety, and legal cases have already arisen

in this general regard in the United States.

Factors involving risk would include a loss of alertness, a loss of

reaction time, a loss of inhibitions, a loss of judgmental capacity,

losses in sensory capacities, losses in motor control, and losses of

reflexes. Especially pertinent to document would be solvents which

may be deliberately inhaled to the loss of consciousness, since the

user might be liable to serious risk (such as overdosage) in that

event. Solvents which produce aversive reactions when inhaled at

higher doses, such as amyl nitrite in the dog (Dewey et al., 1973)

may be relatively safe from the dangers of voluntary inhalation

either to unconsciousness or to death.

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Data will be discussed immediately below on the acute behavioral

toxicity of several of the volatile solvents which have been reported

to sustain inhalant dependencies in man.

literature on a few pure solvents,

There is only a small

and no systematic studies at all

on solvent mixtures.

Nitrous Oxide

Nitrous oxide has probably been more studied for acute behavioral

toxicity at subanesthetic concentrations than any other volatile

solvent. A series of studies by Hannah Steinberg and collaborators appeared in the 1950’s. Steinberg (1954) found that all of a

series of verbal and motor tests were performed less well by subjects given 30% nitrous oxide in oxygen than by controls

breathing air. The more “complex” the verbal task appeared, the

more it tended to be affected. In confirmation, Parkhouse et al.

(1960) found modest changes in analgesia and various verbal tests

at 20% nitrous oxide in oxygen, and larger changes at 30% and

40% nitrous oxide in oxygen. This suggests a threshold for

losses in verbal behavior in the vicinity of 20 vol.%, or of 200,000

ppm (parts per million) of nitrous oxide. The same workers

(Henrie et al., 1961) could find no consistent changes in EEG

(scalp electrodes) at 30% nitrous oxide, despite the behavioral

effects noted.

Porter (1972) reviewed and ingeniously analyzed the data of some 14

studies on nitrous oxide, including the above, in addition to 45

studies on other anesthetics, and concluded that nitrous oxide was

a weak amnestic agent, interfering either with registration or

retrieval of memories for events just preceding or occurring during

nitrous oxide inhalation.

Wallenstein and Rosner (19’76) found that 35% and 50% nitrous oxide

in oxygen produced cortical and hippocampal EEG changes in rats in

the direction of large, and very large irregular activity. The

appearance of the very large irregular activity was said to be

correlated with a reduced likelihood of performing a shuttle

avoidance task, but no behavioral data were presented.

Other behavioral changes have been noted, generally nonquantitatively . Parkhouse et al. (1960) indicated that some subjects under

40% nitrous oxide “... showed a marked tendency to reveal inherent

temperamental instabilities,” and that some subjects become

uncooperative and difficult to manage. The subjects used by

Parkhouse et al. (1960) were all professional personnel who had

volunteered for the experiment and could be considered probably

above average in their motivations to cooperate. Hence, this

description by Parkhouse et al. (1960), which is suggestive of

losses of inhibitory control under these subanesthetic doses, is

indicative of the potentialities for social dysfunction attendant upon

inhalant dependencies.

A phenomenon of a different type, namely transient hearing loss,

has also been reported with nitrous oxide in patients with certain

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ear problems (Patterson and Bartlett, 1976). This resulted from

high middle ear pressures produced by the nitrous oxide. The

extent of transient or permanent acoustic trauma from this

phenomenon if nitrous oxide were repeatedly inhaled is unknown,

A particularly pertinent study is that of Hahn and Rokitka (1976).

They exposed colonies of deer mice to either nitrogen, argon, or

nitrous oxide in mixtures containing normal amounts of oxygen

under hyperbaric conditions continuously for 3 days. Motor

capabilities were scored by observers on a 3-point scale, and

running wheel activity was scored continuously. They

subsequently evaluated the ED50 for narcotic potency of each of

these gases using probit plots of running wheel scores (as percent

of activity at sea level pressures) versus gas pressure. The ED50

of 1.1 atmospheres estimated for N2O from these data is open to

question as discussed by Rahn and Rokitka, but is close to MAC

(1.05 atmospheres), and is smaller than the ED50 estimated by

various authors for abolishing the righting reflex of mice. The

ED5 0 s for nitrogen, argon, and nitrous oxide were exactly

correlated with the lipid solubilities of these three gases (linear on

a log-log plot). The lines identified in their Figure 4 as 95 percent

confidence limits on the linear regression should have been curved

to depict increasing error of regression as the line progresses away

from the point (Snedecor and Cochran. 1967). Nevertheless,

the paper is instructive for the kinds of quantitative methodology

needed in assessing acute toxicities, and also for the use of

hyperbaric conditions to assess the anesthetic potencies of weak

agents.

It can be seen that the literature offers a beginning to the

quantitative behavioral toxicology of nitrous oxide. For example,

no formal estimates of the TLV for different effects were found,

although the data of Parkhouse et al. (1960) are suggestive of a

TLV of perhaps 10-15 vol.% of nitrous oxide in oxygen for various

behavioral effects, including analgesia, and an ED50 of about 37

vol.%. One MAC for nitrous oxide has been listed as 105 vol.%

(Eger, 1974). ED50 values for other behavioral endpoints (righting

reflex and wheel running) range from 160 vol.% down to 110 vol.%.

Other behavioral tests (namely verbal tests) would appear to have

TLV's in the vicinity of 10 vol.%.

No data were found on body burdens of nitrous oxide at various

inhalant concentration, nor on rate of recovery from nitrous

oxide anesthesia, From the data of Wood et al. (in press),

monkeys self-administered nitrous oxide at a rate per hour which

corresponded to a continuous average concentration of nitrous

oxide of 5-20 vol.% over the hour. This dose likely was in the

range of excitant effects, but not depressant effects. This would

be an interesting point to confirm. Free response use of nitrous

oxide in the dependent human is not known Wood noted that

nitrous oxide appeared to be a weak reinforcer for sustaining

self-administration. This is interesting since nitrous oxide is also

only a weak anesthetic.

212
Chlorinated Hydrocarbons in Animals

The acute neurobehavioral toxicities of other inhalant solvents have

been less investigated than has nitrous oxide. Horvath and Frantik

(1973) reviewed data on nine inhalant solvents producing acute

changes in five behavioral measures tested in rats. They listed

“effective concentrations” of vapors and durations of exposure

necessary to achieve various behavioral endpoints, but without

stating whether or not these “effective concentrations” were ED50

values. The behavioral endpoints consisted of a 50 percent decline

in spontaneous motor activity, a 100 percent increase in “inert.

avoidance responses” (presumably referring to passive avoidance),

a 50 percent decrease of total activity in avoidance conditioning, a

15 percent decrease in maximum running velocity, and a 25 percent

decrease in running endurance. For a given solvent, all five of

these behavioral changes were reported induced by about the same

effective dose of the solvent. These behavioral effects were

produced by 6 hours of inhalation of approximately the following

doses and compounds: 6,400 ppm of dichloromethane, or 6,000 ppm

of trichloroethane, or 3,440 ppm of trichloroethylene, or 1,820 ppm

of tetrachloroethane, or 1,500 ppm of tetrachloromethane, or 1,000

ppm of trichloromethane, or 820 ppm of dichloroethane, or 730 ppm

of carbon disulfide, or 450 ppm of tetrachloroethane.

Trichloroethylene in Humans

Behavioral endpoints have been employed in studies bearing on the

TLV for the acute toxicity of trichloroethylene. Stopps and

McLaughlin (1967) reported dose-effect curves for 2-3/4 hours of

exposure to 100, 200, 300, and 500 ppm of trichloroethylene,

measuring human manual dexterity, perceptual reversals of the

Necker Cube, card sorting, and a modified reaction time task (“dial

display”). Their data indicated a TLV in the vicinity of 100 ppm.

Salvini et al. (1971) reported that human performance was significantly decreased by 110 ppm of trichloroethylene during two

4-hour exposures separated by 1-1/2 hours. Tasks included manual

dexterity, complex reaction time, Wechsler memory scale, and the

perception of a tachistiscopic presentation. Unfortunately, they

only presented tables of their statistical analyses, and not of their

data, so the magnitude of the effect was not. reported.

Toluene

Wilson (1943) and Von Oettingen et al. (1942) described intoxication

of the CNS and impairment of coordination and reaction time from

exposure to 200 ppm of toluene. Toluene first stimulates and later

depresses the nervous system (Lewis and Patterson, 1974).

Exposure for 3 hours at 600 ppm can produce a variety of

symptoms, including mental confusion, exhilaration, and fatigue.

Gamberale and Hultengren (1972) reported human reaction time and

perceptual speed to be impaired by 20-minute exposures to toluene

at 100, 300, 500, and 700 ppm The TLV appeared to be in the

vicinity of 100 ppm of toluene.

213
Ishikawa and Schmidt (1973) noted that about seven exposures to 30

minutes of’ toluene at 100 ppm daily produced a “forced turning” or

circling locomotor movement in rats which was reversible if toluene

exposure was discontinued. They reported loss of righting reflex

at this dose, particularly on exposures subsequent to the first, as

well as a characteristic hind leg scratching directed at the lower

costal margin After two to three exposures, the rats “struggled

vigorously” when being placed in the exposure chamber. If toluene

was withdrawn for 14 days, the forced turning was reinstated after

a mean of 1.5 daily reexposures. If toluene was withdrawn for 21 or

34 days, then the number of reexposures needed to reinstate the

forced turning was not significantly different from the number

needed to produce forced turning on the original exposure series.

Weiss et al. (in press) studied keypecking behavior on a “fixed

consccutivc number” schedule in pigeons exposed to 0, 400, 800,

1,601). or 3,200 ppm of toluene in air. The pigeons had to give 20

or more consecutive responses on the left key before switching to

respond to the right key in order to obtain a food reward.

Latencies to recommence keypecking after reinforcement and to

switch from the left to the right. key were suggestive of an

excitatory effect of toluene at 800 ppm and a depressant effect at

3,200 ppm.

Wood (1976) studied toluene self-administration in a squirrel

monkey. For concentrations of 1,000, 2,000, 3,000, and 10,000 ppm

of toluene, delivered for 15 seconds per reinforcement, the monkey

self-delivered 130, 130, 100, and 35 reinforcements per hour

respectively. These reinforcement rates amounted to an average

concentration of toluene over the hour of 540, 1,080, 1,300, and

1.460 ppm. These doses are in the range of excitatory effects (as

measured in the pigeon), and not of depressant effects.

Halothane

The behavioral TLV for halothane may be quite low. Bruce et al.

(1974) tested 40 male humans immediately after 4 hours of inhalation

of either air or air plus 500 ppm of nitrous oxide or air plus 500

ppm of nitrous oxide plus 15 ppm of halothane (these mixtures mimic

the atmospheres to which a surgical team might be exposed).

Subjects exposed to nitrous oxide and air had a decrement on a

digit span test. Those exposed to halothane plus nitrous oxide in

air exhibited deficits on digit span, on word recall, on a visual

tachistoscopic test, and on a complex, compound reaction time test.

This complex reaction time test appears to be an exquisitely sensitive measure of intoxication, since Winter et al. (1975) reported

a 9 percent decrement in this task in humans breathing oxygennitrogen compared to humans breathing oxygen-helium. Since

hyperbaric nitrogen is narcotic (anesthetic), whereas hyperbaric

helium is either nonnarcotic or only weakly narcotic, Winter et al.

(1975) proposed that this test could detect a narcotic effect of

nitrogen at atmospheric pressure.

214
Davison et al. (1975) assessed behavior in men anesthetized for 7.2

(mean) hours with halothane (1-2%) or halothane (.35-1.5%) plus

nitrous oxide. Behavioral measurements were taken before

anesthesia, and at 2, 3, 4, 6, 9, and 30 days after anesthesia.

Somatic symptoms and mood changes were highest at 2 days

postanesthesia, and were still significantly elevated at 4 days.

Similarly, various “intellectual functions” (reading comprehension

and reading speed, verbal reasoning, arithmetic) showed

decrements at 2 and 4 days postanesthesia. All subjects had

essentially recovered to control capabilities by 30 days.

Adam (1973) found that general anesthetics (cyclopropane,

enflurane, and ether) at low doses impaired verbal memory

processes but spared nonverbal, acoustic memory. At higher

doses, a strong amnestic effect was obtained. Subsequently and in

confirmation, Adam (1976) found that halothane or fluroxene

produced a decrement in verbal memory search, but not in visual

memory search, only within 24 hours of recovery from anesthesia.

These reports imply that verbal behavior is particularly sensitive to

anesthetic toxicity, compared to other types of sensory processing.

Porter (1972) reviewed five studies on halothane, which indicated an

amnestic effect of halothane for events just preceding or concurrent

with halothane exposure.

These data offer no quantitative estimate of the TLV for halothane,

but do suggest that intoxication can occur at very low

concentrations of solvent, particularly if the solvent is well retained

in body lipids. In such cases, recovery to normal function can take

several days.

Cumulative Behavioral Toxicity

Behavioral signs of toxicity may occur after repeated exposures to

solvents that do not occur after one or a few exposures. This

cumulative toxicity should not be confused with enduring toxicity,

since many of the examples of cumulative toxicity appear to reverse

within a few days or weeks after termination of solvent inhalations.

The human clinical literature provides numerous examples of

cumulative toxicity for drugs in general (i.e., the well-known

amphetamine psychosis), and also a number of examples in the case

of solvents. To illustrate, daily repetitions of solvent exposures

for months have eventually produced delusions and hallucinations in

the case of gasoline inhalation (Bethell, 1965) or of nitrous oxide

inhalation (Brodsky and Zuniga, 1975). Therefore, experiments

employing only short-term exposures in animals will not be

sufficient to determine the toxicity of inhalant solvents.

Most of the literature on cumulative toxicity of solvents comes from

research on occupational exposure. Knave et al. (1976) reported

increased symptoms of neurasthenia, psychasthenia, and

polyneuropathy in aircraft workers exposed daily for at least 5

years to jet fuel vapors. Since only one of these differences was

215
statistically significant, it is difficult to conclude in favor of

cumulative toxicity on the basis of this study. Nevertheless,

numerous earlier studies of gasoline exposures, cited by Knave et

al. (1976), indicated findings of neurasthenia, psychasthenia, and

polyneuropathy. Knave et al. (1976) had no data available on the

exposure concentrations of the jet fuel vapors, except for one assay

of 3,000 ppm in one workplace and 500 ppm in each of two other

workplaces. Knave et al. (1976) cite Drinker et al. (1943) that

exposure to 1,000 ppm of gasoline caused mild nausea, headache,

and dizziness, and that 2,600 ppm caused intoxication and some

anesthesia; eye and throat irritation was noted at 160 and 270 ppm.

Kerosene does not cause eye irritation (Grant, 1974), and no eye

irritation was noted by Knave et al. (1976) in the workers exposed to jet fuel. Felix (1872, as cited by Knave et al.) reported

anesthesia and sleep following the inhalation of 20-40 gm of gasoline for 8-12 minutes, and nausea, eye and chest. irritation, and

drowsiness after inhalation of 5-15 gm of gasoline for 7-12 minutes.

Workers exposed to various industrial solvents (tri-and

tetrachloroethylene, toluene, xylene and their mixtures) were

compared to workers evidencing carbon disulfide (CS2) poisoning

and to unexposed controls (Lindstrom, 1973). Decrements in

sensorimotor and psychomotor performance and visual accuracy

were observed in the solvent-exposed group. and generally worse

deficits were seen in the CS2-exposed group. No estimates of the

degree of solvent exposure were reported, although tables were

given of the occupations responsible for the exposures, and the

particular major solvents which the workers were exposed to.

House painters were compared to a group of industrial workers of

comparable age, and reported to be worse on reasoning capacity

and psychomotor coordination (Sundell et al., 1975). This was

suggested to be primarily an effect of exposure to the paint

solvents.

Prendergast et al. (1967) reported physiological effects in animals of

long-term inhalation of trichloroethylene, carbon tetrachloride,

trichloroethane, dichlorodifluoromethane and dichloroethylene.

Exposure periods were either continuous for 90 days, or 8

hours/day, 5 days/week for 6 weeks.

These behavioral toxicological data are extremely sketchy and offer

no assessment of the relationship between behavioral measures and

dose-duration parameters of exposure. It must be concluded that

very little is known in the preclinical literature about the

cumulative behavioral toxicity of inhalant solvents. This represents

a serious gap in the toxicological knowledge concerning these

compounds. since the hallmark of solvent dependencies in the

human is long-term, repetitious self-exposure to the solvents.

Many of the behavioral toxicological signs that are most disturbing

in the habitual inhaler of solvents are likely to be the result of

cumulative toxicity.

216
Enduring Behavioral Toxicity of Inhalant Solvents

Probably the most serious toxicological concern attendant upon

solvent dependencies is the possibility of enduring or permanent

damage consequent to the repeated inhalations. The clinical

literature offers a spectrum of testimony on enduring damage.

Wyse (1973), in reviewing inhalation dependencies, noted that the

majority of “...residual effects.. sometimes seen between periods

of inebriation in chronic users. are readily reversible, not lifethreatening, and disappear when the practice is discontinued.”

Yet the exceptions to this generalization, as reported by Wyse

(1973) or as occurring more recently in the literature, can be quite

serious and tragic. Futhermore, clinical studies generally have not

used sufficiently sensitive tests to rule out the possibility of subtle

or covert damage from long-term inhalation dependencies.

Virtually all reports of enduring damage from solvent inhalation deal

with relatively gross or striking physiopathology such as peripheral

neuropathies, ocular nerve damage, and a variety of occasional CNS

lesions. Lehnert et al. (1974), who reported the conclusions and

recommendations of an international conference on long-term effects

of halogenated hydrocarbon solvents, noted the narcotic properties

of these solvents as a reason for investigating their effects on the

CNS, and stated that “. . . insufficient information is available

adequately to assess the effects of exposure on psychomotor

performance and investigations in this field should be promoted.”

Such studies can only rigorously be conducted in animals.

There are three main paradigms of solvent exposure and behavioral

testing which merit study for the occurrence of long-term

toxicity. These paradigms will be considered briefly. Given that

examples of enduring toxicity are discovered, then dose-response

or dose-effect. relationships should be established, and TLV and

ED50 parameters estimated. Despite the serious health

consequences of enduring or permanent toxicity of chronically

inhaled solvents, there is almost no preclinical literature directed

to this issue. This may be related to the major investment in

time and resources needed for such long-term studies.

Solvent Exposures During Neural Development

The teratological vulnerability of the fetus has been pointed out by

Wilson (1965), with special reference to the intrauterine period of

organogenesis, as being the most vulnerable for toxic-induced

malformations. On the other hand, Dobbing (1968) promulgated the

hypothesis that neural tissue is most vulnerable to toxic damage,

not only during its initial period of differentiation, but during its

period of most rapid rate of development. The latter variously

occurs in late gestation or early postnatal life in mammals. Given

that the CNS is limited in its recuperative powers, it is clear that

damage to the CNS is quite apt to be persistent or permanent.

Hence, solvent exposure of the young and developing animal is a

paradigm most likely to yield long-lasting neurobehavioral damage.

217
The very early age at which solvent inhalation dependencies can

develop in the human (as young as 5 years old or less) further

offers strong reason to investigate early postnatal exposures in the

animal.

One halogenated hydrocarbon, halothane, has been studied within

the framework of developmental vulnerability (Quimby et al. ,

1974, 1975). Rats were exposed to 10 ppm of halothane in air for

8 hours/day, 5 days/week. Groups exposed from conception to

Day 60 of life postpartum were tested at 135-150 days of age, and

had deficits in both aversive and appetitive maze learning tasks.

They were also hyperalgesic to electric footshock at 11 months of

age, compared to controls never exposed to halothane (Quimby et

al., 1975). Rats first exposed to 10 ppm of halothane starting at

Day 60 of age, and exposed for 8 hours/day, 5 days/week thereafter, did not suffer from unexposed controls on any of the above

tests. Rats exposed in utero for a single Z-hour duration to

12,500 ppm of halothane (1 MAC) on either Day 3 or Day 10 of

gestation exhibited hyperalgesia and a deficit in aversive learning

similar to the above when tested starting at 75 days postpartum,

while rats exposed on Day 17 of gestation did not differ from

unexposed controls (Bowman, 1976). These data are suggestive

of a neurobehavioral teratological effect of halothane possibly

related to halothane toxicity on developing serotonergic neurons

on Days 11-15 of gestation (Bowman and Smith, 1977). Whatever

the mechanism, these data are indicative that exposure to neuroactive solvents early in life can have behavioral effects lasting for

months to years beyond the termination of the exposure.

Postnatal exposure alone to neurotoxic agents can also have longlasting behavioral effects, as suggested by a study by Sobotka and

Cook (1974) involving exposure of rat pups lo lead. No similar

studies involving solvent exposures were found.

Adult Solvent Exposure Followed by Conception

and Testing of Their Offspring

Toxic agents which are mutagenic might alter the germ plasm of an

adult, so that subsequent offspring conceived by that adult would

exhibit neurobehavioral changes. This possibility is exemplified for

lead toxicity by a study of Bradyd et al. (1975), who found that

either adult male or adult female rats exposed to lead had offspring

which exhibited altered behavior. This exposure-test paradigm has

not been utilized in studies of solvent toxicity Presumably the

mutagenicity of solvents would be crucial to such effects, such as

the report by Forni et al. (1971) of chromosomal damage produced

by benzene.

Adult Solvent Exposure With Subsequent Testing

or the Same Adults

The most common paradigm in studies of toxicity has been to expose

adult animals to the toxicant and then to test the same animals

218
subsequently. The adult should generaloy be less susceptible to

toxic damage than the young or even the adolescent animal, anti

chronic, high dose exposures may generally be the only conditions

producing measurable persisting toxicity.

Aside from the clinical literature on neuropathology, virtually no

data exist regarding the persistence of solvent toxicities in

general, nor of behavioral toxicity in particular. In the

literature on human occupational hazards, Axelson et al. (1976)

reported increased neuropsychiatric incidences with increasing

number of years spent working as a house painter, varnisher,

etc. This may represent either cumulative toxicity or the gradual

accretion of enduring deficits; the data are insufficient to decide

this. In the preclinical literature, Contreras et al. (1976) exposed cats to benzene, toluene, or “thinner” and observed long

term effects (up to 60 days postexposure) on EEG.

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223

SUMMARY

225
Chapter 13

APPROACHES TO THE PROBLEM

Charles W. Sharp

INTRODUCTION

This review has defined the nature of the inhalant abuse problem.

Although the use of volatile substances may not be increasing to

any great extent, it is a serious problem that needs attention.

That the effects on the population are subtle should not be taken

lightly . The consequences of such neurological deficits early in

life may lead to markedly dysfunctional adults because of learning

deficits during their maturation, or even residual neurological

deficits when they reach maturity. Future use of the mixtures

could cause even more serious and numerous incidents. It may

be premature to approach any resolution of inhalant abuse without

a thorough understanding and critical evaluation of the problem.

However, certain steps can and should be taken to reduce its

incidence and seriousness. Meanwhile, more definitive studies

should be conducted to further define the extent and nature of

the various types of inhalant abuse. The following is an attempt

to assemble the thoughts and suggestions discussed by the many

contributors to this monograph. It is intended to be provocative,

if not controversial in order to enlist those with the expertise and

interest to provide a defined course of action. This discussion

will include the futuristic and ultimate goal of prevention, highlights of treatment approaches, as well as some specific guidelines

for future research.

226
PREVENTION

Abuse prevention is interpreted in a number of ways. While the

simplistic goal of total prevention is seldom achieved, modest

progress can be made. No approach can be successful without

recognizing the parties who must be active in any solution. As

the problem has many facets, it will take a concerted effort by

government, industry, and the general public to make progress.

Not only are the capabilities and responsibilities widely dispersed

in government, no one segment of commerce has the opportunity

to oversee and control the abuse potential of the retail products.

Industry is wary of more and more regulations, but it is also

aware of the need to approach and resolve problems before they

get out of hand. This has been brought out by recent court

decisions in Minnesota and Florida related to protecting children

from the dangers of solvent abuse. Those in positions of control

inside and outside the government (administrators, law enforcement people, businessmen, and consumers) should make their

interests known, contribute to discussions of the problem, and

pool their knowledge about how products are formulated, distributed, and misused. Solutions similar to that of the addition of

allyl-isothiocyanate (a noxious substance) to glue may then

become obvious. Many other benefits could come about by this

mutual participation and interaction on a problem particularly

associated with our children.

Some of the potential approaches are discussed below, several of

them emerging from discussion in the previous sections.

Addition of Obnoxious Materials to Solvents

The addition of oil of mustard (allyl-isothiocyanate) to glue was a

response by the Testor Corporation when the widespread fad of

glue sniffing occurred in the sixties. Also, thiols have been

added to cooking gas to warn people of its dangers. Similar

remedies might be utilized for other commercial products that are

inhaled excessively. However, the introduction of these or similar additives to all volatile materials which might be sniffed may

not be desirable. That is, the titrating level of additive necessary to prevent excessive inhalation may leave an undesirable or

toxic odor on the person (e.g., hair sprays, deodorants), on the

wall or in the room (e.g., paint sprays or air odorizers), or in

the food (e.g., pan sprays). In addition, interactions of many

of these compounds with the product may produce toxic compounds either in the product or in the human body. Under ideal

conditions, irritants in products might be useful to alert the

individual that he has titrated his system with enough of the

product to be dangerous.

There are, however, serious questions about such an approach.

How would one measure what is the unsafe amount of a mixture?

What about the dangers of repeated or prolonged exposure to

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these additive substances? Would the buildup of this substance

produce unwarranted side effects? These are major concerns to

those using these substances frequently in their occupations or

around the home. For example, some of these substances could

well become identified in the future as carcinogenic, as have some

of the food additives.

Product Composition Changes to Lessen

Euphoric Effects

There appears to have been an attempt to remove toluene (and

hexane) from various products, especially glues, and to replace it

with substances which may or may not be pleasant to inhale. As

there is at present no known criterion for the identification of

which compounds are likely to be sniffed, changing components on

hunches is risky. The toxicity of the new compounds that are

introduced may well exceed the toxicity of the substance (e.g. ,

toluene) being replaced. Therefore, the “improvement” of the

product may be more wishful thinking than practical action.

There seem to be no good data on what effects this, or any other

action, has had on decreasing the inhalant use of glue. If,

indeed, its use is less now than in the sixties, it may be due

more to fads or a self-preferred switch to other mixtures. We

know little about those elements that are important in the choice

of a substance.

Not only is the approach of substitution carried out somewhat

blindly, but also the measure of the toxicity of any product

inhaled producing a euphoric state can only be tentatively extrapolated from knowledge related to other types of exposure. We

know a good deal about the acute toxicities of these substances.

However, when the subject recovers from a “snort,” as most

inhalant users do, we know very little about the after effects or

how rapidly certain toxic symptoms are likely to occur after many

repeated administrations. Therefore, making mixtures which

would be nontoxic and/or aphoric for a child who might desire to

inhale this material is difficult indeed.

Product Formulation Changes to Reduce Toxicity

Since it is known that the young will experiment, perhaps the

mixture can be made “safer” so that there is an opportunity for

the child to be dissuaded by other methods and approaches before

any major damage has been done. The knowledge about toxicities

of certain compounds alone or in mixtures after prolonged exposure is slowly coming in. For example, methyl butyl ketone and

hexane have recently been implicated as causative agents of

certain resulting neuropathies from exposure in a work environment. Also, potentiation of these toxicities may occur due to the

presence of other volatile materials. These are only the more

prominent examples of what may be occurring after the inhalation

of these mixtures. The identification of these toxicities will lead,

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generally, to not using those substances in many products.

However, a more defined and systematic approach to choosing

which compounds should be excluded from common household mixtures is needed. The distribution of knowledge of certain toxicities is very haphazard and may reach many of the formulators

very slowly. It would be better if there were a simple system for

identifying the more toxic mixtures prior to formulation and

distribution. It may be even more important now that some

changes in formulation are being sought to preserve the ozone

layer. For example, freons may be removed for the purpose of

preserving the ozone, but some substitutes may be utilized which

could be even worse for children.

These replacement substances may in themselves be more toxic

following repeated administration, may be more readily metabolized

(often thought to be a desirable characteristic) to a more toxic

compound, and may cause other undesirable interactions. It

should be possible among various organizations and government

agencies to establish more concrete guidelines for certain products. For instance, at least methyl butyl ketone, hexane, and

benzene should not be included in any generally used consumer

product--especially those which might be inhaled excessively.

Rather than add some different type of substance to mixtures,

maybe one of the solvents or “active ingredients” could be utilized for this purpose. It should be highly volatile, nonreactive,

and irritating so as to make the mixture undesirable for inhalation This would also be suitable as a warning of poor ventilation

in everyday usage. Small amounts of compounds like methylene

chloride might approach those desired properties for some mixtures .

Limitations of Sales and/or Use to Adults

This is a suggestion offered by leading manufacturers, especially

as to the sale of airplane glues. In some areas these sales are

restricted by law. In other situations the limitation may be de

facto; e.g., amyl nitrite substitutes are sold mostly in “adult”

shops in various regions of the country. However, there is no

Federal restriction on who can purchase most volatile solvents,

nor are they regulated now by the Drug Enforcement Agency

(DEA). The Congressional Subcommittee on Alcohol and Drug

Abuse has been examining the information on hand to see what, if

any, action might be appropriate.

With the passage of the Toxic Substances Act (1976), there is an

opportunity for this question to be considered on a broader

basis. It remains to be seen, however, whether this aspect of

solvent toxicity will “fall through the cracks” due to a lack of

interest, awareness, etc. Only if those charged to implement

these regulations consider this problem in their approaches and

regulations will there be any possibility that national uniform

action will be taken to solve this problem.

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Another form of restriction is in usage. In some school districts

there is a limit to the type of glues that children may use (e.g.)

paste or Elmer's) and only teachers have acces to the

containing volatile solvents. Also, marking perns are restricted to

teachers’ use. Since these early encounters with sweet smelling

objects could assist in acquiring a liking for volatiles, restricted

access may be desirable.

Modify Labels

A skull and cross bones label or a symbol of a child reaching for

a spray can with a bold “X” through the symbol could be used on

household solvents, but may be undesirable for a food or cosmetic

spray. There are other possible modifications such as a “sniffing

skull” on the label to make parents and children aware of the

dangers. However, it would be necessary to establish by defined

criteria which items need to be so labeled. This may not be an

easy task, as we do not yet know how to determine those products most likely to be abused.

Community Action

This will take an unusual effort since most inhalant abusers

interrelate very poorly with community action groups. However,

it may be possible for certain social activists to identify and

interact with gang leaders or other inhalant abusers and provide

opportunities for these groups to come together and communicate

on the inhalant situation. Any local (or national) approach to the

problem should benefit from more discussions among the various

active principles in the chain of events, that is, manufacturers,

formulators, social scientists, anthropologists, Federal regulators,

basic and clinical scientists and their supporting agencies, forensic toxicologists, legal and law enforcement officials, and others

in the community, including chronic inhalant users.

One of the best communications networks is TV. Although there

is danger of introducing inhalants lo children who might otherwise

not think lo inhale solvents, certain approaches may be worthwhile. For example, while eliciting concern about the ingestion of

certain undesired solvcnts, one could at the same time caution

against prolonged inhalation (whether accidentally or on purpose)

so that young children would grow up viewing this as a danger.

Some of this information could also be included in general health

pamphlets lo alert and warn parents and other adults of these

additional potential dangers of normal household items. The

dangerous products should be identified, at least by categories

and with examples given

One approach to prevention in school would be to teach general

pharmacology to elementary students. They appear to be attentive and receptive to knowledge of drugs during this period and

seem eager to know the proper, as well as improper, use of

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drugs. Typical situations of “misuse” of some drugs can be

introduced along with the consequences of this misuse without

directly associating these acts with certain abused drugs. A

good general drug “usage” course could be interesting and yet

not appear to be a “put down” on certain drugs (e.g., marihuana) as may be the case where only drugs of abuse are discussed. This would resolve the problem of identifying specific

classes of drugs of abuse and putting them in the spotlight.

The predominant way of handling solvent abusers is by treating

them in the same manner as those intoxicated with alcoholic beverages as the state of behavior produced by most volatile substances (especially solvents and anesthetics) is very similar to

that of alcohol. The condition is briefer both in onset and duration . The extent of “drunkenness” is related to the type of

substance and the duration of inhalation. There is little doubt

that the behavior of these individuals is seriously impaired and

that they should not be driving or working during or soon after

the inhalation episode. As with the prohibition of alcohol, punishment probably is not a major deterrent. However, limitation of

sales by Federal, State, or local governments, limitation of the

production of certain mixtures, and the regulation of other related aspects of the problem may not only be useful but may be

necessary to protect the health of our youth.

Early Warning System

Although an early warning system does not prevent inhalant abuse

certain information obtained therefrom could be utilized in a preventive manner. It should alert agencies to the introduction of

new substances and major increases (or decreases) in the use of

familiar substances. However, there are important features of this

type of system which should not be confused with a valid epidemiological study. Although DAWN (Drug Abuse Warning Network)

may be an appropriate mechanism, this system does not pick up

many trends on inhalant use partly because of the areas (cities)

included in the survey and because the incidences reported by

emergency rooms, medical officers, or crisis centers represent

only a small percentage of the inhalant population. Since most

inhalant users do not need general medical treatment, CODAP

(CIient Oriented Data Acquisition Process) reports have also not

been too successful in measuring inhalant use. The Poison Control Center, likewise, receives incomplete reports from similar

sources. The Center for Disease Control might provide information on this. However, no such approach has been utilized to

date. Also reports on arrests for drunkenness may assist in

identifying inhalant drug users. Since a main source of information about the inhalant abusing population has been in-depth

surveys of communities, it may be that as national and State

mental health and other clinics reach out to resolve other health

problems of the youth, they will also be in a position to obtain

more information on the inhalant problem. Our best information

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to date comes from psychiatric: emergency and rehabilitation

clinics. For those still in the system, more effective use of the

school survey system is also an ‘important source of this information

TREATMENT

General

Outlining appropriate treatments is difficult. for a problem which

has received little attention in most communities. A recent NIDA

survey of CODAP-associated facilities in seven communities identified very few solvent abuse cases receiving any form of treatment

either of a medical or psychiatric nature. Neither were any

unique or unusual treatments for solvent albuse identified.

Generally, the average solvent abuser rarely utilizes any medical

facility or personnel. The acute state of intoxication ends abruptly, usually in complete recovery of physiological state or occasionally in death. Nothing can be clone for these latter cases, and

seldom are specific drugs useful in any case. Inhalant abuse

subjects are treated similarly to other nonopiate drug abusers and

are lumped into what is described as polydrug abuse treatment.

For most, tranquilizing agents or various psychiatric assistance is

given those showing signs of organic brain syndrome and they

are then released. Some may be admitted through psychiatric

emergency or related clinics into some type of remedial program.

Only a small minority are hospitalized with severe complications

needing extensive care and treatment.

For the majority, any impairments are not readily identifiable and

may not be apparent to the subject, his family, or a doctor

unless specifically examined for and diagnosed. Many of the

symptoms that may need treatment are not picked up by the

casual medical checkup. However, serious physiological disorders

may occur and care should be taken to carefully evaluate basic

sight, hearing, cognitive ability, pulmonary involvement, or liver

and kidney damage prior to dismissing the patient’s need for

medical assistance. For example, a case of scotoma was not

picked up early in the treatment of a silk screen operator.

Therefore, she was not removed from the toxic environment as

early as she should have been. Similar problems also occur with

solvent abusers. This points out the need for more critical

screening procedures and cxamination of inhalant abuse subjects

to identify those physiological impairments associated with sniffing

and other overexposures.

In light of these deficiencies, appropriate diagnoses and treatments should be established for inhalant abusers. In order to

develop satisfactory treatments for inhalant abusers, it will be

necessary to rigorously evaluate the immediate or long-term outcomes of some types of treatment It will be necessary not only

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to use appropriate controls or comparative groups whose characteristics of treatment and outcome are thoroughly described, but to

systematically follow up studies of treated subjects, utilize “blind”

methodologies, and adequately analyze data. It may be desirable

to validate outcome measures by use of informants, breath or

urine analysis, as well as dependent measures included in the

primary study. One should carefully define the variables of the

treatment approach, including the failures, so that improved

methodologies and protocols can be adopted for succeeding treatments. Any treatment should take into consideration that more

than one type of “inhalant” subject may exist, e.g., the escapist

or the euphoria-seeker, and that what started them sniffing may

not be what maintains this condition.

A few of the treatments previously used for inhalant abusers will

be briefly discussed in the following paragraphs. Although there

is as yet no specific treatment identified with this group, one or

more of the following might, with modification, provide a useful

therapy. Hopefully, newer and more effective treatments will

result from this and other discussions of the problem.

Psychotherapies

Although few therapies exist for solvent abuse subjects, several

efforts have been invoked to alter their behavior. However, it

has been noted that solvent abusers do not respond as well to

therapeutic intervention, and longer treatments are necessary for

this type of drug-dependent subject. Some aversive techniques

have been used for a limited number of inhalant abusers. Although in one study as many as 50 percent were reported not to

resume sniffing, a validation of this “clean” state is necessary.

Also, the outcome for these subjects should be compared with

other types of drug use, and any potential substitution of other

drugs or other undesired habits needs to be determined. Also,

the use of more extreme types of conditioned aversion such as

use of foul odors or apomorphine injections needs to be critically

approached and undertaken only in competent medical surroundings. Foul odors may not be so innocuous, and adverse reactions

to other drugs may occur more in this population because of

nutritional deficiencies or other associated problems.

The simplest approach of removing the substance has not been

sufficient to deter the abuser. Arrests have been used in many

communities to control this problem. Although no critical analysis

of the outcome exists, it is not likely that this approach will

succeed, just as prohibition of alcohol failed. The inverse approach has even been tried. Subjects were offered money not to

sniff but chose not to accept.

Though not precisely a therapeutic intervention, other negative

reinforcements occur. These include religious sanctions as well

as tribal customs and authority. For example, there are fewer

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inhalant users among those Indian youth who belong to the Native

American Church than those who belong to Protestant or Catholic

Churches. However, it may not necessarily have been the Indian

culture and tradition that limited the number of solvent abusers.

Different types of personalities may have skewed the subject

populations by a preselection process such that fewer of those

who joined the Native American Church would have inhaled under

any circumstances. The influence of cultures or religions on

solvent abuse has not yet been adequately assessed.

Some characteristic needs of solvent abusers which should be

considered uppermost in any treatment paradigm include the

following: improvement of peer relationships, development of

suitable alternative activities, improvement of family interaction,

development of self-esteem, reinforcement of appropriate behavior,

ability to overcome moods of helplessness, increased verbal ability

(intellectual capacity appears comparable to their peers), as well

as improvement of interrelationships within the basic family and

educational systems.

Maintenance

This method is utilized primarily in the treatment of opiate addiction by substituting one drug for another (usually both have

opiate-like effects). However, in the broader concept, one can

visualize the need for maintaining the patient’s physiological and

psychological equilibrium. This may be necessary for some subjects. Types of drug which have been used with inhalant abusers have included the psychotropics and tranquilizers. A word of

caution in the use of depressants is apropos. Any patient who is

taking such medication and then inhales a solvent would be enhancing those depressant effects since these solvents belong to

the general class of depressants (along with alcohol). They also

may be deposited in lipids and residual amounts may exert additive

effects when other sedatives are subsequently administered. A

typical example of this is “degreaser’s flush.” That is, people

who work around degreasing vats using trichloroethylene all day

become flushed after a few drinks after work.

Any state of drug maintenance should not be a major focus or

long-term step in the rehabilitation effort but should probably be

only supportive until more suitable approaches can be deployed.

Also, it does not presently seem necessary or rational to substitute one solvent for another (e.g. , such as when ether use was

substituted for alcohol in Ireland) even though the patient may so

desire.

Other Approaches

Numerous communities have made efforts to resolve the problem of

inhalant drug abuse. For example, efforts in Mexican-American

communities (barrios) where concilios were formed involved par234
ents and neighbors in recreational and art form activities with the

abuser and his peers. The success of this approach and its

impact on the community is presently unknown. Other forms of

vocational, physical, or occupational therapies should also be

considered.

In all of the approaches, the individual variations of different

cultures, races, sexes, ages, types of inhalant, stages of use,

environment, health, and family structures are important considerations. This may well signify the number of different treatments,

or variations thereof, necessary to treat these subjects. Treatment approaches should also take into account that the treatment

may be worse than the habit. and/or that it may lead to a greater

use of inhalants through anti-establishment or anti-family orientations

AREAS OF FOCUS FOR RESEARCH

This section is divided into three major areas for convenience of

discussion but not with the intent of limiting one’s approach to

those problems which cover more than any one or parts of all of

these areas. As an orientation, it should be emphasized here

that future studies should be focused on testing and assessing a

rigorously defined problem area rather than on accumulating yet

more descriptive data on a limited number of subjects or compounds. Any studies should, therefore, thoroughly define a

premise to be evaluated or established, substantiate this with

findings using selective and appropriate measures, and should

omit excessive tests that are redundant or irrelevant to that

premise.

Epidemiological Studies

This is one of the most difficult areas to approach. Several

salient points were discussed in a previous chapter and include

problems of appropriate sample size, cost, choice of study of any

one inhalant from amongst all the varieties used, identifying and

reaching the inhalant population, the time required for Iongitudinal studies, the need for multidisciplinary teams to study the

problem, establishment of standardized survey instruments, the

use of appropriate community ethnographers, poor or incorrect

recording of information at hospitals, clinics, courts, or even in

interviews, and the problems related to clearance for these projects through government agencies. Many of these points need to

be considered in studies in any of the following areas.

Deaths and Other Hazards

Although there has been considerable input into this area, very

little of it is substantive enough to evaluate the problem. Many

coroners and forensic toxicologists do not believe that there is a

major physiological hazard related to inhalant use, yet many admit

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that they do not carefully evaluate whether inhalants may be the

potential cause in some deaths. For example, unless a can, rag,

or some other evidence is found nearby, the examiner may not

suspect solvent overdose. It has also been observed that unless

alveolar air is appropriately sampled. the level of the more insoluble substances (e.g., freons) may be undetected. Appropriate

evaluation of the incidence of this hazard, especially in several

communities where the prevalence of use is high, would assist

greatly in defining the extent of deaths related to inhalant use.

Records would need to be thoroughly examined to evaluate

whether some deaths listed as “cause unknown” might be due to

inhalants. Even then it might be very difficult to get this information, even if the examiners are aware of the difficulties and are

prepared ahead of time to obtain the needed data because, for

different reasons, some people do not want to identify the

deceased as an inhalant abuser.

Similarly, hospital and clinic information is often incomplete so

that it is difficult to evaluate health hazards associated with

inhalant use. Seldom is a good historical or clinical evaluation

made of the admitted patient. This became clear during a recent

NIDA study which utilized CODAP records in seven communities to

examine the treatment of inhalant abusers. The information on

inhalant users admitted appeared to be small. An illness may not

be associated with inhalant use (purposely or unknowingly) as the

acute problems associated with inhalant use arc brief and the

chronic impairments are even difficult for a physician to relate to

any particular agent or mixture, especially since the initiation of

use is so remote from the onset of the disability.

Similar difficulties prevent the use of another system, DAWN, of

the Drug Enforcement Agency. Mentions which are accumulated

therein do not indicate how recent the event is, the amount used,

or how long the person has been using. Also, two or more

mentions may come from one person Therefore DAWN may pick

up different types of drug use, but the system doesn’t provide a

good indication of the seriousness of the incident. It may also

miss many hot spots of activity since only limited major metropolitan areas are surveyed. It might be possible that more State

health centers would increase their vigilance on inhalant abuse

especially through use of the primary school systems visiting

health teams. School absentees would need to be included in any

such analysis.

Although many clinics are set up to analyze for many drugs of

abuse, few are equipped to measure solvents, especially mixtures.

Therefore, validation by the type of inhalant used is unlikely and

the data must come from in-depth personal interviews. This

latter method is much less reliable when the subject knows that

the data will be made available to authorities. Also, even when

the interviewer has the confidence of the subject. the inhalant

user usually has poor recall, especially of the substance used,

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beyond a week or two. This may be due to brain damage resulting from inhalation or to a general lack of desire to know exactly

what was used. Multiple drug use also complicates the approach

to the problem.

In-Depth Surveys

It is difficult and expensive to obtain information on inhalant

abuse at the national level. As we do know of some areas of high

prevalence, it would be most appropriate to focus on some of

these communities. In setting up these studies, one should

consider some of the following aspects: use among different

ethnic and social groups and different economic levels, with

different age groups such as pre- and postadolescent inhalant

users, and among different siblings (why does one sibling “sniff”

and not the other); predisposing factors such as outlook, personality, family relationships and stability, community, tension

release, machoism, aggression, health, achievement or accomplishment of important tasks, etc.; the conditions of inhalation, including different methods, individual or group settings, associated

activities such as sex, gang activities, etc.; the inducements or

causes associated with the use or with the reinforcement of use;

the identification of types of sustances used (e.g. , brand names,

etc.); the rationale for the choice of products and why they

change; the relative weight of cost, availability, irritant or other

disagreeable properties, nice odor or other agreeable properties,

peer suggestion, etc.; the influences of teachers, friends, or

officials on subjects before they become involved and in their

future orientation; the progression from drug use to a drug-free

state, heroin use, or to a more entrenched state of inhalant use,

and the prominent factors associated with each. These investigations could utilize special schools, retraining centers, and various

health clinics, especially psychiatric emergency rooms, where more

of the nonschool subjects (dropouts) may be contacted. It is

known that these subjects are not only hard to find, but are also

difficult to get and keep in rehabilitative programs without small

remunerations. This latter incentive may skew the sample populations obtained through these facilities and therefore usage patterns should be carefully scrutinized to determine the actual

amount and type of use.

Clinical Studies

The need for clinical studies in the area of inhalant abuse is

particularly pressing and at the same time very difficult to meet.

One of the most important issues to resolve is the nature and

extent of the physiological impairment that results from use of

inhalants.

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Impairments

First, the type, onset, and extent of tolerance or dependence

produced by these substances should be determined. For example, is there a behavioral adaptation to the effects, as acquisition of different effects. or is some physiological tolerance involved? Similarly, is there any dependence and in which population(s) does it occur? If so, what are the withdrawal effects

observed for subjects after they have been isolated from the

inhalant scene?

The toxicity of most of these agents is established. However, it

has been difficult to measure any symptoms of toxicity in the

“average” user, There are numerous reports of defined impairments in certain individuals, yet it is unknown if these resulted

from inhalant use or were pre-existing conditions in these subjects. An identified neurological impairment may be correlated

more with one class of solvents than with others; yet there are

almost as many different kinds of “solvents” as there are other

drugs of abuse. The sorting problem may be endless. Recent

evidence indicates that prolonged exposure to low levels of some

of these solvents may be carcinogenic (e.g., benzene and triand perchloroethylene). Findings such as these result in limiting

their use in many household products but may open the way to

the use of other compounds with other toxicities. It would be

especially unfortunate if substances were incorporated that produced irreversible neurological damage not easily detectable by

present testing mechanisms. Also, although toxicities are associated with certain chemicals, it is not yet possible to extrapolate

how much sooner these effects would occur at the repeated high

dose levels of inhalant users. Nor are onsets of the dramatic

the various solvents.

(e.g., cognitive) impairments known nor how they differ among

Specific Symptoms of Inhalant Toxicity

As discussed in the clinical section, it would be important to

characterize specifically the early manifestations of inhalation

toxicity in clinical cases. Then one could possibly devise animal

tests which would identify solvent mixtures that cause these

problems. The cooperation of manufacturers and formulators in

providing detailed information on the constituents of the products

used could greatly facilitate determination of the etiological factors

associated with certain compounds as well as assist in the development of rational approaches to animal studies.

One could possibly measure inhalant effects through a mapping of

the visual field, especially through use of prospective or other

longitudinal studies. More detailed acuity and visual field tests

could then be pursued for those subjects with abnormalities using

techniques such as computerized axial tomography (see neurology

section). Presently electroencephalogram (EEG) measures would

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not appear to be too useful as a test for inhalant effects due to

the complexity and cost of exams. Also, electromyography is

mostly used to validate an already noted muscle weakness and is

not appropriate to measure early neuromuscular involvement.

However, it would be important and useful to determine whether

vision or any other easily measured neurological function is an

early indication of a progressive impairment resulting from the

use of many different inhalants.

Performance Impairments

The rate of progression and quality of performance decrement in

inhalant abusers would be another area of investigation. How

would an evening of intoxication affect an individual’s performance

at school, work, or “behind the wheel”? Also, what are the

residual impairments that persist days, weeks, and months later

and how do these progress with the development of inhalant use?

Some of these impairments have been discussed in these pages.

Although humans must be utilized for most of these studies for

cognitive deficits to be properly evaluated, studies at present are

generally limited to retrospective analysis. In the area of noncognitive deficits, it would help animal investigators if the intoxicated state of the individual could be more critically characterized

in terms of animal behavior and functioning.

Preclinical Studies

Animals must be used for in-depth studies of toxicity and mechanisms . Although the acute toxicity of most solvent compounds

has been determined, few have been studied under chronic exposure conditions and even fewer at the multiple high dose levels of

exposure which snorters resort to. Also, the toxicity of mixtures

has seldom been evaluated. This has led toxicologists and physicians to an overextrapolation of the data in trying to decide when

and whether impairments may have resulted from overexposure to

different substances. Although some studies are now underway

to explore this area, many questions remain to be answered.

Development of Model Toxicity Systems

Determining impairment potential of substances. One goal would

be the development of an inexpensive and simple animal model

which would mimic the exposure situation of the inhalant user and

measure the degree of toxicity produced by different substances.

This model would subsume certain assessments of chronic toxicity

and carcinogenic tests, both of which are very costly and time

consuming. Also, it might be possible to devise a method whereby the exposure period for the effects that occur at the much

higher doses could be extrapolated from chronic low dose studies.

Any model should consider the unusual types of solvent administration and the fact that inhalation abusers do not usually dose

themselves continuously at one defined level.

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Evaluation of mixtures. Another type of study would be establishment of a suitable setup for the comparison of the toxicities of

different mixtures over short periods. This screening method

should be used to identify mixtures with toxicities greater or less

than that of known individual components as determined by other

standard tests. This rapid screening test could be used to

prevent the misuse of what might otherwise appear to be a safe

product. The test system might employ measures of optic nerve

or retinal damage such as measured through use of dynamic

pupillometry. Also, measurement of sciatic nerve damage may be

appropriate (for details refer to the chapter on mixtures).

Behavioral toxicities. Numerous behavioral tests are now being

developed to measure toxicity of industrial and environmental

agents and some may be useful here. More emphasis should be

placed on determining persistent or slowly reversible effects that

would indicate possible disabilities which might result from these

substances. The degree of altered state produced with different

substances or classes of solvents should be compared and/or

classified.

Classification of solvents for abuse liability. A basic problem,

yet, is how to define the human emotional states in terms applicable to an animal model. More thought and new approaches may be

called for to carefully and critically define this state of intoxication . Self-administration has been used to classify many drugs of

abuse. In addition to the problem of a lack of correlation between discrimination on the part of animals and the use of various

euphoric drugs by humans, there are the problems of volatility

(administration) and disruption of the olfactory system. Also,

food deprivation may result from either association with the bad

odor or with the disruption of other senses as well as with a

direct action of the solvent on behavior. Therefore, other behavioral paradigms must be utilized alone or in combination with

the self-administration approaches to establish liability of any

compound. One hypothesis may be worth exploring. Is there an

association between a child’s self-induced dizziness from “going

round and round till he falls down” to the circling behavior of a

rat under similar influences such as solvent intoxication? These

states of dizziness may or may not be an altered state not unlike

“euphoria.”

Other tests that measure pulmonary, cardiac, liver, and kidney

dysfunctions that are associated with inhalant abuse should be

included in the screening program as many of the substances are

known to affect these organs after either acute or chronic exposure.

Mixture-Related Toxicities

Problems associated with physical properties of volatiles. Volatility is an important property to be carefully considered in the

240
protocol for exposing an animal to mixtures. Are the effects

following exposure related more to the highly volatile element or

do the other components of the mixture contribute significantly?

Other factors related to human exposure should also be considered in designing animal studies including: the style of administration (breathing from a bag or through a rag in the mouth),

the frequency of replenishment of the volatile material, the clearance of air and fumes in the surrounding environment, and the

length of titration period to produce the altered state.

As with other drugs, the period in between inhalation episodes is

critical for the development of tolerance, toxicity, and dependence. Once these limits are established, it would be important to

define the rate of onset of certain impairments following different

exposure paradigms. Another related aspect would be a measure

of how poor health (e.g., malnutrition or asthma) or other modified physiological states alter the onset of these conditions.

Problems associated with biochemical properties of volatiles. One

of the reasons given for "snorting” is the fast action one gets.

However, these more rapid acting components are also more lipid

soluble. Therefore, one must be concerned with the lipid depot

of these materials, especially since inhalation is often continued

for several hours. Also, over the long term, some chemicals will

be absorbed at a level below that of producing an altered state

but yet could well be contributing to a toxic reaction because of

their water solubility, metabolism, and/or other properties. With

all the possibilities of different chemical, physiological, and physical interactions, it is difficult to summarize the potential toxicities

even when the retention, metabolism, and excretion of each of the

individual components are known, Therefore, it may be better to

determine the potential toxicity through an evaluation of the whole

mixture. This, of course, leads to the question of how one

chooses the mixtures. With all the regional and yearly variations

in the different types of mixtures, it is not a simple task.

However, this should not deter industry and government from

enthusiastically working on this formidable task.

Problems associated with impurities. Another type of interaction

involves the active ingredients, solvents, and container impurities

or break-down products. Although few of these are probably

worth considering in any detail, any screening method for the

evaluation of the “safety” of various mixtures should also consider

this aspect. This could be accomplished through testing of the

available products which are known to be abused. As previously

learned from studies of pesticides and other chemicals, a minor

component (even at 1 percent) may be important if it is highly

volatile, toxic, stored, etc.

Establishing guidelines. Although the use of threshold limit

values (TLV) or mininum allowable concentrations (MAC) are not

appropriate here, it might be well to grade different types of

241
mixtures and relate their toxicity (time of onset, type of impairment, etc.) to a readily identifiable single chemical substance

and/or gasoline(s).

FINAL COMMENT

Although this discussion has highlighted only a number of the

problems associated with inhalant abuse, the reader is encouraged

to read the preceding chapters and from studies included in the

large bibliography for more pertinent thought and background

related to many of the above discussions. If this discussion has

given investigators in related subject areas a new perspective or

insight into the problem of inhalant abuse, it has been worth the

effort. Also, it is hoped that some of the hurdles have been

visualized so that future efforts can proceed more systematically

and smoothly.

242
BIBLIOGRAPHY

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This bibliography contains all references obtained through several

automated searches of the literature pertaining to preclinical and

clinical effects of inhalants (excluding marihuana, tobacco, and

cocaine) resulting from accidental, purposeful, or occupational

overexposure. (Some additional references available to the editors have been added.)

The search was conducted on the MEDLINE and TOXLINE data

bases as well as the file of Psychological Abstracts and the NTIS

data base.* Overall, the search strategy consisted of retrieval of

references on the toxic effects--physical and behavioral--of solvents in general, or of specific chemicals when used as solvents,

propellants, or in gaseous states. (A detailed description of the

search strategy for each file has been prepared for NIDA for use

in future updating of the bibliography.) The MEDLINE and

TOXLINE searches cover material indexed from 1971 through July

1977; Psychological Abstracts coverage begins in 1967 and is

current through June 1977; NTIS covers 1964 to June 1977. Some

earlier reference texts are also included.

Though the bibliography was available to the authors of the

present monograph, it was not possible nor was it the intention

that they would review all of this material in their chapters.

Indeed, the references at the end of each of the chapters of the

monograph are unique to that particular subject matter and may

or may not be referenced here. This bibliography is intended for

the reader’s use

whole.

as a general reference list to the topic as a

*The editors gratefully acknowledge the skilled assistance of

Mary M. Metter, Coordinator of Automated Reference Services,

Health Sciences Library, University of North Carolina at Chapel

Hill, for performing the MEDLINE and TOXLINE searches, and

Sylvia Deal, North Carolina Science and Technology Research

Center for the search of Psychological Abstracts and NTIS files.

Ms. Metter was especially helpful in the refinement of the search

strategy.

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345
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338
27 PROBLEMS OF DRUG DEPENDENCE, 1979: PROCEEDINGS OF THE 41ST

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. L.S. Harris, Ph.D., ed. Not available from NCDAI.

GPO Stock #017-024-00981-4 $9.00 NTIS PB #80-175482 $37

28 NARCOTIC ANTAGONISTS: NALTREXONE PHARMACOCHEMISTRY AND

SUSTAINED-RELEASE PREPARATIONS. Robert Willette. Ph.D., and

Gene Barnett, Ph.D., eds. Papers report research on sustainedrelease and long-acting devices for use with the narcotic antagonist naltrexone. Not available from NCDAI.

GPO Stock #017-024-01081-2 $7.00 NTIS PB #81-238875 $23.50

29 DRUG ABUSE DEATHS IN NINE CITIES: A SURVEY REPORT. Louis A.

Gottschalk, M.D., et al. Not available from NCDAI.

GPO Stock #017-024-00982-2 $6.50 NTIS PB #80-178882 $17.50

30 THEORIES ON DRUG ABUSE: SELECTED CONTEMPORARY PERSPECTIVES.

Dan J. Lettieri, Ph.D.; Mollie Sayers; and Helen Wallenstein

Pearson, eds. Volume presents summaries of major contemporary

theories of drug abuse by each of 43 leading theorists.

GPO Stock #017-024-00997-1 $10.00 Not available from NTIS

31 MARIJUANA RESEARCH FINDINGS: 1980. Robert C. Petersen, Ph.D.,

ed. The text of the 8th Marijuana and Health report to Congress

and the background scientific papers on which it was based.

GPO out of stock NTIS PB #80-215171 $20.50

32 GC/MS ASSAYS FOR ABUSED DRUGS IN BODY FLUIDS. Rodger L. Foltz,

Ph.D.; Allison F. Fentiman, Jr., Ph.D.; and Ruth B. Foltz. A

collection of methods for quantitative analysis of several

important drugs of abuse by gas chromatography- mass spectrometry.

GPO Stock #017-024-01015-4 $6.00 NTIS PB #81-133746 $19

33 BENZODIAZEPINES: A REVIEW OF RESEARCH RESULTS, 1980. Stephen

I. Szara, M.D., D.Sc., and Jacqueline P. Ludford, M.S., eds.

A RAUS (Research Analysis and Utilization System) Review Report

on the abuse liability of the benzodiazepine "tranquilizers."

GPO Stock #017-024-01108-8 $5.00 NTIS PB #82-139106 $13

34 PROBLEMS OF DRUG DEPENDENCE, 1980: PROCEEDINGS OF THE 42ND

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCDAI.

GPO Stock #017-024-01061-8 $8.00 NTIS PB #81-194847 $34

35 DEMOGRAPHIC TRENDS AND DRUG ABUSE, 1980-1995. Louise G.

Richards, Ph.D., ed. Estimates of probable extent and nature of

nonmedical drug use, 1980-1995, based on age structure and other

characteristics of U.S. population.

GPO Stock #017-024-01087-1 $4.50. NTIS PB #82-103417 $13

349
36 NEW APPROACHES TO TREATMENT OF CHRONIC PAIN: A REVIEW OF MULTIDISCIPLINARY PAIN CLINICS AND PAIN CENTERS. Lorenz K.Y. Ng. M.D.,

ed. Discussions by active practitioners in the treatment of pain.

GPO Stock #017-024-01082-1 $5.50. NTIS PB #81-240913 $19

37 BEHAVIORAL PHARMACOLOGY OF HUMAN DRUG DEPENDENCE. Travis

Thompson, Ph.D., and Chris E. Johanson, Ph.D., eds. Presents a

growing body of data, systematically derived, on the behavioral

mechanisms involved in use and abuse of drugs.

GPO Stock #017-024-01109-6 $6.50 NTIS PB #82-136961 $25

38 DRUG ABUSE AND THE AMERICAN ADOLESCENT. Dan J. Lettieri.

Ph.D., and Jacqueline P. Ludford, M.S., eds. A RAUS Review

Report, emphasizing use of marijuana: epidemiology, sociodemographic and personality factors, family and peer influence,

delinquency, and biomedical consequences.

GPO Stock #017-024-01107-O $4.50 NTIS PB #82-148198 $14.50

39 YOUNG MEN AND DRUGS IN MANHATTAN: A CAUSAL ANALYSIS.

Richard R. Clayton, Ph.D., and Harwin L. Voss. Ph.D. Examines

the etiology and natural history of drug use, with special focus

on heroin. Includes a Lifetime Drug Use Index.

GPO Stock #017-024-01097-9 $5.50 NTIS PB #82-147372 $19

40 ADOLESCENT MARIJUANA ABUSERS AND THEIR FAMILIES. Herbert

Hendin, M.D., Ann Pollinger, Ph.D., Richard Ulman, Ph.D., and

Arthur Carr, Ph.D. A psychodynamic study of adolescents

involved in heavy marijuana use, to determine what interaction between family and adolescent gives rise to drug abuse.

GPO Stock #017-024-01098-7 $4.50 NTIS PB #82-133117 $13

41 PROBLEMS OF DRUG DEPENDENCE, 1981: PROCEEDINGS OF THE 43RD

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris. Ph.D., ed. Not available from

NCDAI.

Not available from GPO NTIS PB #82-190760 $41.50

42 THE ANALYSIS OF CANNABINOIDS IN BIOLOGICAL FLUIDS. Richard L.

Hawks, Ph.D., ed. Varied approaches to sensitive, reliable, and

accessible quantitative assays for the chemical constitutents of

marijuana, for researchers. Not available from NCDAI.

GPO Stock #017-024-01151-7 $5 NTIS PB #83-136044 $16

43 PROBLEMS OF DRUG DEPENDENCE, 1982: PROCEEDINGS OF THE 44TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. Not available from

NCDAI.

GPO Stock #017-024-01162-2 $8.50 NTIS PB #83-252-692/AS $40

350
44 MARIJUANA EFFECTS ON THE ENDOCRINE AND REPRODUCTIVE SYSTEMS.

Monique C. Braude, Ph.D., and Jacqueline P. Ludford, M.S., eds.

A RAUS Review Report of animal studies and preclinical and

clinical studies of effects of cannabinoids on human endocrine

and reproductive functions.

GPO Stock #017-024-01202-5 $4. NTIS PB #85-150563/AS $14.50

45 CONTEMPORARY RESEARCH IN PAIN AND ANALGESIA, 1983. Roger M.

Brown, Ph.D.; Theodore M. Pinkert, M.D., J.D.; and Jacqueline P.

Ludford, M.S., eds. A RAUS Review Report on the anatomy,

physiology, and neurochemistry of pain and its management.

GPO Stock #017-024-01191-6 $2.75 NTIS PB #84-184670/AS $11.50

46 BEHAVIORAL INTERVENTION TECHNIQUES IN DRUG ABUSE TREATMENT.

John Grabowski, Ph.D.; Maxine L. Stitzer, Ph.D., and Jack E.

Henningfield, Ph.D., eds. Reports on behavioral contingency

management procedures used in research/treatment environments.

GPO Stock #017-024-01192-4 $4.25 NTIS PB #84-184688/AS $16

47 PREVENTING ADOLESCENT DRUG ABUSE: INTERVENTION STRATEGIES.

Thomas J. Glynn, Ph.D.; Carl G. Leukefeld, D.S.W.; and

Jacqueline P. Ludford, M.S., eds. A RAUS Review Report on a

variety of approaches to prevention of adolescent drug abuse, how

they can be applied, their chances for success, and needed future

research.

GPO Stock #D17-024-01180-1 $5.50 NTIS PB #85-159663/AS $22

48 MEASUREMENT IN THE ANALYSIS AND TREATMENT OF SMOKING

BEHAVIOR. John Grabowski, Ph.D., and Catherine S. Bell, M.S.,

eds. Based upon a meeting cosponsored by NIDA and the National

Cancer Institute to delineate necessary and sufficient measures

for analysis of smoking behavior in research and treatment

ettings.

GPO Stock #017-024-01181-9 $4.50 NTIS PB 84-145-184 $14.50

49 PROBLEMS OF DRUG DEPENDENCE, 1983: PROCEEDINGS OF THE 45TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed. A collection of

papers which together record a year's advances in drug abuse

research; also includes reports on tests of new compounds for

efficacy and dependence liability.

GPO Stock #017-024-01198-3 $12 NTIS PB 85-159663/AS $22

50 COCAINE: PHARMACOLOGY, EFFECTS, AND TREATMENT OF ABUSE. John

Grabowski, Ph.D., ed. Content ranges from an introductory

overview through neuropharmacology. pharmacology, animal and

human behavioral pharmacology, patterns of use in the natural

environment of cocaine users, treatment, through commentary on

societal perceptions of use.

GPO Stock #017-020-01214-9 $4 NTIS PB 85-150381/AS $14.50

351
51 DRUG ABUSE TREATMENT EVALUATION: STRATEGIES, PROGRESS. AND

PROSPECTS. Frank M. Tims, Ph.D., ed. A state-of-the-art review

of drug abuse treatment evaluation, identifying research needs,

promising approaches, and emerging issues.

GPO Stock #Ol7-020-01218-1 $4.50 NTIS PB 85-150365/AS $17.50

52 TESTING DRUGS FOR PHYSICAL DEPENDENCE POTENTIAL AND ABUSE

LIABILITY. Joseph V. Brady, Ph.D., and Scott E. Lukas, Ph.D.,

eds. Describes animal and human test procedures for assessing

dependence potential and abuse liability of opioids, stimulants,

depressants, hallucinogens, cannabinoids, and dissociative

anesthetics.

GPO Stock #017-024-0204-1 $4.25 NTIS PB 85-150373/AS $16

54 MECHANISMS OF TOLERANCE AND DEPENDENCE. Charles Wm. Sharp,

Ph.D., ed. Review of basic knowledge concerning the mechanism of

action of opiates and other drugs in producing tolerance and/or

dependence.

GPO Stock #017-024-01213-1 $8.50 NTIS PB No. to be assigned.

55 PROBLEMS OF DRUG DEPENDENCE, 1984. PROCEEDINGS OF THE 46TH

ANNUAL SCIENTIFIC MEETING, THE COMMITTEE ON PROBLEMS OF DRUG

DEPENDENCE, INC. Louis S. Harris, Ph.D., ed.

IN PRESS OR PREPARATION

53 PHARMACOLOGICAL ADJUNCTS IN SMOKING CESSATION.

John Grabowski, Ph.D., ed.

56 ETIOLOGY OF DRUG ABUSE: IMPLICATIONS FOR PREVENTION. Coryl

LaRue Jones, Ph.D., and Robert J. Battjes, D.S.W., eds.

57 SELF-REPORT METHODS OF ESTIMATING DRUG USE: MEETING CURRENT

CHALLENGES TO VALIDITY. Beatrice A. Rouse, Ph.D., Nicholas J.

Kozel, M.S., and Louise G. Richards, Ph.D., eds.

58 PROGRESS IN THE DEVELOPMENT OF COST-EFFECTIVE TREATMENT FOR

DRUG ABUSERS. Rebecca S. Ashery, D.S.W., ed.

59 CURRENT RESEARCH ON THE CONSEQUENCES OF MATERNAL DRUG ABUSE.

Theodore M. Pinkert, M.D., J.D., ed.

60 PRENATAL DRUG EXPOSURE: KINETICS AND DYNAMICS. C. Nora

Chiang, Ph.D., and Charles C. Lee, Ph.D., eds.

352

 U.S. GOVERNMENT PRINTING OFFICE : 1985 0 - 480-122 : QL 3
DHHS Publication No. (ADM) 85-533

Printed 1977 Reprinted 1979, 1985