Neurotoxicity: Identifying and Controlling

Poisons of the Nervous System

April 1990

OTA-BA-436

NTIS order #PB90-252511
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Neurotoxicity: Identifying and Controlling

Poisons of the Nervous System, OTA-BA-436 (Washington, DC: U.S. Government Printing

Office, April 1990).

For sale by the Superintendent of Documents

U.S. Government Printing Office, Washington, DC 20402-9325

(order form can be found in the back of this report)
.

Foreword

Extraordinary developments in the neuroscience in recent years have been paralleled by

a growing congressional interest in their policy implications. The designation of the 1990s by

the 101st Congress as the “Decade of the Brain” is one indication of the promise shown by

scientific advances for treating diseases of the nervous system and for increased general

understanding of the human mind. Other advances, however, have led us to the disturbing

realization that many commonly used chemicals can adversely affect the human nervous

system. Concern about this issue provided the motivation for hearings held in October 1985

on ‘‘Neurotoxins in the Home and in the Workplace’ by the Subcommittee on Investigations

and Oversight of the House Committee on Science and Technology.

Another result of heightened congressional interest was a request that OTA undertake a

series of assessments on major public policy issues related to the neuroscience. Requesting

committees included the House Committees on Science, Space, and Technology; Energy and

Commerce; Appropriations; and Veterans’ Affairs; and the Senate Subcommittee on Science,

Technology, and Space of the Committee on Commerce, Science, and Transportation. In

addition, the Senate Committee on Environment and Public Works recently requested a study

of the noncancer health risks posed by toxic substances. This Report, the first of the

neuroscience series, discusses the risks posed by neurotoxic substances—substances that can

adversely affect the nervous system—and evaluates the Federal research and regulatory

programs now in place to address these risks.

One finding of this Report is that considerably more research and testing are necessary

to determine which substances have neurotoxic potential. Neurotoxic effects can often go

unrecognized because symptoms are varied and may not appear for months or even years.

Adverse effects range from impaired movement, anxiety, and confusion to memory loss,

convulsions, and death. Another important finding is the need for greater public awareness.

Neurotoxic chemicals constitute a major public health threat; the social and economic

consequences of excessive exposure to them are potentially very large. Minimizing exposure

requires action not just by regulatory and other public officials, but also by individual citizens

who can take steps to avoid these substances both at home and in the workplace.

Many individuals and institutions contributed their time and expertise to the project.

Scientists and regulatory officials in several Federal agencies and experts in academia and

industry served on the project’s advisory panel, in workshop groups, and as reviewers. OTA

gratefully acknowledges the assistance of these contributors. As with all OTA assessments,

however, responsibility for the content of the Report is OTA’s alone and does not necessarily

constitute the consensus or endorsement of the advisory panel or the Technology Assessment

Board.

 JOHN H. GIBBONS

Director .

.,. Ill
New Developments in Neuroscience Advisory Panel

Peter S. Spencer, Chair

Oregon Health Sciences University, Portland, OR

Robert H. Blank Laurane G. Mendelssohn

Northern Illinois University Lilly Research Laboratories

DeKalb, IL Indianapolis, IN

James F. Childress Franklin E. Mirer

University of Virginia United Auto Workers

Charlottesville, VA Detroit, MI

Fred H. Gage Albert S. Moraczewski

University of California-San Diego Pope John XXIII Center

La Jolla, CA Houston, TX

Bernice Grafstein Herbert Paroles

Cornell University Columbia University

New York, NY New York, NY

Ronald Kartzine} Richard M. Restak

CIBA-GIGY Corp. Neurological Associates, P.C.

Summit, NJ Washington, DC

Alan Kraut

American Psychological Association

Washington, DC

Neurotoxic Substances Study Panel

Stanley H. Abramson

King & Spalding

Washington, DC

Louis W. Chang

University of Arkansas

Little Rock, AR

Alan M. Goldberg

Johns Hopkins University

Baltimore, MD

Marion Moses

University of California-San Francisco

San Francisco, CA

John O’Donoghue

Eastman Kodak Co.

Rochester, NY

Bernard Weiss

University of Rochester

Rochester, NY

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the advisory and study panel

members. The panels do not, however, necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility

for the report and the accuracy of its contents.

iv
Neurotoxicity

Roger C. Herdman, Assistant Director, OTA, Health and Life Sciences Division

Gretchen S. Kolsrud, Biological Applications Program Manager1

OTA Project Staff

Mark Schaefer, Study & Project Director

Timothy P. Condon, Project Director2

Peter R. Andrews, Research Assistant

Joyce Ann Brentley, Analyst

Claire L. Pouncey, Research Assistant

E. Blair Wardenburg, Research Analyst3

Monica Bhattacharyya, Research Assistant

Catherine A. Laughlin, NIH Detailee4

Gladys B. White, Analyst5

Support Staff

Cecile Parker, Office Administrator

Linda Rayford-Journiette, Administrative Secretary

Jene Lewis, Secretary

Sharon Oatman, Administrative Assistant6

Lori B. Idian, Secretary7

Contractors

Zoltan Annau, Johns Hopkins University

Jacqueline Courteau, Hampshire Research Associates

Warren R. Muir, Hampshire Research Associates

George Provenzano, University of Maryland at Baltimore

Brenda Seidman, Environ Corp.

Ellen Widess, University of Texas

Ronald Wood, New York University Medical Center

John S. Young, Hampshire Research Associates

Jeffrey L. Fox, Washington, DC

Blair Potter (editor), Bethesda, MD

Julie Phillips (indexer), Vienna, VA

Raymond Driver (graphics artist), Damascus, MD

OTA Publishing Staff

Kathie Boss, Publishing Officer

Dorinda Edmondson, Desktop Publishing

Christine Onrubia, Graphic Designer/Illustrator

Susan Zimmerman, Graphic Artist

lmou~ September 1989.

2mou@ August 1989.

3~ou~ August 1989.

4Th17Nl@ hdy 1989.

fThrough June 1989.

%ough February 1989

7ThOU#l July 1989.
Contents

Page

Chapter 1. Summary, Policy Issues, and Options for Congressional Action . . . . . . . . . . . . . . . . 3

Chapter 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Chapter 3. Fundamentals of Neurotoxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Chapter 4. Research and Education Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Chapter 5. Testing and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Chapter 6. Assessing and Managing Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Chapter 7. The Federal Regulatory Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

Chapter 8. Economic Considerations in Regulating Neurotoxic Substances . . . . . . . . . . . . . . . . 211

Chapter 9. International Regulatory and Research Activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

Chapter 10. Case Studies: Exposure to Lead, Pesticides in Agriculture, and

Organic Solvents in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267

Appendix A, The Food Additive Approval Process: A Case Study . . . . . . . . . . . . . . . . . . . . . . . . 315

Appendix B. Workshop on Federal Interagency Coordination of Neurotoxicity

Research and Regulatory Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321

Appendix C. Decade of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330

Appendix D. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332

Appendix E. List of Contractor Documents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

Appendix F. Glossary of Terms and List of Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Chapter 1

Summary, Policy Issues, and

Options for Congressional Action
CONTENTS

Page

SUMMARY .. ... .. .. ... .. .. .. .. ... .,. .....+. . . . . . . .....,, . . . . . . . . . . . . . . . . . . . . . . . .

Scope of This Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. .. .. +.. ... .+.+...,

What Is Neurotoxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . .+ .. .. .. .. .. ..+. . . . . . . . . . . . . . . .

Who Is At Risk? ... ... ...+.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Research and Education Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Testing and Monitoring .. .. .. .. .. .. .. .. ... ....+... .. .. .. .. .. .. .. .. ... ... ... ...~.

Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. ... ... +......

Federal Regulatory Response . . . . . . . . . . . . .. .. .. .. .. .. ... +.. ....+...

Federal Interagency Coordination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Economic Considerations in Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .

International Issues . . . . . . . . . . . .

POLICY ISSUES AND OPTIONS

Box

~ o R. 60iek i . l o N. k . A c. t i. 6 N

Boxes

I-A. Vulnerability of the NervousSystem to Toxic Substances . . . . . . . .

,...,.. . . . . . . . .

. . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

. . . . . . . . . . . . . . .

3

4

4

8

9

12

13

15

19

19

21

22

Page

. . . . . . . . . . . . . . . 5

l-13. MPTP and Parkinson’s Disease ......+..........++.. . .. .. .. .+ . . . . . . . . . . . . . . . . . . 6

l-C. had: A Continuing Threat to the Nation’s Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

l-1). Cocaine and the Developing Fetus . . . . . . . . . . . . . . . . . . .+ . . . . . . . . . . . . . . . . . . . . . . . . 10

l-E. Neurotoxic Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

l-F. Limitations of FDA’s Postmarked Monitoring System for

Adverse Drug Reactions: Halcyon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

I-G. Organic Solvents in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..+.. 30

Figures

Figure Page

l-1. Average Annual Motor Neuron Disease Mortality in the United States,

White Males . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,..,.... . . . . . . . . . . . . . . . . . . . . . 3

l-2. The Fundamental Structure of the Nerve Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

l-3. Neurotoxic Effect of MDMA on Serotonin Nerve Fibers in the Cerebral Cortex

of the Monkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . +........ . . . . . . . . . . . . . . 9

l-4.Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s

Top 25 Chemicals Emitted Into the Air 1987 .. .. .. .. .. .. .. .. .. .. ... ... ..+...+ 14

Tables

Table Page

l-1. Federal Funding for Civilian Neurotoxicity-Related Research . . . . . . . . . . . . . . . . . . . .

l-2+ Major Federal Laws Controlling Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

16
Chapter 1

Summary, Policy Issues, and Options for Congressional Action

SUMMARY

Chemicals are an integral part of our daily

lives and are responsible for substantially improving them. Chemicals can also endanger our

health, even our survival. This assessment

focuses on neurotoxic substances, those chemicals that adversely affect the nervous system.

Included among such substances are industrial

chemicals, pesticides, therapeutic drugs, abused

drugs, food, food additives, cosmetic ingredients, and naturally occurring substances. Whether

a substance causes an adverse health effect

depends on many factors, including the toxicity

of the substance, the extent of exposure, and the

age and state of health of an exposed individual.

Minimizing public health risks requires information about the properties and mechanisms of

action of potentially toxic substances to which

humans may be exposed. This information

provides the foundation for safety standards.

More than 65,000 chemicals are in the U.S.

Environmental Protection Agency’s (EPA) inventory of toxic chemicals; and the Agency annually receives approximately 1,500 notices of

intent to manufacture new substances. Since few

of these chemicals have been tested to determine

if they adversely affect the nervous system, no

precise figures are available on the total number

of chemicals in existence that are potentially

neurotoxic to humans. Some estimates have

been developed, however, based on analyses of

certain subsets of chemicals. These estimates

vary considerably, depending on the definition

of neurotoxicity used and the subset of substances examined. For example, some 600

active pesticide ingredients are registered with

EPA, a large percentage of which are neurotoxic

to varying degrees. One investigator estimated

that 3 to 5 percent of industrial chemicals,

excluding pesticides, have neurotoxic potential.

Another investigator found that 28 percent of

industrial chemicals for which occupational

exposure standards have already been developed produce neurotoxic effects. In addition, a

substantial number of therapeutic drugs have

neurotoxic potential.

In recent years, concern about the neurotoxic

effects of chemicals has increased as evidence

has become available linking exposure to chemicals and drugs with long-term changes in the

nervous system. Some scientists believe that

neurotoxic substances play a role in triggering

some neurological disorders, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. For example, investigators

recently found evidence that the incidence of

motor neuron disease (primarily amyotrophic

lateral sclerosis) is increasing particularly in the

elderly (figure 1-1 ). Exposure to toxic chemicals

may be one of the factors contributing to this

increase. More research is necessary to confirm

this trend and to determine the underlying

causative factors.

Human exposure to significant concentrations of most known neurotoxic substances is

normally quite limited. Consequently, the number of substances that pose an actual threat to

public health is considerably less than the total

Figure l-l—Average Annual Motor Neuron Disease*

Mortality in the United States, White Males

Rate per 1001000 population

12

10

8

8

4

2

0 I -1o11

m

c 40 40-4445-4950-5455-59 60-6465-6970-7475-79 80-84 85.

Age

@ Between 1962-1964 m Between 1980-1984

“Most motor neuron disease is diagnosed as amyotrophic lateral sclerosis

(ALS) or Lou Gehrig’s disease.

SOURCE: Adapted from D.E. Lilienfeld, et al., “Rising Mortality From

Motoneuron Disease in the U. S., 1962-1884,” The Lancet, Apr.

1, 1989, pp. 710-713.

-3-
4 ● Neurotoxicity: Identifying and controlling poisons of the Nervous System

number of neurotoxic substances in existence.

The number of substances that pose a significant risk to public health and the extent of

that risk are unknown because the potential

neurotoxicity of only a small number of

chemicals has been evaluated adequately.

Scope of This Study

This study examines many, but not all, of the

classes of neurotoxic substances. The assessment includes discussion of industrial chemicals, pesticides, therapeutic drugs, substance

drugs, foods, food additives, cosmetic ingredients, and such naturally occurring substances as lead and mercury. It does not

include radioactive chemicals, nicotine (from

cigarette smoke), alcohol (ethanol), biological

and chemical warfare agents, microbial, plant,

and animal toxins, and physical agents such as

noise.

What Is Neurotoxicity?

The nervous system comprises the brain, the

spinal cord, and a vast array of nerves and

sensory organs that control major body functions. Movement, thought, vision, hearing,

speech, heart function, respiration, and numerous other physiological processes are controlled

by this complex network of nerve processes,

transmitters, hormones, receptors, and channels

(figure 1-2).

Every major body system can be adversely

affected by toxic substances, but the nervous

system is particularly vulnerable (see box l-A).

Many toxic substances can alter the normal

activity of the nervous system. Some produce

effects that occur almost immediately and last

for several hours. Examples include an alcoholic

beverage or fumes from a can of paint. The

effects of other neurotoxic substances may

appear only after repeated exposures over weeks

or even years: e.g., regularly breathing the

Photo credit: W Eugene Smith and Aileen Smith

A child victimized by mercury poisoning during the Minamata Bay, Japan, incident in the 1950s is bathed by his mother.

This is one of the most dramatic poisoning incidents involving a neurotoxic substance.
Chapter l---Summary, Policy Issues, and Options for Congressional Action ● 5

Figure 1-2—The Fundamental Structure of the Nerve Cell

LVk\ Axo n

term[nal

Cell body

2 /

///-- Synapse

Myelin

SOURCE: Office of Technology Assessment, 1990. ‘1

ndri

Box l-A—Vulnerability of the Nervous System to Toxic Substances

The nervous system is particularly vulnerable to toxic substances because:

. Unlike other cells that make up the body, nerve cells, or neurons, normally cannot regenerate once

lost—toxic damage to the brain or spinal cord, therefore, is usually permanent.

● Nerve cell loss and other regressive changes in the nervous system occur progressively in the second half

of life—toxic damage may therefore progress with aging.

● Certain regions of the brain and nerves are directly exposed to chemicals in the blood, and many neurotoxic

chemicals cross the blood-brain barrier with ease.

● The peculiar architectural features of nerve cells, with their long processes, provide a vast surface area for

chemical attack and are therefore inherently susceptible to chemical interference,

● The dependence of the nervous system on a delicate electrochemical balance for proper communication of

information throughout the body provides numerous opportunities for foreign chemicals to interfere with

normal function.

● Even minor changes in the structure or function of the nervous system may have profound consequences

for neurological, behavioral, and related body functions.

SOURCE: P.S. Spencer, personal communication, 1989.

tes
6 ● Neurotoxicity: Identifying and controlling Poisons of the Nervous System

fumes of a solvent in the workplace or eating

food or drinking water contaminated with lead.

Some substances can permanently damage the

nervous system after a single exposure-certain

organophosphorous pesticides and metal compounds such as trimethyl tin are examples (box

l-B). Other substances, including abused drugs

such as heroin and cocaine, may lead to

addiction, a long-term adverse alteration of

nervous system function. Many neurotoxic substances can cause death when absorbed, inhaled,

or ingested in sufficiently large quantities.

Neurotoxic substances play a significant causal

role in the development of some neurological

and psychiatric disorders; however the precise extent of the contribution is unclear.

Care must be taken in labeling a substance

neurotoxic because factors such as dose and

intended effects must be taken into consideration. A substance may be safe and beneficial at

one concentration, but neurotoxic at another.

For example, vitamins A and B6 are required in

the diet in trace amounts, yet both cause

neurotoxic effects in large doses. In other cases,

a substance that is known to be neurotoxic may

confer benefits that are viewed as outweighing

the risk of adverse side-effects. For example,

thousands of individuals suffering from schizophrenia have been able to live relatively normal

lives because of the beneficial effects of antipsy -

chotic drugs. However, chronic use of prescribed doses of some of these drugs may give

rise to tardive dyskinesia—involuntary movements of the face, tongue, and limbs—sideeffects so severe that they may incapacitate a

patient.

Box 1-B—MPTP and Parkinson’s Disease

In recent years, the hypothesis that Parkinson’s disease and other neurological disorders might be triggered by

environmental factors has become more widely accepted. Although toxic substances have long been considered

possible contributors to the cause of some disorders of the nervous system, the MPTP incident has focused more

attention on this environmental hypothesis.

MPTP is the abbreviation for l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, a compound that can be created

during the production of synthetic heroin. Remarkably, in just 5 to 15 days, this highly neurotoxic substance can

induce a syndrome virtually identical to Parkinson’s disease—a disease that usually occurs late in life and develops

slowly over a period of years. Both Parkinson’s disease and the MPTP-induced syndrome are characterized by

tremors and lack of muscular control that stem from degeneration of neurons in the substantial nigra, a region deep

in the central area of the brain. Neurons in the substantial nigra synthesize and secrete the neurotransmitter dopamine,

hence Parkinson’s patients are treated with levodopa, a precursor of this neurotransmitter.

The discovery of the link between MPTP and Parkinson’s disease has dramatically changed the nature of

research on this disease. Much work has focused on MPP+, a metabolize of MPTP that is responsible for the adverse

effects on the brain. Recently, researchers discovered that a monoamine oxidase inhibitor, a type of drug sometimes

used to treat depression, blocks the conversion of MPTP to MPP+. Other researchers have shown that the

monoamine oxidase inhibitor Deprenyl, administered to Parkinson’s patients in combination with levodopa,

reduces the symptoms of the disease and extends their lives. It was found that Deprenyl slows the rate of

degeneration of neurons in the substantial nigra, perhaps making it useful in the treatment of Parkinson’s disease.

The MPTP story illustrates how a neurotoxic substance might cause or contribute to the development of

neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. The

relative contributions of environmental and genetic factors to the causes of these diseases are not understood and

are the subject of considerable research and debate within the scientific community. Although the extent to which

a neurotoxic substance contributes to the cause of Parkinson’s disease is unclear, the MPTP story serves as an

example of how neurotoxicological research can lead to abetter understanding of the causes of neurological disease

and ways to treat it.

SOURCES: I.J. Kopin and S.P. Markey, ‘‘MPTP Toxicity: Implications for Research in Parkinson’s Disease,’ Annual Review o~~ewoscknce

11:81-96, 1988; J.W. Langston, P. Ballard, J.W. Tetrud, et al., “Chronic Parkinsonism in Humans Due to a Product of

Meperidine-Analog Synthesis, ” Science 219:979-980, 1983; R. Lewin, “Big First Scored With Nerve Diseases,” Science

245:467468, 1989.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 7

Broadly defined, a substance is considered to

have neurotoxic potential if it adversely affects

any of the structural or functional components of

the nervous system. At the molecular level, a

substance might interfere with protein synthesis

in certain nerve cells, leading to reduced production of a neurotransmitter and brain dysfunction.

At the cellular level, a substance might alter the

flow of ions (charged molecules, e.g., sodium

and potassium) across the cell membrane, thereby

perturbing the transmission of information between nerve cells. Substances that adversely

affect sensory or motor function, disrupt learning and memory processes, or cause detrimental

behavioral effects are neurotoxic, even if the

underlying molecular and cellular effects on the

nervous system have not been identified. Exposure of children to lead, for example, leads to

deficits in I.Q. and poor academic achievement;

however, the mechanisms by which this occurs

are not understood. In addition, researchers

recently found evidence that phenobarbital, a

drug prescribed to children to prevent seizures

associated with fevers, reduces intellectual ability. But as is the case for lead, the underlying

mechanism is unknown.

For the purposes of this study, the Office of

Technology Assessment (OTA) defines neurotoxicity or a neurotoxic effect as an adverse change

in the structure or function of the nervous

system following exposure to a chemical

agent. This is the definition currently used by

EPA. However, as the preceding discussion

illustrates, this definition should be used in

conjunction with information on the intended use of the substance, the degree of

toxicity, and the dose or extent of exposure of

humans or other organisms. The definition

hinges on interpretation of the word "adverse,” and there is disagreement among

scientists as to what constitutes “adverse

change.” Determining whether a particular

neurological or behavioral effect is adverse

requires a comprehensive analysis of all

available data. Although certain effects are

clearly adverse (e.g., hallucinations, convulsions, loss of memory, permanent neurological

damage, death) others are more difficult to

define (e.g., temporary drowsiness, a brief

headache). The circumstances of exposure and

a variety of other factors must be taken into

account in borderline cases. For example, drowsiness in the evening at home may be of little

consequence, but drowsiness during the day

while operating machinery in the workplace

may be detrimental or even life-threatening.

———.— — — A

— ——-———

— .

———

. . —~ . . .-“1’

Illustrated by: Ray Driver
8 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Who Is At Risk?

Everyone is at risk of being adversely affected

by neurotoxic substances, but individuals in

certain age groups, states of health, and occupations face a greater probability of adverse

effects. Fetuses, children, the elderly, workers in occupations involving exposure to

relatively high levels of toxic chemicals, and

persons who abuse drugs are among those in

high-risk groups.

The developing nervous system is particularly vulnerable to some neurotoxic substances,

for several reasons. It is actively growing and

establishing cellular networks, the blood-brain

barrier that protects much of the adult brain and

spinal cord from some toxic substances has not

been completely formed, and detoxification

systems are not completely developed. Lead is

a potent neurotoxic substance that is particularly

harmful to children (box l-C). Toxic substances

can contribute to neuropsychiatric disorders in

children. The National Academy of Sciences

recently reported that 12 percent of the 63

million children under the age of 18 in the

United States suffer from one or more mental

disorders, and it identified exposure to toxic

substances before or after birth as one of the

several risk factors that appear to make certain

children vulnerable to these disorders.

The elderly are more susceptible to certain

neurotoxic substances because decline in the

structure and function of the nervous system

with age limits its ability to respond to or

compensate for toxic effects. In addition, decreased liver and kidney function increases

susceptibility to toxic substances. Aging may

also reveal adverse effects masked at a younger

age. Persons who are chronically ill, especially

those suffering from neurological or psychiatric

disorders, are at risk because neurotoxic substances may exacerbate existing problems. Also,

many elderly Americans take multiple drugs

that may interact to adversely affect nervous

system function. According to the Department

Box l-C—Lead: A Continuing Threat to the Nation’s Children

Lead is an especially troublesome neurotoxic substance because it occurs naturally in the environment and

therefore may be found in food, water, and air, as well as in the byproduct.. of manufacturing and industry.

Environmental Protection Agency (EPA) and Food and Drug Administration (FDA) measures to reduce lead in

gasoline and food have been largely successful, but some sources of exposure remain, and some sources that are

not major contributors now may become so in the future.

Despite lead reduction in a number of areas, lead poisoning remains a major public health problem, particularly

among children, who are both more sensitive to lead’s neurotoxic effects and more likely to be exposed to certain

sources, such as paint chips from older houses, school water coolers containing lead-lined tanks, and home water

supplies contaminated with lead from old piping. According to the Department of Health and Human Services, 17

percent of the Nation’s children (in standard metropolitan statistical areas) have levels of lead in their blood that

may be adversely affecting their nervous systems. The percentage is much higher for urban children from poor

families. As tests become more sensitive, neurotoxic effects become apparent at progressively lower levels of lead

in children’s blood. In addition, relatively low exposures to lead in early years appear to have developmental and

neurobehavioral effects that persist into young adulthood. Because of the widespread nature of the problem, it would

be prudent to consider a nationwide screening program of lead poisoning in children.

There is some concern that existing EPA regulations cannot adequately remove lead from drinking water, and

it is unclear whether water suppliers or property owners bear the responsibility for removing lead plumbing. The

same problem of responsibility exists for the removal of lead-based paint from older houses. Without any central

reporting system, it is difficult to ascertain the extent of lead poisoning in individual States; and since funding for

lead poisoning prevention was placed under the block grant umbrella, it is difficult to determine the extent to which

Federal funds are being spent on lead poisoning prevention.

SOURCES: H.L. Needleman, A. Schell, D. Bellinger, et al., “The Long Term Effects of Exposure to Imw Doses of Lead in Childhood,” New

EnglandJournalofh4edicine 322:83-88, 1990. K.L. Florini, G.D. Krumbhaar, Jr., and E.K. Silbergeld, “Ugacy of Gad: America’s

Continuing Epidemic of Childhood Lead Poisoning,’ Environmental Defense Fund, Washington, DC, 1990.
Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 9

of Health and Human Services (DHHS), people

age 60 and older represent 17 percent of the

U.S. population but account for nearly 40

percent of drug-related hospitalizations and

more than half the deaths from drug reactions. Common adverse effects include depression, confusion, loss of memory, shaking

and twitching, dizziness, and impaired

thought processes.

Workers in industry and agriculture often

experience substantially greater exposures to

certain toxic substances than the general population does. Neurotoxic pesticides and solvents

are common sources of exposure in the

workplace. The National Institute for Occupational Safety and Health (NIOSH) has identified

neurotoxic disorders as one of the Nation’s 10

leading causes of work-related disease and

injury. Other leading causes of work-related

disease and injury include noise-induced hearing loss and psychological disorders, both of

which are mediated by the nervous system.

NIOSH has estimated that several million workers are exposed to neurotoxic substances on a

regular basis.

Persons who abuse psychoactive drugs may

face particularly severe neurotoxic effects. The

National Institute on Drug Abuse (NIDA) reported that in 1986 drug abuse led to more than

119,000 emergency room visits and 4,138

deaths. Some drugs can permanently damage

the nervous system. Damage may be so severe

as to cause personality changes, neurological

disease, mental illness, or death. Persons who

abuse drugs are often not aware of, or do not take

seriously, the threat these substances pose to

their health. Drugs such as cocaine, heroin,

MDMA (ecstasy), and phencyclidine (PCP) are

neurotoxic and threaten the health of many

Americans. Figure 1-3 illustrates how one

abused drug, MDMA, can destroy nerve fibers

in the brain. Abuse of psychoactive drugs by

pregnant women poses a major risk to the

developing nervous system of the fetus (see

box l-D).

Figure 1 -3--Neurotoxic Effect of MDMA on Serotonin

Nerve Fibers in the Cerebral Cortex of

the Monkey

A. Control

B. MDMA

Repeated administration of MDMA (5mg/kg, 8 doses) to a

Cynomolgus monkey produced degeneration of most serotonin

nerve fibers in this region of the cortex, which is involved in the

perception of touch and position sense. Similar toxic effects are

seen in most areas of the cerebral cortex.

SOURCE: M.A. Wilson and M.E. Molliver, Department of Neuroscience,

Johns Hopkins University School of Medicine.

Research and Education Programs

Federal research related to neurotoxic substances is conducted primarily at the National

Institutes of Health (NIH), the Alcohol, Drug

Abuse, and Mental Health Administration

(ADAMHA), and EPA. Limited research programs are under way at the Food and Drug

Administration (FDA), the Centers for Disease

Control (CDC), the Department of Energy, the

Department of Agriculture, and other agencies.
10 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box l-D-Cocaine and the Developing Fetus

When a pregnant women abuses a psychoactive drug, she alters not only the activity of her nervous system,

but that of her unborn child as well. Depending on the abused substance, the frequency of use, the dose, and other

factors, the mother’s quest for a high can lead to permanent damage of the rapidly developing fetal nervous system.

According to a recent survey by the National Association for Perinatal Addiction Research and Education, each year

as many as 375,000 infants may be adversely affected by substance abuse, Maternal substance abuse is frequently

not recognized by health-care professionals during pregnancy. Consequently, treatment or prevention programs

often come too late. According to the National Institute on Drug Abuse, approximately 6 million women of

childbearing age (15 to 44) are current users of an illicit drug, about 44 percent have tried marijuana, and 14 percent

have used cocaine at least once.

A recent study of 50 women who used cocaine during pregnancy revealed a 31 percent incidence of preterm

delivery, a 25 percent incidence of low birthweight, and a 15 percent incidence of sudden infant death syndrome.

These types of parameters are easy to quantify. The biochemical and neurobehavioral effects are more difficult to

document, but they are just as real. Early research indicates that cocaine babies suffer abnormal development of the

nervous system, impaired motor skills and reflexes, seizures, and abnormal electrical activity in the brain.

Cocaine is so addictive that it can suppress one of the most powerful human drives-maternal care. As one

pregnant crack addict put it: “The lowest point is when I left my children in a park for like 3 or 4 days. I had left

my kids with a girl that I know and told her. . . ‘watch them. . . I’ll be back’ and I didn’t come back. So that was

like—when I finally came down off of that high, I realized that I needed help. ” Sick and abandoned children of

cocaine mothers have placed a heavy burden on a number of the Nation’s hospitals. During a l-week period at one

hospital, 1 in 5 black infants and 1 in 10 white infants were born on cocaine. Taxpayers usually end up paying the

health-care bill—a bill that can exceed $100,000 per infant.

SOURCES: National Association for Perinatal Addiction Research and Education, News, Aug. 28, 1988; J.H. Khalsa, “Epidemiology of

Matemat Drug Abuse and Its Health Consequences: Recent Finding,’ National Institute on Drug Abuse, in preparation; CBS News,

“Cocaine Mothers: Suffer the Children,” West57th Street, July 15, 1989.

.-.

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Photo credit: Courtesy of Dr. Emmaiee S. Bandstra, M. D., Division of Neonato/ogy, University of MiamtiJ&son Memorial ikfedkal Canter
Chapter I-Summary, Policy Issues, and Options for Congressional Action 11

Table l-l-Federal Funding for Civilian

Neurotoxicity-Related Research

Agency Researcha ($ millions)

National Institutes of Healthb 

. . . . . .

Alcohol, Drug Abuse, and Mental

Health Administrationc . . . . . . . . . .

Environmental Protection Agency. . .

National Institute for Occupational

Safety and Health . . . . . . . . . . . . .

Food and Drug Administration . . . . .

Department of Energyd 

. . . . . . . . . . .

Department of Agriculture . . . . . . . . .

Total . . . . . . . . . . . . . . . . . . . . . . . .

32.6

26.6

3.9

0.7

1.8

0.5

0.4

66.5

aTotals are based primarily on fiscal year 1988 data.

bExcludes resewch related to nicotine and smoking.

GExcl@es research related to alcohol and a~oholism.

dEx~udes research related to radiation.

SOURCE: Office of Technology Assessment, 1990.

As indicated in table 1-1, total Federal funding

for civilian neurotoxicology -related research

(excluding research related to nicotine and

smoking, alcohol and alcoholism, and radiation)

is about $67 million. The bulk of this funding

(89 percent) is through ADAMHA and NIH and

tends to focus on the toxicity of drugs and the

biochemical mechanisms underlying neurological and psychiatric disorders. A number of other

Federal agencies and organizations provide

limited funding for research related to neurotoxicity as well. Given the threat that neurotoxic

substances pose to public health and the lack

of knowledge of the mechanisms by which

these substances exert adverse effects, OTA

found that, in general, Federal research

programs are not adequately addressing

neurotoxicity concerns.

Research related to environmental neurotoxicology is confined primarily to the intramural

program at EPA and the extramural program at

the National Institute of Environmental Health

Sciences (NIEHS) within NIH. The NIEHS

extramural grants program supports a substantial number of research projects in academia.

However, OTA found that, with the exception of

the neurobehavioral section of the Laboratory of

Molecular and Integrative Neuroscience within

NIEHS, NIEHS intramural research programs

are focused on the basic neuroscience rather

than on environmental neurotoxicology, resulting in a prominent intramural research gap at

NIH in the environmental neurotoxicology field.

Of the approximately $3 million NIEHS spent

on intramural research in the neuroscience in

fiscal year 1988, OTA found that only about

one-fourth was devoted to studies in which

neurotoxicology was the primary focus.

Academic research in neurotoxicology is

supported almost exclusively by NIH and

ADAMHA. Most extramural research funded

by NIH is through NIEHS and the National

Institute of Neurological Disorders and Stroke

(formerly the National Institute of Neurological

and Communicative Disorders and Stroke),

although several other Institutes have substantial programs. The extramural grants program at

NIEHS has been particularly effective in funding research grants in the neurotoxicity field.

ADAMHA funds grant programs through NIDA

and the National Institute of Mental Health.

EPA has a relatively large intramural

research program in neurotoxicology which

has been limited in recent years by lack of

funding for supplies and equipment. EPA

lacks an extramural grants program in neurotoxicology. The Agency has only a small

grants program that has rarely funded neurotoxicology-related projects. Traditionally, Federal

agencies have supported both intramural and

extramural efforts to ensure a balanced, comprehensive, and cost-effective program.

In recognition of the need to expand its

research programs in the neurotoxicology area,

EPA recently submitted to the Office of Management and Budget (OMB) a request to expand

its research budget by $1.5 million. Approximately $1.0 million was requested for the

development of in vitro neurotoxicology tests;

another $0.5 million was requested to examine

adverse effects associated with cholinesterase

inhibition and the utility of cholinesterase inhibition as a biomarker for exposure. However,

OMB allowed no funding for either research

effort. In vitro test development is often cited as

a high-priority research need because of the

requirement to rapidly screen toxic chemicals
12 ● Neurotoxicology: Identifying and controlling Poison of the Nervous System

and to try to minimize the use of animals in

research. A technical EPA panel recently recommended that the Agency initiate studies to

examine the relationship between cholinesterase

inhibition and other adverse effects on the

nervous system.

FDA funds a small number of research

projects related to neurotoxicology, primarily

through its intramural research programs. The

National Center for Toxicological Research is

conducting a number of intramural research

projects related primarily to developmental

neurotoxicology. The Center for Food Safety

and Applied Nutrition has a small in-house

program and is supporting three extramural

research projects.

Within CDC, NIOSH has small intramural

and extramural programs devoted to the identification and control of neurotoxic substances in

the workplace. CDC’s Center for Environmental Health and Injury Control conducts

epidemiological investigations of human exposure to environmental hazards, but few studies

focus on neurotoxic effects.

Industry supports neurotoxicology -related research through several mechanisms, including

in-house scientists, contract laboratories, consortia, contracts with universities, and grants to

universities. Toxicity evaluations conducted as

part of internal applied research are necessary to

develop safe and effective products, to protect

employees, to protect the environment, and to

control liability costs. Research programs vary

considerably depending on the types of products

manufactured and various economic considerations.

OTA found that education of research

scientists in the neurotoxicology field is

limited, in part, by inadequate Federal support for training programs. Part of the difficulty in obtaining funding is due to the nature of

neurotoxicology-the intersection of neuroscience

and toxicology. Few academic departments

devote significant resources to neurotoxicology,

and few Federal research organizations devote

major efforts to it. NIEHS supports training in

the neurotoxicology field; however, funding

limitations allow for support of only a relatively

small number of trainees.

Millions of American workers are exposed to

neurotoxic substances in the workplace, but

illness stemming from these exposures often

goes undetected and untreated. The subtlety of

neurotoxic responses is one reason for this

situation; for example, complaints of headache

and nervousness are often ascribed to other

causes. Another reason is the lack of adequately

trained health-care professionals to diagnose

and treat neurotoxic disorders. Medical schools,

in general, devote little of their curricula to

occupational health issues. After medical

school, physicians may undertake residency

training in occupational medicine, but in 1987

only about 1 in every 1,000 residents was

specializing in occupational medicine. Nurses

are also needed in the occupational health field

to provide emergency services, to monitor

employee health, and to provide counseling and

referral to physicians. In addition, industrial

hygienists are needed to evaluate and control

health hazards in the workplace.

Testing and Monitoring

Controlling toxic substances is a two-part

process. The first step is to identify existing

substances that adversely affect the nervous

system and take action to minimize human

exposure to them. The second step is to identify

new neurotoxic substances in use and either

prevent their manufacture (if they cause serious

neurotoxic effects) or limit human exposure to

them and release of them into the environment.

Very few new and existing chemicals have

been evaluated specifically for neurotoxicity.

The effects of toxic substances on the nervous

system may be evaluated through animal tests,

cell and tissue culture (in vitro) tests, and human

tests. Each approach has advantages as well as

limitations. The best way of predicting adverse

effects on human health is to test potentially

toxic substances directly on human subjects.

However, this approach is often difficult and in

many situations is unethical. Therefore, it is
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 13

usually necessary to rely on animal and in vitro

tests to predict effects on human health. In some

cases, in vitro tests can be used to detect

neurotoxic effects; at present, however, animal

testing is used to obtain a neurotoxicological

and behavioral evaluation. As more in vitro

testing techniques become available and are

validated, they may be used in the initial

screening process or to complement animal

tests.

Several industrial and Federal organizations

have developed animal tests to evaluate the

effects of known and potential neurotoxic substances. In industry, several testing methods are

currently used on a limited basis to assess the

neurotoxic potential of some toxic substances.

In the Federal arena, EPA recently developed

guidelines for a series of neurotoxicity tests to

supplement its general toxicological tests. Core

neurotoxicological tests used in initial screening

for toxicity include the functional observational

battery (a series of rapid neurological tests to

evaluate toxic effects on animals), tests of motor

activity, and neuropathological examinations.

Additional tests that may be used include

schedule-controlled operant behavior tests, acute

and subchronic delayed neurotoxicity tests for

organophosphorous substances, and developmental

examinations. Neurophysiological evaluations

are also useful in identifying neurotoxic substances and in evaluating their adverse effects.

Several human tests are in use to determine

the neurotoxic potential of suspected and known

toxic substances. These include neurobehavioral evaluations and various neurophysiological tests. In addition, computer monitoring

devices are rapidly advancing to aid in studies of

neurotoxicity.

Monitoring the release of toxic substances is

critical to regulatory programs. In 1986, Congress enacted the Federal Emergency Planning

and Community Right-to-Know Act, which

mandated that EPA develop a Toxics Release

Inventory of more than 300 toxic chemicals

released by industry into the environment. The

first data were published in 1989, and the

inventory will be updated annually. Such a

database will undoubtedly prove to be very

useful in monitoring releases of neurotoxic

substances. As indicated in figure 1-4, 17 of the

top 25 toxic substances released into the environment have neurotoxic potential.

Monitoring exposure to neurotoxic substances

is a critical component of public health and

environmental protection efforts. Monitoring

may be conducted by regularly surveying contaminants in the food supply, banking animal

specimens, and collecting biological data on

humans. Biological specimens can be used to

measure contamination levels over periods of

many years and to document adverse effects.

Human biological monitoring programs can be

undertaken to detect exposure to toxic substances and to aid in making decisions about

health risks. Such programs may be particularly

useful in monitoring exposures in the workplace.

Risk Assessment

Risk assessment is the analytical process by

which the nature and magnitude of risks are

identified. Risk, as it pertains to the health

effects of toxic substances, is the probability of

injury, disease, or death for individuals or

populations undertaking certain activities or

exposed to hazardous substances. It is sometimes expressed numerically (e.g., 1 in 1 million); however, quantification is not always

possible, and risk may sometimes be expressed

in qualitative terms such as high, medium, or

low risk. Risk management, a process guided by

risk assessment, and by political, social, ethical,

economic, and technological factors as well,

involves developing and evaluating possible

regulatory actions and choosing among them.

Some degree of risk is associated with almost

every aspect of modern living. For example,

traveling in an automobile involves a risk of

accidental death of 1 in 4,000, a relatively high

risk. In contrast, the risk of being killed by

lightning is 1 in 2 million. Whether a risk is

acceptable or not depends on many factors,

including benefits. Defining acceptable risk is

the task not only of scientists and regulatory
14 ● neurotoxici(-y: Identifying and Controlling Poisons of the Nervous System

Figure l-4-neurotoxic Substances Are Prominent Among the Toxics Release inventory’s Top 25

360

300

250

200

160

100

50

0

Chemicals Emitted Into the Air in 1987

Millions of pounds

Listed as a neurotoxIc substance by

_ Anger end Johnson ( 1985], or

su bje cl to TSCA Sect Ion 4 les I r u I e

tor neurotox IC subs lance s

n Not I I a ted a8 a neurotox Ic su bsla nc e

Dlm_l AM TO ME AC IT MK XY CD DI CH AO ET F R HA TR PR GE NA TE ST BE Ml CL CS SA

AM - Ammonl a MK - Mnthvl Fthv I KaInnc, F R - F reon 113 ST - SI yrene - ~ ., - r --- -

TO - Tol u e n e X V - Xy I e n e ( m I xe d I s o mer a ] H A - H yd-roc h I Or IC AC I d

CD - Car bon Dlsu I tid e

BE - Benzene

ME - Mel hanol T R - Tr Ich Ioroel hy Iene Ml - Met hyl Isobu t y I Ke tone

AC - Acetone

DI - Dlch Ioromethane P R - P ropy I ene CL - Ch Iorotor m

CH - Ch I or Ine G E - G I Ycol Ethers CS - Car bony I SU I fide

1 T - 1,1.1- Tr I - AO - Aluminum Oxide NA - N-Bu 1 y I Alcohol 5A - Sul fur IC Ac8d

ch Ioroethane ET - Ethylene T E - Te I r ach I o ro e t h y I e ne

SOURCES: Data obtained from W.K. Anger and B.L. Johnson, “Chemicals Affecting Behavior,” neurotoxicity of Industrial and Commercial Chemicals, vol.

1, J.L. O’Donoghue (cd.) (Boca Raton, FL: CRC Press, 1965), tables 1 and 2, pp. 70-141; TSCAsec. 4,52 FR 31445; TSCAsec. 4,53 FR 5932;

54 FR 13470; 54 FR 13473; U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, The Toxics Release Inventory:

A National Perspective, 1987, EPA 560/4-89-006 (Washington, DC: 1989).

officials, but of society in general. Everyone

evaluates risks on a daily basis and makes

individual choices depending on experience and

other factors.

Risk assessment practices are the subject of

ongoing debate within the regulatory and scientific communities, and in the last two decades

strategies to regulate toxic substances have

changed considerably. In the early 1970s, environmental legislation focused on regulating a

relatively small number of pollutants of known

toxicity. Today, concern is focused on thousands of toxic substances, for many of which

little information is available. This change has

been forced in part by improved methods of

detecting toxic substances in the environment,

improved capabilities for identifying the adverse effects of these substances, and the

difficulty of determining threshold levels below

which no adverse effects occur.

Policies regarding risk assessment have been

controversial. Some people believe that Federal

agencies overestimate risk by making overly

conservative assumptions in developing risk

assessments. Others feel that risk assessment

practices do not take into account the complex

interactions of multiple pollutants that often

occur in the environment. Still others point out

that risk assessments focus primarily on adverse

effects on human health and devote little attention to other organisms and the environment in

general. Critics of established risk assessment
—. — . . . . . .-

Chapter 1-Summary, Policy Issues, and Options for Congressional! Action ● 15

w.

I

Illustrated by: Ray Driver

procedures believe that too little attention is

being paid to the potential effects of toxic

substances on children, infants, and the unborn.

Regardless of the various viewpoints, risk

assessment has become an integral component

of regulatory strategies, and it is important to

appreciate the scientific issues underlying this

process in order to understand how toxic substances are controlled.

Concerns about carcinogenicity have dominated discussions about the risks posed by

toxic substances. However, the adverse effects on organs and organ systems, particularly the nervous system, may pose an equal

or greater threat to public health. Consequently, it is important to devise risk assessment strategies to address noncancer health

risks. An important difference between neurotoxicity and carcinogenicity is the extent to

which the effects are reversible. The endpoint of

carcinogenicity is considered to be irreversible

(although some argue that, strictly speaking, a

‘‘cure’ would render the effect reversible),

whereas the endpoints of neurotoxicity may be

either reversible or irreversible, depending on

the specific effect, the duration and frequency of

exposure, and the toxicity of the substance.

Reversibility requires the introduction of a new

variable into the risk assessment equation.

Since the nervous system is perhaps the most

complex organ system of the body, evaluating

the neurotoxic potential of environmental agents

is a particular challenge. For example, testing

for a toxic effect on one component of the

nervous system (e.g., hearing), may or may not

reveal a toxic effect on another component (e.g.,

vision). Furthermore, an effect on one nervous

system function is not necessarily predictive of

an effect on another nervous system function.

The results of toxicological analyses are

strongly influenced by the age of the organism

being examined. For example, mice exposed to

methylmercury during prenatal development

may not exhibit adverse effects until late in their

lives. With age, the functional capacity of the

brain declines significantly, and chronic exposure to some neurotoxic substances is thought to

accelerate this process. Hence, some scientists

and regulatory officials believe that risk analyses should consider adverse effects over a range

of ages and should take into account latent

effects.

Federal Regulatory Response

It is the task of regulatory agencies to limit

public exposure to toxic chemicals through

programs mandated by law. Because of the great

diversity of toxic substances, many statutes exist

to control their use. These laws are administered

by various Federal agencies, but primarily by
16 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table 1-2--Major Federal Laws Controlling

Toxic Substances

Agency primarily

Act responsible

Toxic Substances Control Act . . . . . . . . . . . . . . . . .

Federal Insecticide, Fungicide, and Rodenticide

Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Federal Food, Drug, and Cosmetic Act . . . . . . . . . .

Occupational Safety and Health Act . . . . . . . . . . . .

Comprehensive Environmental Response,

Compensation, and Liability Act . . . . . . . . . . . . .

Clean Air Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Federal Water Pollution Control Act and

Clean Water Act . . . . . . . . . . . . . . . . . . . . . . . . . .

Safe Drinking Water Act . . . . . . . . . . . . . . . . . . . . . .

Resource Conservation and Recovery Act . . . . . . .

Consumer Product Safety Act . . . . . . . . . . . . . . . . .

Federal Hazardous Substances Act . . . . . . . . . . . .

Controlled Substances Act . . . . . . . . . . . . . . . . . . . .

Federal Mine Safety and Health Act . . . . . . . . . . . .

Marine Protection, Research, and Sanctuaries

Act . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . . . .

Lead-Based Paint Poisoning Prevention Act . . . . .

Lead Contamination Control Act . . . . . . . . . . . . . . .

Poison Prevention Packaging Act . . . . . . . . . . . . . .

EPA

EPA

FDA

OSHA

EPA

EPA

EPA

EPA

EPA

CPSC

CPSC

FDA

MSHA

EPA

CPSC

HHS

CPSC

KEY: CPSC-Consumer Product Safety Commission; EPA-Environmental Protection Agency; FDA-Food and Drug Administration;

HHS--Department of Health and Human Services; MSHA—Mine

Safety and Health Administration; OSHA-Oocupational Safety and

Health Administration.

SOURCE: Office of Technology Assessment, 1990.

EPA, FDA, and the Occupational Safety and

Health Administration (OSHA) (table 1-2).

OTA found that very few substances have been

regulated as a result of neurotoxicity concerns.

New and existing industrial chemicals are

regulated by the Toxic Substances Control Act

(TSCA). Pesticides are controlled by the Federal

Insecticide, Fungicide, and Rodenticide Act

(FIFRA), and toxic substances in the workplace

are regulated by the Occupational Safety and

Health Act (OSH Act). The Federal Food, Drug,

and Cosmetic Act (FFDCA) regulates food and

food additives, drugs, and cosmetics. These

laws address the vast majority of toxic substances, and more than a dozen other acts focus

on other substances and sources of exposure.

Although neurotoxicity is generally not explicitly mentioned in legislation mandating the

regulation of toxic substances, it is implicitly

included as a toxicity concern.

Under the authority of this diverse framework

of legislation, regulatory agencies have promulgated equally diverse regulations for protecting

human health. Some regulatory programs require substantial testing of chemicals to screen

for toxic effects; others are not empowered to

require any such testing. Some regulations call

for screening substances before they are allowed

to enter the marketplace; other regulations are

reactive, coming into effect only when evidence

indicates that an existing chemical can or does

cause harmful effects.

Federal laws governing toxic effects can be

divided into three general categories:

1.

2.

3.

licensing and registration laws for new

and existing chemicals, which entail explicit review processes and may include

requirements for toxicity testing;

standard-setting laws for chemicals used

in specific situations, under which regulatory agencies determine recommended or

required limits on toxic substances in

various environmental media (air, water,

or soil) or emitted by a given source, or

dictate appropriate labeling of products

that contain toxic substances; and

control-oriented measures for dealing

with chemicals, groups of chemicals, or

chemical processes that are explicitly identified in the laws as targets of concern.

Distinctions among the three categories are not

absolute—there is more of a continuum than a

discrete grouping in the legislative language—

but this classification indicates the basic types of

approaches that have been developed to protect

the public and the environment from the adverse

effects of toxic substances.

Consistency of the Federal Regulatory Effort

There are numerous differences in regulatory

practice under different laws, even within the

group of Incensing laws (TSCA, FIFRA, FFDCA).

These differences do not, for the most part,

apply specifically y to the regulation of neurotoxic

effects, but rather to regulation of all toxic

effects. Thus, consistency of regulation for

specific neurotoxic effects hinges on consistency of regulation in a more general sense.
Chapter 1-Summary, Policy issues, and Options for Congressional Action ● 17

Statutory requirements for chemical regulatory programs differ in several important respects, among them the number of chemicals

evaluated, the time available for review, the

amount and type of data available at the

beginning of the review process, the ability of

the reviewer to acquire additional data after

review has begun, and the burden of proof

regarding safety. For example, the Premanufacture Notice (PMN) process under TSCA necessitates review of hundreds of chemicals every

year; each review is allotted only 90 days

(although an extension is possible), and substantive toxicity data are rarely submitted. EPA can

obtain additional data or impose controls on

chemicals only if it finds that there may be an

unreasonable risk associated with use of the

chemical. Without significant toxicity data,

predicting risk is difficult and must rely on

hypothetical relations between chemical structure and biological activity. However, little is

known about structure-activity relationships

with respect to neurotoxicity. Applicants for

registration of a pesticide under FIFRA must

submit extensive general toxicological data

according to specified test protocols, the review

process extends over a period of years, the

applicant is required to submit additional data if

the basic data raise concerns, and the applicant

must establish that the pesticide will be both safe

and effective under the proposed conditions of

use. Few data relating to neurotoxicity concerns

are presently required. However, the agency is

considering expanded testing requirements.

That there are differences in the degree of

regulatory scrutiny under the various Federal

regulatory programs is widely acknowledged.

Often, these disparate regulatory requirements

reflect real differences in the potential risks

represented by the chemicals each program

regulates. It may be that the more intense

scrutiny reserved for some types of chemicals is

an appropriate reflection of the likelihood that

they will threaten human health or the environment.

Current laws are generally based on the

premise that chemicals for which there is a

greater probability of exposure should meet a

higher standard of safety. This is most clearly

illustrated by the prohibition of carcinogenic

substances as direct food additives and of

pesticides that concentrate in foods (the Delaney

clause of FFDCA). No such general prohibition

applies to general industrial or commercial

chemicals under TSCA or the OSH Act.

The stringency of the evaluation process for

new chemicals under the various laws generally

matches the presumption of risk—the combination of hazard and exposure potential-posed by

each class (in the view of regulatory officials)

and the number of new class members introduced each year. Thus, drugs are not to be

permitted on the market until proven safe and

effective in clinical trials. New pesticides and

food additives are evaluated nearly as stringently; however, human trials are not performed. Commercial chemicals, whether intended for industrial or consumer use, receive

the least scrutiny.

There are two exceptions to these trends, one

minor and one significant. Consumer chemicals

have not received any procedurally different

scrutiny than those intended for industrial use,

despite the fact that larger numbers of persons

may be exposed as consumers than as industrial

workers. Moreover, FFDCA does not require

that cosmetics and cosmetic ingredients undergo

premarket toxicity testing. Industry voluntarily

tests cosmetic ingredients for acute toxic effects,

but few are examined for chronic toxicity. Some

have been found to have acute and chronic

neurotoxic effects on laboratory animals.

While many scientists find some comfort in

the observation that the stringency of review of

a chemical matches its presumptive risk (except

for cosmetics), public interest groups have

voiced concerns over such odds playing. For

example, the chemicals regulated under TSCA

make up the largest classes of chemicals, yet

they receive relatively little scrutiny by EPA.

TSCA does offer options for selecting high-risk

chemicals for further scrutiny, but the vast

majority of chemicals receive only a limited
18 ● Neurotoxcity: Identifying and Controlling Poisons of the Nervous System

review. Critics of EPA argue that regulatory

resource considerations and a desire not to

burden industry, rather than presumptive

risk, are in fact driving chemical review

criteria. They raise the question of whether

the minimal screening given to the majority

of chemicals is adequate to deal with highrisk chemicals that are not members of

known risk categories.

Regulation of New v. Existing Chemicals

Existing chemicals are subject to varying

degrees of review and reevaluation. In contrast

to procedures for reviewing new chemicals,

however, procedures for reexamining existing

chemicals do not necessarily reflect the inherent

risks of the chemical classes involved.

EPA attempts to ensure the adequacy of the

data supporting continued pesticide registration

through a regular review process. The registration standards program, which examines 25

chemicals per year, has thus far addressed only

a small portion of the active ingredients of

registered pesticides and has been the subject of

considerable concern. At the present rate, active

pesticide ingredients would be reviewed on an

average of only once every 12 years or more.

The 1988 FIFRA amendments mandated that

the review schedule be accelerated so that all

active ingredients are reviewed by 1997. To

meet this goal, EPA will need to streamline its

existing review process.

Under section 4 of TSCA, existing chemicals

are ranked for probable risk or high exposures

prior to entering the test rule or consent order

regulatory process. In the period from 1977 to

1988, final rules were issued on only 25

chemicals or related sets of chemicals, consent agreements were reached on three, with

nine proposed rules pending. Clearly, these

rules address only a very small fraction of the

60,000 chemicals in the TSCA inventory.

FDA’s various procedures for reviewing

existing drugs and food and color additives are

less formal than those for pesticides or toxic

substances. FDA tracks physicians’ reports of

adverse drug reactions and reports them to the

original evaluators of the drugs. Food and color

additives have been notable exceptions to the

review of existing chemicals. Until recently,

once an additive was registered, there was no

monitoring of adverse reactions. For aspartame,

FDA established voluntary reporting programs,

but most food additives are not the subject of

formal reporting programs. Although FDA does

not require reporting on the use of approved

food and color additives, it could track such

information and use it to assess the risks

associated with approved uses.

Specific neurotoxicological Considerations

Regulatory differences in general strategies

for evaluating toxicity entail corresponding

differences in the evaluation of neurotoxi c

effects. Thus for human drugs, preclinica l

toxicity tests are only used to guide observations

on clinical trials and to elucidate possible

mechanisms of toxicity, rather than to directly

assess toxic potential. For pesticides and food

and color additives, in contrast, animal toxicity

data are used directly in predicting human risk.

However, even within programs that hav e

essentially similar approaches to assessing toxic

risks, there are differences with respect to

consideration of neurotoxic risks.

Regulatory programs have adopted one of

three basic approaches to toxicity evaluation,

depending on which of three underlying assumptions they hold. One approach is based on

the assumption that general toxicity tests using

high doses are adequate to detect neurotoxic

potential and that neurotoxicological evaluations are needed only if general tests, data on

structural analogues, or other specific knowledge about a chemical indicate a potential for

neurotoxicity. Among these are FDA’s preclinical testing program for drugs and its current

program for approving food additives. Th e

second approach, represented by the pesticide

registration program under FIFRA, accepts

more general structural information in guiding

neurotoxicity testing. All organophosphorous

compounds are evaluated for the potential to
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 19

induce delayed neuropathy, but nonorganophosphorous compounds are not specifically

evaluated for neurotoxic potential. All pesticides undergo a general toxicity screen; however, specific neurotoxicity tests are not presently required. Finally, under section 4 of

TSCA, specific neurotoxicity testing is required

for any chemical with high exposure potential,

as well as for chemicals specifically suspected

of being neurotoxic. Such testing presumes that

standard toxicity tests are not adequate to

evaluate neurotoxic effects.

OTA found that Federal efforts to control

neurotoxic substances varied considerably between agencies and between programs within

agencies. Improving the Federal response will

require increased neurotoxicity testing, improved monitoring programs, and more aggressive regulatory efforts.

Federal Interagency Coordination

Interviews with toxicologists and neurotoxicologists in various Federal agencies indicated that

there is little formal coordination among agencies, although neurotoxicologists at different

agencies maintain regular informal contacts.

There are also several coordinated research

efforts mediated by interagency agreements and

by personal contact In the spring of 1989, .

OTA and EPA cosponsored a workshop on

Federal interagency coordination at which

Agency representatives decided to establish

an Interagency Working Group on Neurotoxicology to foster increased interaction

among Federal agencies responsible for research and regulatory programs.

neurotoxicologists at different agencies maintain regular informal contact, but this contact

has not fostered a consensus on the best

approach to regulating neurotoxic hazards. Real

differences of scientific opinion remain, and

data that would resolve these differences have

not been developed by the agencies involved.

Restrictions on revealing confidential business

information hinder the transfer of potentially

useful toxicological information, both to the

public and between Federal agencies. Moreover,

even within agencies, neurotoxicologists and

other toxicologists sometimes disagree on the

proper role of neurotoxicity in safety evaluations.

An agency’s approach to neurotoxicity evaluation often corresponds to the presence o r

absence of neurotoxicologists on the staff.

Although this presumably reflects personnel

considerations—if an agency is not evaluating

neurotoxicological data, it does not require

people trained to do so-it does raise th e

question of whether persons who evaluat e

general toxicological data understand the contributions of directed testing to the prediction of

neurotoxic effects. General toxicologists are

essential to the review process; however, individuals with specialized expertise are often

necessary to ensure a comprehensive evaluation. Variations in the hiring of neurotoxicologists by Federal agencies reflect a more general

problem of toxicological assessment, that of

determining the appropriate degree of spe -

cialization required to evaluate the many organ

systems potentially affected by a toxic substance. OTA found that effectiveness in addressing neurotoxicological concerns at Federal agencies is dependent on the presence of

neurotoxicologists in regulatory program offices. Improving Federal programs will require increased employment of neurotoxicologists trained in risk assessment and regulatory procedures.

The Federal regulatory response to neurotoxicity is fragmented not only by differences in

scientific judgment, but also by differences in

regulatory responsibility. The decision to evaluate drugs, pesticides, and food additives by

stricter standards than are applied to commercial

chemicals is based not only on the views of

scientists, but also on national consensus. Thus,

the perception of risk by the public can strongly

influence regulatory policies related to toxic

substances.

Economic Considerations in Regulation

Regulating neurotoxic substances involves

consideration of both the economic benefits of
20 Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

using these substances and their actual or

potential costs. The problem of balancing benefits, costs, and risks of regulation is not unique

to the control of neurotoxic substances; it arises

in all forms of health, safety, and environmental

regulation. Regulations that are designed to

reduce or prevent neurotoxic risks can benefit

society through improvements in public health

and environmental amenities. In most cases,

however, society incurs costs to achieve these

regulatory ends. The costs of complying with

health and safety regulations may also result in

increases in market prices, reductions in industry profits, and declines in new product innovation.

Many of the key Federal laws under which

neurotoxic substances are regulated require

agencies to ascertain the positive and negative

economic consequences of regulation. In implementing these laws, Congress has generally

intended that agencies prepare regulatory analyses and document the balancing of benefits,

costs, and risks of proposed alternatives.

The Costs and Benefits of neurotoxicity Testing

Experience with neurotoxicity testing is still

relatively limited, creating uncertainty regarding the available cost estimates for this type of

testing. Because of the uncertainty regarding

these costs, OTA obtained estimates of the costs

of several types of neurotoxicity tests from a

number of individuals in government, industry,

and academia.

The median estimates derived from OTA’s

survey indicate that a complete set of neurotoxicity tests, including a functional observational

battery, motor activity, and neuropathology,

may add from 40 to 240 percent to the costs of

conventional toxicity tests currently required by

EPA. By far the largest portion of the added cost

comes from the neuropathology evaluations,

which are needed to determine whether structural change in the nervous system has occurred

and the nature and significance of the change.

Based on its survey, OTA found that acute

neurotoxicity tests (including EPA’s functional

observational battery, motor activity test, and

neuropathology evaluations) may add a total of

about $50,000 to standard toxicity test costs.

Subchronic neurotoxicitytests may add $80,000,

and chronic tests may add about $113,000. The

EPA subchronic schedule-controlled operant

behavior test may add about $64,000. However,

the functional observational battery alone would

add only $2,500 to the cost of a conventional

acute toxicity test. A conventional acute test of

oral exposure presently costs about $21,000.

Testing costs should be viewed in the context

of the health benefits of minimizing public

exposure to neurotoxic substances, the total cost

to industry of marketing a new product, potential profits resulting from the sale of the product,

and the impact high initial costs have on the

innovation process.

The benefits of regulating neurotoxic substances can be measured in terms of the human

and monetary values placed on reduction of risk.

A number of approaches have been used to

assign monetary values to reduction of the risks

of mortality, morbidity, and disability. Lead has

been the subject of an in-depth economic

analysis. A 1985 study estimated that the total

health benefits of reducing the neurotoxic

effects of lead on U.S. children would amount

to more than $500 million annually between

1986 and 1988. If adult exposure to lead,

including workers’ exposure, were included,

the benefits would be considerably larger.

Although the health and economic benefits of

limiting public exposure to neurotoxic substances are more difficult to estimate than the

costs of regulation, the example of lead

illustrates the importance of considering the

potentially large monetary benefits of regulatory actions. Like other toxicity testing, neurotoxicity testing is conducted to prevent adverse

health effects; hence, the benefits of such testing

may not be readily apparent and may accrue well

into the future. Often, the immediate costs of

testing receive considerable attention by regulatory officials, but the sizable potential economic

benefits of preventing public exposure to a

hazardous substance receive comparatively little attention.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 21

As indicated earlier, neurotoxic substances, in

particular abused drugs, play a significant,

causal role in the development of neurological

and psychiatric disorders; however, the precise

extent of the contribution remains unclear.

Mental disorders and diseases of the nervous

system contribute substantially to health

costs in the United States. In 1980, they

ranked as the third and fifth most expensive

medical conditions in terms of personal

health-care expenditures. The estimate of

nearly $40 billion (1980 dollars) for these two

categories of morbidity does not include values

for lost productivity, restricted activity, and

other social costs (e.g., criminal activity, law

enforcement, and rehabilitation for drug and

alcohol abuse) that frequently accompany mental illness or other forms of mental impairment.

International Issues

Like most environmental concerns, neurotoxicity is a problem that is not limited by national

boundaries. Pollutants readily cross national

borders, hazardous chemicals are frequently

imported and exported between industrialized

and developing nations, and adulterated food

and commercial products enter the United States

despite current regulatory efforts. Strategies to

limit human exposure to neurotoxic substances

should be devised in the context of both national

and international regulatory and research initiatives.

International Regulatory Activities

Despite numerous regulations governing the

export and import of neurotoxic chemicals and

products containing them, some countries do not

have the regulatory framework and resources to

adequately protect human health and the environment from these substances. Many nations,

including the United States, have policies and

procedures in place, but too often they work

only on paper. In practice, they may allow

neurotoxic substances to slip through the regulatory cracks. Some developing nations have

regulations to protect workers and consumers

from the adverse effects of neurotoxic substances, but these nations often lack the resources to enforce them. This lack of effective

regulation and enforcement in developing nations has a negative impact not only on public

health and environment in the user country, but

also in industrialized nations, including the

United States, where people process and consume products imported from developing nations.

Both TSCA and FIFRA contain provisions

exempting certain U.S. products produced for

export from the requirements that apply to

products sold for use in the United States. In

most instances, the requirements of TSCA do

not apply to substances manufactured, processed, or distributed for export. The requirements will, however, apply if it is determined

that the mixture or article will present an

unreasonable risk of injury to health within the

United States or to the environment of the

United States. In addition, because pesticides

intended solely for export are exempt from the

public health protection provisions of FIFRA,

pesticide manufacturers can legally export

banned, severely restricted, or never-registered

substances that have been deemed too hazardous

for use in this country. Companies that do so are

required to notify the importing country that the

pesticides in question have been banned, severely restricted, or never registered for use in

the United States. Sometimes such pesticides

are used on food crops that are imported back

into the United States for consumption. Critics

of this practice have termed it the ‘‘circle of

poison. ’

On January 15, 1981, several days before the

end of his term, President Jimmy Carter issued

an Executive Order that set controls on exports

of substances that were banned or severely

restricted in the United States. Several days after

becoming President, Ronald Reagan revoked

this order.

International Research Activities

Active interest in neurotoxicity began in the

United Kingdom during and after World War II.

Since that time, research efforts in the United

States have gradually increased. The United
22 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

States is now the world leader in environmental

legislation and government funding of neurotoxicology research.

International research activities tend to focus

on the heavy metals (lead and mercury), organic

solvents, and pharmaceutical agents. Scandinavian countries have been active in research on

the neurotoxicity of organic solvents. Other

European countries have supported research on

compounds of particular concern in occupational settings, such as pesticides and heavy

metals. Foreign neurotoxicology -related scientific papers published in international journals

most often originate from authors in Canada,

England, Italy, Australia, and Japan. A number

of papers originate from authors in France,

India, Sweden, Finland, and Mexico, as well.

neurotoxicology research has been primarily

an intranational effort. In recent years, some

international cooperation has been initiated by

the World Health Organization and the U.S.

National Toxicology Program, but thus far

cooperation has occurred only in specific areas

such as lead toxicity, solvent toxicity, and the

development of testing methodologies. The

limited scope of international cooperation is

largely due to the lack of funds available for

such efforts.

In some European countries, notably the

Federal Republic of German and Sweden,

environmental movements are becoming increasingly influential. It is likely that these

nations will play leading roles in supporting

research and in developing regulations to control toxic substances. The Federal Republic of

Germany has already acted to remove lead from

gasoline and to fund studies of lead toxicity in

children. All of the Scandinavian countries

(Sweden, Denmark, Norway, and Finland) have

traditionally supported research on solvents.

These patterns are likely to continue and may

broaden to include the investigation of other

toxic substances as environmental movements

grow. Political events in the Soviet Union have

led to the emergence of an environmental

movement, and it appears that the Soviet

government will also take a more active role in

these issues. Finally, in the Far East, both the

People’s Republic of China and Japan are facing

major pollution problems and are becoming

increasingly involved in toxicological issues.

POLICY ISSUES AND OPTIONS FOR

CONGRESSIONAL ACTION

Six broad policy issues related to the identification and regulation of neurotoxic substances

were identified during the course of this assessment:

1.

2.

3.

4.

5.

6.

adequacy of the Federal regulatory framework,

adequacy of Federal and federally sponsored research programs,

coordination of Federal regulatory and

research programs,

availability of adequately trained research

and health-care professionals,

communication of information to workers

and the public, and

adequacy of international regulatory and

research programs.

Associated with each policy issue are several

options for congressional action, ranging in each

case from taking no action to making substantial

changes. Some of the options involve direct

legislative action. Others involve the executive

branch, but with congressional oversight or

direction. The order in which the options are

presented does not imply any priority. Moreover, the options are not, for the most part,

mutually exclusive; adopting one does not

necessarily disqualify others within the same

category or in any other category. A careful

combination of options might produce the most

desirable effects. It is also important to keep in

mind that changes in one area may have

repercussions in other areas.

ISSUE 1: Is the current Federal regulatory

framework addressing neurotoxicity adequately?

The Federal regulatory framework has been

built on the foundation established by four
Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 23

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Illustrated by: Ray Driver

major Acts: 1) Toxic Substances Control Act; 2)

Federal Insecticide, Fungicide, and Rodenticide

Act; 3) the Federal Food, Drug, and Cosmetic

Act; and 4) Occupational Safety and Health Act.

At least a dozen other acts address general

toxicological concerns. Many of them explicitly

or implicitly mandate regulation of neurotoxic

substances. Options related to this issue are

organized around the Federal agency with lead

responsibility for implementing a particular law.

Environmental Protection Agency

EPA is responsible for implementing two of

the major acts, TSCA and FIFRA, and several

others pertaining to neurotoxic substances, including the Clean Air Act; the Federal Water

Pollution Control Act and Clean Water Act; the

Safe Drinking Water Act; the Comprehensive

Environmental Response, Compensation, and

Liability Act; the Marine Protection, Research,

and Sanctuaries Act; and the Resource Conservation and Recovery Act.

Option 1: Take no action.

If no congressional action is taken, EPA will

continue to be responsible for carrying out the

provisions of the existing statutes, which implicitly address neurotoxicity in the context of

general toxicological concerns. The degree to

which neurotoxic substances are regulated will

vary according to program priorities, resources,

the expertise of Agency personnel, and interpretation of pertinent laws by Agency officials. To

date, few toxic substances have been regulated

on the basis of known or suspected adverse

effects on the nervous system. Even in the

absence of congressional action, this situation is

likely to change, given greater public and

Agency awareness of neurotoxicological concerns and the institution of new neurotoxicity

testing guidelines under TSCA and FIFRA. For

example, EPA is actively considering requiring

functional observational battery, motor activity,

and neuropathological tests for all new pesticides and for all existing pesticides undergoing

reregistration.

Option 2: Mandate more extensive neurotoxicity

“ testing under TSCA and FIFRA.

neurotoxicity test guidelines developed by

EPA to support regulatory programs mandated

by TSCA and FIFRA will allow the Agency to

require neurotoxicity testing of a wide range of

industrial chemicals and pesticides. The extent

and frequency of testing EPA may require is not

clear at this time.

If it wishes to mandate additional neurotoxicity testing, Congress could require EPA to test

new and existing chemicals if certain production

volume and human exposure levels are reached

and if structure-activity relationships or other
24 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

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Illustrated by: Ray Driver

information suggests that the substance may be

neurotoxic. Volume and exposure levels can be

effective triggers for testing. Production volume

is currently being used as a trigger by the Federal

Republic of Germany, and this testing approach

has been considered by EPA in the past.

However, triggered testing does have important

limitations-some substances may have potent

neurotoxic effects at low doses. Congress may

also wish to request that EPA consider novel

approaches to obtaining more extensive data

from industry under TSCA, perhaps through the

use of economic incentives. EPA could work

with industry representatives to devise incentives for voluntary neurotoxicity testing. EPA

could also work more closely with scientists in

industry and academia to develop and validate

neurotoxicity tests.

Congress could amend FIFRA, mandating

that new and existing pesticides being considered for registration undergo neurotoxicity testing under the newer, more extensive guidelines.

This would formalize EPA’s pending policy and

would underscore congressional concern regarding the potential adverse effects of neurotoxic pesticides on public health. Currently,

EPA plans to require the use of three neurotoxicity tests: the functional observational battery,

motor activity, and neuropathological evaluations. Congress could also mandate that certain

classes of inert ingredients undergo neurotoxicity evaluations as well. Congress may wish to

request that EPA consider developmental neurotoxicological and behavioral tests in addition to the

three core neurotoxicity tests for certain pesticides. Such tests are considered by some scientists to be particularly important in evaluating

the effects of neurotoxic substances on children.

Congress could also mandate that risk assessments devote increased attention to the potential

adverse effects of pesticides on children.

Option 3: Require that EPA and other Federal

agencies revise the confidential business

information provisions of various toxic substances control laws and regulations to allow

greater access to toxicological information.

Under TSCA, for example, much of the

information submitted to EPA by chemical

manufacturers or processors can be claimed to

be confidential business information. Information covered by such a claim cannot be divulged

to anyone outside the small group of EPA

employees who have been granted a special

clearance, primarily selected EPA staff and

contractors. The aim of confidentiality provisions is to prevent commercially valuable infor-
Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 25

mation from being disclosed to the submitter’s

competitors. Other environmental statutes contain similar provisions regarding confidential or

trade secret information.

Toxicity data per se cannot be claimed as

confidential under TSCA, but much of the other

information relevant to assessing toxic risks

can—including the identity of the chemical for

which toxicity data are presented, its physicalchemical properties, and its intended uses. This

renders the health and safety data of little use to

anyone without a special clearance.

The strong confidentiality provisions in TSCA

can present significant barriers to efficient

regulation. The requirement for a special clearance prevents the use of confidential data by

anyone without a clearance, even if they are

EPA officials or officials of other Federal

agencies who are attempting to regulate the

same chemical or closely related chemicals

under different laws. The limited exchange of

information can lead to duplication of effort,

particularly when several agencies are constrained by confidentiality provisions.

The inability to share information, either

inside the government or with outside parties,

often interferes with research efforts. For example, much of the information on a chemical’s

structure-activity relationship is covered by

claims that it is confidential business information. Scientists in industry, academia, and other

government agencies cannot gain access to this

information, even when it might contain valuable data for developing improved methods of

predicting neurotoxicity and other toxic effects.

At the same time, claims of confidentiality may

prevent EPA from obtaining expert advice or

consensus opinions from academic or industrial

scientists.

Public interest groups and other interested

individuals do not have access to information

that would allow them to question-or to

accept—EPA’s actions on many toxic substances. Nor can individuals take action to

protect themselves if they do not have access to

information regarding the identity of toxic

chemicals or the products that might contain

them.

Few persons would dispute the need for some

form of protection for trade secrets. However,

many persons believe that there is good reason

to question whether the burden imposed by

strong confidentiality provisions and similar

statutes on the government, the public, and

industry is justifiable.

Congress could disallow certain kinds of

information, including the precise chemical

identification of a substance and all toxicological data on a substance, from claims of confidentiality. It could mandate that more information

about the chemical properties, potential adverse

effects, and production and release of toxic

substances be made available to the public. It

could amend existing laws or write new laws to

enable sharing of information between Federal

regulatory programs. Congress could also create

a centralized confidential database, administered by one designated agency, or a consortium of agencies, and divert all reporting to the

designated agency. In addition, it could require

more extensive labeling of the contents of

chemical products.

Option 4: Take action to provide agricultural

workers with greater protection from the

adverse effects of pesticides.

Congress could amend FIFRA, giving EPA

greater regulatory authority to protect farmworkers and others from the adverse effects of

pesticides (see box l-E).

Option 5: Mandate that neurotoxicity concerns

be addressed in regulatory activities under

various other laws for which EPA has regulatory responsibilities.

Congress could mandate that neurotoxicity

receive greater attention under any or all of the

following laws: the Clean Air Act; the Clean

Water Act; the Safe Drinking Water Act; the

Comprehensive Environmental Response, Compensation, and Liability Act; and the Resource

Conservation and Recovery Act. Each law

addresses toxicological concerns in a different
26 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box l-E—neurotoxic Pesticides

Organophosphorous and carbamate insecticides

are the most neurotoxic classes of pesticides used in

the United States and are the most common causes of

agricultural poisoning. They pose a significant threat

to a substantial portion of the 4 to 5 million Americans

who work in agriculture. At the biochemical level, they

may affect humans in the same manner that they affect

the insects for which they are intended-through

inhibition of the enzyme that breaks down the neurotransmitter acetylcholine. The acute health effects of

organophosphorous and carbamate insecticides include hyperactivity, neuromuscular paralysis, visual

problems, breathing difficulty, restlessness, weakness,

dizziness, and possibly convulsions. The organochlorine class of pesticides is also very toxic because

these substances accumulate in the body and cause

persistent overstimulation of the central nervous system. Acute or subacute intoxication from organochlorines produces excitability, apprehension, dizzine

weakness, muscle twitching, tremors, convulsions, and

Photo credit.’ Doug/as Watts/Christopher Brady

ss, headache, disorientation, confusion, loss of balance,

coma.

What scientific and epidemiological data there are suggest pesticide poisoning prevails despite existing

protective measures. The Environmental Protection Agency (EPA) is aware of the shortcomings of the protections

currently in effect for farmworkers and others who work with pesticides. The Agency has proposed regulations to

improve them, but critics have already deemed the proposals inadequate. EPA claims to be restricted by the Federal

Insecticide, Fungicide, and Rodenticide Act, which grants the Agency only limited regulatory power. Inadequate

funding has also contributed substantially to the weaknesses of Agency programs.

The possible occurrence of neurobehavioral disorders after chronic low-level exposure or acute poisoning

deserves further study. Neuropsychological assessments of occupational groups have yielded inconsistent results,

perhaps reflecting differences in the type and scope of tests used. Few studies have had an adequate follow-up to

assess the length of impairment. Field studies have not provided sufficient data on levels of pesticides in children’s

blood or duration of exposure to understand dose-response relationships, nor have most studies controlled for age,

education, or other potential confounding factors. Few or no studies have examined exposed workers prospectively,

subgroups of women or aging workers, interactions between pesticides, or interactions between pesticides and

pharmacological agents (including ethanol and common medications).

SOURCE: Office of Technology Assessment, 1990.

reamer. Congress could take action as these levels of pesticide residues in foods. Potential

laws are amended, as funds are appropriated,

and/or through various oversight activities.

Such action might include making specific

reference to neurotoxic substances or the adverse effects of chemicals on the nervous

system, or both, in legislation addressing toxic

substances and requiring that neurotoxic potential be considered when conducting risk assessments. With respect to FIFRA specifically,

Congress could mandate that neurotoxic potential be carefully considered in setting tolerance

adverse effects of pesticides on the developing

nervous system could be cited as a particular

concern.

Congress could also request that EPA review

the effectiveness of agency programs in regulating neurotoxic substances and examine approaches to improve existing activities.

Food and Drug Administration

The Federal Food, Drug, and Cosmetic Act

covers a wide range of substances. It authorizes
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 27

FDA to require submission of specific toxicity

test data before permitting food additives, drugs,

and other substances to be marketed. This

authority could be used to incorporate neurotoxicity evaluations in FDA test guidelines or to

require neurotoxicity testing during the application process if initial toxicological data indicate

potential neurotoxic effects. FDA does not have

authority to require premarket toxicity testing of

cosmetic ingredients.

Option 1: Take no action.

If Congress chooses to take no action, FDA is

likely to continue to address the potential

neurotoxicity of food additives, drugs, and other

substances in the context of general toxicological concerns. FDA does not routinely require

specific neurotoxicity testing for food additives

and drugs; instead, it evaluates the potential for

neurotoxic effects in the context of a broad

toxicological profile. Some scientists, including

most FDA officials, believe that specific neurotoxicity testing of drugs and food additives is not

necessary and that existing general toxicological

testing approaches adequately detect adverse

effects on the nervous system. Other scientists

believe that existing general toxicological approaches are not sensitive enough to detect

many neurotoxic effects and that specific neurotoxicity tests are essential for a complete toxicological evaluation.

Option 2: Commission an independent study by

the National Academy of Sciences to determine whether specific neurotoxicity tests

should be routinely required by FDA in

evaluating the safety of drugs, food additives,

and other substances regulated under FFDCA.

This option would address the issue of the

adequacy of existing testing approaches. Such a

study could include a retrospective analysis to

determine whether conventional toxicological

tests have failed to detect neurotoxic effects. It

could also include a symposium at which

scientists from academia, industry, government,

and elsewhere could present varying views on

this subject and attempt to reach a consensus on

the proper course of action.

Option 3: Mandate more extensive neurotoxicity

testing under FFDCA for drugs, food additives, and other substances.

Congress could mandate that FDA revise its

‘‘Toxicological Principles for the Safety Assessment of Direct Food Additives and Color

Additives Used in Food,” commonly referred to

as the ‘Red Book, ’ to require routine neurotoxicological screening of new food additives and

to formulate improved processes for postmarked

surveillance of new and existing additives.

Congress could also require that some generally

regarded as safe (GRAS) compounds undergo

neurotoxicity testing. It could require that new

drugs, particularly psychoactive drugs, undergo

increased neurotoxicity testing through the use

of specific neurotoxicological tests. In particular, Congress could mandate that FDA require

complete neurotoxicity testing of psychoactive

drugs that may be prescribed to children and

pregnant women. Choosing this option would

involve agreeing with scientists who believe that

present toxicological testing practices at FDA

do not adequately address potential adverse

effects on the nervous system and that specific

neurotoxicological tests are necessary to establish the safety of food additives and drugs.

Option 4: Amend FFDCA to require premarket

toxicity testing of cosmetics and cosmetic

ingredients.

FDA does not have the statutory authority to

require premarket toxicity testing of cosmetics

and cosmetic ingredients. Industry voluntarily

conducts general testing of many products. If

FDA finds that a cosmetic product has not been

adequately tested, it can require that it be

packaged with a warning label stating that ‘the

safety of this product has not been determined. ’

In addition, FDA can take regulatory action

against any poisonous or deleterious substance

in cosmetics. Congress could amend FFDCA to

require that cosmetics and cosmetic ingredients

undergo premarket toxicity tests consistent with

those required of drugs. Testing requirements

could include a screen for neurotoxicological

effects. A general toxicological evaluation, at
28 ● neurotoxic@: Identifying and Controlling Poisons of the Nervous System

least, would ensure a degree of safety comparable to that of other products regulated under

FFDCA.

Option 5: Mandate more extensive postmarked

surveillance and monitoring of the adverse

effects of drugs, food additives, cosmetics,

and other substances and require that such

information be made more readily available

to the public.

Congress could mandate that FDA substantially expand postmarked surveillance and monitoring of the adverse effects, particularly neurotoxic effects, of drugs, food additives, cosmetics, and other substances. Congress could mandate that health-care professionals report adverse effects directly to FDA. Congress could

mandate that surveillance and monitoring data

be made more readily available to the public. It

could also mandate expanded patient packaging

information in drug products. Additional information could be provided to patients on potential adverse neurotoxic effects of drugs, particularly at higher than recommended doses, and on

adverse effects that should be reported to a

health-care professional (box l-F).

Occupational Safety and Health Administration

OSHA is authorized under the OSH Act to

regulate toxic substances in the workplace in

order to ensure that no employee suffers material impairment of health or functional capacity.

Recently, OSHA promulgated a far-reaching

revision and update of existing standards. The

new standards affect 428 chemicals, lowering

existing permissible exposure limits for 212

substances and establishing new exposure limits

for 164 others. However, in devising the new

standards, OSHA relied to a large extent on the

recommendations of the American Conference

of Governmental Industrial Hygienists, a private

organization, instead of NIOSH, the Federal

scientific advisory organization on occupational

health issues. The advisability of this approach

is likely to be a subject of continuing controversy in the occupational health field (box l-G).

The adequacy of OSHA’s efforts to protect the

Nation’s workers from toxic substances in

general and neurotoxic substances in particular

is a controversial issue. There are varying views

on the extent to which OSHA regulatory actions

take into account neurotoxicological concerns

and the adequacy of industrial programs to

monitor worker exposure to neurotoxic substances. There is also the question of why

farmworkers, a segment of the work force that

regularly comes into contact with pesticides

with neurotoxic properties, are not afforded the

same legal protections as most other U.S.

workers.

Option 1: Take no action.

If no congressional action is taken, OSHA

will continue to be responsible for carrying out

the existing provisions of the OSH Act, which

assure that no employee suffers “material

impairment of health or functional capacity. ”

Under these provisions, neurotoxic effects are

implicitly, but not explicitly, covered. Therefore, the limited attention given to neurotoxicity

will continue to be determined by agency

priorities, resource considerations, public concerns, and the expertise of regulatory officials.

Option 2: Mandate that neurotoxicity concerns

receive greater attention under the OSH Act.

Congress could use the authorization and

appropriations process to communicate to OSHA

its concern regarding neurotoxicity. The current

law could be strengthened by incorporating an

explicit reference to neurotoxic substances or

the adverse effects of chemicals on the nervous

system, or both. Congress could mandate that

Material Safety Data Sheets clearly describe

potential adverse affects on the nervous system.

Congress could encourage industry to assure

that health-care professionals, safety officers,

and employee supervisors are aware of the

neurotoxic potential of the chemicals to which

employees are exposed. In addition, Congress

could request that the General Accounting

Office evaluate the effectiveness of OSHA’s

enforcement program with respect to neurotoxic

substances.
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 29

Box l-F—Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:

Halcion, A Case Study

Halcion, the most widely prescribed sleeping medication in the United States, was first approved for use in late

1982 with a recommended usual adult dose of 0.25 to 0.50 mg. Its package insert included mentions of amnesia,

confusion, agitation, and hallucinations as possible side-effects. Over the next few years, FDA’s adverse reaction

monitoring system recorded an excess of adverse reports for Halcion in comparison to other benzodiazepine

hypnotics--even after correcting for market share of the drug. In 1987, as a result of the reports and the apparent

dose-relatedness of some adverse effects, several labeling and marketing changes were made. The usual adult dose

was changed to 0.25 mg, two paragraphs mentioning the apparent dose-relatedness of some side-effects were added

to the package insert, and a “Dear Doctor” letter was issued detailing the labeling changes. In early 1988, Upjohn,

the manufacturer, discontinued the 0.50 mg tablet.

Following these changes, public concern about possible problems associated with Halcion use increased,

largely because of a September 1988 article in California Magazine and a story on the ABC television program

20/20 in February 1989. The number of adverse reports received, which was expected to decline as a result of the

labeling changes and Halcion’s status as an “older” drug (the number of adverse reports associated with a drug

normally decreases over time), rose. In September 1989, FDA convened an expert panel to review the reporting data

on Halcion and to discuss whether further changes should be made in the labeling or marketing of the drug.

Discussion at that meeting illustrates the difficulties of drawing conclusions from the spontaneous adverse

reporting process. In a comparison of adverse reports for Halcion (45 million prescriptions written since 1982) with

adverse reports for Restoril (35 million prescriptions written since 1980), a drug prescribed to patients with similar

sleeping problems, the following data were presented:

Total number of reports received by FDA

Adverse event Halcion Restoril

Amnestic events 267 4

Hallucinations, paranoid behavior 241 12

Confusion and delirium 304 17

Hostility and intentional injury 48 2

Overall, an average of 38 adverse reports per million prescriptions was received for Halcion, while 7.5 adverse

reports per million prescriptions were received for Restoril.

These seemingly dramatic results, however, were tempered by myriad complicating variables. The influence

of publicity, differences in reporting rates by manufacturers, lack of dosage information in about one-half of the

adverse reports for Halcion, and ‘‘new drug’ v. ‘‘older drug’ effects all obscured the significance of differences

between the sets of data. The 4-week period following the 20/20 episode, for example, produced twice as many

adverse reports for Halcion as the 4-week period preceding the show. The FDA panel finally concurred that the data

were too unreliable to warrant action, except possibly in the case of amnesia.

The unreliable data generated by the postmarketing monitoring system now in place effectively limit FDA

review to premarket trials. Unexpected interactions with other medications or long-term side-effects may easily be

missed. This is particularly disturbing from the standpoint of neurotoxicity, since drugs not expected to have

neuropharmacological effects are not necessarily subjected to specific neurotoxicity testing. Changes which could

improve the present system might include a requirement that all adverse report forms be sent directly to FDA as

well as a requirement that physicians submit reports for all ‘‘serious” adverse reactions observed.

Because of the inherent limitations in FDA’s drug approval and adverse reaction monitoring systems, it is

important that physicians and patients be aware of the possible adverse effects of the medications they prescribe

and consume. Drugs are approved for use under certain conditions and at certain doses, and complicating factors

such as age, other medications, or illness may significant y alter the effects of these drugs. In most cases, the decision

to take any medication is a personal choice for the patient; an individual cannot make an informed decision without

access to information about potential adverse effects.

SOURCES: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Psychopharmacological

Drugs Advisory Committee, Transcript o~l’roceedings, Thirty-First Meeting (Rockville, MD: September 1989); “When Sleep

Becomes a Nightmare, ” 20/20, ABC, Feb. 17, 1989; Pharmaceutical Data Services, ‘‘Top 200 Drugs of 1989,’ American Druggisr,

in press.
30 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 1-G-Organic Solvents in the Workplace

Organic solvents and mixtures of solvents with other organic solvents or other toxic substances are widely used

in the workplace. Millions of workers come into contact with solvents every day through inhalation or contact with

the skin, Some solvents profoundly affect the nervous system. Acute exposure to organic solvents can affect an

individual’s manual dexterity, response speed, coordination, and balance. Chronic exposure of workers may lead

to reduced function of the peripheral nerves and such adverse neurobehavioral effects as fatigue, irritability, loss

of memory, sustained changes in personality or mood, and decreased ability to learn and concentrate.

The National Institute for Occupational Safety and Health (NIOSH) recommends that employers inform and

educate workers about the materials to which they are exposed, potential health risks involved, and work practices

designed to minimize exposure to these substances. NIOSH also recommends that employers assess the conditions

under which workers may be exposed to solvents, develop monitoring programs to evaluate the extent of exposure,

establish medical surveillance for adverse health effects resulting from exposure, and routinely examine the

effectiveness of control methods being employed.

The Occupational Safety and Health Administration has recently updated the permissible exposure limits for

approximately 428 substances, including many solvents. The new ruling established lower exposure limits for

approximately 212 substances already regulated by the agency. Permissible exposure limits are established for the

first time for another 168 substances, while existing limits for 25 substances are reaffirmed. This marks the first time

in 17 years that a new set of exposure standards has been established. For many companies, meeting the new

standards may require stricter engineering controls or more frequent use of respirators and other personal protective

devices, or both. Continued education of workers, improved methods of preventing exposure, and plans or

procedures to maintain compliance with the new ruling are required.

SOURCE: Office of Technology Assessment, 1990.

Option 3: Mandate increased efforts to monitor which they are exposed, access to exposure and

adverse neurological and behavioral effects

of substances in the workplace.

Congress could mandate increased monitoring of adverse neurological and behavioral

effects of toxic substances in the workplace.

This would include enhanced efforts to detect

toxic chemicals and improved reporting of

known or potential adverse effects of chemicals

on the nervous system, including the incidence

of neurological or psychiatric disorders or

diseases. Congress could mandate improved

postmarketing surveillance of new products.

Congress could also mandate that OSHA

conduct a review of its regulatory programs and

examine ways to more effectively protect workers from neurotoxic substances.

Option 4: Mandate the extension to farmworkers of legal rights under the OSH Act.

Congress could mandate the OSH Act to

include farmworkers under its provisions. This

would give workers the right to know about the

toxicity of pesticides and other chemicals to

medical records, and protection against retaliation by employers for taking steps to protect

their health. Congress could consider extending

these rights without preempting the more extensive standards that now exist in some States.

Consumer Product Safety Commission

The Consumer Product Safety Commission

(CPSC) is an independent regulatory commission charged with protecting the public from

“unreasonable risks of injury associated with

consumer products.’ Risk of injury is defined as

‘‘risk of death, personal injury, or serious or

frequent illness.’ The Federal Hazardous Substances Act provides for the protection of public

health by requiring that hazardous substances be

labeled with various warnings, depending on the

nature of the hazard. The Poison Prevention

Packaging Act requires that CPSC prevent

inadvertent poisoning of small children by

specially packaging hazardous substances to

make it “significantly difficult for children

under 5 years of age to open or obtain a toxic or
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 31

harmful amount of the substance therein within

a reasonable time. ’

Option 1: Take no action.

Present laws treat neurotoxic substances in

the context of general toxicological concerns.

Therefore, the degree to which CPSC specifically addresses neurotoxic substances depends

on program priorities, resources, and the expertise of regulatory officials. Views regarding

CPSC’s current degree of concern about neurotoxic effects vary.

Option 2: Mandate that neurotoxicity concerns

receive greater attention under various Federal laws for which CPSC has regulatory

responsibilities.

Congress could mandate that a private commission or organization examine the effectiveness

of CPSC’s present regulatory activities in protecting the public, especially high-risk groups

such as children, from neurotoxic and other

toxic substances. In addition, congressional

authorization and appropriations committees

could request that CPSC programs place a

higher priority on concerns related to the

adverse effects of toxic substances on the

nervous system, including a requirement that the

Commission ensure that products with neurotoxic potential be clearly labeled.

Department of Housing and Urban Development

The Lead-Based Paint Poisoning Prevention

Act of 1971 required that the Department of

Housing and Urban Development (HUD) eliminate as far as practicable the hazards of lead

paint in existing houses, and mandated that the

Department promulgate necessary regulations.

However, the General Accounting Office reported in 1981 that HUD had not fulfilled its

responsibility to eliminate lead-based paint in

Federal housing. Following litigation and a

court order, HUD revised its regulations in 1986

and 1987, and in 1988 Congress amended that

Act requiring that HUD promulgate additional

regulations to address the problem.

Option 1: Take no action.

HUD is making progress in meeting congressional mandates to address lead-based paint in

housing, however, the pace of progress is slow.

In the absence of congressional action, HUD

will continue to move forward, but large numbers of children will continue to be exposed to

lead-based paint in older homes.

Option 2: Amend the Lead-Based Paint Poisoning Prevention Act to better address the

problem of lead paint in older homes.

If Congress wished to take action to expedite

removal of lead-based paint from older homes,

it could amend the had-Based Paint Poisoning

Prevention Act establishing new programs to

address the problem and providing funds to

support paint removal efforts.

Option 3: Establish a major new program to

provide findingfor the removal of lead-based

paint from older homes.

Congress may wish to enact a new law to

facilitate removal of lead-based paint from older

homes. One proposal recently developed by the

Environmental Defense Fund (EDF) recommends establishment of a trust fund financed by

an excise fee on the production and importation

of lead. The EDF proposal calls for a program

jointly administered by EPA and the Department of Health and Human Services.

ISSUE 2: Is the current Federal research

framework addressing neurotoxicity adequately?

The current Federal research framework for

addressing neurotoxicity is composed of major

extramural programs sponsored by NIH and

ADAMHA. A sizable intramural program is

located at EPA, and more limited intramural

programs are under way at ADAMHA and NIH.

FDA has a substantial developmental neurotoxicology program at its National Center for

Toxicological Research, but research efforts

elsewhere are very limited in scope. OTA found

that, in general, Federal research programs are

not adequately addressing neurotoxicological

concerns.
32 ● neurotoxiciq: Identifying and Controlling Poisons of the Nervous System

Environmental Protection Agency

EPA has a large intramural research program

devoted to environmental neurotoxicology. Although the Agency has a small extramural grants

program, it is not currently supporting any

projects in which neurotoxicology is a major

focus. EPA supports intramural program initiatives through a small number of contracts and

cooperative agreements.

Option 1: Take no action.

Without congressional action, EPA intramural programs will continue at moderate levels.

However, in the absence of an Agency policy

change, lack of funding for supplies and equipment may continue to hamper some research

efforts. Failure to expand EPA’s intramural

program will make it difficult to move into new,

priority areas such as the development of in vitro

neurotoxicity testing approaches and the analysis of structure-activity relationships of chemicals.

Option 2: Provide funding for expansion of

intramural research programs.

Congress could choose to provide greater

support to EPA’s Office of Research and

Development to fund additional research in the

environmental neurotoxicology field. Budget

increases would also alleviate problems associated with the lack of funds for supplies and

equipment. Substantial increases would allow

EPA to move into new areas of research that

would strengthen its regulatory capabilities,

including its efforts to understand the relationship between chemical structure and neurotoxic

effects and further development and validation

of neurotoxicity testing protocols, particularly

in vitro and developmental tests.

Option 3: Provide funding for extramural grant

programs to support neurotoxicological and

neuroepidemiological research.

EPA’s total extramural grants program for

environmental issues is small; fiscal year 1989

funding for the entire program (addressing all

environmental concerns) was $8.2 million to

support individual academic investigators and

$4.5 million to support eight Environmental

Research Centers (in addition, the Superfund

program provides $2.5 million in grants to

investigators and $5.0 million to support five

hazardous substances research centers). Currently, EPA is funding no neurotoxicologyrelated research grants to individual investigators through its extramural program. Federal

research programs are normally composed of

both intramural and extramural efforts: extramural programs enable talented investigators in

academia and elsewhere to carry out research of

interest to the sponsoring agency. They also

allow an agency to complement its short-term

intramural efforts, required to meet regulatory

needs, with long-term studies that will help

guide future research.

EPA is considering substantial expansion of

its extramural programs. Congress could support such expansion or mandate programs that

go beyond EPA’s plans, or both. A grants

program in neurotoxicology would greatly improve the scientific foundation of the Agency’s

regulatory decisionmaking. Areas that would

particularly benefit from increased support are

monitoring and neuroepidemiology, which aid

in tracking the contribution of environmental

contaminants to adverse human effects, including neurological and psychiatric disorders. In

addition, extramural research designed to improve the Agency’s ability to predict neurotoxic

effects (e.g., through a better understanding of

chemical structure-activity relationships) would

greatly benefit regulatory programs. Research

on the neurotoxicological properties of specific

substances would aid in regulatory decisionmaking, and would enhance the Agency’s

ability to understand and predict the neurotoxicity of other substances.

National Institutes of Health

NIH supported more than 200 neurotoxicologyrelated research projects in fiscal year 1988.

Most of the projects were extramural competitive grants to investigators in public and private
Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 33

institutions. A few intramural projects were

conducted.

Option 1: Take no action.

In the absence of congressional action, NIH

will continue to conduct limited intramural

research related to neurotoxicology, primarily at

the National Institute of Neurological Disorders

and Stroke (NINDS) and the National Institute

on Deafness and Other Communication Disorders (NIDCD). The very small intramural research effort in environmental neurotoxicology

at NIEHS might be enhanced. Institute managers could require that existing basic neuroscience research efforts change their focus to

neurotoxicological concerns.

Extramural programs that fund neurotoxicological research projects are sponsored by several

Institutes, particularly the three mentioned above.

Without congressional action, these programs

will continue to fund a core group of neurotoxicologists in academia at moderate levels. It is

unlikely that the number of individual research

projects funded would increase significantly.

Option 2: Enhance National Institutes of Health

research efforts related to neurotoxicology,

If Congress wishes to enhance the NIH effort,

it could mandate development of a 5-year plan

to address neurotoxicological concerns. Such a

plan could include an analysis of current NIH

intramural and extramural programs, as well as

development of an integrated and comprehensive approach to neurotoxicological research in

the years ahead. NIH would also benefit from an

outside review of the missions of individual

Institutes and the current intramural and extramural programs supporting those missions.

Increased interaction among Institutes and between Institutes and other Federal agencies

would improve NIH’s response to neurotoxicity

concerns. Congress could expand the 5-year

plan to include all relevant programs in the

Department of Health and Human Services.

This would include NIH, ADAMHA, FDA,

NIOSH, the Agency for Toxic Substances and

Disease Control, and other organizations. Development of such a plan would lead to a

coordinated Federal effort to address the neurotoxicity issue.

Congress could provide additional funding to

NIH to expand extramural grant programs,

allowing various Institutes to enhance research

efforts on such subjects as the mechanisms by

which drugs cause adverse neurotoxic effects,

the mechanisms by which environmental contaminants adversely affect the nervous system,

and the extent to which toxic substances contribute to neurological and psychiatric disorders.

High-priority research goals might include the

structure-activity relationships of toxic chemicals, the vulnerability of developing and aging

nervous systems to toxic substances, and the

variation in sensitivity of individuals to these

substances.

Congress could fund additional intramural

research into high-priority areas of neurotoxicology research. It could also mandate reestablishment of an intramural neurobehavioral

toxicology program at the National Institute of

Environmental Health Sciences and request that

the National Toxicology Program give a higher

priority to neurotoxicity concerns.

Alcohol, Drug Abuse, and Mental Health

Administration

ADAMHA funds extensive neurotoxicity research at all three of its Institutes (OTA has

excluded research on alcohol and alcoholism

from this study). The National Institute on Drug

Abuse (NIDA) and the National Institute of

Mental Health (NIMH) both fund a substantial

number of extramural research grants. Intramual research programs related to neurotoxicology are somewhat limited in size and scope.

Option 1: Take no action.

If Congress chooses to take no action,

ADAMHA programs will continue at moderate

levels. However, without budget increases or

significant reprogramming of funds, it will be

difficult for these institutes to expand research

efforts in the neurotoxicology field.
34 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Option 2: Encourage greater research emphasis on the impact of abused drugs on the

nervous system and on the potential contributions of toxic substances to neuropsychiatric

disorders.

Congress may wish to encourage ADAMHA

to devote increased resources to the potential

long-term and permanent adverse effects of drug

abuse, particularly the effects of maternal drug

abuse on the developing nervous system of the

fetus. Congress could also encourage greater

emphasis on research to understand the mechanism by which psychoactive drugs and other

therapeutic drugs act on the central nervous

system, and particularly on how to prevent

moderate to severe adverse side-effects of these

drugs. ADAMHA could also focus more attention on neurotoxicity issues associated with the

use of multiple psychoactive drugs for long

periods of time by the elderly. Research advances in these areas would promote the development of safer, more effective drugs. Congress

could support expanded research on the biochemical processes underlying addiction to

abused drugs at NIDA’s Addiction Research

Center.

Food and Drug Administration

Research programs within FDA are conducted at the National Center for Toxicological

Research (NCTR) in Jefferson, Arkansas, and at

the Center for Food Safety and Applied Nutrition in Washington, D.C. Research programs

related to neurotoxicology are very small, with

the exception of the intramural developmental

neurotoxicology research program at NCTR.

Option 1: Take no action.

Without congressional action, neurotoxicology research programs within FDA will remain

very limited in scope. Relatively little research

is currently devoted to neurotoxicological concerns. This is of particular significance because

so many substances regulated under the Food,

Drug, and Cosmetic Act have neurotoxic potential. Although some funds, particularly at NCTR,

could be redirected to this area, present fiscal

limitations on FDA research leave little room

for flexibility.

Option 2: Provide funding to expand or initiate

intramural and extramural research programs related to the adverse effects on the

nervous system of drugs, cosmetics, food

additives, naturally occurring toxic substances

in food, and other substances.

Congress could choose to provide FDA with

funds to support both intramural and extramural

research related to the potential neurotoxic

effects of substances regulated under FFDCA. A

sizable research effort in this area would substantially improve FDA’s ability to protect

public health through an improved understanding of the effects of toxic substances on the

nervous system. To promote substantive research efforts in critical areas, Congress could

consider establishing research centers at academic institutions to focus on specific neurotoxicological concerns (e.g., structure-activity relationships, development of neurotoxicological

tests, epidemiological studies, mechanisms of

action). Congress could also provide funds to

support a major neurotoxicology research unit

within FDA.

National Institute for Occupational Safety

and Health

NIOSH, located within CDC, has identified

neurotoxic disorders as one of the Nation’s 10

leading causes of work-related disease and

injury. To aid in understanding the extent and

nature of this problem, NIOSH supports a small

number of intramural and extramural research

activities. The intramural program is devoted

primarily to evaluation of testing approaches

and to analysis of selected neurotoxic substances found in the workplace. The NIOSH

extramural program funds a very small number

of grants devoted to understanding the mechanisms by which toxic substances adversely

affect the nervous system.

Option 1: Take no action.

If no action is taken, NIOSH research programs related to neurotoxicity will continue at a
Chapter l-Summary, Policy Issues, and Options for Congressional Action . 35

low level. Given the magnitude of the problem

of exposure to neurotoxic substances in the

workplace, the present level of effort will not

ensure an adequate database to support the

anticipated needs of the Occupational Safety

and Health Administration.

Option 2: Expand intramural and extramural

neurobehavioral research programs at NIOSH.

This option would lead to improvements in

understanding the extent to which workers are

exposed to neurotoxic substances, the mechanisms by which these substances exert adverse

effects, and means of preventing exposures in

the workplace. Substantive increases in funding

for research would provide a better foundation

for OSHA’s regulatory activities related to

neurotoxicity. Priority research needs include a

better understanding of dose-response relationships, mechanisms of action, and structureactivity relationships. Methods for evaluating

worker exposures need to be developed, improved, and validated. Epidemiological studies

are needed to reveal the extent of workplace

exposure to neurotoxic substances and the

contribution of such exposure to neurological,

psychiatric, and other disorders and injuries.

More research is needed on latent neurological

disorders that may result from chronic, lowlevel exposure to neurotoxic substances.

Substantially increased NIOSH funding of

extramural neurotoxicology and neurobehavioral research would improve scientific understanding of workers’ exposure to toxic chemicals. Such an increase would encourage research

scientists to enter the field of environmental

neurotoxicology by supporting laboratories that

focus on occupational health issues. It would

also be an important source of training for

physicians.

Other Federal Agencies and Organizations

Other Federal agencies and organizations that

undertake neurotoxicity-related research include

the Center for Environmental Health and Injury

Control and the National Center for Health

Statistics within CDC, the Agency for Toxic

Substances and Disease Registry, the Department of Energy, the Department of Agriculture,

the Department of Veterans Affairs, and the

National Aeronautics and Space Administration. The Department of Defense conducts

neurotoxicology -related research, particularly

as it relates to chemical warfare; however,

defense-related research is not included in this

report. The National Science Foundation presently supports very little research in this area.

Option 1: Take no action.

If Congress chooses to take no action, small

research programs in these organizations are

likely to continue. In some of them, limited

efforts may be appropriate; in others, particularly those within DHHS, small efforts may

hamper the ability of other agencies and individuals to address neurotoxicity-related issues. For

example, the National Center for Health Statistics provides most of the current information on

the prevalence, mortality, and morbidity associated with neurological and other diseases in the

United States. Because of budget cuts in recent

years, neuroepidemiologists have had difficulty

in obtaining the statistical information necessary for studies of how neurotoxic substances

contribute to neurological and psychiatric disorders.

Option 2: Mandate that various Federal organizations and agencies undertake or expand

research programs addressing neurotoxicity -

related concerns.

Several organizations could support research

efforts in neurotoxicology that would enhance

their own programs and those of others. Congress could mandate that these agencies adjust

program priorities to better address neurotoxicityrelated concerns, it could selectively provide

increased funds for these programs, or it could

do both. For example, enhanced efforts at the

Center for Environmental Health and Injury

Control, National Center for Health Statistics,

and Agency for Toxic Substances and Disease

Registry would benefit many Federal and State

agencies and would provide support to academic

investigators. The Department of Energy has
36 ● neurotoxici~: Identifying and Controlling Poisons of the Nervous System

recently reemphasized research on the toxicological effects of chemicals. Its existing programs are focused on nuclear-related health

concerns; support of nonnuclear, neurotoxicity -

related research is minimal. Studies of the

neurotoxic substances generated by energyproducing technologies would be beneficial.

The National Science Foundation could spur

academic research into the mechanisms by

which toxic substances adversely affect the

nervous system by providing support for basic

research in the neurotoxicology field,

ISSUE 3: Should Congress take steps to

improve interagency coordination of Federal research and regulatory programs

related to neurotoxicity?

Until recently there was little coordination of

Federal research and regulatory programs related to neurotoxic substances. At a workshop

sponsored by OTA and EPA, representatives of

various Federal agencies decided to establish an

Interagency Working Group on neurotoxicology

l to aid in interagency coordination.

Option 1: Take no action.

Without congressional action, the new interagency coordinating group may succeed in

enhancing the exchange of regulatory and research information among Federal agencies.

The success of an initiative of this kind is largely

determined by the willingness of senior agency

administrators, program managers, and technical personnel to participate and voluntarily

share information. Whether an adequate level of

interest will be maintained is not clear. Another

important question is whether the group will

have sufficient support at the senior management levels to carry out research and regulatory

initiatives.

Option 2: Mandate and formalize the establishment of an organization to foster coordination of Federal interagency research and

regulatory programs related to neurotoxicology.

Congress could formalize the existing interagency coordinating group by mandating establishment of an organization to ensure maximum use

of U.S. research and regulatory resources.

Congress could mandate that all significant

Federal programs be represented in the organization, and it could require the submission of a

report every 5 years on the state of the Federal

neurotoxicology research and regulatory effort.

This interagency organization would benefit

from a board of advisors from academia, industry, and elsewhere who could evaluate existing

programs and provide guidance on future directions. Choosing this option would require the

redirection of existing agency funds or the

appropriation of new funds.

ISSUE 4: Are current Federal educational

and research policies and programs ensuring an appropriate number of adequately

trained research and health-care professionals to address neurotoxicity concerns?

A significant portion of our current understanding of the effects of toxic substances on the

nervous system comes from application of basic

research to environmental health problems.

However, too few scientists are trained in both

neuroscience and toxicology to provide an

adequate supply of neurotoxicologists. In addition, other environmental health professionals

are needed to address neurotoxicological concerns, including neuroepidemiologists, occupational physicians, and nurses with training in

neurotoxicology.

Option 1: Take no action.

Without congressional action, the focus of

federally supported training programs will continue to be determined by individual agencies,

and funding will continue at low levels. Inadequate Federal support of training is partly

responsible for the shortage of adequately

I@ ~t. 26, 1989, tie ~me ~m changed t. the “Interagency Committee on Ne~otoxicology ” (ICON). The committee is administered ~OU@

the neurotoxicology Division of EPA’s Health Effects Research Laboratory in Research Triangle Park, NC.
Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 37

trained research and health-care professionals in

the field of neurotoxicology.

Option 2: Take steps to encourage individuals to

establish careers in research and health-care

fields that address toxicological, particularly

neurotoxicological, concerns.

If Congress wishes to take this approach, it

could mandate expansion of pre- and postdoctoral research training programs in neurotoxicology by increasing the number of training

grants to individuals and/or research centers.

This would primarily involve expansion of

existing programs supported by NIH and NIOSH.

Congress could encourage training of medical

students in occupational medicine, including

course work in neurotoxicology. It could promote training of graduate students in neurotoxicology by providing additional funds to NIH,

ADAMHA, and NIOSH for this purpose or by

funding a new training program that would be

administered by EPA. It could also encourage

physician residency training in occupational

medicine by increasing the funds (through Title

VII of the Health Professionals Education Act)

for establishing such programs. Finally, it could

encourage training of occupational safety and

health specialists through continued or increased funding of the NIOSH training grants

program, in particular the Educational Resource

Centers.

ISSUE 5: Are workers and the public receiving sufficient information to allow them to

make informed decisions about exposure

to neurotoxic substances?

Preventing adverse effects of exposure to

neurotoxic substances depends largely on understanding the threat that neurotoxic substances pose to human health and knowing how

to limit exposure to these substances. In recent

years, Congress has taken steps to increase the

quantity and quality of information available to

the public concerning health risks posed by toxic

substances. For example, the Federal Emergency Planning and Community Right-to-Know

Act of 1986 has resulted in a large database,

Photo credit: UnitedAutomobik, Aerospace, and Agricultural Implement

Workers of America-UAW Public Relations Department

Respirators may be useful in minimizing exposure to

solvent vapors when engineering or work practice controls

are inadequate.

accessible to the public, on the release of more

than 300 toxic chemicals at facilities throughout

the United States. In 1987, the Department of

Labor expanded the OSHA hazard communication standard. This standard gives employees the

right to know what chemicals they may encounter in the workplace. In general, information is

transmitted through hazard communication programs, which use labels on containers and other

warning signs; post appropriate safety information, including material safety data sheets; and

train and educate employees about the chemical

properties and hazardous effects of the toxic

substances to which they are or may be exposed.

Option 1: Take no action.
38 . neurotoxicity: Identifying and Controlling Poisons of the Nervous System

In the absence of congressional action, existing hazard communication and right-to-know

laws will provide the public and workers with

useful information about the health risks posed

by neurotoxic substances. The relevance of this

information to neurotoxicity concerns will continue to be determined to a large degree by the

perceptions and priorities of officials in the

various agencies with regulatory responsibilities. Federally mandated worker information

programs tend to focus on the carcinogenic and

teratogenic potential of toxic substances; noncancer health risks such as neurotoxicity tend to

receive less attention, even though they may

pose an equal or greater health threat.

Option 2: Take action to ensure that the risks

posed by neurotoxic substances are explicitly

described to the public through hazard communication and right-to-know laws.

Choosing this option will result in enhanced

communication of neurotoxic health risks to the

public. Congress could require that information

provided to workers under the Hazardous Communication Standards of the Occupational Safety and

Health Act include a description of significant

hazards posed by neurotoxic substances, and it

could mandate improved enforcement of the

hazardous communication provisions of this

Act. Congress could also require that neurotoxicity concerns be explicitly addressed in information developed and released under the Federal Emergency Planning and Community Rightto-Know Act. Information on trends in annual

data would also be useful in monitoring progress, in limiting releases, and in minimizing

public exposure.

Option 3: Take additional steps to inform the

public of the short- and long-term adverse

effects of abuse of psychoactive drugs on the

nervous system.

Congress could provide NIDA with funding

for an aggressive campaign to inform the public

of the potential long-term consequences of drug

abuse on the nervous system. Congress could

mandate that particular attention be devoted to

the abuse of psychoactive drugs by pregnant

women and the severe effects these substances

may have on the nervous system of the developing fetus.

Option 4: Mandate improved labeling of consumer products with respect to potential

neurotoxic effects.

Congress could take steps to assure that

substances purchased by consumers that have

neurotoxic potential are appropriately labeled

and contain appropriate warnings when necessary. Congress could request that agencies

devote particular attention to substances that

\ ’

\\ ,’ --- -

=.. \

‘\ \ “.

Illustrated by: Ray Driver
Chapter l--Summary, Policy Issues, and Options for Congressional Action ● 39

may adversely affect the developing nervous

system.

In addition, Congress could mandate that all

toxic product ingredients, including those sometimes referred to as ‘inert’ substances, be listed

on product labels. This is particularly important

with respect to pesticide products.

ISSUE 6: Should the United States more

actively encourage and participate in international regulatory and research programs

related to neurotoxic substances, and

should the United States revise its policies

with regard to the export of neurotoxic

substances?

The adverse effects on the nervous system of

occupational and environmental exposure to

toxic chemicals are a major problem in the

developing regions of the world. The United

States is the leader in the international research

effort to understand the health risks posed by

neurotoxic substances. Because of this expertise, many persons believe that the United States

should participate more actively in cooperative

international efforts to address the problem. In

addition, many question current U.S. policies

regarding the export of neurotoxic substances

that have been banned, severely restricted, or

never registered for domestic use.

Option 1: Take no action.

At the present time, U.S. scientists actively

participate in international conferences pertaining to toxic substances and human health risks.

To a more limited extent, public and private

agencies in the United States and foreign

countries cooperate in research and regulatory

activities. In the absence of congressional action, informal international activities will continue, but significant formal arrangements for

coordinating research and regulatory efforts are

unlikely.

Even though the United States is capable of

training individuals from foreign countries in

the fields of neurotoxicology and neuroepidemiology, it is very difficult for U.S. academic

institutions to obtain funds to support such

efforts. In the absence of congressional action,

little funding will be available for training of this

kind.

Without congressional action, the United

States will continue to export neurotoxic substances that are banned, severely restricted, or

never registered for use in this country. Persons

who support current export policies believe that

such practices are appropriate as long as the

health risks posed by the chemical are communicated to the receiving country. Persons who

oppose these policies believe that, despite efforts at hazard communication, many receiving

nations do not have the expertise to judge the

nature of the health risks; further, they argue that

risk-related information is often not adequately

communicated to users. The use of banned,

severely restricted, or never-registered pesticides in developing countries is often cited as a

particular problem.

Option 2: Encourage Federal agencies to initiate and participate in joint international

testing efforts to evaluate the toxicity of new

and existing chemicals.

Because so many chemicals have not been

adequately tested for neurotoxicity, some persons believe it would be advantageous to test

certain chemicals under joint international agreements. If standardized testing procedures could

be agreed on, such an approach might result in

a more equitable sharing of the chemical testing

burden throughout the international community.

The International Program on Chemical Safety

(a joint venture of the United Nations Environment Program, the International Labor Organization, and the World Health Organization) has

sponsored efforts to develop methods for assessing the neurotoxic effects of exposure to chemicals. Congress could encourage and support

international programs of this kind. It could also

encourage the development of an international

toxicity database accessible to developing countries at minimal cost.

Option 3: Provide or redirect finding to encourage neurotoxicological and epidemiological
40 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

research and information exchange between

public and private U.S. organizations and

those offoreign nations.

This option would promote international

programs to evaluate the health risks posed by

neurotoxic substances and would encourage

cooperative efforts to minimize human exposure

to chemicals and naturally occurring substances

that pose a public health risk. It is currently

difficult for U.S. researchers to obtain grant

support for projects involving international

collaboration. Modest funding to encourage

such collaboration would lead to mutually

beneficial research efforts. U.S. neurotoxicologists and other scientists have few contacts in

Third World countries, where their expertise

could promote research and training of foreign

personnel. Creation of a grants program to foster

these relationships would not only respond to

these needs, but also enlarge the perspective of

U.S. scientists and promote international cooperation.

This option would encourage Federal agencies to provide grant support to academic

institutions for partial sponsorship of international conferences and working groups on

neurotoxicological questions. In addition, Congress could encourage continued U.S. participation in international toxicological research and

policy planning activities. In particular, it could

encourage the design and implementation of

educational programs to inform people in developing countries about the risks posed by exposure to neurotoxic substances.

Option 4: Allow academic institutions receiving

Federal funds for training grants to use a

designated percentage of funds to support

non-U.S. residents.

At the present time, NIH can support foreign

research fellows through various mechanisms;

however, Federal funds are not available to help

support foreign students at U.S. academic institutions. Allowing U.S. institutions to use a

designated percentage of training funds to

support non-U.S. nationals and residents would

facilitate the exchange of graduate students and

postdoctoral fellows and aid foreign nations in

developing their own research and regulatory

programs. Congress could also make Federal

funds available to encourage public and private

institutions to sponsor research and training of

persons in developing countries by U.S. personnel working in those countries.

Option 5: Revise existing laws governing the

export of hazardous substances.

Congress could take action under various

laws to ensure that regulations limiting the

exposure of U.S. citizens to toxic substances are

extended to individuals in foreign nations. This

could involve prohibiting or limiting the export

of neurotoxic substances that are banned, severely restricted, or never registered for domestic use. Such action would address the ethical

concerns of persons who believe that current

policies place the United States in a position of

profiting from the export of chemicals that are

considered to be too hazardous for domestic use.

It would also help to minimize the exposure of

U.S. citizens to hazardous chemicals through the

import of foods, food products, and other

consumer goods containing toxic substances

that have been banned, severely restricted, or

never registered in the United States.

Specifically with respect to pesticides, Congress could take steps to ban or restrict the

export of those products that are not registered

in the United States. It could prohibit or restrict

the export of particularly hazardous pesticides

to countries that do not have adequate regulatory, monitoring, and public and worker health

protection programs. Congress could also require proper labeling of all exported pesticide

products, including clearly written warnings in

appropriate languages. Warning labels could be

required to include the use of generally understood poison and health protection symbols.

Steps could be taken to prohibit or restrict the

import of food products containing the residues

of pesticides not registered for use in the United

States.
Chapter 2

Introduction

‘‘Chemicals are an everyday fact of life in modern society. They enhance our lives in ways too numerous to

count, but progress has its price, and too often the price of the role of chemicals in our society is human illness

and disease.

Representative Harold L. Volkmer

Committee on Science and Technology

U.S. House of Representatives

October 8, 1985

‘‘Nervous system dysfunction during advanced age seems destined to become the dominant disease entity of

the twenty-first century. Neither I, nor anyone else, can tell you how much of that dysfunction might be

attributable to toxic chemicals in the environment. So far, hardly anyone has looked. ”

Bernard Weiss, Ph.D.

Testimony before the Committee on Science and Technology

U.S. House of Representatives

October 8, 1985
WHAT IS NEUROTOXICITY? .

SCOPE OF THIS STUDY . . . . . .

WHO IS AT RISK? . . . . . . . . . . . .

EXAMPLES OF neurotoxic

Industrial Chemicals . . . . . . . . .

Pesticides . . . . . . . . . . . . . . . . . . . .

Therapeutic Drugs . . . . . . . . . . .

Abused Drugs . . . . . . . . . . . . . . . .

Food Additives . . . . . . . . . . . . . . .

Cosmetics . . . . . . . . . . . . . . . . . . .

CONTENTS

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......’ ...*.*. ● .@

. . . . . . . . . . . . . . . . . . . . . . . . . . . ....... ....... ....... ...

. . . . . . . . . . . . . . . . . . . . . . . ..+..... ..+.*,*. ........ “.

SUBSTANCE S. . . . . . . . . . . . . .. .+ .. .. ... ..+. . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........ ~.....+. ● ☛☛

✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ ✎ .....$+, -....... .......+ . . . . . ,,.... .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page

TOXIC SUBSTANCES AND NEUROLOGICAL AND PSYCHIATRIC

DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IDENTIFYING neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . . .

REGULATING neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ECONOMIC CONSIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . . . . . . . . . . .

INTERNATIONAL CONCERNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +

CHAPTER 2 REFERENCES . . . . . . . . . . . . + . . . . . . . . . . . . . . . . . . . + . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . .

Fibers in the Cerebral

. . . . . . . . . . . . . . . . . . . . .

the United States,

. . . . . . . . . . . . . . . . . . . . .

in the United States,

. . . . . . . . . . . . . . . . . . . . .

to Toxic Substances .

. . . . . . . . . . . . . . . . . . . . .

43

45

45

45

48

49

50

51

52

52

54

55

56

56

56

57

Page

. . . . . . . . . . . 49

. . . . . . . . . . . 53

Page

Cortex

. . . . . . ,....5 2

. . . . . . . . . . . . 55

. . . . . . . . . . . 55

Page

. . . . . . . . . . . 46

. . . . . . . . . . . 47
Chapter 2

Introduction

Chemicals are an integral part of our daily lives

and are responsible for substantially improving

them. Yet chemicals can also endanger our health,

even our survival. This report focuses on neurotoxic

substances, those chemicals that adversely affect the

nervous system. Included among such substances

are industrial chemicals, pesticides, therapeutic drugs,

abused drugs, foods, food additives, cosmetic ingredients, and naturally occurring substances. Whether

a substance causes an adverse health effect depends

on many factors, including the toxicity of the

substance, the extent of exposure, and an individual’s age and state of health. Minimizing public

health risks requires knowledge about the properties

and mechanisms of action of potentially toxic

substances to which humans may be exposed. This

knowledge provides the foundation for safety standards.

More than 65,000 chemicals are in the Environmental Protection Agency’s (EPA’s) inventory of

toxic chemicals, and each year the Agency receives

approximately 1,500 notices of intent to manufacture new substances (30). Since few of these

chemicals have been tested to determine if they

adversely affect the nervous system (or other systems), no precise figures are available on the total

number of chemicals in existence that are potentially

neurotoxic to humans. Some estimates have been

developed, however, based on analyses of certain

subsets of chemicals. These estimates vary considerably, depending on the definition of neurotoxicity

used and the subset of substances examined. For

example, some 600 active pesticide ingredients are

registered with EPA (27), a large percentage of

which are neurotoxic to varying degrees. One

investigator estimated that 3 to 5 percent of industrial chemicals, excluding pesticides, have neurotoxic potential (41). Another investigator found that

28 percent of industrial chemicals for which occupational exposure standards have already been developed demonstrate neurotoxic effects (1). In addition,

a substantial number of therapeutic drugs and many

abused drugs have neurotoxic potential.

Human exposure to most known neurotoxic

substances is normally quite limited. Consequently,

the number of substances that pose an actual threat

to public health is considerably less than the total

number of neurotoxic substances in existence. The

number of neurotoxic substances that pose a

significant public health risk is unknown because

the potential neurotoxicity of only a small number of chemicals has been evaluated adequately.

WHAT IS neurotoxicITY?

The nervous system comprises the brain, the

spinal cord, and a vast array of nerves that control

major body functions. Movement, thought, vision,

hearing, speech, heart function, respiration, and

numerous other physiological processes are controlled by this complex network of nerve processes,

transmitters, hormones, receptors, and channels.

20-812 -90 - 2 : QL 3 -43-
44 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Although every major body system can be adversely affected by toxic substances, the nervous

system is particularly vulnerable to them. Unlike

many other types of cells, nerves have a limited

capacity to regenerate. Also, many toxic substances

have an affinity for lipids, fat-like substances that

make up about 50 percent of the dry weight of the

brain, compared to 6 to 20 percent of other organs

(8).

Many toxic substances can alter the normal

activity of the nervous system. Some produce effects

that occur almost immediately and last for a period

of several hours: examples include a drug that

prevents seizures, an alcoholic beverage, and fumes

from a can of paint. The effects of other neurotoxic

substances may appear only after repeated exposures

over weeks or even years, for example, regularly

breathing the fumes of a solvent in the workplace or

eating food or drinking water contaminated with

lead. Some substances can permanently damage the

nervous system after a single exposure: certain

organophosphorous pesticides and metal compounds

such as trimethyl tin are examples. Other substances,

including abused drugs such as heroin and cocaine,

may lead to addiction, a long-term adverse alteration

of nervous system function. Many neurotoxic substances can cause death when absorbed, inhaled, or

ingested in sufficiently large quantities.

Care must be taken in labeling a substance

neurotoxic because factors such as dose and intended effects must be taken into consideration. A

substance may be safe and beneficial atone concentration but neurotoxic at another. For example,

vitamins A and B6 are required in the diet in trace

amounts, yet both cause neurotoxic effects in large

doses (50). In other cases, a substance that is known

to be neurotoxic may confer benefits that are viewed

as outweighing the adverse effects. For example,

thousands of individuals suffering from schizophrenia have been able to live relatively normal lives

because of the beneficial effects of the antipsychotic

drugs. However, chronic use of prescribed doses of

some of these drugs may give rise to tardive

dyskinesia-involuntary movements of the face,

tongue, and limbs—side-effects so severe that they

may incapacitate the patient (50).

Another factor that complicates efforts to evaluate

neurotoxicity is the potential additive effects of toxic

substances. For example, independent exposure to

two toxic substances may lead to no observable

adverse effects, but simultaneous exposure could

result in damage to the nervous system. In addition,

the body has an effective but limited capacity for

detoxifying many chemical agents. Some chemicals

thought to be relatively nontoxic may cause adverse

effects if exposure occurs after the body’s detoxifying systems have been saturated (17). Such situations might occur following chronic exposure to a

complex mixture of chemicals in the workplace or to

chemicals at hazardous waste sites.

Broadly defined, any substance is considered to

have neurotoxic potential if it adversely affects any

of the structural or functional components of the

nervous system. At the molecular level, a substance

might interfere with protein synthesis in certain

nerve cells, leading to reduced production of a

neurotransmitter and brain dysfunction. At the

cellular level, a substance might alter the flow of

ions (charged molecules such as sodium and potassium) across the cell membrane, thereby perturbing

the transmission of information between nerve cells.

Substances that adversely affect sensory or motor

functions, disrupt learning and memory processes,

or cause detrimental behavioral effects are neurotoxic, even if the underlying molecular and cellular

effects on the nervous system have not been

identified. Exposure of children to lead, for example,

leads to deficits in I.Q. and poor academic achievement (40). Behavioral effects are sometimes the

earliest signs of exposure to neurotoxic substances

(56). In addition, there is evidence that the adverse

effects of some toxic substance-induced neurodegenerative diseases may not become apparent until

years after exposure (49).

For the purposes of this study, the Office of

Technology Assessment (OTA) defines neurotoxicity or a neurotoxic effect as an adverse change in

the structure or function of the nervous system

following exposure to a chemical agent. This is the

definition currently used for regulatory purposes by

EPA (50 FR 188). However, as the preceding

discussion illustrates, this definition should be used

in conjunction with information on the intended use

of the substance, the degree of toxicity, and the dose

or extent of exposure of humans or other organisms.

The definition hinges on interpretation of the

word “adverse,” and there is disagreement

among scientists as to what constitutes “adverse

change.” The nature and degree of impairment, the

duration of effects (especially irreversible effects),

and the age of onset of effects are among the many
Chapter 2-Introduction .45

factors taken into account in determining whether or

not an effect is adverse. The definition is further

complicated by the possibility that adverse effects

on the nervous system maybe secondary effects of

the action of a toxic substance on other organs. For

example, kidney or liver damage may lead to

adverse effects on the nervous system (26). Determining whether a particular neurological or behavioral effect is adverse requires a comprehensive

analysis of all available data, including consideration of social values (1 1).

SCOPE OF THIS STUDY

This study examines many, but not all, of the

classes of toxic substances. The assessment includes discussion of industrial chemicals, pesticides, therapeutic drugs, substance drugs, foods,

food additives, cosmetic ingredients, and such

naturally occurring substances as lead and mercury. It does not include radioactive chemicals;

nicotine (from cigarette smoke); alcohol (ethanol);

biological and chemical warfare agents; microbial,

plant, and animal toxins; and physical agents such as

noise.

WHO IS AT RISK?

Everyone is at risk of being adversely affected by

neurotoxic substances, but individuals in certain age

groups, states of health, and occupations face a

greater probability of adverse effects. The developing nervous system is particularly vulnerable to

some neurotoxic substances, for several reasons. It

is actively growing and establishing cellular networks, the blood-brain barrier that protects much of

the adult brain and spinal cord from some toxicants

has not been completely formed, and detoxification

systems are not fully developed. Consequently,

fetuses and children are more vulnerable to the

effects of certain neurotoxic substances than are

adults (44). The National Academy of Sciences

(NAS) recently reported that 12 percent of the 63

million children under the age of 18 in the United

States suffer from one or more mental disorders and

identified exposure to toxic substances before or

after birth as one of the several risk factors that

appear to make certain children vulnerable to these

disorders (31).

The elderly are more susceptible to certain

neurotoxic substances because decline in structure

and function of the nervous system with age limits

its ability to respond to or compensate for toxic

effects (17). In addition, decreased liver and kidney

function increases susceptibility to toxic substances.

Aging may also reveal adverse effects masked at a

younger age. Persons who are chronically ill,

especially those suffering from neurological or

psychiatric disorders, are at risk because neurotoxic

substances may exacerbate existing problems. Also,

many elderly Americans take multiple drugs that

may interact to adversely affect nervous system

function. According to the Department of Health and

Human Services (DHHS), people 60 and older

represent 17 percent of the U.S. population but

account for nearly 40 percent of drug-related hospitalizations and more than half the deaths resulting

from drug reactions (19). Common adverse effects

include depression, confusion, loss of memory,

shaking and twitching, dizziness, and impaired

thought processes.

Workers in industry and agriculture often experience substantially greater exposures to certain toxic

substances than the general population. The National Institute for Occupational Safety and

Health (NIOSH) has identified neurotoxic disorders as one of the Nation’s 10 leading causes of

work-related disease and injury. Other leading

causes of work-related disease and injury include

noise-induced hearing loss and psychological disorders, both of which are mediated by the nervous

system. Evaluating the risk posed by neurotoxic

substances is critical to the regulatory process. Risk

assessment issues are discussed in chapter 6.

EXAMPLES OF neurotoxic

SUBSTANCES

neurotoxic substances include naturally occurring elements such as lead and mercury, biological

compounds such as botulinum toxin (produced by

certain bacteria) and tetrodotoxin (found in the

puffer fish, a Japanese delicacy), and synthetic

compounds, including many pesticides and industrial solvents. Some commonly encountered substances are neurotoxic but may not be recognized as

such. For example, certain antibiotics and hexachlorophene (once frequently used as an antibacterial

agent in soaps) are neurotoxic when sufficiently

large quantities are ingested or absorbed through the

skin; however, exposures to large quantities are rare.

Many therapeutic drugs and abused substances also

have neurotoxic potential.
46 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Illustrated by: Ray Driver

neurotoxic substances can cause a variety of

adverse health effects, ranging from impairment of

muscular movement to disruption of vision and

hearing, to memory loss and hallucinations. Some

substances can cause paralysis and death. Often,

neurotoxic effects are reversible, that is, the effects

diminish with time after exposure ceases and no

adverse effects on the nervous system are thought to

remain. At times, the effects are irreversible and lead

to permanent changes in the nervous system. Table

2-1 summarizes some of the most frequently reported neurobehavioral effects of exposure to toxic

substances (2). The adverse effects of neurotoxic

substances and the mechanisms through which they

occur are discussed in chapter 3.

neurotoxicity has been an important public health

concern for many years, and incidents of human

poisoning have occurred periodically throughout the

world for centuries. Some of the major incidents are

Table 2-l-Neurological and Behavioral Effects of

Exposure to Toxic Substances

Motor effects:

convulsions

weakness

tremor, twitching

lack of coordination,

unsteadiness

paralysis

reflex abnormalities

activity changes

Mood and personality effects:

sleep disturbances

excitability

depression

irritability

restlessness

nervousness, tension

delirium

hallucinations

Sensory effects:

equilibrium changes

vision disorders

pain disorders

tactile disorders

auditory disorders

Cognitive effects:

memory problems

confusion

speech impairment

learning impairment

Genera/ effects:

loss of appetite

depression of neuronal activity

narcosis, stupor

fatigue

nerve damage

SOURCE: Adapted from W.K. Anger, “Workplace Exposures,” Neurobehavioral Toxicology, Z. Annau (cd.) (Baltimore, MD: Johns

Hopkins University Press, 1986), pp. 331-347.

indicated in table 2-2. The neurotoxicity of heavy

metals, widely distributed in the soil of the Earth’s

surface, has been recorded in fable and fact for many

centuries. The toxicity of lead, for example, has been

a concern since Hippocrates first recognized it in the

mining industry (39).

Lead is a widely distributed metal. In its natural

state, it is referred to as inorganic lead. Major

sources of inorganic lead include industrial emissions, lead-based paints, food, and beverages. Organic lead compounds include the anti-knock gasoline, tetraethyl lead. had has profound effects on the

nervous system. At relatively low levels it can cause

a variety of neurobehavioral problems, including

learning disorders (54). Despite years of research

and considerable regulatory action, the extent and

consequences of lead poisoning in children remain

a major public health problem. In 1988, a Federal

agency reported that about 17 percent of American children in metropolitan statistical areas

(MSAs) have concentrations of lead in their blood

above 15 micrograms per deciliter, a concentration that may adversely affect the nervous system

(54). The percentage is much higher for urban

children from poor families. Over the years, numerous Federal regulations have been developed to

decrease human exposure, but the debate on acceptable levels in children continues. Lead will be

discussed in detail in chapter 10.
Chapter 2----introduction ● 47

Table 2-2-SeIected Major neurotoxicity Incidents

Year(s) Location Substance Comments

400 B.C.

1930s

1930s

1932

1937

1946

1950s

1950s

1950s

1950s-1970s

1956

1956

1956-1977

1959

1960

1964

1968

1969

1971

1971

1973

1974-1975

1976

1977

1979-1980

1980s

1981

1985

1987

Rome

United States

(Southeast)

Europe

United States

(California)

South Africa —

Japan

(Minamata)

France

Morocco

United States

—

Turkey

Japan

Morocco

Iraq

Japan

Japan

Japan

United States

Iraq

United States

(Ohio)

United States

(Hopewell, VA)

United States

(Texas)

United States

(California)

United States

(Lancaster, TX)

United States

Spain

United States

and Canada

Canada

lead

TOCP

Apiol (w/TOCP)

thallium

TOCP

tetraethyl lead

mercury

organotin

manganese

AETT

endrin

HCB

clioquinol

TOCP

mercury

mercury

PCBs

n-hexane

hexachlorophene

mercury

MnBK

chlordecone

(Kepone)

Ieptophos

(Phosvel)

dichloropropene

(Telone II)

BHMH

(Lucel-7)

MPTP

toxic oil

aldicarb

domoic acid

Hippocrates recognizes lead toxicity in the mining industry (5)

Compound often added to lubricating oils contaminates “Ginger-Jake,” an

alcoholic beverage; more than 5,000 paralyzed, 20,000 to 100,000 affected (1)

Abortion-inducing drug containing TOCP causes 60 cases of neuropathy (1 )

Barley laced with thallium sulfate, used as a rodenticide, is stolen and used to

make tortillas; 13 family members hospitalized with neurological symptoms;

6 deaths(1)

60 South Africans develop paralysis after using contaminated cooking oil (1)

More than 25 individuals suffer neurological effects after cleaning gasoline

tanks (4)

Hundreds ingest fish and shellfish contaminated with mercury from chemical plant;

121 poisoned, 46 deaths, many infants with serious nervous system damage (1 )

Contamination of Stallinon with triethyltin results in more than 100 deaths (1)

150 ore miners suffer chronic manganese intoxication involving severe

neurobehavioral problems (1)

Component of fragrances found to be neurotoxic; withdrawn from market in

1978; human health effects unknown (1)

49 persons become ill after eating bakery foods prepared from flour contaminated with the insecticide endrin; convulsions resulted in some instances (5)

Hexachlorobenzene, a seed grain fungicide, leads to poisoning of 3,000 to

4,000; 10 percent mortality rate (3)

Drug used to treat travelers’ diarrhea found to cause neuropathy; as many as

10,000 affected over two decades (1)

Cooking oil contaminated with lubricating oil affects some 10,000 individuals (1)

Mercury used as fungicide to treat seed grain used in bread; more than 1,000

people affected (6)

Methylmercury affects 646(1 ,6)

Polychlorinated biphenyls leaked into rice oil, 1,665 people affected (9)

93 cases of neuropathy occur following exposure to n-hexane, used to make

vinyl sandals (1)

After years of bathing infants in 3 percent hexachlorophene, the disinfectant is

found to be toxic to the nervous system and other systems (5)

Mercury used as fungicide to treat seed grain is used in bread; more than 5,000

severe poisonings, 450 hospital deaths, effects on many infants exposed

prenatally not documented (3,6)

Fabric production plant employees exposed to solvent; more than 80 workers

suffer polyneuropathy, 180 have less severe effects (1)

Chemical plant employees exposed to insecticide; more than 20 suffer severe

neurological problems, more than 40 have less severe problems (1)

At least 9 employees suffer serious neurological problems following exposure

to insecticide during manufacturing process(1)

24 individuals hospitalized after exposure to pesticide Telone following traffic

accident (1 O)

Seven employees at plastic bathtub manufacturing plant experience serious

neurological problems following exposure to BHMH (8)

impurity in synthesis of illicit drug found to cause symptoms identical to those of

Parkinson’s disease (11 )

20,000 persons poisoned by toxic substance in oil, resulting in more than 500

deaths; many suffer severe neuropathy (2)

More than 1,000 individuals in California and other Western States and British

Columbia experience neuromuscular and cardiac problems following ingestion of melons contaminated with the pesticide aldicarb (7)

Ingestion of mussels contaminated with domoic acid causes 129 illnesses and 2

deaths. Symptoms include memory loss, disorientation, and seizures (12)

SOURCES: (1) P.S. Spencer and H.H. Schaumburg,Experirnerrfa/ and C/inica/ I’Veurofoxmry (Balttmore, MD: Wilhams& Wilkins, 1980); (2) H. Altenkirch et al., “The

neurotoxicologlcal Aspects of the Toxic Oil Syndrome (TOS) in Spare,” Toxkmbgy 49:25-34, 1968; (3) B. Weiss and T.W. Clarkson, “Toxic Chemical

Disasters and the Implications of Bhopal for Technology Transfer,” Mi/bank Ouartedy 64:216-240, 1986; (4) D.A.K. Cassells and E.C. Dodds, “Tetra-ethyl

Lead Poisoning,” British Medica/ Journal 2:681, 1946; (5) CD. Klaassen, M.O. Amdur, and J. DouII (eds.), Casaret? and DOUWS Toxicology (New York, NY:

Macmillan Publishing Co., 1986); (6) World Health Organization, Principles and Methods for the Assessment of neurotoxicity Assoc/aWd With Exposure to

Chemica/s, Environmental Health Criteria 60 (Geneva: 1986); (7) Morbidity and Mortalny Weekly Report, “Aldicarb Food Poisoning From Contaminated

Melons< alifornia,” Journa/ of American the Medica/ Association 256:1 75-176, 1986; (8) J.M. Horan et al., “Neurologlc Dysfunction From Exposure to

2-+-Butulazo-2-Hydroxy -5-Methylhexane (BHMH). A New Occupational Neuropathy,” American Journal of Public Health 75:513-517, 1985; (9) G.G. Goetz,

“Pesticides and Other Environmental Toxins, ” Neurotoxins m C/inica/ Pract/ce (New York, NY’ Spectrum Publications, Inc., 1985), pp. 107-131; (10) U.S.

Public Health Service, Centers for Disease Control, Morbldlty and Mortality Weekly Report, “Acute and Possible Long-Term Effects of 1,3-dlchloropropeneCalifornia,” Feb. 17, 1978, pp. 50, 55; (11) I.J Kopln and S.P. Maukey, “MPTP Toxlclty” Implications for Research In Parkinson’s Disease,” Annual Revmw

of Neuroscience 11 :81 -96, 1988; (12) J.M. Hungerford and M.M. Wekell, “Control Measures In Shellfish and Flnfish Industries: USA, ” Bothell, VA, U S. FDA,

m press.
48 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Mercury compounds are potent neurotoxic substances and have caused a number of human

poisonings worldwide. Common symptoms of exposure include lack of coordination, speech impairment, and vision problems, In the mid-1950s, a

chemical plant near Minamata Bay, Japan, discharged methylmercury, a highly toxic organic form

of mercury, into the bay as part of waste sludge (17).

Fish and shellfish became contaminated and were

consumed by local inhabitants, resulting in an

epidemic of mercury poisoning and severe neurotoxicological and developmental effects. Mercury used

as a fungicide in treating seed grain was the cause of

a very serious epidemic in Iraq in 1971, resulting in

more than 450 deaths (57) (see box 2-A).

Manganese is required in the diet in trace quantities but is highly toxic when relatively large amounts

are inhaled. Hundreds, perhaps thousands, of miners

in several countries have suffered from ‘manganese

madness, ’ a disorder characterized by hallucinations, unusual behavior, emotional instability, and

numerous neurological problems (43). Other metals,

including aluminum, cadmium, and thallium, are

neurotoxic in varying degrees. It is particularly

challenging to limit public exposure to metals

because they occur naturally in the environment.

Industrial Chemicals

Thousands of chemicals are produced by industry,

and new substances are constantly entering the

marketplace. Organic solvents are a class of industrial chemicals that have the potential for significant

human exposure. This is due in large part to their

volatility; that is, in the presence of air they change

rapidly from liquids to gases, which may be readily

inhaled. Their fat volubility and other chemical

properties make many solvents neurotoxic in varying degrees. Exposures may be accidental, as often

occurs in the industrial or household setting, or

deliberate, as in glue-sniffing, a common form of

inhalant abuse. Many solvents, including ethers,

hydrocarbons, ketones, alcohols, and combinations

Photo credit: W. Eugene Smith end Aileen Smith

A child victimized by mercury poisoning during the Minamata Bay, Japan, incident in the 1950s is bathed by his mother.

This is one of the most dramatic poisoning incidents involving a neurotoxic substance.
Chapter 2-Introduction . 49

Box 2-A—Mass Mercury Poisoning in Iraq, 1971

Wheat is believed to have been domesticated first in the fields of the Fertile Crescent, an area extending from

the Persian Gulf to the Palestinian coast, including much of what is now Iraq. Following a major drought in 1971

that ruined the wheat harvest of this region, the Iraqi government decided to switch to a more resilient variety of

wheat from Mexico, known as Mexipak. The Iraqis requested that the wheat seed be treated with mercury to protect

it from fungal infections. However, in placing the order, a single-letter typographical error was made in the name

of the fungicide, resulting in treatment of the grain with highly toxic methylmercury instead of the relatively

harmless form of organic mercury normally used.

In the fall of 1971, the largest commercial order of wheat in history (178,000 tons) was delivered to Iraq and

distributed throughout the country. In some areas the wheat arrived too late for planting and was used instead to

make bread. The sacks contained labels warning against consumption, but the labels were in Spanish. The grain had

also been colored by a pink dye to indicate that it was poisonous, but the farmers were not aware of the significance

of the color. Some of the sacks still carried the original warning labels from the U.S. manufacturer, with the skull

and crossbones poison designation; however, the Iraqi farmers were not familiar with this symbol.

The mercury-treated grain was consumed by thousands of Iraqis over a period of a few weeks. Indeed, the pink

color of the bread was thought to be attractive. Weeks later, the effects of mercury poisoning began to appear. At

first the symptoms were a burning or prickling sensation of the skin and blurred vision. These symptoms were

followed by uncoordinated muscular movements, blindness, deafness, coma, and in some cases death. Tragically,

one village was not aware of the delayed effects of mercury poisoning and assumed that the traditional yellow wheat

they had just eaten was responsible for the poisoning. Their efforts to obtain the pink variety, which they had recently

run out of, were unfortunately successful. The estimated toll of the mass poisoning was 6,000 hospitalizations, 5,000

severe poisonings, and 450 hospital deaths. Since many persons were not admitted to hospitals, the actual totals are

not known; however, the number of individuals significantly affected has been placed at more than 50,000 and the

number of deaths at 5,000.

The effects on developing fetuses in mothers who ate the bread have not been fully documented, but subsequent

analyses indicate that the fetus may be more than 10 times as sensitive to mercury poisoning as the adult. Afterbirth,

the exposed child may suffer seizures, abnormal reflexes, and delayed development. Severe cases involve cerebral

palsy. The extent and consequences of this tragedy still are not completely documented.

SOURCE: B. Weiss and T.W. Clarkson, “Toxic Chemical Disasters and the Implications of Bhopal for Technology Transfer, ” Milbank

Quarterly 64:216-240, 1986.

of these, have caused neurological and behavioral often unaware of the permanent damage that this

problems in the workplace. For example, in 1973,

workers at a fabric production plant in the United

States were discovered to have neuropathies, or

degeneration of nerve fibers. These workers had

been regularly exposed to methyl-n-butyl ketone

(MnBK), a dye solvent and cleaning agent introduced to the plant the previous year (25). Subsequent

laboratory studies implicated MnBK as the causative agent. neurotoxic solvents in the workplace will

be discussed further in a case study in chapter 10.

Solvents are commonly used in glues, cements,

and paints. The fumes of toluene-based spray paints,

various solvents, and modeling cements are sometimes inhaled as intoxicants. Inhalant abuse, an

important public health problem (13,38,45), can

cause severe degeneration and permanent loss of

nerve cells. About one in five high school students

has tried inhalants. Unfortunately, young people are

type of substance abuse can cause (46). -

Pesticides

Pesticides are one of the most commonly encountered classes of neurotoxic substances. In this report

‘‘pesticide’ is used as a generic term and includes

insecticides (used to control insects), fungicides (for

blight and mildew), rodenticides (for rodents such as

rats, mice, and gophers), and herbicides (to control

weeds), among others. More than 1 billion pounds of

pesticides are used annually in the United States

alone. Some 600 active pesticide ingredients used on

crops are registered with EPA. These active ingredients are combined with so-called inert substances to

make thousands of different pesticide formulations.

The organophosphorous insecticides, which account for about 40 percent of the pesticides registered in the United States, have neurotoxic proper-
50 ● neurotoxicity; Identifying and Controlling Poisons of the Nervous System

ties (10), as do other classes of pesticides, including

the carbamate and organochlorine insecticides. Because of the biochemical similarities between the

insect and human nervous systems, insecticides can

adversely affect humans as well, Organophosphorous and carbamate insecticides inhibit acetylcholinesterase, an enzyme responsible for inactivating the

neurotransmitter acetylcholine (a common chemical

messenger in the nervous system) after it has been

released by stimulation of a nerve cell. Consequently, these pesticides cause acetylcholine to

accumulate in the synapses (or points of contact)

between nerves and muscles. This leads to overstimulation of many nerves, including those that control

muscle movement, some organ systems, and thought

and emotional processes. Indeed, it is this property

that led to the development and use of organophosphorous compounds as “nerve gas” weapons.

Acute human poisoning from organophosphorous

insecticides can cause muscle weakness, paralysis,

disorientation, convulsions, and death. Of particular

concern are the delayed neurotoxic effects of some

of the organophosphorous insecticides. Some of

these compounds cause degeneration of nerve processes in the limbs, leading to changes in sensation,

muscular weakness, and lack of coordination (29).

Because of this property, the EPA requires that

organophosphorous insecticides undergo special

testing for delayed neurotoxicity.

In the mid-1970s, the American public became

acutely aware of the threat to human health posed by

neurotoxic substances when a number of workers at

a chemical plant in Hopewell, Virginia, were exposed to the insecticide chlordecone (a chlorinated

hydrocarbon marketed as Kepone). A previously

unidentified neurological disorder resulted, characterized by tremors, muscle weakness, slurred speech,

lack of coordination, and other symptoms (24). Of

the 62 verified cases, more than a third displayed

disabling neurological symptoms. The symptoms

appeared from 5 days to 8 months after onset of

exposure to large amounts of the insecticide and

remained in several of the workers for months after

cessation of exposure and closing of the plant (29).

This incident illustrates the difficulty physicians

face in diagnosing poisoning episodes. Affected

workers reported that the overt signs of poisoning

were preceded by a feeling of ‘‘nervousness, ’ a

symptom that might not lead a physician to suspect

exposure to a neurotoxic substance.

Because of their widespread use, pesticides are

dispersed in low concentrations throughout the

environment, including the Nation’s food and water

supplies. Between 1982 and 1985, the Food and

Drug Administration (FDA) detected pesticide residues in 48 percent of more than two dozen frequently

consumed fruits and vegetables (28). However,

OTA recently found that FDA’s analytical methods

detect only about one-half of the pesticides that

contaminate fruits and vegetables (53). Use of

pesticides has been so widespread that measurable

levels are frequently found in human tissues. DDT,

for example, was banned a number of years ago, yet

nearly everyone born since the mid-1940s has

measurable levels of this pesticide or its metabolizes

in their fatty tissues (29). Some scientists believe

that the levels of the persistent pesticides present in

humans pose no risk; others think there is cause for

concern and that more research is needed to evaluate

the public health risk of chronic, low-level exposures. The possible effects on the developing nervous system of chronic exposure to pesticides are of

particular concern.

Exposure to agricultural pesticides is highest

among mixers, loaders, applicators, farmworkers,

and farmers. Some 2 million seasonal and migrant

farmworkers harvest the Nation’s crops (9). Accurate statistics on the total number of these farmworkers who develop adverse health effects due to

pesticides are not available, but in California, where

physicians are required by law to report suspected

cases of pesticide-related illnesses, 1,093 cases were

reported in 1981. Of these, 613 cases were related to

agricultural activities, and 235 involved field workers exposed to pesticide residues (60). Reported

cases seem to reflect only a fraction of the actual

number, however (16). The issue of neurotoxic

pesticide use in the agricultural setting is the subject

of a case study in chapter 10. Poisonings are a

particular problem in developing countries, where

the misuse of pesticides is relatively common (see

ch. 9).

Therapeutic Drugs

Therapeutic drugs often alter the function, and

less often the structure, of the nervous system.

Generally, this alteration is desirable, as, for example, in the case of the tranquilizing effects of a drug

to treat anxiety or the mood-lifting effects of a drug

to treat depression. But such drugs can have

undesirable effects on the brain also. As mentioned
Chapter 2-Introduction ● 51

earlier, some drugs that effectively control the

symptoms of schizophrenia may also severely affect

neuromuscular function. Drugs that are used to treat

illnesses or health problems unassociated with the

nervous system (e.g., some anticancer drugs) may

have neurotoxic side-effects. Often, the adverse

effects of drugs are poorly documented or may go

undetected.

Of particular concern are the effects of therapeutic

drugs on the developing fetus. Most prescription

drugs given to pregnant women have not been tested

for potential effects on the fetus, nor have over-thecounter drugs been evaluated for use during pregnancy (14). Physicians normally exert particular

caution in prescribing drugs for pregnant women.

The Federal Food, Drug, and Cosmetic Act

requires that drugs be both safe and effective. Some

persons assert that FDA does not require adequate

neurotoxicity testing of prescription drugs and that

neurotoxic concerns are not being adequately addressed in the FDA review and regulatory process.

Others suggest that FDA moves too slowly in

approving drugs and that regulations are overly

burdensome. However, FDA officials believe that

current testing and evaluation procedures adequately

address neurotoxicological concerns (58).

The reported adverse effects of drugs listed in the

Physicians Desk Reference (42) and similar publications illustrate that many prescription drugs, especially psychoactive drugs, have neurotoxic sideeffects of varying significance. Some adverse effects

are an accepted consequence of drug therapy. When

a drug has been properly tested for neurotoxic

effects, doctor and patient can make informed

decisions about using it. However, inadequate testing for neurotoxicity exposes the public to unnecessary risk. There is scientific disagreement regarding

whether or not the safety of food additives and drugs

can be established in the absence of specific

neurotoxicity testing.

Abused Drugs

In 1986, drug abuse in the United States led to

more than 119,000 emergency room visits and 4,138

deaths (37). Many more cases go unreported. As

users and their families and friends sometimes

discover, substance abuse can permanently damage

the nervous system. In some cases, damage is so

severe as to cause personality changes, neurological

disease, mental illness, or death. Persons who abuse

Photo credit: John Boyle, Drug Enforcement Agency

drugs are often not aware of, or do not take seriously,

the threat these substances pose to their health.

Although the adverse effects of drugs are often

short-lived, some effects can be prolonged or

permanent. MPTP, an impurity sometimes formed

during the illicit synthesis of an analog of the drug

meperidine, can cause irreversible brain damage and

long-term dysfunction characteristic of Parkinson’s

disease (18,20,21). LSD, a highly potent hallucinogen, can seriously affect nervous system function

(17). Other drugs may have more subtle neurotoxic

effects. The chemically sophisticated, illicit “designer drugs” can dramatically alter normal brain

functions. MDMA, known on the street as “Adam’

or ‘‘ecstasy, ’ is a synthetic drug that causes

euphoria and hallucinations. It also causes confusion, depression, severe anxiety, blurred vision, and

paranoia (3,33). Some of these effects may occur

weeks after taking the drug. It was recently discovered that MDMA, at relatively high doses, causes

selective degeneration of brain cells producing the

neurotransmitter serotonin (4). Figure 2-1 illustrates

the degeneration of nerve fibers in a region of the
52 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

monkey’s cerebral cortex involved in the perception

of touch and position sense. Similar degeneration is

seen in most areas of the cortex. Until it became

illegal, MDMA was occasionally used as an adjunct

to psychotherapy because of the belief that it

removed barriers to communication between doctor

and patient.

Phencyclidine (PCP) is another major abused

drug. In 1984, it was responsible for 11,000 hospital

emergency room visits and more than 225 deaths.

Chronic use of PCP leads to depression, speech

difficulties, and memory loss (32,36).

Cocaine (known as ‘crack’ in its smokable form)

is currently the most frequently abused street drug in

the United States. More than 22 million Americans

have used cocaine at some time in their lives (34). In

1986, approximately 25,000 high school seniors

reported that they had used cocaine in the past year

and were unable to stop using it (35). Cocaine blocks

reabsorption of the neurotransmitter dopamine into

nerve cells. Feelings of euphoria are thought to be

due to excess dopamine in the synapses between

cells. Large concentrations of dopamine cause

changes in nerve cells, making them less responsive

to normal levels of the transmitter. Consequently,

when individuals stop using the drug they experience depression and want to take more to feel

“normal.” They are then caught in the addiction

cycle (35). Recently, it was reported that cocaine use

by pregnant women alters the development of the

brains of fetuses and infants (59). “Cocaine babies’

are a tragic consequence of drug abuse by pregnant

women (see box 2-B).

Food Additives

Food additives serve a variety of purposes, such

as to prolong shelf-life or to improve flavor, and

hundreds of them are used during the preparation,

manufacture, and marketing of foods. The use of

these substances is regulated by FDA, which maintains a list of additives that are generally recognized

as safe and may be used without specific approval.

All other food additives must be approved prior to

use. However, few additives have undergone neurotoxicity testing. In 1984, the NAS reported that 73

percent of the food additives it examined had not

been tested for neurobehavioral toxicity (30). Although animal testing of food additives is required

under the Federal Food, Drug, and Cosmetic Act to

evaluate their safety, studies in humans are not

Figure 2-1-neurotoxic Effect of MDMA on

Serotonin Nerve Fibers in the Cerebral Cortex

of the Monkey

A. Control

B. MDMA

Repeated administration of MDMA (5mg/kg, 8 doses) to a

Cynomolgus monkey produced degeneration of most serotonin

nerve fibers in this region of the cortex, which is involved in the

perception of touch and position sense. Similar toxic effects are

seen in most areas of the cerebral cortex.

SOURCE: M.A. Wilson and M.E. Molliver, Department of Neuroscience,

Johns Hopkins University School of Medicine.

required. Approval of drugs, however, does require

human testing. Many observers believe that food

additives should come under the same scrutiny as

drugs, particularly because many of them are regularly ingested by millions of people. The food

additive approval process is examined in a case

study in appendix A.

Cosmetics

Some 3,400 chemicals are used as cosmetics or

cosmetic ingredients in U.S. products (30). The
Chapter 2-Introduction ● 53

Box 2-B-Cocaine and the Developing Fetus

When a pregnant women abuses a psychoactive drug, she alters not only the activity of her own nervous

system, but that of her unborn child as well. Depending on the abused substance, the frequency of use, the dose,

and other factors, the mother’s quest for a temporary high can lead to permanent damage of the rapidly developing

fetal nervous system. According to a recent survey by the National Association for Perinatal Addiction Research

and Education (NAPARE), each year as many as 375,000 infants may be adversely affected by substance abuse.

Maternal substance abuse is frequently not recognized by health-care professionals during pregnancy.

Consequently, prevention and treatment programs are often too late. According to the National Institute on Drug

Abuse, approximately 6 million women of childbearing age (15 to 44) use illicit drugs, about 44 percent have tried

marijuana, and 14 percent have used cocaine at least once.

A recent study of 50 women who used cocaine during pregnancy revealed a 31 percent incidence of preterm

delivery, a 25 percent incidence of low birthweight, and a 15 percent incidence of sudden infant death syndrome.

These types of parameters are easy to quantify. The biochemical and neurobehavioral effects are more difficult to

document, but they are just as real. Early research indicates that cocaine babies suffer abnormal development of the

nervous system, impaired motor skills and reflexes, seizures, and abnormal electrical activity in the brain.

Cocaine is so addictive that it can suppress one of the most powerful human drives-maternal care. As one

pregnant crack addict put it: “The lowest point is when I left my children in a park for like 3 or 4 days. I had left

my kids with a girl that I know and told her. . . ‘watch them . . . I’ll be back’ and I didn’t come back. So that was

like—when I finally came down off of that high. I realized that I needed help. ” Sick and abandoned children of

cocaine mothers have placed a heavy burden on a number of the Nation’s hospitals. During a l-week period at one

hospital, one in five black infants and one in ten white infants were born on cocaine, Taxpayers usually end up

paying the health-care bill—a bill that can easily exceed $100,000 per infant.

SOURCES: National Association for Perinatal Addiction Research and Education, news release, Aug. 28, 1988; J.H. Khalsa, “Epidemiology

of Maternal Drug Abuse and Its Health Consequences: Recent Finding,’ National Institute on Drug Abuse, in preparation; ‘Cocaine

Mothers: Suffer the Children,” West 57th Street, CBS, July 15, 1989.

Courtesy of Dr. Emmalee S. Bandstra, M. D., Division of Neonatology, University of Miami/Jackson Memorial Medical Center
54 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

neurobehavioral toxicity of only a small percentage

of these has been reviewed. Indeed, the National

Academy of Sciences evaluated a representative

sample of cosmetics in 1984 (focusing on publicly

available documents) and found that none had

undergone adequate testing to identify potential

neurobehavioral effects (30).

The consequences of inadequate toxicity testing

are illustrated by the AETT incident. In 1955, AETT

(acetylethyl tetramethyl tetralin) was introduced

into fragrances; years later it was found to cause

degeneration of neurons in the brains of rats and

marked behavioral changes in rats, including irritability and aggressiveness. In 1978, it was voluntarily

withdrawn from use by the fragrance industry. Its

effects on humans through two decades of use will

probably never be known (50).

FDA lacks the authority to require premarket

testing of cosmetics. The agency may initiate an

investigation, however, if a basis is presented for

doubting a particular product’s safety. The regulation of cosmetics is discussed further in chapter 7.

TOXIC SUBSTANCES AND

NEUROLOGICAL AND

PSYCHIATRIC DISORDERS

Concerns about the effects of neurotoxic substances on public health have increased recently

because of new evidence that some neurological or

psychiatric disorders may be caused or exacerbated

by toxic agents in the environment. A noted case in

point is Parkinson’s disease. Researchers recently

discovered that exposure to small amounts of the

toxic substance MPTP can cause Parkinson-like

symptoms (20). Exposure to small quantities over a

period of days to a few weeks leads to the muscle

weakness and rigidity that is characteristic of

Parkinson’s disease.

Because of this finding, the possibility that toxic

chemicals might be causative agents in some cases

of Parkinson’s disease is being actively considered

by researchers. Some recent findings support this

hypothesis. For example, it has been reported that in

cases in which Parkinson’s disease afflicts several

members of a family, the onset of the disease tends

to cluster in time (5,21). Normally, if a disorder has

a purely genetic basis, onset of symptoms occurs at

similar ages, not at similar times. Evidence that

Parkinson’s disease does not occur more frequently

in identical than fraternal twins also argues against

a hereditary determinant of the disorder (18). A

recent epidemiological study revealed that between

1962 and 1984, U.S. mortality rates for Parkinson’s

disease substantially increased in individuals over

the age of 75 (figure 2-2). Environmental factors

appear to have played a significant role in the

increase (23). The relative roles of hereditary and

environmental factors in triggering Parkinson’s

disease remain to be determined.

Evidence for a substantial increase in the incidence of motor neuron disease (MND), primarily

amyotrophic lateral sclerosis (ALS), or Lou

Gehrig’s disease, in the United States has also

recently been reported (22). This disease is characterized by the progressive degeneration of certain

nerve cells that control muscular movement. MND

is a relatively rare disease, and its cause has eluded

researchers for more than a century. Recent data

indicate that between 1962 and 1984, the MND

mortality rate for white men and women in older age

groups rose substantially (figure 2-3). The increase

is thought to be largely due to environmental factors

(22).

Naturally occurring toxic substances can also

affect the nervous system. An unusual combination

of the neurodegenerative disorders ALS, Parkinson’s disease, and Alzheimer’s disease endemic to

Guam (known as Guam ALS-Parkinson’s dementia)

puzzled investigators for many years because of the

correlation between incidence of the disease and

preference for traditional foods. During food shortages, residents of the island ate flour made from the

false sago palm, a member of the neurotoxic cycad

family. The cycad contains one or more naturally

occurring toxic substances that appear to cause a

neuromuscular disease in cattle and trigger slow

degeneration of neurons (49), As old age approaches

and natural brain cell death accelerates, the effects of

the degeneration become apparent and the neurological symptoms appear, This possible link between a

naturally occurring compound and a neurodegenerative disease has stimulated the search for other toxic

substances that may trigger related neurological and

psychiatric disorders. This work and that of others

led to the hypothesis that Alzheimer’s disease,

Parkinson’s disease, and ALS could be due in part to

damage to specific regions of the central nervous

system caused by environmental agents and that the

damage may not become apparent until several

decades after exposure (6). Aluminum and silicon,
Chapter 2-Production ● 5 5

Figure 2-2—Average Annual Parkinson’s Disease

Mortality in the United States, White Males

Rate per 100,000 population

60 ! -

I

50

I

40

30

20 & 6

10 9

00 10 21 4 2

o-–

~ 50 50-54 55-59 60-64 65-69 70-74 75-79 80-04 85*

Age

@ Between 1962-1964 _ Between 1980-1984

SOURCE: Adapted from D.E. Lilienfeld et al., “Two Decades of Increasing

Mortality From Parkinson’s Disease Among United States

Elderly,” Archives of Neurology, in press.

Figure 2-3-Average Annual Motor Neuron Disease*

Mortality in the United States, White Males

Rate per 100,000 population

‘2~

10

8

6

5

4

4

3 3

2 2

2

0 0

111 1

8

c 40 40-4445-4950-5455-59 60-6465-6970-74 75-7980-84 85*

Age

@ Between 1962-1964 _ Between 7980-1984

● Most motor neuron disease is diagnosed as amyotrophic lateral sclerosis

(ALS), or Lou Gehrig’s disease.

SOURCE: Adapted from D.E. Lilienfeld, et al., “lncreasing Mortality From

Motor neuron Disease in the United States During the Past Two

Decades,” Lancet, Apr. 1, 1989, vol. 1, pp. 710-713.

for example, have been hypothesized to be causative

agents in Alzheimer’s disease; however, numerous

other possible causes have been proposed, and no

link between a toxic chemical and the disease has

been conclusively demonstrated (52).

Several other foods contain known neurotoxic

substances and can be responsible for severe neurological disorders. The drought-resistant grass pea

causes lathyrism, a disease characterized by weakness in the legs and spasticity and resulting from

degeneration of the spinal cord. The disease has been

known since ancient times and has been responsible

for several epidemics in Europe, Asia, and Africa

(48,50). Studies currently under way indicate that

the prevalence of lathyrism in an Ethiopian population that consumes the grass pea is 0.6 to 2.9 percent,

an unusually high incidence for a neurodegenerative

disease. Similarly, a large segment of the African

population regularly eats a species of cassava

(Manihot esculenta) that also damages the nervous

system and causes irreversible spasticity (47). Cassava (manioc), one of many cyanide-releasing foodstuffs in the human diet, is found with increasing

frequency in U.S. supermarkets.

Understanding the relationship between toxic

substances and biochemical and physiological neurological disease requires concerted epidemiological analyses. The extent to which toxic substances

contribute to major neurological and psychiatric

disorders is not known. Considerable research is

needed to define the role of neurotoxic substances as

causative agents.

IDENTIFYING neurotoxic

SUBSTANCES

Controlling neurotoxic substances is a two-step

process. The first step is to identify existing substances that adversely affect the nervous system and

take action to minimize human exposure to them.

The second step is to identify new neurotoxic

substances being generated by industry and take

action either to prevent the manufacture of those that

cause serious neurotoxic effects or limit the release

of the substances into the environment and hence

prevent human exposure to them. Testing is the key

to both objectives; however, as indicated earlier,

relatively few substances are evaluated specifically

for neurotoxicity. There are numerous examples of

neurotoxic substances that have entered the marketplace because of failure to conduct sufficient tests.

A classic example of testing inadequacy is BHMH

(Lucel-7), a catalyst used in the manufacture of

reinforced plastics such as bathtubs. The substance

had only been used for a few weeks at a plant in

Lancaster, Texas, before workers began experiencing neurological symptoms ranging from dizziness

and muscle weakness to visual disturbances and

memory loss. Two years later, several workers were

still experiencing some of these symptoms. Prelimi-
56 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

nary animal studies suggested that, BHMH was

neurotoxic, however regulatory action had not been

taken (15). Animal studies conducted after the

exposure demonstrated that rats experienced adverse

effects similar to those seen in humans. BHMH

might not have been marketed had appropriate

neurotoxicological tests been conducted and had the

data been properly analyzed and reported.

An important consideration in controlling toxic

substances is the need for efficient, economical, and

scientifically sound tests to identify substances that

should be regulated. Numerous tests are currently

available to evaluate neurotoxicity. A number of

these tests are described in detail in chapter 5. At the

present time, animal tests are an essential component

of neurotoxicological evaluations.

In vitro testing, based on tissue and cell culture, is

also useful in evaluating the neurotoxic potential of

chemicals (12). Two likely advantages are that many

substances can be screened in a relatively short

period of time and that costs may be considerably

less than the costs associated with animal tests (51).

In vitro tests may someday prove to be useful as a

rapid toxicity screening tool; however, further test

development is necessary. Like all tests, in vitro tests

have inherent limitations. For example, they are

probably of little use in identifying behavioral

effects because such evaluations require the intact

nervous system. Also, testing drugs or other chemicals in vitro makes it difficult to evaluate active

metabolizes that may form or accumulate following

administration to the intact animal.

REGULATING neurotoxic

SUBSTANCES

Regulatory agencies are responsible for limiting

public exposure to toxic chemicals through programs mandated by Congress. Because of the

diversity of toxic substances, numerous laws are in

place to control their production, use, and disposal.

These laws are administered by a variety of Federal

agencies, but primarily by EPA, FDA, and the

occupational Safety and Health Administration.

New and existing industrial chemicals are regulated under the Toxic Substances Control Act.

Pesticides are controlled by the Federal Insecticide,

Fungicide, and Rodenticide Act, and exposure to

toxic substances in the workplace is regulated by the

Occupational Safety and Health Act. In addition, the

Federal Food, Drug, and Cosmetic Act regulates

food additives, drugs, and cosmetics. Although these

laws address most toxic substances, more than a

dozen other acts focus on less prevalent but equally

important substances. While neurotoxicity is often

not explicitly mentioned in laws regulating toxic

substances, it is implicit in general toxicity concerns.

Regulating toxic substances on the basis of any

single endpoint such as carcinogenicity may not

adequately protect the public health. Effects on

organ systems and other toxicities may pose an equal

or greater threat than carcinogenicity itself. Lead, for

example, is both neurotoxic and carcinogenic; however, the neurotoxic concerns have far outweighed

the carcinogenic concerns in decisionmaking. Complete characterization of the risk posed by exposure

to toxic substances should include an evaluation of

both carcinogenic and noncarcinogenic risk, including the potential for neurotoxicity. The Federal

framework for regulating toxic substances in general, including neurotoxic substances, is described in

detail in chapter 7.

ECONOMIC CONSIDERATIONS

Although it is expensive to evaluate any chemical

for its potential toxic effects, these costs may be

small relative to the costs associated with development of a new product, care of injured persons,

workers’ compensation, or litigation resulting from

injury. Furthermore, the costs to society of public

exposure to toxic substances, measured in terms of

medical care and lost productivity, are potentially

very high.

Society must weigh carefully the positive health

and economic impacts of use of hazardous chemicals

against the negative health and economic consequences of human exposure to substances whose

toxicity has not been adequately evaluated. If

industry is required to do additional testing, regulatory agencies should ensure that the tests are

appropriate and cost-effective. Chapter 8 focuses on

the challenge of balancing economic costs and

benefits.

INTERNATIONAL CONCERNS

neurotoxicity is an international as well as

national problem. Of particular concern to many

persons is the export of neurotoxic substances from

the United States to other nations. Tens of thousands

of tons of pesticides, for example, are exported each
Chapter 2-Introduction . 57

year by U.S. manufacturers, even though the use of

some of these substances is banned or severely

restricted in the United States. Critics of this policy

raise questions regarding the ethics of a wealthy,

industrialized nation profiting from the export of

such substances to developing nations that may not

have the resources to ensure protection of the public.

In what has been called the ‘circle of poison,” foods

imported into the United States sometimes contain

residues of exported pesticides that are unregistered,

restricted, or banned for U.S. use (55).

In 1979, a Federal Interagency Hazardous Substances Export Policy Task Force prepared guidelines governing the export of pesticides, drugs, and

other materials. Its recommendations led to an

Executive Order on Federal Policy Regarding

Banned or Significantly Restricted Substances. The

order was signed by President Jimmy Carter in

January 1981, several days before the end of his

term, but it was revoked by President Ronald Reagan

shortly thereafter. Consequently, policy regarding

the export of banned and restricted hazardous

substances, whether pesticides, foods, or other

materials, remains a topic of debate. These and other

international issues are discussed in more detail in

chapter 9.

1.

2.

3.

4.

5.

6.

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Chapter 3

Fundamentals of neurotoxicology

‘ ‘The upsurge of interest in recent years in academia, industry, and government on the effects of toxic

chemicals on the nervous system has created a new discipline of neurotoxicology.”

Peter S. Spencer, Ph.D.

Herbert H. Schaumburg, Ph.D.

Experimental and Clinical neurotoxicology, 1980

"

. . . the recognition that a chemical component in street heroin [causes] Parkinson’s disease or [a]

Parkinsonian disease or [a] Parkinsonian state comes like a lightning bolt to the medical community. . . . Now

suddenly, with this new awareness, the neurological community is beginning to ask questions about other

disorders, such as Lou Gehrig’s disease, Alzheimer’s disease. Could this possibly be the result of chemical

exposure?

Bernard Weiss, Ph.D.

Testimony before the House Committee on Science and Technology

October 8, 1985

<<

. . . this is not a situation where we get depressed and anxious first and then developed these symptoms in

our mind. This is a situation where these symptoms came along from exposure to fumes and chemicals and

then we got severely depressed and anxious. ’

Aerospace Worker

Testimony before the Senate Committee on Environment and Public Works

July 15, 1989
CONTENTS

Page

OVERVIEW OF TOXICOLOGICAL PRINCIPLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Absorption, Distribution, Biotransformation, and Excretion . . . . . . . . . . . . . . . . . . . . . . . .

Interaction of Multiple Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... ..,...,+

THE NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Development and Aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

EFFECTS OF TOXIC SUBSTANCES ON THE NERVOUS SYSTEM . . . . . . . . . . . . . . .

Structural Changes . . . . . . . . . . . . . . . . . . . . . . . . . . .,,.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Functional Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Behavioral Effects .+ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Susceptibility to neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CLASSES OF neurotoxic SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Actions

Actions

Actions

Actions

Actions

Further

on the Neuronal Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

on Neuronal Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

on Glial Cells and Myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

on the Neurotransmitter System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

on Blood Vessels Supplying the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . .

Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

63

64

64

65

67

67

67

69

70

70

71

72

72

74

74

74

76

76

76

Boxes

Box Page

3-A. The Ginger-Jake Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

3-B. The Endangered Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71

3-C. MPTP and Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

3-1. The Fundamental Structure of the Nerve Cell. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-2. Chemical Communication at the Synapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .+...

65

66
Chapter 3

Fundamentals of neurotoxicology

Toxicology is concerned with the adverse effects

of natural or synthetic chemicals on the biochemical,

physiological, and behavioral processes of living

organisms. Because of the large number of chemicals in commerce and the wide variety of effects they

may cause, toxicology is a broad science and

toxicologists tend to specialize in one or more areas

of the field. Biochemical toxicologists study the

effects of toxic chemicals at the molecular and

cellular levels. Regulatory toxicologists evaluate the

risks posed by these substances and recommend

actions that can be taken to reduce human exposure

and environmental contamination. Clinical toxicologists examine the effects of drugs and toxic

chemicals on human health and develop treatments

to mitigate adverse effects. Behavioral toxicologists

are concerned with the effects of toxic substances on

animal and human behavior. Environmental toxicologists address the effects of pollutants on plants and

animals, including humans (10).

neurotoxicology is concerned with the adverse

effects of chemicals on the nervous system. Research in this field involves examining the modes by

which neurotoxic substances enter the body, the

effects of these substances on the various components of the nervous system, the biochemical and

physiological mechanisms by which these effects

occur, the prevention of damage to the nervous

system, and the treatment of neurological and

psychiatric disorders associated with exposure to

toxic substances. Although scientists have made

tremendous progress in understanding the nervous

system, there is still much to learn about its function

under both normal and abnormal circumstances.

OVERVIEW OF

TOXICOLOGICAL

PRINCIPLES

In order for a toxic substance to cause adverse

health effects, it, or its metabolic products, must

enter the body and reach the target organ(s) at a

sufficient concentration and for a sufficient length of

time to produce a biological response. Chemicals

differ in toxicity, with some being toxic in very

small quantities and others having little effect at

even very high doses. This relationship between

exposure to a toxic substance and the extent of injury

or illness resulting from it is called the “doseresponse” relationship. In addition to dose, other

critical variables determining toxicity are the properties of the chemical (e.g., its volubility), the means

of exposure (through the lungs, stomach, or skin),

the health and age of the exposed individual, and the

susceptibility of the target organ or tissues (10).

._.——

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Illustrated by: Ray Driver
64 ● neurotoxic@: Identifying and Controlling Poisons of the Nervous System

Absorption, Distribution, Biotransformation,

and Excretion

Toxic substances normally enter the body through

the lungs (inhalation), the skin (absorption), or the

gastrointestinal tract (ingestion). In the industrial

setting, most exposures occur through inhalation or

absorption. After the substance enters the bloodstream, it is partitioned into body tissues, where it

may act on target organs or tissues. For various

reasons, including insolubility, some substances are

not distributed through the body. Ultimately, toxic

substances are eliminated from the bloodstream

through accumulation in various sites in the body

and through biotransformation and excretion.

Sites of accumulation of toxic substances mayor

may not be the primary sites of toxic action. Carbon

monoxide, for example, reaches its highest concentration in red blood cells, where it competes successfully with oxygen for binding sites in hemoglobin;

it then causes widespread brain damage when these

red blood cells fail to supply an adequate amount of

oxygen to the brain. Lead, a potent neurotoxic

substance, is found in highest concentrations in bone

but exerts its most serious effects on the brain. The

liver and kidney are major sites of accumulation of

toxic substances, probably because of their large

blood capacities and their roles in eliminating toxic

substances from the body. Lipophilic toxic chemicals (i.e., chemicals soluble in fat-like materials; also

termed hydrophobic) tend to accumulate in lipidrich areas such as body fat. The brain may be

particularly vulnerable to these toxic substances

since 50 percent of the dry weight of the brain is

lipid, compared to 6 to 20 percent of other organs of

the body (5).

The body has a number of ways to detoxify

foreign substances. The liver is the principal organ

involved in detoxification, but other organs such as

the kidney, the intestine, and the lung also play

major roles. In fact, nearly every tissue tested has

some capacity for detoxification; these capacities,

however, are often limited to particular types of

compounds. Adverse effects may occur when the

quantity of the substance ingested overwhelms

detoxification mechanisms, when an injury or illness

has compromised the body’s capabilities for detoxification, or when no mechanism is available to

modify or remove the particular substance.

Before excretion, a substance may undergo biotransformation, the biochemical process by which it

is converted into new chemical compounds which

are often more easily excreted. This process usually

changes lipophilic compounds to compounds which

are more hydrophilic (water soluble) and therefore

more easily excreted. Although biotransformation

normally aids in the detoxification of substances, it

sometimes results in compounds that are more toxic.

Therefore, when analyzing neurotoxic substances

and the health risks they pose, it is important to

remember that the compound originally ingested or

absorbed by an organism may not be the toxic

substance that eventually acts on the nervous system.

Excretion of toxic chemicals from the body occurs

through a variety of routes. Many substances are

removed by the kidney and excreted through the

urine. The liver is effective in detoxifying and

removing substances that enter the body through the

gastrointestinal tract. Some toxic substances, such as

lead and mercury, are excreted from the liver into the

bile and then into the small intestine, bypassing the

blood and the kidneys (10).

Toxic substances are more easily removed from

the body if they are hydrophilic or if they can be

biotransformed into a more hydrophilic compound.

Lipophilic toxic substances are removed from the

body through a number of mechanisms; these

include excretion in feces and bile, excretion of

water-soluble metabolizes in the urine, expiration

into the air, and excretion through the skin.

Interaction of Multiple Toxic Substances

The health effects of toxic substances are frequently examined with the assumption of a single

chemical acting alone on a particular organ or type

of tissue. Such an analysis has limitations, however.

In some cases, an individual may be exposed to

multiple chemicals that act on different organs and

tissue types, and one cannot assume that the effect of

these substances combined is the same as the

combined effects of separate exposures. Chemical

interactions may take place between substances.

Sometimes the effects are additive (i.e., the combined effects are equal to the sum of the effects of

each of the substances individually); at other times,

the effects may be synergistic (i.e., the combined

adverse effects exceed the sum of the individual

effects).
Chapter .3-Fundamentals of neurotoxicology . 65

A substance that is not toxic may increase the

toxicity of another substance through a process

called potentiation. More rarely, two toxic chemicals may result in no adverse effect when present

together, a phenomenon called antagonism. Synergism, potentiation, and antagonism must be taken

into account when examining exposure to complex

mixtures of toxic substances such as those found in

contaminated drinking water, smoke from an industrial fire, and fumes from a hazardous waste site (10).

THE NERVOUS SYSTEM

The fundamental unit of the nervous system is the

nerve cell, or neuron (figure 3-l). While neurons

have many of the same structures found in every cell

of the body, they are unique in that they have axons

and dendrites, extensions of the neuron along which

nerve impulses travel, and in that they synthesize

and secrete neurotransmitters, specialized chemical

messengers that interact with receptors of other

neurons in the communication process.

Certain nerve cells are specialized to respond to

particular stimuli. For example, chemoreceptors in

the mouth and nose send information about taste and

smell to the brain. Cutaneous receptors in the skin

are involved in the sensation of heat, cold, and touch.

Similarly, the rods and cones of the eye sense light.

Glial cells appear to perform functions which

support neurons-i. e., supplying nutrition, structural support, and insulation. Certain glial cells, for

example, produce myelin, a fatty substance that

covers the axons of many neurons throughout the

body and acts as insulation.

Electrical information in the form of nerve

impulses travels along the axons and dendrites of

n Figure 3-l—The Fundamental Structure of the Nerve Cell

Cell body

A

.

SOURCE: Office of Technology Assessment, 1990. ‘

“Ites
66 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

neurons. The impulses are generated by a rapidly

changing flow of charged ions, primarily sodium

and potassium, through channels in the nerve cell

membrane. The insulating myelin sheath surrounding many nerves allows the electrical impulses

(action potentials) to travel farther and faster than

they otherwise could. Impulses generally travel

away from the cell body of the neuron along axons

and interact with the dendrites of other neurons. The

point of interaction between adjacent nerve cells is

called the synapse (figure 3-2). Here, neurotransmitters stored in vesicles in the axon terminal are

released by electrical impulses, travel across the

synaptic cleft, and bind to receptors on adjacent

nerve cells, triggering biochemical events that lead

to electrical excitation or inhibition. Information

may also be transmitted from nerves to muscle

fibers; in this case the point of interaction is called

the neuromuscular junction.

Neurotransmitters are chemical messengers that

can be subdivided into two categories: the classical

neurotransmitters and the neuropeptides. Classical

neurotransmitters include serotonin, dopamine, acetylcholine, and norepinephrine; the neuropeptides

include endorphin, enkephalin, substance P, and

vasopressin. Classical neurotransmitters are typically secreted by one neuron into the synaptic cleft,

where they interact with receptors on the surface of

the adjacent cell. Neuropeptides, on the other hand,

may act over long distances, traveling through the

bloodstream to receptors on other nerve cells or in

other tissues. Binding of a transmitter to a receptor

triggers a series of biochemical events that ultimately affect the electrical activity, or excitability,

of the neuron. Depending on the type of transmitter

released and the type of receptors, the effect of the

chemical interaction is either to inhibit or to

stimulate the electrical activity of the adjacent cell.

When multiple neurons impinge on a single neuron,

that neuron integrates the inputs, resulting in a net

excitation or inhibition.

The nervous system is anatomically separated

into two major divisions: the central nervous system

and the peripheral nervous system. The central

nervous system encompasses the brain and spinal

cord, while the peripheral nervous system encompasses the nerves that travel to and from the spinal

cord, sense organs, glands, blood vessels, and

muscles.

Figure 3-2-Chemical Communication at the Synapse

Synapse

A

G):..:.n J“:~:; ~

~ik- Qo

~ Q :“ .

. . . .

, . . .

. .. . . .

‘.

- . . “ ; .“ : Receptors

. . .

. ..

. .

Neurotransmttter

.. . vesicles

I

Axon

terminal I

Synaptic

cleft

Dendnte

SOURCE: Office of Technology Assessment, 1990.

The brain is composed of between 10 billion and

100 billion cells organized into vast networks of

interacting axons and dendrites which comprise on

the order of 1015 connections (17). The brain and

spinal cord control vital functions of the body

(including vision, hearing, speech, learning, memory, and muscular movements) through these complex networks and through a wide variety of

neurotransmitters.

Information from sensory receptors is sent to the

spinal cord and brain, where it is translated and

integrated with other information. Sometimes the

sensory information leads to muscular movement—

for example, if one touches a hot stove. This reflex

circuit involves both sensory neurons, which sense

the heat and send the information to the spinal cord,

and motor neurons, which send instructions to the

muscles.

Most of the central nervous system is partially

protected by the blood-brain barrier, a layer of

tightly juxtaposed cells in blood vessel walls that

allow some substances to pass from blood to neural

tissue while keeping others out. This selective

barrier protects much of the nervous system from

substances that are either not necessary for metabolic functions or that may be damaging. Smaller

compounds and compounds that are soluble in lipids

tend to cross the barrier more easily, while larger

compounds and substances which are soluble in

water may be kept out. In addition, some compounds
Chapter 3-Fundamentals of neurotoxicology ● 67

cross the barrier with the help of carrier proteins

which bind specifically to them. Drugs intended to

act directly on the nervous system must therefore be

designed in such a way as to pass through the

blood-brain barrier into the brain. Most tranquilizers, narcotics, and anesthetics readily traverse the

barrier.

Development and Aging

The first signs of the nervous system are exhibited

around the 10th to 14th day of fetal development,

when a flat sheet of around 125,000 cells forms from

the outer layer of the ball of undifferentiated

embryonic cells. The sheet then rolls into a tube,

called the neural tube, which will eventually develop

into the spinal cord and brain. Over the next 2

months these cells multiply, migrate, and begin

differentiating into specific types of neurons and

glia. The mechanism by which the undifferentiated

embryo develops is unknown; however, embryologists believe that the cells’ chemical environments

play large roles in these determinations.

At approximately the 20th week, the neurons

begin to extend axons and dendrites, initiating

development of the nervous system’s complex

network of synaptic contacts. The nervous system is

not fully developed until sometime during infancy.

However, small modifications in the network do

appear to take place even in the adult nervous system

(7).

The nervous system undergoes major changes

with aging. At the tissue and cellular level, the aging

process results in nerve cell loss, neurofibrillary

tangles (abnormal accumulation of certain filamentous proteins), and neuritic plaques (abnormal clusters of proteins and other substances near synapses).

Neurons have a very limited capacity to regenerate;

thus, as cells die, the complex neuronal circuitry of

the brain becomes impaired. Aging is also accompanied by alterations in neurotransmitter concentration

and the enzymes involved in the synthesis of these

transmitters. Some neurons gradually lose their

insulating myelin sheath, slowing conduction of

electrical impulses along the axons.

Some-components of the nervous system appear

to age differently than others. In a healthy person, for

example, intellectual abilities such as memory,

vocabulary retention, and comprehension seem to be

maintained at least until the mid-70s, while motor

skills, coordination, and sensory functions gradually

become impaired (15). Specific areas of the brain

may age at different rates. The locus ceruleus and the

substantial nigra, two discrete areas of the brain,

undergo a period of cell loss between the ages of 30

and 50, with the decline in cell number slowing

thereafter (9). Between the ages of 20 and 80, the

number of cells in the cerebral cortex may be

reduced by half. In contrast, the Purkinje cells of the

cerebellum decline in a linear fashion throughout

life, while other clusters of cells are maintained at

the same levels regardless of age.

EFFECTS OF TOXIC SUBSTANCES

ON THE NERVOUS SYSTEM

Structural Changes

Toxic substances can alter both the structure and

the function of cells. Structural alterations include

changes in the morphology of the cell and the

subcellular structures within it, and destruction of

groups of cells. The long axons of some neurons, the

inability of neurons to regenerate, and the nervous

system’s dependency on a delicate electrochemical

balance for the proper communication of information make the system especially vulnerable to the

effects of toxic chemicals.

When a toxic substance enters the human body, it

can affect the biochemistry and physiology of

neurons and glia in a variety of ways. The cells may

swell, their internal contents may become more

acidic, and biochemical processes such as protein

synthesis and neurotransmitter secretion may be

inhibited. Often these changes result from anoxia—

i.e., oxygen deprivation. Neurons require relatively

large quantities of oxygen because of their high

metabolic rate and are therefore more vulnerable

than other cells to anoxia.

At the morphological level, toxic substances seem

to act selectively on the various components of the

nervous system, damaging the neuronal bodies

(neuropathy), axons (axonopathy), and myelin

sheaths (myelinopathy). A common type of structural change induced by toxic substances on axons

is central-peripheral distal axonopathy (CPDA).

Degeneration of this type usually begins at the end

of the axon and proceeds toward the cell body, hence

it is often referred to as the “dying-back” process.

Some organophosphorous insecticides can cause

this type of damage after a single exposure; however, for the majority of chemicals producing this
68 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

E

a

E

u

46

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x
Chapter 3-Fundamentals of neurotoxicology ● 69

effect, continuous or prolonged intermittent exposure is necessary. Thousands of people were paralyzed during Prohibition after ingesting a popular

alcohol substitute contaminated with an organophosphorous chemical (see box 3-A).

Toxic substances often cause a slow degeneration

of the nerve cell body or axon that may result in

permanent neuronal damage. Acute carbon monoxide poisoning, for example, can produce a delayed, progressive deterioration of portions of the

nervous system that may lead to psychosis and death

over a period of weeks (8).

Functional Changes

Toxic chemicals can induce functional changes

that involve modifications of motor and sensory

activities, emotional states, and integrative capabilities such as learning and memory. Numerous sensory systems can be adversely affected, including

sight, hearing, and touch and pain sensation. These

effects may be caused by destruction of the myelin

sheath that surrounds neurons (a process known as

demyelination), damage to the neuron itself, or

damage to the neurotransmitter system. Sensory

changes are often reported as numbness or a tingling

sensation. Methyl mercury is one chemical that is

extremely toxic to the visual, sensory, and motor

systems. Several episodes of large-scale human

intoxication by this organic heavy metal have been

described (3). In recent years, tests have been

developed to detect sensory changes, particularly in

visual and auditory functions resulting from exposure to toxic substances.

Organophosphorous and carbamate insecticides

can induce functional changes by inhibiting acetylcholinesterase, an enzyme that breaks down the

neurotransmitter acetylcholine. The functionalchanges

include hyperactivity, neuromuscular paralysis, weakness, vomiting, diarrhea, and dizziness, with more

severe cases exhibiting convulsions, coma, or death.

The onset and duration of symptoms depend on the

inherent toxicity of the insecticide, the dose, the

route of exposure, and preexisting health conditions.

Some organophosphorous pesticides can produce

delayed and persistent neuropathy by damaging

neurons in the spinal cord and peripheral nervous

Box 3-A—The Ginger-Jake Syndrome

During Prohibition, contamination of a popular ginger extract with triorthocresyl phosphate led to an epidemic

of partial paralysis that came to be known as the Ginger-Jake syndrome. The case serves as a dramatic example of

the neurotoxic potential of organophosphorous substances.

Extract from the Jamaica ginger had been used in the United States since the 1860s as a medicinal tonic. A

typical preparation contained 70 to 80 percent alcohol by weight and reputedly aided in digestion, prevented

respiratory infections, and promoted menstrual flow. Nicknamed ‘‘Jake," the tonic became especially popular in

the early 1900s in areas where local legislation outlawed the sale of alcoholic beverages.

During Prohibition, the legal sale of ginger extract was limited to a “fluidextract” which contained 5 grams

of ginger per cubic centimeter of alcohol (usually ethanol). Since the high concentration of ginger yielded a solution

too irritating to drink, the requirement was supposed to confine its use to medicinal purposes. Department of

Agriculture agents would occasionally check for the appropriate ginger content by boiling off the alcohol and

weighing the solid residue. However, bootleggers soon saw the possibility of dissolving small amounts of ginger

into alcohol and substituting adulterants, such as molasses or castor oil, for the remaining required solid content.

The result was a potable alcohol source that could be sold at bargain prices.

In 1930, perhaps in response to an increase in the price of castor oil, one bootlegger tried Lyndol, a

heat-resistant oily material used in lacquers and varnishes, as an adulterant. When consumed, the triorthocresyl

phosphate in Lyndol caused axonal degeneration in neurons of the central and peripheral nervous systems.

Depending on the severity of the case, symptoms ranged from temporary numbness and tingling in the extremities

to permanent partial paralysis. Estimates vary widely, but between 20,000 and 100,000 people were permanently

affected before all the poisonous shipments were seized.

SOURCES: M.B. Abou-Doniaand D.M. Lapadula, “Mechanisms of Organophosphorus Ester-Induced Delayed neurotoxicity: Type I and Type

II, ” Annuuf Review of Pharmacology and Toxicology 30:405440, 1990; S.D. Davis and R.J. Richardson, “Organophosphorus

Compounds, ” Experimental and Cfinical Neurofoxicofogy, P.S. Spencer and H.H. Schaumburg (eds.) (Baltimore, MD: Williams

& Wilkins, 1980); J.P. Morgan, “The Jamaica Ginger Paralysis,” Journal of the American Medical Associatwn 248; 1864-1867,

1982; J.P. Morgan, City University of New York, personal communication, Jan. 4, 1990.
70 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

system; in these cases, the resulting muscle weakness may progress to paralysis (4, 26).

Motor and sensory functions are closely linked

within the nervous system. Body movements, for

example, involve complex feedback interactions

between motor and sensory neurons to allow

smooth, controlled movements. Consequently, damage to sensory systems can indirectly affect certain

motor functions. Some toxic substances affect motor

neurons directly; others damage both sensory and

motor neurons (a condition termed mixed neuropathy). Neurophysiological tests are available to monitor the conduction velocity of impulses along nerve

axons, and various neurological tests can be used to

detect muscle weakness and lack of control of

muscular movements.

Toxic substances often affect the higher functions

of the nervous system such as learning, memory, and

mood. Exposure to inorganic lead can lead to mental

retardation in children; at lower levels of exposure,

however, it may manifest itself as a shortened

attention span or a learning disability (16, 23).

Various tests are available to detect impairment of

these processes, some of which are described in

chapter 5.

Behavioral Effects

Behavioral changes may be the first indications of

damage to the nervous system. An individual

exposed to a toxic substance may initially experience vague feelings of anxiety or nervousness.

These feelings may progress to depression, difficulty in sleeping, memory loss (see box 3-B),

confusion, loss of appetite, or speech impairment. In

severe cases, a person may exhibit bizarre behavior,

delirium, hallucinations, convulsions, or even death.

Often, behavioral toxicological testing can detect an

impairment for which investigators have not yet

found a physiological or biochemical mechanism.

Exposure to neurotoxic chemicals during pregnancy may not produce obvious symptoms of

behavioral toxicity until long after the exposure has

ceased. This phenomenon has given rise to the field

of behavioral teratology (18). An issue of particular

concern to neurotoxicologists is the latency of some

neurotoxic effects. One explanation for latent, or

“silent,” damage is that at younger ages the brain

may be able to compensate for some adverse effects.

With age, this ability to compensate diminishes, and

the damage inflicted early in life may become

apparent (19, 25). It has been proposed that exposure

to toxic substances may trigger biochemical events

that may later contribute to the cause of certain

neurological diseases such as Parkinson’s disease,

amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s

disease), or Alzheimer’s disease. This hypothesis,

sometimes referred to as the environmental hypothesis, has recently been the subject of increased

interest following the MPTP incident (see box 3-C)

and the Guam-ALS episode (19). (See ch. 2).

Susceptibility to neurotoxic Substances

Everyone is susceptible to the adverse effects of

neurotoxic substances, but individuals in certain age

groups and persons with certain health problems

may be particularly at risk. The developing nervous

system is especially vulnerable to certain toxic

substances. Its cells are actively growing, dividing,

migrating, and making synaptic connections, and the

blood-brain barrier is not yet fully developed.

During the first weeks of prenatal development,

toxic substances may interrupt closure of the neural

tube, leading to such birth defects as spina bifida (a

defect in which the vertebral column is exposed) and

anencephaly (the absence of all or part of the brain).

During later development, the risks of exposure have

diminished for many components of the nervous

system; however, the cerebrum and cerebellum,

major portions of the brain responsible for functions

such as sight and movement, remain particularly

vulnerable (15, 22).

Factors such as dose of the toxic substance and

nutritional deficiencies in the mother also influence

the extent of damage. Ethanol (alcohol), cocaine,

antibiotics, and steroids, for example, can all adversely affect the fetal nervous system (18). Since

few drugs have been adequately evaluated for effects

on the developing fetus, physicians are advised to

exert special care in prescribing drugs to pregnant

women.

As the structure and function of the nervous

system decline with age, individuals become more

susceptible to the effects of many neurotoxic substances. Adverse effects that might have been

masked at a younger age by a vital, healthy nervous

system may become apparent. Those suffering from

neurological disorders are at greater risk because

toxic chemicals may exacerbate existing problems.

Persons suffering from multiple sclerosis or neuromuscular disorders, for example, are vulnerable
Chapter 3-Fundamentals of neurotoxicology . 71

Box 3-B—The Endangered Hippocampus

Deep inside the brain is a crescent-shaped structure that acts as a switching and information storage center. The

hippocampus, as it is called, is a site of convergence of many neural pathways and is in a strategic position to

modulate chemical information as it is transferred from one region of the brain to another, It is a major component

of the limbic system, which, along with the hypothalamus and amygdala, is involved in the control of emotion and

motivation. In recent years, evidence has mounted that the hippocampus is important if not critical, to learning and

memory processes. These processes are significantly impaired if the hippocampus or certain nerve pathways

entering it or leaving it are destroyed.

Learning and memory are often adversely affected by toxic substances, and some researched believe that the

hippocampus is an important target site of these substances. A number of toxic chemicals preferentially affect the

hippocampus, including many metals, some abused drugs, and certain viruses (including those responsible for

rabies and AIDS). The hippocampus is also adversely affected in neurodegenerative disorders such as Alzheimer’s

disease and in Down’s syndrome.

Many of the cells of the hippocampus appear to use the excitatory amino acids glutamate and aspartate as

neurotransmitters, Under normal circumstances the synthesis, storage, and release of these transmitters is delicately

balanced. However, adverse conditions associated with trauma, stroke, or exposure to toxic chemicals and drugs

may upset this balance, sometimes leading to an event known as excitotoxicity. This is a process by which

excitatory neurotransmitters released from neurons flood neighboring cells and weaken their membranes, leading

to cell death. The mechanism of this cascade of events is being examined closely in the case of glutamate because

the characteristics of the receptor that binds this transmitter are beginning to be understood. Recently, it was

discovered that the drug PCP blocks glutamate receptors and that other compounds that effectively block this

receptor are virtually identical to PCP.

There is much to learn about the transmitter systems in the hippocampus and the mechanisms by which toxic

substances alter these systems. Clues to how some aspects of learning and memory are altered by toxic substances

may ultimately be found in the biochemical machinery of this region of the brain.

SOURCES: S. Blakeslee, ‘Pervasive Chemical, Crucial to the Body, Is Indicted as an Agent in Brain Damage,” New York Times, Nov. 29, 1988;

TJ. Walsh and D.F. Emerich, “The Hippocampus as a Common Target of neurotoxic Agents,” Toxicology 49:137-140, 1988.

because the neural targets of these diseases are the the liver (15). This problem is especially relevant for

same as those of many neurotoxic substances.

Persons suffering from mental disorders may also be

more susceptible to neurotoxic substances because

of possible augmentation of their symptoms. Toxic

chemicals can cause or exacerbate anxiety, depression, mania, and psychosis. Most adverse effects are

short-term and reversible; however, long-term effects, including permanent damage to mental health,

can occur.

Diseases involving organs such as the kidney or

liver can indirectly affect the nervous system. The

build-up of waste products in the bloodstream due to

kidney failure or diabetes, for example, can cause

adverse effects on nervous tissue similar to those

caused by environmental exposure to toxic chemicals.

Malnourished individuals are generally at greater

risk of harm from neurotoxic substances than are

individuals with adequate diets. A person with a

thiamine (vitamin Bl

) deficiency, for example, is

more susceptible to the toxic effects of ethanol on

developing nations-that face regular food shortages.

CLASSES OF neurotoxic

SUBSTANCES

neurotoxic substances can be categorized according to the structural or functional changes they

cause. The following categorization, which groups

neurotoxic substances according to where they

appear to act, is a summary of a scheme developed

by Spencer and Schaumburg (20). The scheme

includes the following targets: neurons, glial cells

and myelin, the neurotransmitter system, and blood

vessels supplying the nervous system.

Some adverse effects may not be included in this

approach. For example, neurotoxic substances may

also affect cells of the immune system, which can in

turn influence nervous system function at any of

these neural sites. Interactions between the immune

and nervous systems have become the subject of
72 ● neurotoxiciV: Identifying and Controlling Poisons of the Nervous System

Box 3-C-MPTP and Parkinson’s Disease

In recent years, the hypothesis that Parkinson’s disease and other neurological disorders might be triggered by

environmental factors has become more widely accepted. Although toxic substances have long been considered

possible contributors to the cause of some disorders of the nervous system, the MPTP incident has focused more

attention on this environmental hypothesis.

MPTP is the abbreviation for l-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine, a compound that can be created

during the production of synthetic heroin. Remarkably, in just 5 to 15 days, this highly neurotoxic substance can

induce a syndrome virtually identical to Parkinson’s disease—a disease that usually occurs late in life and develops

slowly over a period of years. Both Parkinson’s disease and the- MPTP-induced syndrome are characterized by

tremors and lack of muscular control that stem from degeneration of neurons in the substantial nigra, a region deep

in the central area of the brain. Neurons in the substantial nigra synthesize and secrete the neurotransmitter dopamine,

hence Parkinson’s patients are treated with levodopa, a precursor of this neurotransmitter.

The discovery of the link between MPTP and Parkinson’s disease has dramatically changed the nature of

research on this disease. Much work has focused on MPP+, a metabolize of MPTP that is responsible for the adverse

effects on the brain. Recently, researchers discovered that a monoamine oxidase inhibitor, a type of drug sometimes

used to treat depression, blocks the conversion of MPTP to MPP+. Other researchers have shown that the

monoamine oxidase inhibitor Deprenyl, administered to Parkinson’s patients in combination with levodopa,

reduces the symptoms of the disease and extends their lives. It was found that Deprenyl slows the rate of

degeneration of neurons in the substantial nigra, perhaps making it useful in the treatment of Parkinson’s disease.

The MPTP story illustrates how a neurotoxic substance might cause or contribute to the development of

neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. The

relative contributions of environmental and genetic factors to the causes of these diseases are not understood and

are the subject of considerable research and debate within the scientific community. Although the extent to which

a neurotoxic substance contributes to the cause of Parkinson’s disease is unclear, the MPTP story serves as an

example of how neurotoxicological research can lead to a better understanding of the causes of neurological disease

and ways to treat it.

SOURCES: LJ. Kopin and S.P. Markey, “MPTP Toxicity: Implications for Research in Parkinson’s Disease,’ Annuul Review of Neuroscience

11:81-96, 1988; J.W. Langston, P. Batlard, J.W. Tetrud, et al., “Chronic Parkinsonism in Humans Due to a Product of

Meperidine-Analog Synthesis, ” Science 219:979-980, 1983; R. Lewin, “Big First Scored With Nerve Diseases,” Science

245:467468, 1989.

considerable interest in recent years, leading to a causing numbness in the face, neck, and limbs. This

new field of research known as neuroimmunology.

Actions on the Neuronal Membrane

As described earlier, the neuron consists of the

cell body and the dendrites and axons projecting

from it. The neuronal membrane contains a complex

system of pumps, receptors, and channels through

which charged molecules (ions such as sodium,

calcium, and potassium) travel into and out of the

cell. Toxic substances may act on any of these

components. Determining the mechanism of action

of neurotoxic substances often requires researchers

to investigate possible adverse effects on a variety of

receptors and channels.

Naturally occurring toxic substances such as

tetrodotoxin (from the puffer fish) and saxitoxin

(from the marine alga responsible for paralytic

shellfish poisoning) block ion channels, initially

is followed by difficulty in speaking and swallowing

and by an inability to coordinate muscular movements. In severe cases, respiratory paralysis may

result.

Toxic substances can also act to increase the flow

of ions across the membrane, resulting in many of

the same symptoms as those caused by the channel

blockers. Scorpion toxin and the pesticide DDT, for

example, act by increasing the flow of sodium ions.

Pyrethroid pesticides are an example of widely used

commercial compounds that exert toxic effects in

this manner.

Actions on Neuronal Structures

Substances such as mercury and lead cause

degeneration of the central nervous system. Intoxication by organic mercury, particularly in children,

can cause degeneration of neurons in the cerebellum
Chapter 3-Fundamentals of neurotoxicology ● 73

and can lead to tremors, difficulty in walking, visual

impairment, and even blindness. Lead adversely

affects the cortex of the immature brain, causing

irreversible mental retardation in young children

(23).

The peripheral nervous system is particularly

vulnerable to the effects of toxic substances because

it lies outside the central nervous system which is

partially protected by the blood-brain barrier. The

antitumor agent doxorubicin, for example, causes

degeneration of both central and peripheral nerve

axons (21).

Degeneration of the axon is one of the most

frequently encountered neurotoxic effects. Many

chemicals and drugs will cause axonopathy but will

not affect the cell body. In most cases, repeated or

chronic exposure is required before adverse effects

occur. The precise mechanisms by which axonal

degeneration occurs are not understood. Some

research suggests that toxic substances block the

Photo credit: U.S. Environmental Protection Agency

transport of substances between the cell body and

regions of the axon.

Often, degeneration begins at or near the end of

the axon and proceeds toward the cell body. As

noted earlier, this type of pathological effect is called

central-peripheral distal axonopathy (CPDA). An

afflicted individual may experience loss of sensation

in the hands and feet or muscular weakness. In some

cases, the effects gradually worsen, and the loss of

sensation progressively ascends to the limbs as

shorter nerves become affected. With time and

removal from exposure, recovery is often possible.

Numerous toxic substances cause CPDA, including such industrial chemicals as carbon disulfide

(discussed further in ch. 10), hexane, acrylamide,

and Lucel-7 (discussed in ch. 2). Drugs that cause

this axonopathy include thalidomide (whose other

tragic side-effects on the developing fetus have been

well documented) and vincristine, a drug used to

treat cancer. Alcohol abuse, some organophosphorous pesticides, and natural toxins present in buck-
74 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

thorn (from the fruit of the shrub Karwinskia

humboldtiana) also adversely affect the nervous

system in this manner.

A less common form of axonal degeneration,

central-distal axonopathy, is characterized by adverse effects on the spinal cord but not on the

peripheral nervous system. Some 10,000 cases

occurred in Japan between 1956 and 1972, when the

drug clioquinol was considered a safe and effective

nonprescription treatment for diarrhea caused by an

amoeba. Affected individuals experienced abdominal discomfort, numbness in the feet, weakness in

the legs, blurred vision, and, in cases where large

amounts of the drug were consumed, encephalitis

(inflammation of the brain).

The most serious form of neurotoxicity involves

the complete loss of nerve cells. Sensory nerve cells

may be lost in patients treated with megavitamin

doses of vitamin B6

; hippocampal neurons undergo

degeneration with trimethyltin poisoning; motor

nerve cells are affected in cycad toxicity, which has

been linked tentatively to Guam-ALS-Parkinsonism

dementia (19).

Actions on Glial Cells and Myelin

A large number of neurotoxic substances can

cause degeneration of glia1 cells and the myelin that

these cells produce. Diphtheria toxin, for example,

interferes with the cell bodies of myelin-producing

glial cells. Hexachlorophene interferes with the

energy-producing mitochondria within glial cells.

Perhexilline maleate, a drug used to treat the chest

pain of angina pectoris, sometimes causes degeneration of myelin and leads to numbness in the hands

and feet and muscle weakness.

Actions on the Neurotransmitter System

Other toxic substances may affect the neurotransmitter systems of neurons. The nicotine in cigarettes

and some insecticides, for example, mimic the

effects of the neurotransmitter acetylcholine. Organophosphorous compounds, carbamate insecticides,

and nerve gases act by inhibiting acetylcholinesterase,

the enzyme that inactivates the neurotransmitter

acetylcholine. This results in a build-up of acetylcholine and can lead to loss of appetite, anxiety,

muscle twitching, and paralysis.

Amphetamines stimulate the nervous system by

causing the release of the neurotransmitters norepinephrine and dopamine from nerve cells. Cocaine

affects both the release and reuptake (the process by

which neurotransmitters and their metabolizes are

recycled) of norepinephrine and dopamine. Both

amphetamines and cocaine can cause paranoia,

hyperactivity, and aggression, as well as high blood

pressure and abnormal heart rhythms.

Some drugs act by altering the action of the

neurotransmitter serotonin. LSD, a drug widely

abused in the United States, especially in the 1960s,

is a potent hallucinogen. Although it is not known

precisely how LSD functions, it does interfere with

the activity of the neurotransmitter serotonin. Mescaline and psilocybin (from the hallucinogenic

mushroom Psilocybes) act in a similar fashion.

Opium-related drugs such as morphine and heroin

act at specific opioid receptors in the brain. These

receptors interact with the endogenous brain neuropeptides, such as the enkephalins and endorphins,

which control the perception of pain and give rise to

feelings of euphoria. Consequently, drugs acting at

opioid receptors cause sedation and euphoria and

reduce pain. They also tend to slow the heart rate and

may cause nausea, convulsions, and slow breathing

patterns. They are highly addictive, leading to as yet

unidentified changes in the structure and function of

the nervous system. Researchers are actively seeking to understand the mechanisms by which addiction to opiates occurs. Withdrawal from this class of

drugs leads to impaired vision, restlessness, and

tremors.

A relatively recent phenomenon of increasing

concern to health-care workers is the addicted

infants born to women who use drugs such as

cocaine. These infants suffer from a variety of

behavioral abnormalities. Many of the symptoms of

withdrawal seen in adults can also be seen in these

infants immediately after birth (see box 2-B).

Actions on Blood Vessels Supplying the

Nervous System

The nervous system is supplied by an extensive

system of blood vessels and capillaries. The brain

needs large quantities of oxygen and nutrients and

relies on an extensive circulatory system to supply

needed substances and to remove toxic waste

products. Lead damages capillaries in the brain and

leads to the swelling characteristic of encephalopathy. Other metals (e.g., cadmium, thallium, and

mercury) and organotins (e.g., trimethyltin) cause
Chapter .3-Fundamentals of neurotoxicology ● 75

Crack is Cocaine ,/ ~

Crack Only Looks Harmless

Deadly Cycle

Instan t

Physical Effects

Tragedy

Users Say:

*

.

.

.

The Scope of Use

WHO

Signs of Use

Photo credit: U.S. Department of Education
76 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

rupturing of vessels that can result in encephalopathy as well.

Further Information

Neurobiology and toxicology are rapidly expanding scientific fields that cut across many disciplines.

A brief chapter can only touch on some of the

general scientific principles underlying neurotoxicology, which lies at the intersection of these two

fields. The interested reader may wish to consult any

of several textbooks or nontechnical books for

further information.

SUMMARY AND CONCLUSIONS

The complexity of the nervous system has made

the field of neurotoxicology one of the most

demanding disciplines in toxicology. In the last

decade, neurotoxicologists have been able to differentiate the effects of many chemicals in terms of

where they act and the symptoms they produce, but

in most cases they have not yet been able to

determine the mechanisms of action. Very few

suspected neurotoxic chemicals have been evaluated

in the laboratory and even fewer have been tested

thoroughly. These chemicals act at many levels of

the nervous system and exert their effects in a variety

of ways, with consequences ranging from mild

sensations of tingling in the extremities to severe

mental retardation, loss of sensory function, and

death. The chemicals may be particularly toxic to

susceptible populations such as the unborn, the

young, the sick, and the elderly. In order to safeguard

human populations against the potentially damaging

effects of these chemicals, it is necessary to study the

consequences of prolonged low-level exposures as

well as the effects of neurotoxic chemicals on

sensitive populations.

CHAPTER 3 REFERENCES

1.

2.

3.

Abou-Donia, M. B., and Lapadula, D. M., “Mechanisms of Organophosphorus Ester-Induced Delayed

neurotoxicity: Type I and Type II,” Annual Review

of Pharmacology and Toxicology 30;405-440, 1990.

Blakeslee, S., “Pervasive Chemical, Crucial to the

Body, Is Indicted as an Agent in Brain Damage,”

New York Times, Nov. 29, 1988.

Chang, L. W., “Mercury,” Experimental and Clinical neurotoxicology, P.S. Spencer and H.H. Schaumburg (eds.) (Baltimore, MD: Williams & Wilkins,

1980).

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

Cherniak, M. G., “Organophosphorus Esters and

Polyneuropathy,” Annals of Internal Medicine 104:

264-266, 1986.

Cooper, J.R., Bloom, F.E., and Roth, R.H., The

Biochemical Basis of Neuropharmacology (New

York, NY: Oxford University Press, 1982).

Davis, S. D., and Richardson, R.J., “Organophosphorus Compounds, Experimental and Clinical Neurotoxicology, P.S. Spencer and H.H. Schaumburg

(eds.) (Baltimore, MD: Williams& Wilkins, 1980).

Ferry, G., “The Nervous System: Getting Wired

Up,” New Scientist, Inside Science 19:1-4, Mar. 4,

1989.

Ginsburg, M.D., “Carbon Monoxide,” Experimental and Clinical neurotoxicology, P.S. Spencer and

H.H. Schaumburg (eds.) (Baltimore, MD: Williams

& Wilkins, 1980).

Katzman, R., and Terry, R. (eds.), The Neurology of

Aging (Philadelphia, PA: F.A. Davis, 1983).

Klaassen, C,, “Principles of Toxicology” and “Distribution, Excretion, and Absorption of Toxicants, ”

Casarett and Doull’s Toxicology, C. Il. Kkiassen,

M.O. Arndur, and J. Doull (eds.) (New York, NY:

Macmillan, 1986).

Kopin, I.J,, and Markey, S.P., “MPTP Toxicity:

Implications for Research in Parkinson’s Disease,”

Annual Review of Neuroscience 11:81-%, 1988.

Langston, J. W., Ballard, P., Tetrud, J. W., et al.,

“Chronic Parkinsonism in Humans Due to a Product

of Meperidine-Analog Synthesis, ’ Science 219:979-

980, 1983.

bwin, R., ‘‘Big First Scored With Nerve Diseases,”

Science 245:467-468, 1989.

Morgan, J. P., “The Jamaica Ginger Paralysis,”

Journal oftheAmericaniUe&”caL4ssociatwn 248:1864-

1867, 1982.

National Research Council, Drinking Water and

Health (Washington, DC: National Academy Press,

1986).

Needleman, H. L., “Epidemiological Studies,” Neurobehavioral Toxicology, Z. Annau (cd.) (Baltimore,

MD: Johns Hopkins University Press, 1986), pp.

279-287.

Restak, R. M., The Brain (New York, NY: Bantam

Books, 1984).

Riley, E.P., and Vorhees, C.V. (eds), Handbook of

Behavioral Teratology (New York, NY: Plenum

Press, 1986).

Spencer, P. S., Nunn, P. B., Hugon, J., et al., “Guam

Amyotrophic Lateral Sclerosis-Parkinsonism-Dementia Linked to a Plant Excitant Neurotoxin, ” Science

237:517-522, 1987.

Spencer, P. S., and Schaumburg, H. H., “An Expanded Classification of neurotoxic Responses Based

on Cellular Targets of Chemical Agents, ” Acta

Neurological Scandinavia 100:9- 19(suppl.), 1984.
Chapter 3-Fundamentals of neurotoxicology ● 77

21.

22.

23.

Spencer, P. S., and Schaurnburg, H.H. (eds.), Experimental and Clinical neurotoxicology (Baltimore,

MD: Williams & Wilkins, 1980).

Suzuki, K., “Special Vulnerabilities of the Develop- 24.

ing Nervous System to Toxic Substances, ’ Experimental and Clinical neurotoxicology, P.S. Spencer

and H.H. Schaumberg (eds.) (Baltimore, MD: Wil- 25.

liams & Wilkins, 1980).

U.S. Department of Health and Human Services,

Public Health Service, Agency for Toxic Substances 26.

and Disease Registry, The Nature and Extent of Lead

Poisoning in Children in the United States: A Report

to Congress (Atlanta, GA: Centers for Disease

Control, 1988).

Walsh, T.J., and Emerich, D.F., “The Hippocampus

as a Common Target of neurotoxic Agents,” Toxicology 49:137-140, 1988.

Weiss, B., “Neurobehavioral Toxicity as a Basis for

Risk Assessment,” Trends in Pharmacological Sciences 9:59-62, 1988.

Young, B. B., ‘‘neurotoxicity of Pesticides,’ Journul

of Pesticide Reform 6:2, 1986.
Chapter 4

Research and Education Programs

“There is increasing concern that basic research directed towards predicting, detecting, and understanding

neurotoxicity is being neglected by government, industry, and academic researchers.

Committee on Science and Technology

U.S. House of Representatives

September 16, 1986

“I would say that the methyl n-butyl ketone outbreak was the key episode in bringing attention to the field

of behavioral toxicology. That signaled a shift in thinking about behavioral problems. Before Columbus,

many of us thought, ‘Well, people who work with some chemicals might have trouble concentrating, or maybe

even some temporary or unimportant changes. After Columbus, we could see that even relatively safe

chemicals, in concentrations that pose no danger to other systems of the body, can bring serious and

sometimes irreversible damage to the nervous system.

W. Kent Anger, Ph.D.

Psychology Today

July 1982

“Much more work on mechanisms of chemical neurotoxicity will be required before structure-toxicology

considerations prove generally useful as a screen for neurotoxicity.

Peter Spencer, Ph.D.

“Testimony before the House Committee on Science and Technology

October 8.1985
CONTENTS

Page

FEDERAL RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

Environmental Protection Agency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

National Institutes of Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Alcohol, Drug Abuse, and Mental Health Administration . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Food and Drug Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88

Agency for Toxic Substances and Disease Registry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Department of Defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Department of Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Department of Agriculture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

National Aeronautics and Space Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

ACADEMIC RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Factors Influencing Academic Research Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92

Cooperative Agreements Between Government and Academia ..,..... . . . . . . . . . . . . . . 94

INDUSTRIAL RESEARCH ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Pesticide Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94

Pharmaceutical Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Consumer Product Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Specialty and Commodity Chemical Industries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

INTERACTIONS AM0NG GOVERNMENT, ACADEMIA, AND INDUSTRY . . . . . . 96

Industry and Government Consortia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Industry Research Consortia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Cooperation in Epidemiological Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Charitable Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

EDUCATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Education of Research Scientists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Education of Health-Care Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Figures

Figure Page

4-1. Resources for EPA’s neurotoxicology Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83

4-2. Funding for NIOSH Research Grants... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

Table

Table Page

4-1. Federal Funding for civilian neurotoxicity-Relatec! Research . . . . . . . . . . . . . . . . . . . 81
Chapter 4

Research and Education Programs

Increasing public concern about the effects of

toxic substances on the nervous system has led to

some expansion of research programs in government, academia, and industry in recent years. Even

so, the research programs are relatively small, and

questions are frequently raised as to whether they are

capable of addressing the threat that neurotoxic

substances pose to public health. The style and

purpose of research differs in each of these settings,

yet each makes important contributions. An optimal

national research program requires effective cooperation among researchers in all sectors and an

appropriate balance of effort.

This chapter describes current programs in the

United States and future needs for research into the

causes, extent, and consequences of exposure to

neurotoxic substances. The first half of the chapter

describes Federal research programs; the second half

addresses research efforts under way in academia

and industry. State research programs are not

described in this report.

FEDERAL RESEARCH

ACTIVITIES

Federal research related to neurotoxic substances

is conducted primarily at the National Institutes of

Health (NIH), the Alcohol, Drug Abuse, and Mental

Health Administration (ADAMHA), and EPA. Limited research programs are under way at the Food

and Drug Administration (FDA), the Centers for

Disease Control (CDC), the Department of Energy,

the Department of Agriculture, and other agencies.

As indicated in table 4-1, total Federal funding for

neurotoxicology -related research (excluding research

related to nicotine and smoking, alcohol and alcoholism, and radiation) is $67 million. The bulk of

this funding (89 percent) is through ADAMHA and

NIH and tends to focus on the toxicity of drugs and

the biochemical mechanisms underlying neurological and psychiatric disorders. A number of other

Federal agencies and organizations provide limited

funding for research related to neurotoxicity as well.

Given the threat that neurotoxic substances pose

to public health and the lack of knowledge of the

mechanisms by which these substances exert

adverse effects, OTA found that, in general,

Federal research programs are not adequately

addressing neurotoxicity concerns.

Environmental Protection Agency

The principal research component of EPA is the

neurotoxicology Division (NTD) within the Health

Effects Research Laboratory at Research Triangle

Park, North Carolina. This division was organized in

1978 and has gradually grown into an effective

interdisciplinary research program. A committee of

EPA’s Science Advisory Board recently reviewed

NTD’s program and described it as “the leading

Federal neurotoxicology research organization” (30).

NTD research programs range from development of

methods to evaluate the neurotoxicity of chemicals

to testing of specific substances and determining the

mechanisms by which toxic substances adversely

affect nervous system structure and function.

The NTD is divided into three branches: the

Neurophysiology and Neuropathology Branch, the

Behavior and Neurochemistry Branch, and the

Systems Development Branch, which provides engineering and technical support services to the first

two. Recently, the Science Advisory Board review

committee recommended that consideration be given

to developing a branch to focus on cellular and

molecular toxicology (30)0

EPA has developed a multidisciplinary program

to examine how toxic substances adversely affect

the nervous system. The overall program strategy

stresses the development of test methods and approaches for identifying and characterizing neurotoxicity and for predicting risk to humans. Studies

conducted to evaluate the cellular and molecular

Table 4-l-Federal Funding for Civilian

neurotoxicity-Reiated Research

Agency Researcha ($ millions)

National Institutes of Healthb 

. . . . . . 32.6

Alcohol, Drug Abuse, and Mental

Health Administrationc . . . . . . . . . . 26.6

Environmental Protection Agency. . . 3.9

National Institute for Occupational

Safety and Health . . . . . . . . . . . . . 0.7

Food and Drug Administration . . . . . 1.8

Department of Energyd . . . . . . . . . . . 0.5

Department of Agriculture . . . . . . . . . 0.4

Total . . . . . . . . . . . . . . . . . . . . . . . . 66.5

aTotalS are b~ed primarily on fiscal year 1988 data.

bExcludes research related to nicotine and smoking.

cExcludes research related to alcohol and alcoholism.

dExclu&S research related to radiation.

SOURCE: Office of Technology Assessment, 1990.

-81-
82 . neurotoxicity: Identifying and Controlling Poisons of the Nervous System

basis for chemically induced functional changes in

the central and peripheral nervous systems are

designed so that effects on laboratory animals can be

extrapolated to humans.

Behavioral research is aimed at evaluating autonomic, sensory, motor, and cognitive functions;

developing measures to screen chemicals for neurotoxic potential; and evaluating specific behavioral

processes that are disrupted by exposure to toxic

substances (12). Research to determine the utility of

short-term behavioral tests for measuring neurotoxic

effects helps EPA regulatory program offices in the

development of test guidelines. Long-term research

goals include the development of animal models that

can be used to predict behavioral toxicity in humans.

Cellular and molecular research focuses on locating biochemical and anatomical sites of toxicantinduced changes in the nervous system. This includes developing biochemical markers to identify

the targets of toxic substances within the nervous

system and performing morphological studies to

determine the structural consequences of exposure

to neurotoxic substances. NTD’s long-term goals are

to develop cellular and molecular approaches that

improve neurotoxicity testing and provide a better

understanding of the neurobiological basis for risk

assessment.

The neurophysiology component of the research

program is aimed at attaining a better understanding

of how physiological processes are disrupted by

neurotoxic chemicals. A primary focus is the electrophy biological evaluation of sensory systems,

which allows for direct measurement of nervous

system activity. Where possible, the program uses

methods that have direct counterparts in human

research, in order to make extrapolation easier (9).

EPA regulatory program offices need more methods of evaluating neurotoxicity, largely because of

the general requirements of the Federal Insecticide,

Fungicide, and Rodenticide Act (FIFRA) and the

Toxic Substances Control Act (TSCA) (see ch. 7).

When EPA requires industry to conduct neurotoxicity testing under TSCA, it must specify the types

of tests required and the data it expects from them.

At times, industry may request permission to deviate

from EPA guidelines (e.g., in the case of test rule

development under TSCA), but these alternative test

methods must be evaluated by the Agency. NTD

provides much of the technical expertise necessary

to support EPA program offices in this regard.

NTD is actively developing and validating two

major neurotoxicity screening tests: the functional

observational battery and automated testing of

motor activity (see ch. 5). These tests are validated

by evaluating how well they confirm the neurotoxicity of known, representative toxic substances. In

this way, profiles can be developed for classes of

neurotoxic chemicals.

Other approaches to neurotoxicity testing are also

being developed. Electrophysiological approaches

are being refined to enable investigators to monitor

the excitability of individual nerve cells or groups of

nerve cells or regions of the brain. Behavioral tests

are being developed to assess the effects of toxic

substances on memory, learning, and muscular

coordination. In addition, methods are being devised

to evaluate the effects of toxic substances on the

developing nervous system. A variety of molecular

and cellular approaches are being developed to

determine the effects of toxic substances on various

proteins in nerve cells (including enzymes) and on

several biochemical processes, including the transport of substances along the axons of nerves. Tests

designed to evaluate exposures at toxic waste sites

and at chemical spills are also being developed and

refined:

Because EPA’s neurotoxicology Division is the

principal Federal intramural research organization in

the environmental neurotoxicology field, and because resource information on the program has been

available since its inception, OTA analyzed the

funding of this program in some detail. The total

number of principal investigators (including some

postdoctoral fellows and on-site contractors) fell to

23 in fiscal year 1988, down from 25 in fiscal years

1986 and 1987 (figure 4-1A). Funds for on-site

contract support remained constant over these years

at $1.7 million, up from $0.9 million in 1984 (figure

4-l B). Funds for outside contracts and cooperative

agreements have fluctuated considerably (figure

4-lC). Budget stability has been a continuing

administrative problem. According to the EPA

Science Advisory Board committee’s analysis, funds

for NTD are frequently cut with little prior notice,

impeding in particular the development of longrange plans. As indicated in figure 4-lD, NTD’s

supplies and equipment budget has dropped precipitously in recent years. In 1985, NTD allocated

$23,500 in supplies and equipment to each principal

investigator. In 1988, only $8,100 could be allocated

(figure 4-lE). In its recent review, the Science
Chapter 4-Research and Education Programs . 83

Figure 4-l-Resources for EPA’s neurotoxicoiogy Division

A. Total Principal Investigators

Thousands of dollars

28

24

20

16

12

8

4

0

25 25

23

11

14

22

17

1980 1981 1982 1983 1984 1985 1986 1987 1988

C. R&D Funds: Outside Contracts

and Cooperative Agreements

Thousands of dollars

800 T–—— -

——–-— — ‘-

o >- — ~ ‘

-

-

- 

‘ T

—, – — . — , —— i

1979 1980 1981 1982 1963 1984 1965 1986 1987 1988

B. R&D Funds: On-site Support Contracts

Thousands of dollars

2,000 1 I

1,800

1,600

1,400

1,200

1,000

600

600

400

I

~,

200

1

,-

/ /

() < -. , — - — T J

I ‘T –

,—— —

1979 1980 1981 1982 1983 1984 1985 1986 1987 1986

D. Funds: Supplies and Equipment

Thousands of dollars

600

500

400

300

200

100

0

—

470

369

270

234

187

1984 1985 1986 1987 1988

E. Supplies and Equipment per Principal Investigator

Thousands of dollars

30 ~ - –

25 { 23.5

15

i

10

1

5

16.8

9.4

10.8

1984 1985 1986 1987

SOURCE: Based on R. Dyer, U.S. Environmental Protection Agency, personal communication,

1968

19aa
84 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Illustrated by: Ray Driver

Advisory Board committee described NTD’s

supply budget as “totally inadequate” and concluded that “important research is not carried

out” because of budgetary restrictions (30).

EPA has rarely funded extramural grants in the

neurotoxicology field. A substantial grants program

in this area would be a valuable adjunct to its

intramural program.

In recognition of the need to expand its research

programs in the neurotoxicology area, EPA recently

submitted to the Office of Management and Budget

(OMB) a request to expand its research budget by

$1.5 million. Approximately $1.0 million was requested for the development of in vitro neurotoxicology tests; another $0.5 million was requested to

examine adverse effects associated with cholinesterase inhibition and the utility of cholinesterase

inhibition as a biomarker for exposure. However

OMB allowed no funding for either research effort.

In vitro test development is often cited as a

high-priority research need because of the requirement to rapidly screen toxic chemicals and to try to

minimize the use of animals in research. A technical

EPA panel recently recommended that the agency

initiate studies to examine the relationship between

cholinesterase inhibition and other adverse effects

on the nervous system.

National Institutes of Health

Approximately 250 neurotoxicology -related research projects were funded by NIH in fiscal year

1988 (29). Most were funded through competitive

grants to investigators in public and private institutions; the rest were conducted at NIH itself. About

80 percent of the neurotoxicology -related research

(based on fiscal year 1988 expenditures) is funded

through or conducted at the National Institute of

Neurological and Communicative Disorders and

Stroke (NINCDS) and at the National Institute of

Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. (NIEHS is the

only NH-I institute not located in Bethesda, MD.)

Individual research projects averaged about $120,000.

NIH expenditures on neurotoxicology -related research (excluding projects at the National Cancer

Institute related to nicotine and cigarette smoking)

totaled approximately $33 million. This is 0.5

percent of the total $6.5 billion ND-I research budget

(44). In comparison, NIH spends approximately $1.5

billion on cancer research (44), which accounts for

about 23 percent of the total research budget.

OTA found that NIH supports few programs in the

field of neuroepidemiology. NIH supports a relatively large number of research projects designed to

elucidate how toxic substances influence the nervous system but devotes few resources to projects

examining the extent to which these substances

contribute to human neurological disorders. Although the latter studies are often expensive and

time-consuming, they are critical to understanding

the extent to which toxic substances adversely affect

public health and in determining the direction and

scope of regulatory programs.
Chapter 4-Research and Education Programs ● 85

National Institute of Neurological and

Communicative Disorders and Strokel

In fiscal year 1988, NINCDS funded 71 research

projects related to neurotoxicity. All but three of

these were extramural grants to investigators at

public and private institutions. Research sponsored

by NINCDS covers abroad range of problems, from

the level of the gene, to the cell, to the whole

organism. Much of the work focuses on the mechanisms by which toxic substances adversely affect the

nervous system: for example, how the flow of ions

through membrane channels is altered by toxic

substances, how these substances cause degeneration of nerves, how they alter other biochemical

components of the nerve cell, and how toxic

substances cause or contribute to neurological disorders. Several projects focused on how the chemical

MPTP affects the nervous system and how it induces

symptoms of Parkinson’s disease. Other projects

examined how therapeutic drugs influence the structure and function of the nervous system. For

example, drugs used in cancer chemotherapy may

adversely affect the nervous system. It is important

to understand how and when this occurs in order to

help maximize effects on cancerous cells and

minimize damage to healthy cells.

Three intramural projects are under way at

NINCDS laboratories. The largest was funded at

more than $400,000 and is examining how cells

derived from the brain of mammals perceive and

respond to signals in their environment. A second

project is examining the neurological and behavioral

effects of MPTP on the monkey, and the third is

devoted to the mechanism by which nerves lose their

myelin sheaths.

National Institute of Environmental

Health Sciences

NIEHS conducts and supports research related to

the effects on human health of chemical, physical,

and biological agents in the environment. NIEHS

has an extensive extramural program, and it sponsored more than 80 grants related to the neurotoxicity of environmental contaminants and other substances in fiscal year 1988. The NIEHS extramural

grants program is the largest source of Federal

funds for research grants in the environmental

neurotoxicology field. Funding for these projects

amounted to nearly $12 million. NIEHS also received nearly $900,000 from EPA’s Superfund

program (through an interagency agreement) to

support four extramural projects. In addition, NIEHS

funded three neurotoxicology-related contracts totaling $755,000. The extramural projects focused on

a broad range of neurotoxic substances, including

metals, pesticides, solvents, natural toxins, PCBs,

and other industrial chemicals. NIEHS also funded

grants to several academic institutions.

Until 1987, an intramural Laboratory of Behavioral and Neurological Toxicology existed within

NIEHS. Following a management change, the laboratory’s emphasis shifted to basic neuroscience

research (specifically, molecular and cellular neurobiology) and its name was changed to the Laboratory

of Molecular and Integrative Neuroscience (LMIN).

This laboratory comprises three sections and several

smaller working groups, only one of which, the

Neurobehavioral Section, focuses primarily on environmental neurotoxicology problems. (The neurotoxicologist who headed that section left the Institute in 1989.) An OTA analysis of fiscal year 1988

research projects found that many LMIN research

projects in the neuroscience were only generally

related to toxicology. Of the $3 million expended on

intramural research in the neuroscience, OTA

found that only about one-fourth was devoted to

studies in which neurotoxicology was the primary

focus. Hence, OTA found that, with the exception of

the Neurobehavioral Section of LMIN, there is little

distinction between intramural basic neuroscience

research programs at NIEHS and those at other NIH

and ADAMHA institutes. This has lead to a prominent intramural research gap at NIH in the environmental neurotoxicology field.

National Toxicology Program

The National Toxicology Program (NTP) was

established in 1978 by the Secretary of the Department of Health and Human Services (DHHS) to

coordinate DHHS activities related to the testing of

toxic chemicals. The program was initiated to

develop information about the toxicity of selected

chemicals, to test selected chemicals for toxicity, to

develop and validate tests and protocols, and to set

priorities for testing needs and communicate results

1~ ]ate 1988, the Nation~ kstitute of Neurolo@c~ and Communicative Disorders and Stroke became the National Institute of Nwdogicd

Disorders and Stroke (NINDS), and the National Institute on Deafness and Other Communication Disorders (NIDCD) was formed. Since OTA’s analysis

was based on fiscal year 1988 programs, this discussion will refer to NINCDS programs.
86 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

to government agencies, the scientific community,

and the public. NTP coordinates toxicology-related

programs within the NIEHS, the National Institute

for Occupational Safety and Health (NIOSH), and

the U.S. Food and Drug Administration’s (FDA)

National Center for Toxicological Research (NCTR).

NTP is administered by the Director of NIEHS.

Program activities are overseen by an executive

committee made up of the senior administrators of

Federal health research and regulatory agencies. The

quality of technical research programs is ensured by

an independent Board of Scientific Counselors.

After receiving nominations from participating Federal agencies and other public and private organizations, NTP selects chemicals to be tested. Testing is

then performed by outside organizations through

contract arrangements. Federal regulatory agencies

have rarely requested neurotoxicity studies by NTP.

From 1982 to 1988, only one substance had been

nominated for neurotoxicity by the multiagency

nominating committee (16). Consequently, NTP has

sponsored little extramural neurotoxicology research

as of fiscal year 1988. One of the few projects funded

by NTP resulted in development of an automated

assessment of behavior in the home cage (13,14).

Intramurally, NTP has developed a neurobehavioral

test battery to be used as part of its analysis of target

organ toxicity. This battery will be used in a tiered

testing approach to determine whether more specialized testing is necessary (43).

Within NIEHS, NTP is located under the Division

of Toxicology Research and Testing. The division is

composed of four branches: Carcinogenesis and

Toxicologic Evaluation, Cellular and Genetic Toxicology, Chemical Pathology, and Systemic Toxicology. Toxicological concerns focus on carcinogens

and mutagens (and to a limited degree on teratogens). NTP also evaluates the toxic effects of

environmental agents on organ systems, including

the nervous system. When health hazards are identified by NTP, additional studies characterizing the

hazard are often undertaken by researchers in other

government agencies, industry, and academia (16).

Although the Division of Toxicology Research

and Testing at NIEHS is the primary toxicological testing organization within the Federal Government, in 1988 it employed no neurotoxicologists.

As of 1989, expert in-house scientific advice was

provided through periodic consultation with the

chief of the Neurobehavioral Section of LMIN. NTP

is presently restructuring its program to address

neurotoxicological concerns more effectively. Representatives of the NTP agencies participating in

research efforts are preparing cooperative program

plans to address neurotoxicologica.1 concerns specifically (16).

National Cancer Institute

The National Cancer Institute sponsored eight

neurotoxicity-related projects in fiscal year 1988.

Half of them focused on the adverse effects of cancer

chemotherapy agents on the nervous system. The

other four examined such problems as the induction

of brain tumors by neurotoxic agents and the

treatment of pain caused by cancer. Although

smoking and nicotine are not included in this report,

it should be noted that the Institute sponsored 64

projects related to smoking and nicotine addiction.

Total funding for these 64 projects was in excess of

$26 million in fiscal year 1988.

National Institute on Aging

The National Institute on Aging (NIA) sponsored

10 neurotoxicology -related research grants in fiscal

year 1988. Several of these projects examine the

possible role of metals in causing Alzheimer’s

disease; recent work has suggested that aluminum

may contribute to the development of the structural

changes in the brain that are characteristic of this

disease. Other projects analyze age-related changes

in the concentrations of excitatory amino acids

(aspartate and glutamate) and the reduction in brain

glutamate receptors seen in individuals with Alzheimer’s disease, Two projects focus on MPTP, the

aging process, and induction of Parkinson’s diseaselike symptoms. NIA is particularly interested in the

question of why certain populations of nerve cells

are particularly vulnerable to neurodegenerative

diseases. Because the mechanism of cell death may

be similar in different diseases, NIA is encouraging

research into the molecular events underlying cell

death (28). A 1988 workshop, sponsored by NIA,

examined issues related to the susceptibility of the

aging nervous system to infections and toxic substances.

The NIA has two intramural projects underway to

examine the influence of toxic metals on aging

processes and their possible role in the onset of

dementia. The distribution of metals in the brain is

being examined, as are the factors controlling the

transport of metals across the blood-brain barrier.
Chapter Research and Education Programs ● 87

In 1988, NIA sponsored a small workshop on the

epidemiology of pesticide exposure and cognitive

disorders in aging migrant and seasonal farmworkers. The effects on the human nervous system of

long-term, low-level exposure to neurotoxic agricultural pesticides and herbicides are not known. The

workship assessed the feasibility of using seasonal

and migrant farmworkers, resident farmers, and

others as research subjects in epidemiological studies.

National Institute of Child Health and

Human Development

The National Institute of Child Health and Human

Development sponsored 11 research projects related

to neurotoxicity in children in fiscal year 1988, with

funding totaling approximately $1.2 million. Six of

these projects focus on lead, which adversely affects

the developing nervous system (see ch. 10). Two of

the projects analyzed the effects of drugs used to

treat epilepsy on the fetuses of mothers who must

take these drugs. There is evidence that valproic

acid, a drug widely used to treat epilepsy, adversely

affects the nervous system of the developing fetus.

The effects of valproic acid and phenytoin (another

antiseizure drug) on the development of the nervous

system of rhesus monkeys are being examined.

Another project is evaluating the effects of diets

high in sugar or the artificial sweetener aspartame, or

both, on the behavior and mental development of

children. Other projects are examining mechanisms

by which acrylamide, alcohol, and other substances

affect the developing brain.

Division of Research Resources

The Division of Research Resources funded a

total of 47 neurotoxicity-related research projects at

various private and public research institutions.

Projects focused on a broad range of toxic substances, including lead, pesticides, chemotherapy

agents, ethanol, mercury, MPTP, and natural venoms and toxins. Total funding for these projects in

fiscal year 1988 was $788,000.

Other NIH Institutes and Organizations

The National Institute of Allergy and Infectious

Diseases (NIAID), National Institute of General

Medical Sciences (NIGMS), National Heart, Lung,

and Blood Institute (NHLBI), National Center for

Nursing Research, Fogerty International Center

(FIC), and National Institute of Dental Research

Photo credit: John O’Donoghue

This photograph illustrates the swelling of axons (dark

areas) that can occur following exposure to a neurotoxic

substance, in this case, 2,5-hexanedione.

sponsored several projects concerned with neurotoxicity. These include projects investigating the actions of a paralytic toxin from a snail (NIGMS), the

adverse effects of an antibiotic on hearing (NIGMS),

how bacteria degrade and avoid the effects of

organophosphates (NIGMS), the possible neurotoxic effects of drugs used to treat Herpes virus

infections (NIAID), the side-effects of drugs used to

treat high blood pressure (NHLBI), and the effects of

antipsychotic drugs on brain dopamine receptors

(FIC).

National Library of Medicine

The National Library of Medicine (NLM) supports toxicological research by maintaining automated toxicology databanks and providing information services. The Toxicology Information Program

was established in 1967 in response to a recommendation made by the President’s Science Advisory

Committee that efforts to handle toxicological

information be enhanced. The NLM maintains

several computerized, interactive retrieval services,

including Toxline, Toxnet, and Chemline. Toxline

provides information on the toxicological effects of

drugs and chemicals. Toxnet contains information

on potentially toxic or hazardous substances. Chemline is a chemical dictionary providing chemical

names, synonyms, registry numbers, molecular formulas, and related information.
88 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Alcohol, Drug Abuse, and Mental Health

Administration

ADAMHA is composed of the National Institute

on Alcohol Abuse and Alcoholism (NIAAA), the

National Institute on Drug Abuse (NIDA), and the

National Institute of Mental Health (NIMH). As

indicated in chapter 2, OTA is excluding research on

alcohol and alcoholism from this assessment; consequently, research programs at NIAAA will not be

described. Both NIDA and NIMH have extensive

research programs to examine the neurotoxic effects

of drugs (NIDA) and the influence of neurotoxic

substances on mental health (NIMH).

National Institute on Drug Abuse

NIDA sponsors a large research program related

to the neurotoxicity of abused drugs. In fiscal year

1988, it funded 110 neurotoxicity-related grants.

Total extramural funding was $15.5 million, or

approximately $140,000 per grant. The extramural

program addresses a broad range of issues from a

variety of perspectives, including biochemical, pharmacological, pathological, and behavioral studies

(14) and supports studies on all abused drugs. In

1988, it spent $1.5 million on in vitro studies of the

neuropathological effects of drugs and on the

neurotoxicity of designer drugs, cocaine, and inhaled solvents. An interagency agreement with

NCTR supported studies of marijuana neurotoxicity

(11).

Intramural research at NIDA is conducted at the

Addiction Research Center in Baltimore, Maryland.

Scientists at the center are examining the adverse

effects of drugs such as MDMA (’ ‘ecstasy’ and the

related drug fenfluramine, cocaine, and THC, the

active component of marijuana. The center’s neurotoxicology-related research is conducted primarily

in its neurobiology laboratory, but projects are also

being carried out in its molecular pharmacology,

preclinical pharmacology, neuropharmacology, neuroendocrinology, immunology, and cognitive sciences laboratories. Through an interagency agreement, FDA has provided the Addiction Research

Center with funding to develop and validate methodologies for assessing the neurotoxicity of various

drugs currently prescribed or under consideration for

treatment of neuropsychiatric disorders. The center

has been asked by the Drug Enforcement Administration to assess the neurotoxicity of some substances that are currently under consideration for

regulatory scheduling (8). Funding for intramural

neurotoxicity-related research in fiscal year 1989

was approximately $256,000 (8).

National Institute of Mental Health

A sizable portion of NIMH’s research effort is

devoted to neurotoxicity-related concerns. In fiscal

year 1988, it funded 65 extramural grants totaling

$8.6 million (excluding alcohol-related research), an

average of some $132,000 per grant. These grants

supported research into such issues as the mechanisms by which psychoactive drugs influence nervous system function, ways of minimizing the adverse effects of psychoactive drugs, and the contribution of toxic substances to neuropsychiatric disorders (14).

NIMH spent $2.2 million on eight major intramural research programs related to neurotoxicity. These

programs are examining how toxic substances influence behavior and memory, how toxic substances

may contribute to such diseases as Parkinson’s

disease and dementia, the mechanisms by which

toxic substances disrupt biochemical processes within

nerve cells, and methods of detecting toxic substances in the brain (14).

Food and Drug Administration

FDA’s primary responsibility is to protect “the

health of the Nation against impure and unsafe

foods, drugs and cosmetics, and other potential

hazards” (27). neurotoxicity research at FDA is

limited in size and scope. A small research program

(within one laboratory) exists in the Center for Food

Safety and Applied Nutrition (CFSAN), but there is

no significant research program in the Center for

Drug Evaluation and Research. Several intramural

research projects related to developmental neurotoxicology and one extramural project are underway at

the National Center for Toxicological Research.

Center for Food Safety and Applied Nutrition

The General and Molecular Toxicology Branch of

CFSAN conducts toxicological research related to

food and nutrition and examines approaches to

assessing health risks posed by food additives. The

Neurobehavioral Toxicology Team (NBT), one of

five teams within this branch, conducts neurotoxicological studies in this area. With the recent

departure of a principal investigator, NBT currently

consists of only the team leader, one laboratory

biologist, and several laboratory assistants.
Chapter 4-Research and Education Programs ● 89

In recent years, FDA has interacted closely with

EPA’s Health Effects Research Laboratory, and for

some time FDA has transferred funds to EPA as part

of an interagency agreement (37,38). NBT is currently examining how altered ratios of carbohydrates

to proteins affect brain function and how toxic

chemicals are distributed in the brain. The team is

also developing dog and miniature swine model

systems that may eventually prove useful in predicting the effects of toxic substances on the human

nervous system. Efforts are being made to assess the

reliability and sensitivity of the model through a

collaborative effort with investigators at NIMH.

The FDA is sponsoring three extramural projects

related to aspartame and the influence of dietary

amino acids on brain function (see app. A). One

contractor is examining how changes in the relative

concentrations of dietary amino acids affect the

function of transmitters and receptors at neuronal

synapses. Under an interagency agreement with

FDA, NIEHS is determining whether an altered

amino acid balance affects neuronal excitability or

induces behavioral changes, or both, in adult and

developing animals. FDA also has an interagency

agreement with the Federal Aviation Administration

to conduct clinical studies of the effects of aspartame

on cognitive functions (39).

National Center for Toxicological Research

Located in Jefferson, Arkansas, NCTR conducts

toxicology research programs that:

. . . study the biological effects of potentially toxic

chemical substances found in the” environment,

emphasizing the determination of the health effects

resulting from the long-term, low-level exposure to

toxicants and the basic biological processes for

chemical toxicants in animal organisms; develops

improved methodologies and test protocols for

evaluating the safety of chemical toxicants and the

data that will facilitate the extrapolation of toxicological data from laboratory animals to man; and

develops Center programs under the National Toxicology Program (27).

neurotoxicity-related research at NCTR currently

focuses on developmental issues. NCTR is well

qualified to carry out investigations of toxicological

problems. Expertise is available in the areas of

neurochemistry, neuropathology, neuropharmacology, behavioral pharmacology, primatology, developmental neurotoxicology, and nutritional influence

on neurotoxicity.

Approximately one-third of the intramural research conducted within NCTR’s Division of Reproductive and Developmental Toxicology is devoted

to developmental neurotoxicology and related issues. The approximately $1.3 million intramural

neurotoxicology effort includes seven to eight fulltime scientists, seven to eight laboratory technicians,

and two to three graduate students (32).

From fiscal year 1983 to 1988 NCTR conducted

a study of the effects on primates of chronic

exposure to marijuana. This project was not funded

by FDA, but through an interagency agreement with

NIDA. Cumulative fiscal year 1983 to 1987 funding

was $1.8 million. The project was then extended for

1 year (through fiscal year 1988) at $748,000.

NCTR has the facilities, equipment, and personnel to expand interdisciplinary research in neurotoxicity and to conduct research related to therapeutic

drugs and food additives, but it is currently constrained by lack of funds. NCTR recently decided to

consider establishing a formal neurotoxicology unit.

Agency for Toxic Substances and

Disease Registry

The Agency for Toxic Substances and Disease

Registry (ATSDR) is responsible under the Comprehensive Environmental Response, Compensation,

and Liability Act of 1980 (CERCLA, or Superfund)

and the Superfund Amendments and Reauthorization Act of 1986 to carry out applied research on

health effects of exposure to hazardous substances.

Hazardous waste sites contain solvents, pesticides, and metals, all of which are known to be

neurotoxic. These chemicals have been released

from waste sites into the air, soil, and water

however, it is not known what neurotoxic effects, if

any, will be caused by long-term exposure to these

chemicals in the environment. The neurotoxic effects on sensitive and vulnerable populations, for

example, pregnant women, young children, and the

elderly, are also not understood.

ATSDR is required by statute to compile a list of

the 200 most toxic substances found at Superfund

sites. This list contains hazardous substances known

to cause neurotoxic effects (e.g., toluene and others).

ATSDR is also required to fill in any significant gaps

in data on adverse health effects associated with

exposure to these chemicals. For many of these

chemicals, little is known about their neurotoxic
90 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

effects. ATSDR is collecting information on the

neurotoxicity of these substances for dissemination

to the public (4).

Another way that citizens may come into contact

with solvents, pesticides, and metals is when one or

more of these chemicals is spilled during transport.

The acute and chronic neurotoxic effects in rescue

workers and others who respond to spills and in

citizens who do not have the time, knowledge, or

ability to evacuate an area are not known. These

situations can be serious because frequently there is

a large concentration of the chemical in one location,

the incident occurs suddenly, and the populations

exposed may not know how to minimize adverse

effects (4). Although ATSDR does not conduct or

sponsor laboratory research in this area, it recently

supported the National Academy of Sciences study

neurotoxicology and Models for Assessing Risk, and

was a cosponsor of the Third International Symposium on Neurobehavioral Methods in Occupational

and Environmental Health.

National Institute for Occupational Safety

and Health

NIOSH has identified neurotoxic disorders as one

of the 10 leading occupational problems in the

United States. NIOSH funds intramural and extramural activities designed to implement a program to

identify, characterize, and control exposure to neurotoxic agents.

Intramural activities include an extensive surveillance program directed toward identification of a

wide range of possible endpoints that may include,

but are not restricted to or focused exclusively on,

neurotoxic agents. These activities include the

development of a database describing exposures

from an extensive sampling of workplaces throughout the Nation, in order to identify patterns of use of

known neurotoxicants, and a health hazard evaluation program that responds to requests for workplace

assessments throughout the Nation (and which has

identified cases of neurotoxic exposure in the past).

The identification and characterization of neurotoxic agents are conducted through both the intramural and extramural programs. Current intramural

research includes the evaluation of possible longlatency effects of chronic exposure to ethylene and

propylene oxide in primates and the effects of acute

exposures to aliphatic carbons on motor activity and

physiology of rodents. A human study is also being

designed to evaluate the impact of exercise on

exposure to combinations of chemicals. Effects of

exposure will be assessed by means of behavioral

measures and will be correlated with pharmacological information. A study of workers exposed to

pesticides is in the early stages of development.

The primary thrust of NIOSH’s intramural program is methods assessment. The Institute is participating in the National Health and Nutrition Survey,

in which approximately 6,000 people from around

the Nation will be given three tests from the

Neurobehavioral Evaluation System (NES) in order

to develop baseline data for future evaluations of

exposure to neurotoxic chemicals. Similarly, NIOSH

is one of three organizations conducting the international, cross-cultural assessment of the Neurobehavioral Core Test Battery (NCTB) recommended by

the World Health Organization. The NCTB assessment has been conducted jointly with an evaluation

of the NES. In this study, people in different age

ranges were administered both batteries, thus providing information on the effects of participant age

and means of administration. The NES is administered by a computer, and the NCTB is administered

by a psychologist or other suitably trained professional (6).

Funding for that portion of the intramural program

directed exclusively at assessing neurotoxic disorders includes nine full-time-equivalent staff (including four persons with Ph.D.s) and $90,000 for the

four projects currently funded.

Funding for neurotoxicology-related grants makes

up a small portion of the total NIOSH extramural

budget. In 1989, that total was $6.1 million, with

$0.2 million (6), or less than 4 percent, devoted to

neurotoxicology -related research. Since 1985, funding for neurotoxicology -related grants has declined,

reflecting in part a decline in NIOSH’s total extramural grants budget (figure 4-2). The current NIOSH

budget has approximately half the buying power it

did in 1980, due to inflation and budget cuts (47).

NIOSH extramural grant programs are clearly weak

in the neurotoxicology area.

Center for Environmental Health

Toxicology research at the Center for Environmental Health (CEH) in Atlanta, Georgia, is conducted under two divisions. The Division of Environmental Hazards and Health Effects is responsible

for design, implementation, and analysis of expo-
Chapter 4-Research and Education Programs ● 91

Figure 4-2—Funding for NIOSH Research Grants

~ Millions of dollars

-

L

All NIOSH grants 7

(current dollars)

\

‘+— /

-— .:k --

6

\

- (w- . . -? /

/

3

1

All NIOSH grants

(constant 1980 dollars)* Neurotoxicology -related

2

grants (current dollars)

I

L

i.

o --- --+- + t i

f:

t --- ~U•ŒèÇ*•ˆ••Œ ̧æ·• , ~ÿ•

1980 1981 1982 1983 1984 1985 1986 1987 1988 1989

‘Based on the Biomedical Research and Development Price Index

SOURCE: Office of Technology Assessment, 1990.

sure assessments and epidemiological studies. The

Division of Environmental Health Laboratory Services develops and standardizes laboratory methods.

CEH is designing sensitive laboratory tests to

assess the impact of toxic chemicals on public

health. A major objective of its program is to

develop tests that will enable investigators to

evaluate toxic substances under a variety of biological conditions. Another major objective is to conduct tests at sites of environmental hazards to

determine the threat to human health.

CEH conducts epidemiological investigations of

human exposure to environmental hazards, including man-made and naturally occurring toxic substances, and determines the health effects resulting

from exposure. It also provides emergency response

to environmental disasters.

Department of Defense

The Department of Defense conducts and supports research related to neurotoxicity, much of

which is relevant to the toxicity of chemical warfare

agents. Defense-related neurotoxicology research

programs were not evaluated by OTA for this report.

Department of Energy

The Department of Energy (DOE) supported only

two research projects related to neurotoxicology

through grants to public institutions in fiscal year

1988. Total funding of these projects was $487,000

(46). The first project examined the effects of

environmental agents (as well as endogenous

hormones and neurotransmitters) on cultured brain

cells, A major goal of the project was to analyze the

sensitivity of three major types of brain cells to

environmental agents and to identify chemicals that

influence the survival, proliferation, and differentiation of these cells.

The second project focused on the biological

effects of magnetic fields. This type of non-ionizing

radiation emanates from magnetic resonance imaging devices used in medicine and to a lesser extent

from high-voltage power lines. There is considerable debate as to whether magnetic fields in the

vicinity of high-voltage power lines adversely affect

the nervous system. In this project, researchers have

used several techniques to examine a series of

physiological parameters, including possible effects

on vision and other nervous system functions.

The Department of Energy Organization Act of

1977 mandates that DOE carry out the planning,

coordination, support, and management of a balanced and comprehensive energy research and

development program. The Act requires that DOE

advance the goals of restoring, protecting, and

enhancing environmental quality and assuring public health and safety (Public Law 93-577, Title 42).

For several years, DOE supported applied research on the neurotoxicological and behavioral

effects of chemicals. Recently, however, it changed

the focus of some of its research programs from

energy-related issues to fundamental biological

questions, for example, sequencing the human

genome. This shift in direction appears to have led

to reductions in applied toxicological research,

including work in the neurobehavioral field.

DOE research programs are currently not adequately addressing neurotoxicological concerns. DOE

could be conducting neurotoxicological research

into the health effects of energy-related processes

and products including lead and lead substitutes in

gasoline, methanol, and other fuels, and heavy

metals used in nuclear and nonnuclear processes. It

could be examining the effects of combustion

products on the nervous system, and it could be

working with Federal agencies and other public and

private organizations to develop new and better

toxicological tests to evaluate these effects.

20-812 - 90 - 3 : QL 3
92 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Department of Agriculture

The U.S. Department of Agriculture (USDA)

supports a small number of extramural research

projects related to neurotoxicology. These projects

are administered through the Cooperative State

Research Service and fall into four major categories:

1. USDA competitive research grants,

2. special grants to State Agricultural Experiment

Station scientists,

3. animal health funds, and

4. Hatch Act funds (34).

In fiscal year 1988, USDA supported 25 research

projects related to neurotoxicology, nearly all of

them involving insecticides and their metabolizes.

Total funding for these projects was $422,000. Most

of the research was supported by Hatch Act funds;

the remainder was supported by special grants,

animal health funds, and competitive grants. USDA

research efforts span a wide range of objectives,

from molecular biology and biochemistry, to structureactivity relationships, monitoring of agriculture

workers, and the development of poisoning antidotes (21,33).

National Aeronautics and Space

Administration

Toxicology research within the National Aeronautics and Space Administration (NASA) is conducted in the Biomedical Laboratories at the

Johnson Space Flight Center in Houston, Texas.

Space flight involves prolonged confinement in an

artificial atmosphere with an array of equipment and

materials. The Biomedical Laboratories evaluate

spacecraft equipment and materials to ensure that

flight crews are not exposed to harmful levels of

toxic substances.

In the last several years, NASA has evaluated the

neurobehavioral effects of many potentially toxic

substances, including polyurethane thermal decomposition products, bromothifluoromethane, and various fire-extinguishing agents. In 1988, NASA completed a study of continuous low-dose exposure to

Halon 1301, the active component in fire extinguishers in the space shuttle cabin.

NASA has established maximum allowable concentrations (MACs) of atmospheric contaminants in

manned spacecraft for missions of up to 7 days.

These criteria are used in the development of all

materials that will be used in space vehicles to

ensure a nontoxic cabin atmosphere. In 1981, MACs

were established or revised for some 200 chemicals

that might be used in spacecraft.

ACADEMIC RESEARCH

ACTIVITIES

Research interest in the neuroscience has increased rapidly in the last decade, as evidenced by

growth in the membership of the Society for

Neuroscience. The neurobehavioral sciences have

made major advances in recent years, and society

can continue to expect new and important discoveries that will not only improve understanding of the

brain and behavior, but also make substantial

contributions to public health. In the last decade,

neurobehavioral toxicology has become an increasingly active field. Scientific papers are published in

an array of journals, including two specialty journals

(Neurotoxicology and Neurotoxicology and Teratology). A neurotoxicology specialty section has been

organized within the Society of Toxicology, and two

small scientific societies have been formed, the

Behavioral Toxicology Society and the Behavioral

Teratology Society. Behavioral scientists and neuroscientist have been appointed to the editorial

review boards of the journals of the Society of

Toxicology and participate in the peer review

process of the extramural grants programs sponsored

by NIH, ADAMHA, and EPA (48). However,

despite recent advances, U.S. neurotoxicology research programs are small relative to the threat

neurotoxic substances pose to public health.

Factors Influencing Academic Research

Directions

Neurotoxicology will continue to benefit from the

rapid advances being made in understanding the

structure and function of the nervous system. With

the tools of modern molecular biology and pharmacology, investigators are mapping and redefining the

brain itself. As researchers learn more about the

brain and its molecular components, they gain

insights into how chemicals can alter nervous

system structure and function. The detailed study of

simple neuronal systems in invertebrates or in tissue

culture can aid in understanding the mechanisms by

which chemicals exert their effects in mammals;

such studies should assist in screening for neurotoxicity. Improved understanding of the behavioral

determinants of chemical actions will assist in the

construction of test systems that will facilitate both
Chapter Research and Education Programs . 93

Illustrated by: Ray Driver

the detection and characterization of toxic effects.

Increased efforts in academia, as well as in industry

and government, are necessary in order to move

beyond basic research and to apply basic knowledge

to the development and validation of neurotoxicity

tests.

The challenge in the years ahead will be to foster

basic research and to persuade investigators and

students that the field of neurotoxicology offers

substantial opportunities for increasing our understanding of the structure and function of the nervous

system. The neuroscience could provide novel and

beneficial approaches to many important occupational and environmental health problems. These

include identifying subtle neurological and psychiatric disorders occurring in exposed populations;

exploring why some individuals appear to be particularly sensitive to chemicals; and developing preparations targeted at health problems associated with

single chemicals, industries, occupations, modes of

transportation, sources of energy, urban environments, and dietary habits. If occupational and

environmental chemicals do play a key role in

causing neurodegenerative disorders, for example,

Parkinson’s disease and Alzheimer’s disease, prevention becomes an important goal.

The contributions of colleges, universities, and

research institutes to neurotoxicology depend on

continued grant support for research and graduate

education. Neurotoxicology research and training

take place in many university and medical center

contexts, for example, departments of pharmacology, toxicology, pathology, psychology, neurology,

psychiatry, anatomy, obstetrics and gynecology,

ophthalmology, pediatrics, epidemiology, and occupational, environmental, preventive, and community

medicine. There are only a few laboratories or

institutes around the country that focus on neurotoxicology. There are no broadly based centers or

departments of neurotoxicology. Thus, there are few

environments in academia where neurotoxicology or

behavioral toxicology is a major focus. As in any

academic research environment, the spatial, financial, and personnel resources available, as well as the

professional advancement and remuneration of the

investigator, depend on the perceived merits of the

research and on the interest and goodwill of the

researcher’s colleagues (48).

What leads an investigator to study a particular

neurotoxic substance? In many cases, a chemical is

of interest not because of its impact on human health,

but because of its usefulness as a tool to study

nervous system structure or function. Such studies

provide necessary information about the substrates

on which chemicals exert their effects and the

mechanisms by which the effects occur. Knowing

the mechanism of action of a toxic substance not

only advances our knowledge, but aids in predicting

what other chemicals will have similar effects. In

other cases, a neurotoxic substance is selected for

study because it has produced human injuries that

have been well described or, if the compound has

injured only a few people, because the injuries

produced a severe impairment, repeatable in animals, that is of interest to the investigator, a funding

agency, or public interest organization. There is also

academic interest in understanding the possible role
94 ● Neurotoxicity: Identfying and Controlling Poisons of the Nervous System

of toxic chemicals in triggering neurodegenerative

diseases.

Universities see basic research as one of their

principal missions; routine toxicity evaluations are

not usually considered to be an appropriate use of

university resources or faculty time. There is little

interest in studying either proprietary products or

chemicals about which little or nothing is known

unless the study offers insight into the mechanisms

by which related chemicals exert known effects.

Funding pressures play a substantial role in an

investigator’s choice of research project. Two factors are at work: 1) the difficulty of finding a

sponsoring agency, and 2) the short duration of

typical grant awards. Neurotoxicology, like other

emerging areas of toxicology, is a discipline that

generates relatively small numbers of grant applications. Consequently, for the most part, there are no

initial review groups, that is, expert committees

appointed by Federal agencies to review the merits

of neurotoxicology grant proposals. A study section

charged with reviewing occupational or environmental health problems may understand the consequences of human exposure to a compound but not

be able to review adequately the scientific methods

of a research proposal or to balance its merit and

relevance against those of other studies. If the

proposal is forwarded to a study section that is

competent to review the techniques involved, it may

still face difficulties. A proposal deemed an appropriate application of existing techniques to an

“applied” problem would not fare well in competition with a proposal that advances “basic” knowledge. One funding strategy that has been productive

is to integrate neurotoxicity studies with a larger,

multidisciplinary center or program project. In

general, the success of any grant application depends

largely on both accurate identification of the funding

agency and specific tailoring of the proposal to the

initial review group (48).

Funding usually extends for 3 to 5 years and takes

the form of an individual grantor a multidisciplinary

program project or center grant. Progress, as measured by publications, is necessary to maintain a

research career. In order to achieve results rapidly,

investigators are frequently drawn to compounds

that produce easily recognized and reproducible

effects after exposing animals for brief periods.

Experiments involving agents that require inhalation

exposure or chronic administration are more costly

and require more effort, hence the number of journal

articles produced at the end of the project is - .

correspondingly reduced.

Cooperative Agreements Between

Government and Academia

Government agencies sometimes channel intramural funds to ‘investigators in universities or

research institutes. These negotiated agreements

tend to focus on projects of mutual interest and

usually address specific problems. They have the

advantage of permitting questions to be examined

more rapidly and at less expense than would be

possible intramurally. As a means of supporting

extramural research programs, however, they have

drawbacks: they often do not benefit from the

intense scrutiny of the peer review process, and they

tend to devalue research that does not produce data

and conclusions in the short term. In times of tight

budgets, this pattern of funding is the frost to be cut,

because it is usually derived from the resources

available to support intramural programs.

INDUSTRIAL RESEARCH

ACTIVITIES

Industrial research falls into several categories

and is funded by several mechanisms:

1. internal basic and applied research,

2. research conducted in contract laboratories,

3. research conducted through consortia,

4. contract research through universities, and

5. research grants for universities.

Toxicity evaluations conducted as part of internal

applied research are necessary to develop safe and

effective products, to protect employees, to protect

the environment, and to control cost liability.

Research programs vary considerably, depending on

the types of products manufactured and economic

considerations.

Pesticide Industry

The search for new pesticides begins with screening tests, which are designed to provoke a particular

biological response. The toxicity profiles developed

from screening tests may be considered to be

proprietary information, because disclosure of them

could give the competition information useful for

product development. There are, however, methods
Chapter 4-Research and Education Programs ● 95

of giving outside experts data without compromising trade secrets.

Industry is willing to perform tests to obtain or

maintain product registration, but it is cautious about

devoting funds to the development of test protocols

that might not satisfy regulatory authorities. Government and academic scientists may suggest testing

strategies that they judge to be appropriate but may

find it difficult to defend a specific testing scheme if

there is an inadequate history of testing for the class

of compounds in question or the extent of the public

health hazard and possible economic impacts on

society are difficult to predict (48).

Pharmaceutical Industry

Drug development begins with screening and

development of structure-activity relationships. Acute

and subchronic toxicity information emerges early

in the process, but characterization of chronic

toxicity usually develops more slowly. The quest for

biological activity has produced some compounds

that reach the market, but most are important

research tools for the neuroscience and have no

clinical utility or are too toxic to be used clinically.

Pharmaceutical industry research on toxic substances is directed largely toward therapy for central

nervous system impairments and the development of

animal models for screening drugs to ameliorate the

signs and symptoms of nervous system damage.

Examples of such injuries include oxygen starvation, MPTP-induced Parkinsonism, seizures induced by convulsant drugs, and brain injuries

produced by excitotoxins (chemicals that produce so

much activity in localized areas of the brain that the

cells there die). The pharmaceutical industry also

evaluates compounds in behaviorally normal animals and in the offspring of mothers exposed to toxic

substances. It has promoted the development of a

variety of neurotoxicity tests. The research contributions of the pharmaceutical industry emerge as a

product nears approval. However, as is true in other

sectors, much information generated by industry is

never made public, even though it may be important

in other contexts (48).

Consumer Product Industry

Information about the toxicity of consumer products typically emerges from premarket testing,

human exposures, accidental ingestions by consumers, or in response to regulatory demand. Manufacturers of consumer products frequently maintain

vigorous product development research teams. Their

work sometimes produces serendipitous findings of

wider interest, but it seldom sheds light on the

possible neurotoxicity of their products.

Little information on the neurotoxicity of consumer products has been generated as a result of

these recommendations. The laws administered by

the Consumer Product Safety Commission (CPSC)

permit the agency to require some toxicity evaluations as part of compliance with labeling and

packaging regulations (15 U.S.C. 1261—Federal

Hazardous Substances Act). For several years CPSC

has encouraged regulated groups to develop voluntary standards. One such group is the art supplies

industry, which developed recommendations for

minimizing injuries through product labeling. (Some

materials used by artists have neurotoxic potential.)

Labeling standards may, in turn, prompt manufacturers to reformulate products in order to minimize

toxicity and the need for warnings at the point of

purchase. These recommendations were recently

given the force of law in the Art Materials Labeling

Act (Public Law 100-695).

Specialty and Commodity Chemical Industries

Chemical companies have a mixed record with

respect to minimizing the adverse effects of chemicals on the health of their workers. Like other

industries, however, they have no interest in marketing chemical products that may become substantial

liabilities. Some companies rely on developing

information of such high quality that it defines the

state of the science—this is no doubt the best defense

of a successful and prestigious corporation. To

achieve this end, good scientists must be recruited

and maintained as vigorous members of a corporate

team. A good example is the publication by scientists at one major U.S. corporation of a series of

high-quality papers describing the role of diketones

in causing peripheral neuropathy (20). Unfortunately, less well capitalized companies cannot afford

to invest in research of this kind, instead testing

solely to comply with regulatory requirements.

Commodity chemicals are produced by a number of

different companies, so it is generally not in the

interest of any one company to assume responsibility for evaluating the adverse health effects of a

particular substance. The companies that manufacture and distribute such chemicals could be compelled to address the chemical’s toxicity under
96 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

TSCA, or they could avoid such regulation by

supporting a testing program under the auspices of

a trade association.

INTERACTIONS AMONG

GOVERNMENT, ACADEMIA,

AND INDUSTRY

Industry and Government Consortia

Industry and government consortia devoted to

environmental health are rare. One such consortium

is the Health Effects Institute (HEI), an independent,

nonprofit corporation ‘‘organized and operated to

study the health effects of emissions from motor

vehicles . . .’ (18). HEI serves as a potential model

for other consortia. The institute makes no regulatory or social policy recommendations; its goal is

, “simply to gain acceptance by all parties of the data

that may be. necessary for future regulations” (34).

It has joined together the regulator and the regulated

industry in mutual support of research activities

targeted at joint concerns, and it does so by deriving

funding jointly from EPA and the automobile

industry.

The institute has recognized the importance of the

effects of automobile emissions on the nervous

system and on the quality of life in general. It has

conducted a review of the topic (48) and has

solicited research proposals in this area, The HEI

model is a promising one for circumstances in which

health concerns are generic and in which proprietary

and competitive interests do not interfere with

industry’s participation.

Industry Research Consortia

The Chemical Industry Institute of Toxicology

(CIIT) is a research institute funded by a consortium

of chemical companies to study commodity chemicals of concern to members. CIIT has achieved a

reputation for conducting excellent toxicological

research targeted at a broad range of problems and

has generated considerable goodwill in the process.

Interest in neurotoxicity issues has recently been

evidenced in the publications of the institute. However, in the absence of a significant new initiative,

the contributions of this organization to knowledge

of neurobehavioral effects may be limited.

CIIT could serve as a model for other industries

with common interests, particularly industries meeting similar regulatory challenges. The pesticide

industry as a group makes proprietary products, and

it is unlikely that a group of competitors would be

willing to share the cost of generating information

about a single member’s profit-making product. The

companies are bound together by a common desire

to be regulated appropriately and efficiently, however, and they could benefit from a joint research

program that would help advance the state of the art

in toxicology and risk assessment. This would

include advances in the development of in vitro

testing, the extrapolation of data from rodents to

primates, the validation of screening approaches

tailored to the needs of the pesticide industry, and

the detailed characterization of identified toxicities

and their mechanisms of actions, an important

contribution to the risk assessment process.

Other industries with profitable products are

challenged periodically by a rule-making activity or

judicial finding requiring them to provide toxicity

information. Such organizations might find it in

their interest also to be part of a larger, standing

organization with a governance structure that ensures that its research and testing of products are of

the highest quality.

Cooperation in Epidemiological Investigations

Since individuals working in the chemical industry almost invariably experience higher levels of

exposure to chemicals than do other groups in

society, they are at greater risk of suffering the

adverse effects of exposure to toxic substances.

Thus, workers also serve as a sentinel population for

the detection of neurotoxic disorders that occur in

the general population. Often, workers are the first

to identify adverse effects and bring them to the

attention of their doctors. Epidemiological studies

can be initiated by a number of organizations, but

they are most often conducted by the CDC, ATSDR,

and State health authorities. CERCLA and TSCA

require manufacturers to collect and keep information regarding exposure and effects on health.

Unions can play an important role in obtaining

cooperation and in ensuring compliance with these

efforts.

Unions can also help stimulate research activities

pertinent to the health of their members. The United

Auto Workers recently established jointly administered research programs with Ford, General Motors,

and Chrysler in which studies of neurobehavioral
Chapter 4-Research and Education Programs . 97

toxicity were identified as a priority. The funding

was directed predominantly at human studies (26,49).

Charitable Organizations

The Third World Medical Research Foundation is

a small, U.S.-based, nonprofit organization that

encourages university and other biomedical scientists worldwide to find innovative solutions to toxic,

nutritional, and other disorders of importance to

developing countries. Working with university and

NIH scientists, it was able to demonstrate the

association of African cases of spasticity with

infection by the HTLV-1 virus and to disprove a

proposed causal association with methylmercury.

More recently, it has focused on promoting the

development of non-neurotoxic strains of the grass

pea to prevent the spastic disease lathyrism and to

generate safe, drought-resistant food and animal

feed for drought-stricken areas of Africa and Asia.

EDUCATION

Education of Research Scientists

A significant portion of current knowledge about

the effects of neurotoxic substances comes from

basic research and the application of that research to

environmental health problems. Yet many observers

believe that there are too few scientists adequately

trained in both neuroscience and toxicology. As

discussed earlier in this chapter, research training

exists in a variety of universities and medical

centers, but there are few places in academia where

neurotoxicology is a major focus.

The National Institute of Environmental Health

Sciences awards grants to educational institutions

for the training of environmental toxicologists.

These grants support approximately 200 doctoral

students in 24 universities. Only about half the

schools offer intensive training in any aspect of

neurotoxicology. Few institutions have comprehensive academic programs with adequate faculties to

undertake a substantial research program. Since it

takes about 5 years for a graduate student to earn a

doctorate, fewer than 40 students supported by these

training grants finish their degrees each year. Only

some 10 to 15 students graduate from strong

programs in neurotoxicology in the United States

each year. While this does not mean that positions

demanding an education in neurotoxicology will

necessarily go unfilled—there are many other,

usually small, programs that award the doctorate but

do not have training grants-it does mean that the

primary Federal program targeted to the Nation’s

manpower needs in toxicology can make only a

small contribution in the area of neurotoxicology

(23).

The NIEHS institutional training grants also

support about 80 postdoctoral trainees, and another

5 students receive fellowships directly though individual training grants. Of course, many of these trainees

come from predoctoral training programs in toxicology and thus represent no net gain in numbers. Since

postdoctoral training takes a minimum of 2 years

and only a fraction of the trainees stay in the field of

neurotoxicology, this source yields only a small

number of fully trained neurotoxicologists per year

(23).

The American Board of Toxicology (ABT) certifies professionals in general toxicology. The certification examination includes neurotoxicology and

clinical toxicology. More than 90 percent of the

ABT-certified toxicologists possess a doctorate and

have more than 3 years of professional experience.

Questions about neurotoxicology and clinical toxicology are a routine part of the examination,

including questions on the neurotoxicity of pesticides, the behavioral effects of metals, and neurotoxic drugs. Certification is for 5 years, and recertification includes continuing education and practice in

toxicology (5).

Education of Health-Care Professionals

Much of the illness resulting from exposure to

neurotoxic substances occurs among workers. Often,

neurotoxic chemicals are first identified because of

the occupational illness they have caused. Increased

research and testing are needed so that harmful

chemicals can be identified and worker exposure

limited. Prevention of occupational illness is a

challenging undertaking and involves identifying

hazards, controlling hazards at the source, monitoring workers, and educating, training, and disseminating information to all persons involved. These

topics have been addressed in a previous OTA report

(45) and will not be covered in detail in this section.

Instead, this discussion will be limited to the

potential role that better education of health-care

professionals might play.

Physicians, nurses, and industrial hygienists deliver most health care to workers who have been

exposed to toxic substances in the workplace. The
98 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

number of professionals trained in the area of

occupational health is not adequate to meet public

health needs in the United States.

Physicians

A large percentage of physicians who provide

occupational health services are employed by industry, yet many workers have no source of occupational health services and must rely on their family

physicians. Family physicians are rarely trained in

occupational medicine and thus are less likely to

obtain histories of occupational exposure.

General training in occupational medicine during

medical school is not extensive. Two surveys of

medical schools, one conducted in 1977-78 (24) and

the other in 1982-83 (25), found that the proportion

of medical schools offering courses in occupational

health in the preclinical years increased from 50

percent at the time of the first survey to 66 percent

at the time of the second. The proportion of schools

requiring that students take such courses increased

from 30 percent to 54 percent. However, in those

schools that required coursework in occupational

health, there was a median curriculum time of only

4 hours over 4 years. A survey conducted by the

Association of American Medical Colleges found

that 70 percent of medical schools offer clinical

electives in occupational medicine or environmental

health. However, of the students responding to the

survey (65 percent), only 1 percent actually took the

offered elective (42).

Residency programs in primary care specialties—

namely, family and general practice, pediatrics,

internal medicine, obstetrics and gynecology, and

psychiatry-rarely include training in occupational

medicine. However, organizations such as the American College of Occupational Medicine, whose

members are board-certified in occupational medicine, sponsor conferences and seminars to educate

primary care and other physicians about occupational health issues (19).

Occupational medicine is one of the areas in

which physicians specializing in preventive medicine can choose to be certified. The Institute of

Medicine recently emphasized the need for a greater

number of physicians specializing in occupational

medicine. In 1987, there were 25 residency programs with 118 residents (0.1 percent of the total

number of residents that year) (7). Between 1955 and

April 1989, the American Board of Preventive

Medicine certified 1,378 physicians in occupational

medicine. The number of those physicians no longer

practicing is not known (17). The requirements for

board certification include 1 year of postgraduate

training in preventive medicine; 1 year of residency

in occupational health; 1 year of training, research,

teaching, or practice of occupational medicine; and

the completion of a master’s degree in public health.

The requirements are somewhat different for physicians who graduated from medical school before

January 1984 (40).

Some effort to encourage medical students to

enter the field of occupational medicine is being

made. The American College of Occupational Medicine has a scholarship fund for medical students and

residents interested in occupational medicine (41).

Also, there is a mechanism under current law by

which Congress could encourage the training of

physicians in occupational health. Public Law 100-

607 (sec. 613) states that:

The Secretary [of the Department of Health and

Human Services] may make grants to and enter into

contracts with schools of medicine, osteopathy, and

public health to meet the costs of projects (A) to plan

and develop new residency training programs and to

maintain or improve existing residency training

programs in preventive medicine; and (B) to provide

financial assistance to residency trainees enrolled in

such programs.

Advocates of expanded training programs in occupational medicine note that the current language in

the law says “may” and that changing the wording

to “shall” would strengthen the law.

Nurses

Nurses provide a crucial aspect of care for workers

exposed to toxic substances in the workplace.

Indeed, they constitute the largest group of health

professionals in the workplace-approximately 24,000

in 1980 (10). Occupational health nursing synthesizes principles from several disciplines in the health

sciences, including, but not limited to, nursing,

medicine, safety, industrial hygiene, toxicology,

administration, and public health epidemiology.

Activities focus on promotion, protection, maintenance, and restoration of health. The occupational

health nurse is primarily concerned with the preventive approach to health care, which includes early

detection of disease, health teaching, and counseling

(2).
Chapter 4-Research and Education Programs ● 99

The American Board of Occupational Health

Nurses is the only board that certifies nurses in

occupational health. It has certified over 45,000

nurses since 1973 and estimates that 2,800 of them

are still practicing (36). Certification requires a

passing score on a national examination. Eligibility

for the examination entails 5 years of experience in

the specialty and a satisfactory record of formal and

continuing education in designated subjects (3).

University-based baccalaureate programs in nursing provide courses and clinical experience in

community and public health nursing and adult

health that are basic to the practice of occupational

health nursing. Specialty education in occupational

health at the master’s degree level is offered in

several schools of nursing and public health. Although programs differ in their course requirements,

most include adult health, elements of workplace

exposures, epidemiology, toxicology, biostatistics,

and opportunities for field work. Some programs

provide education in neurotoxicology through courses,

clinical experiences, and reviews of research (l).

Doctoral-level education for nurses in occupational

health has been offered for the past 10 years, and

graduates are employed in the private sector as well

as by governmental agencies and universities.

Federally supported programs for occupational

health nurses have provided significant resources

and continue to encourage training in this field.

Since 1977, graduate-level academic programs have

been funded as one component of the interdisciplinary Educational Resource Centers. These regional

centers were developed under the Occupational

Safety and Health Act of 1970 in response to the

need for an adequate supply of trained professionals

in occupational health (l).

The American Association of Occupational

Health Nurses is the professional organization that

represents registered nurses engaged in that specialty as practitioners, managers, consultants, and

educators. The association develops standards of

practice, monitors legislation related to occupational

and environmental health, sponsors continuing education, and publishes a journal (l).

Industrial Hygienists

The role of the industrial hygienist is to recognize

and reduce occupational health hazards in the

workplace. Industrial hygienists thus attempt to

anticipate, recognize, evaluate, and control those

environmental factors or stresses stemming from the

workplace that cause sickness, discomfort, or inefficiency among workers or members of the community (31). Industrial hygienists examine the overall

safety of the working environment and recommend

plant improvements. Part of their duty is to collect

samples of dust, gases, liquids, vapors, and raw

materials and determine the extent of worker exposure. For example, an industrial hygienist might

sample the air inhaled by an employee working with

organic solvents throughout an 8-hour shift (many

organic solvents have potential or known neurotoxic

properties, see ch. 10).

Most industrial hygienists have a bachelor’s

degree in engineering, physical science, biological

science, or natural science, and some also obtain a

master’s degree in industrial hygiene. There are two

levels of industrial hygienists, certified and uncertified. To become certified, one must complete a

baccalaureate degree in the sciences or engineering,

have 5 years of practical industrial hygiene experience, and pass a 2-day written examination given by

the American Board of Industrial Hygiene. Hygienists may seek certification in the general field of

industrial hygiene, or they may specialize in a

number of areas, one of which is toxicology.

Currently, there are approximately 4,000 certified

industrial hygienists in the United States (35). Those

hygienists who are uncertified rely on their skills,

training, and experience but are not required to meet

any minimum standards established by a governmental or professional organization (22).

The American Industrial Hygiene Association is

a nonprofit professional society for persons practicing industrial hygiene in industry, government,

labor, academic institutions, and independent organizations. The association, composed of some 7,400

members, publishes a journal and sponsors continuing education courses in industrial hygiene (15).

NIOSH Educational Resource Centers

Many of the professional organizations for toxicology, occupational medicine, occupational nursing, and occupational hygiene offer conferences and

seminars as continuing education. The Federal

Government also plays a role, through NIOSH’s

Educational Resource Centers, mentioned earlier.

There are 14 centers located within universities

throughout the United States. The centers conduct

both ongoing research projects and programs offering academic degrees and continuing education. The
100 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

four main areas on which they focus are industrial

hygiene, occupational medicine, occupational

health nursing, and occupational safety. Courses are

offered in toxicology and to a limited extent in

neurotoxicology (1,47).

NIOSH also offers some in-house courses. None

of these focuses on toxicology or neurotoxicology

specifically, but some address the broader issues of

occupational health and industrial hygiene.

SUMMARY AND CONCLUSIONS

Federal research related to neurotoxic substances

is conducted primarily at the National Institutes of

Health; the Alcohol, Drug Abuse, and Mental Health

Administration; and the Environmental Protection

Agency. Limited research programs are under way

at the Food and Drug Administration, the Centers for

Disease Control, the Department of Defense, the

Department of Energy, the Department of Veterans’

Affairs, the Department of Agriculture, and the

National Aeronautics and Space Administration.

Total Federal funding for neurotoxicology -related

research (excluding research related to alcoholism

and cigarette smoking) is $56.8 million. The bulk of

this funding (85.2 percent) is through NIH and

ADAMHA and tends to focus on the toxicity of

drugs and the biochemical mechanisms underlying

neurological and psychiatric disorders. A number of

other Federal agencies and organizations provide

limited funding for neurotoxicological research.

Research related to environmental neurotoxicology is confined primarily to the intramural program

at EPA and the extramural program at the National

Institute of Environmental Health Sciences within

NIH.

The extent of academic research related to neurotoxicology is strongly dependent on the availability

of grant support from the Federal Government.

Academic research in neurotoxicology is supported

almost exclusively by NIH and ADAMHA. Most

extramural research funded by NIH is through the

National Institute of Neurological Disorders and

Stroke and the National Institute of Environmental

Health Sciences, although several other Institutes

have substantial programs. ADAMHA funds research through the National Institute on Drug Abuse

and the National Institute of Mental Health.

EPA has a relatively large intramural neurotoxicology research program that has been limited in

recent years by lack of funding for supplies and

equipment. EPA has a small extramural grants

program that has rarely funded neurotoxicologyrelated projects. Traditionally, Federal agencies

have supported both intramural and extramural

efforts to ensure a balanced, comprehensive, and

cost-effective program.

FDA funds several research projects related to

neurotoxicology, primarily through its intramural

research programs. The National Center for Toxicological Research is conducting a number of intramura1 research projects related primarily to developmental neurotoxicology. The Center for Food Safety

and Applied Nutrition has a small in-house program

and is supporting three extramural research projects.

Within CDC, the National Institute for Occupational Safety and Health has small intramural and

extramural programs devoted to the identification

and control of neurotoxic substances in the

workplace. CDC’s Center for Environmental Health

and Injury Control conducts epidemiological investigations of human exposure to environmental hazards.

Industry undertakes neurotoxicology-related research through several mechanisms, including inhouse scientists, contract laboratories, consortia,

contracts with universities, and grants to universities. Toxicity evaluations conducted as part of

internal applied research are necessary to develop

safe and effective products, to protect employees, to

protect the environment, and to control liability

costs. Research programs vary considerably, depending on the types of products manufactured and

various economic considerations. Industry and government consortia, such as the Health Effects

Institute, which studies the health effects of emissions from motor vehicles, are useful in bringing the

regulated and the regulator together to support

research projects of mutual interest.

The education of research scientists in neurotoxicology is limited, in part, by inadequate Federal

support for training programs. Part of the difficulty

in obtaining funding is due to the nature of neurotoxicology—the intersection of neuroscience and toxicology. Few academic departments devote significant resources to neurotoxicology, and few major

Federal organizations devote their primary efforts to

it. The National Institute of Environmental Health

Sciences supports training in the neurotoxicology
Chapter Research and Education Programs ● 101

field; however, funding limitations allow for support

of only a relatively small number of trainees.

Millions of American workers are exposed to

neurotoxic substances in the workplace, but illness

stemming from these exposures often goes undetected and untreated. The subtlety of neurotoxic

responses is one reason for this situation; for

example, complaints of headache and nervousness

are often ascribed to other causes. Another reason is

the lack of adequately trained health-care professionals to diagnose and treat neurotoxic disorders.

Medical schools, in general, devote little of their

curricula to occupational health issues. After medical school, physicians may undertake residency

training in occupational medicine, but in 1987 only

about 1 in every 1,000 residents was specializing in

occupational medicine. Nurses are also needed in the

occupational health field to provide emergency

services, monitor employee health, and provide

counseling and referral to physicians. Industrial

hygienists are needed to evaluate and control health

hazards in the workplace.

CHAPTER 4 REFERENCES

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1988.

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Disease Registry, personal communication, 1989.

Bean, J. R., U.S. Department of Energy, personal

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Biersner, R., National Institute for Occupational

Safety and Health, personal communication, 1989.

Crowley, A. E., and Etzel, S.1., “Graduate Medical

Education in the United States, ” Journal of the

American Medical Association 260: 1093-1101,1988.

de Souza, E.R., Addiction Research Center, National

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personal communication, 1988.

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Evans, H. L., Institute of Environmental Medicine,

New York University, personal communication, July

1989.

Evans, H. L., “Behaviors in the Home Cage Reveal

Toxicity: Recent Findings and Proposals for the

Future,” Journal of the American College of Toxicology 8:35-51, 1989.

Gause, E., Alcohol, Drug Abuse, and Mental Health

Administration, personal communication, Apr. 25,

1989.

Gerbec, L., Administrative Assistant for Member

Services, American Industrial Hygiene Association,

personal communication, Apr. 6, 1989.

Griesemer, R. A., National Institute of Environmental

Health Sciences, personaI communication, June 8,

1989.

Griest, J., Administrative Assistant, American Board

of Preventive Medicine, personal communication,

Apr. 6, 1989.

Health Effects Institute, 2987 Annual Report (Cambridge, MA: 1988).

19. Imbus, H. R., “Is Occupational Medicine a Specialty?” American Journal of Industrial Medicine

14:109-1 16, 1988.

20. Krasavage, W. J., O’Donoghue, J. L., DiVincenzo,

G. D., et al., “The Relative Neurotoxicity of Methyl

n-Butyl Ketone and Its Metabolizes, ” Toxicology

and Applied Pharmacology 52:433-441, 1980.

21. Kunde, M. L., U.S. Department of Agriculture, personal communication, Sept. 14, 1989.

22. Landrigan, P. J., and Markowitz, S. B., Occupational

Disease in New York State: Proposal for a Statewide

Network of Occupational Disease Diagnosis and

Prevention Centers: Report to the New York State

Legislature (New York, NY: Department of Cornrnunity Medicine, Mount Sinai School of Medicine of

the City University of New York, 1987).

23. Laties, V., University of Rochester, School of Medicine, personal communication, 1989.

24. kVY, B. S., ‘‘The Teaching of Occupational Health in

American Medical Schools,” Journal of Medical

Education 55:18-22, 1980.

25. kVY, B. S., ‘‘The Teaching of Occupational Health in

American Medical Schools: Five-Year Follow-Up of

an Initial Survey,” American Journal of Public

Health 75:79-80, 1985.

26. Mirer, F., United Auto Workers, personal communication, Jan. 10, 1990.

27. National Archives and Records Administration, Office of the Federal Register, U.S. Government h4anual 1988/89 (Washington, DC: U.S. Government

Printing Office, 1988).

28. National Institute on Aging, Neuroscience and Neuropsychology of Aging Program, Aging and Neurotoxins, correspondence to OTA, June 1989.
102 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

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Science Policy and Legislation, correspondence to

OTA, November 1989.

Nelson, N., Griesemer, R. A,, and McMillan, D., letter

to Ue M, Thomas, Adrninistrator, U.S. Environmental Protection Agency, Sept. 9, 1988.

Olishifski, J.B. (cd.), Fundamentals of Industrial

Hygiene (Chicago, IL: National Safety Council,

1983).

Paule, M. G., National Center for Toxicological

Research, personal communication, July 17, 1989.

Ragsdale, N.N., U.S. Department of Agriculture,

personal communication, June 15, 1989.

Ruckelshaus, W. D., speech before the World Industry Conference on Environmental Management, Nov.

14, 1984.

Snow, B., Administrative Assistan~ American Board

of Industrial Hygiene, personal communication, May

1, 1989.

Snyder, M., Executive Director, American Board of

Occupational Health Nurses, personal communication, Apr. 7, 1989.

Sobotka, T., U.S. Department of Health and Human

Services, Food and Drug Administration, Center for

Food Safety and Applied Nutrition, personal communication, Sept. 15, 1987.

Sobotka, T., U.S. Department of Health and Human

Services, Food and Drug Administration, Center for

Food Safety and Applied Nutritio~ personal communication, Jan. 27, 1989,

Sobotka, T., U.S. Department of Health and Human

Services, Food and Drug Administration, Center for

Food Safety and Applied Nutrition, personal communication, May 30, 1989.

“Special Report: Establishing Eligibility for Examination in the Specialty of Occupational Medicine, ’

Journal of Occupational h4edicine 28:303-305, 1986.

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Strasser, A. L., ‘Occupational Medicine Matures into

Diverse, Specialized Field,” Occupational Health

and Safety Special, sec. 52, April 1988.

Swanson, A., Association of American Medical

Colleges, personal communication, Feb. 7, 1989.

Tilson, H. A., “Animal Neurobehavioral Test Battery

Used in NTP Assessments,” paper presented at the

Third International Symposium on Neurobehavioral

Methods in Occupational and Environmental Health,

Washington, DC, Dec. 12-13, 1988.

U.S. Congress, House of Representatives, Committee on Appropriations, Subcornrnittee on the Departments of Labor, Health and Human Services, Education, and Related Agencies, Appropriations for 1990,

hearings Mar. 21 through Apr. 3, 1989 (Washington,

DC: U.S. Government Printing Office, 1989).

U.S. Congress, Office of Technology Assessment,

Preventing Illness and Injury in the Workplace,

OTA-H-256 (Washington, DC: U.S. Government

Printing Office, April 1985),

U.S. Department of Energy, OffIce of Energy Research, Office of Health and Environmental Research, correspondence to OTA, Nov. 29, 1988.

U.S. Department of Health and Human Services,

Public Health Service, Centers for Disease Control,

National Institute for Occupational Safety and

Health, Projects of the National Institute for Occupational Safety and Health (Cincinnati, OH: 1988).

Wood, R., “Neurotoxicity Research-Current Activities and Future Directions, ’ paper prepared for the

Office of Technology Assessment, November 1988.

‘‘Worker Participation in Health and Safety: Lessons

From Joint Programs of the American Automobile

Industry,” presentation to the American Industrial

Hygiene Conference, San Francisco, CA, May 16,

1988.
Chapter 5

Testing and Monitoring

“Over the last 10 to 15 years, cancer had dominated the discussion of occupational standards and it continues

to remain terribly important. At the same time, information on neurotoxins has increased. The notion of

chronic and subclinical neurotoxicity has developed. Although these things are progressive and don’t occur

overnight, you’ll see more attention paid to neurotoxicity in the years ahead. ”

Philip Landrigan

Occupational Hazards 49:36, 1987

“The reasons for inadequate neurobehavioral testing of chemicals. . relate to economic factors and political

decisions, not to inadequacies of the test methods. ”

Donald McMillan

Occupational Hazards 49:37, 1987

‘‘We need to know a lot more about how toxicity is expressed in behavior. We need to be able to recommend

tests for chemicals before they move into the marketplace. This is why we need more of what NIOSH is doing.

As it is, we are still using workers as part of an early-warning system. ”

Ronald Wood

Psychology Today, July 1982, p. 30
CONTENTS

Page

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .., .., ,. .. .. .. ”. .”- C” ”” ””O.C”

ANIMAL TOXICITY TESTS . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .., .. .. ... .”. ””””.””

Designing Useful Tests . . . . . . . . . . . . . . . . . . . . .. .................++.” ... ”+”....””””

Evaluating Chemicals for Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . .. .........+.””.

Types of Animal Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...”....”...””..+

Animal Testing Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,+.+~~”.~..”’o.o+woo

ALTERNATIVES TO ANIMAL TESTS . . . . . . . . . . . . .. .. .. .. .. .. .. ... +.. ...+.... ...

In Vitro Neurotoxicity Test Development . . . . . . . . . . . . . . . . . . .. .. .. .. ....+.... ..+..

Applications of In Vitro Techniques to Neurotoxicity Testing .. .. .. .. ..+. . . . . . . . . .

Advantages and Limitations of In Vitro Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

HUMAN TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . o..

Overview of Human Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Human Exposure Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . .. .....+... “..

Legal and Ethical Considerations in Neurotoxicity Testing and Monitoring ... ....+.

Prevention of Human Exposure to Neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . .

MONITORING OF TOXIC SUBSTANCES .. .. ., .. .. .. .. .~. ... ... .......+ . . . . . . .

Specimen Banking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...

Biological Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..”.+.’...

Other Monitoring Programs . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. . ... . .......+. .. ...+...

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..

Boxes

Box

5-A. Tiered Animal Testing To Identify Adverse Neurobehavioral

Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5-B. Conducting the EPA Functional Observationa1 Battery . . . . .

. . . . . . . . . . . . . . . . . . . .

Effects of

,.,.... . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

5-C. Ethical Issues Associated With Chronic Exposure to a Neurotoxic Agent . . . . . . . .

5-D. Neurotoxicants Released Into the Environment by Industry: The Toxics

Release Inventory Supplies New Evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figures

Figure

5-1.

5-2.

5-3.

The Effects of Toxic Substances on Motor Activity . . . . . . . . .

Pattern Reversal Evoked Potential (PREP) and Flash Evoked

. . . . . . . . . . . . . .

Potential (FEP)

After Treatment With Chlordimeform. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +....

Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s

Top 25 Chemicals Emitted Into the Air in 1967 .. .. ... .. .....+... . . . . . . . . . . . . . .

Tables

Table

105

105

106

109

110

121

121

122

123

124

125

125

128

130

130

132

132

133

134

136

137

Page

110

112

131

135

Page

113

120

136

Page

5-l, Subject Factors Influencing Neurobehavioral Test Results . . . . . . . . . . . . . . . . . . . . . . 126

5-2. Behavioral Test Battery for Toxicopsychological Studies Used at the

Institute of Occupational Health in Helsinki .. ..’..... . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

5-3. WHO Neurobehavioral Core Test Battery. . . . . . . . . . . . . . . . . . . .. . . .. . . . ....+.... 127
Chapter 5

Testing and Monitoring

INTRODUCTION

People are exposed to chemicals every day in the

course of eating, working, and recreation. Some of

these chemicals are synthetic; others, whose properties may be unknown, occur naturally in the environment and in food. Modern society could not exist

without them. However, the same chemicals that

contribute to our high standard of living may also

produce unanticipated and undesired effects. Regulatory officials are concerned with weighing the

benefits of use against the risks of adverse health

effects.

All substances, even water, can be toxic at a high

enough level of ingestion. Determining the risk

posed to human health by toxic substances requires

information about the potential hazard and about the

expected level of exposure, resulting in an estimate

of the probability that a substance will produce harm

under certain conditions (see ch. 6) (105).

There are many approaches to testing for neurotoxicity, and each has both advantages and limitations. Toxic substances can be evaluated through

whole animal (in vivo) tests, tissue and cell culture

(in vitro) tests, and tests on human subjects. The

latter is the best means of predicting the effects of

potentially toxic substances on human health. This

approach, however, is generally difficult, expensive,

and in some circumstances unethical. Consequently,

it is usually necessary to rely on animal or in vitro

tests.

Most toxicity testing is performed on animals,

usually mice and rats. Animals are used for several

reasons, one of which is that, biologically, they

resemble humans in many ways and can often serve

as adequate models for toxicity studies. On the other

hand, it can be difficult to extrapolate the results of

animal studies to humans. It is also important to keep

in mind that the biochemical and physiological

processes underlying human neurological and psychiatric problems are highly complex and often

cannot be modeled in any single system.

In vitro tests can be used to complement animal

tests and reduce the number of animals used in

routine toxicity testing. In vitro testing may also be

less expensive and less time-consuming. By understanding the structure or function affected by a toxic

substance in vitro, it is sometimes possible to predict

adverse effects in the whole animal. Like all testing

strategies, in vitro tests have limitations, including

the inability to analyze behavioral effects such as

loss of memory or irritability.

Some human toxicological data are derived from

accidental exposures to industrial chemicals and

some from epidemiological studies. Prescription

drugs are tested on humans to determine safety and

efficacy.

This chapter briefly describes some methods of

neurotoxicity testing and the advantages and limitations of each. The first section addresses animal

toxicity tests, including the types of neurotoxicity

tests currently proposed for regulatory use by the

U.S. Environmental Protection Agency (EPA). The

second section describes alternatives to animal tests,

including in vitro approaches, and the third section

describes human testing. Finally, approaches to

monitoring of toxic substances are briefly discussed.

ANIMAL TOXICITY TESTS

In designing animal tests and evaluating data,

appropriate weight is given to the following factors

on a case-by-case basis, taking into account the

seriousness of the hazard and the assumptions

needed to estimate human health risks (105):

●

●

●

●

●

●

●

the relationship between dose and response;

the effects at the molecular, cellular, organ,

organ system, and whole organism levels;

the reproducibility of the study results and

possible explanations for lack of reproducibility;

the effects of structurally similar substances on

humans or animals;

any known metabolic differences between humans and the test species that could affect

response;

statistical uncertainties and difficulties in extrapolating to a low dose; and

other factors, such as sex, species differences,

and route of administration.

An Office of Technology Assessment (OTA) report,

Alternatives to Animal Use in Research, Testing,

and Education, contains a detailed discussion of the

use of animals in research and associated ethical

-105-
106 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

concerns (105). The issues raised there will not be

readdressed in this report.

Toxicity testing should aim to obtain all the data

needed for accurate risk assessment at the lowest

possible cost. Factors that influence cost include the

number of appropriate test species, the nature of the

parameters studied, the choice of test subjects, the

controls required, and the skilled staff necessary to

perform the studies. In addition, toxicity testing

requires a substantial investment in labor. Aside

from the maintenance needs of the animals used,

many observations are necessary. Acute studies

often involve observations of behavior and appearance as well as histopathological observations.

Subchronic and chronic studies require more detailed pathological studies as well as weekly clinical

examinations of all the animals used in the studies

(92). Testing costs will be discussed in more detail

in chapter 8.

Designing Useful Tests

Animal tests are used to determine the functional,

structural, and biochemical effects of toxic substances. Experimental animal models have limitations, however, and the accuracy and reliability of a

quantitative prediction of human toxicity depend on

a number of conditions, such as choice of species,

choice of tests, similarity of human and animal

metabolism, design of the experiment, and method

of extrapolation of animal data.

When designing animal toxicity tests, therefore, it

is essential that the examiners clearly define the

objective of their study and understand how the

resulting data will be used. Several questions should

be answered in advance: Will the data obtained from

the animal tests be meaningful? Will the data be

useful in the risk assessment process? Can the data

be extrapolated from animals to humans?

The World Health Organization (WHO) recently

suggested several general objectives of neurotoxicology testing (123):

●

●

●

identify whether the nervous system is altered

by the toxic substance,

characterize the nervous system alterations

associated with exposure,

ascertain whether the nervous system is the

primary target for the chemical, and

● determine dose- and time-effect relationships

to establish no observed adverse effect levels

(NOAELs).

The initial goal is to determine whether or not the

nervous system is affected by a substance for which

no toxicological data exist. This often involves

screening for neurotoxicity using tests that predict

the potential of a substance to produce adverse

effects. To be most effective, the tests should be

simple, rapid, and economical to administer. Once a

chemical is known to produce a neurotoxic effect,

further studies can be performed in order to characterize the nature and mechanism of the alterations.

Screens are generally designed to explore the

consequences of exposure and to indicate whether or

not the nervous system is adversely affected.

Chemicals are unlikely to affect all major components of the nervous system at the doses tested;

therefore, it is important to use a variety of tests that

measure different functional, morphological, or

chemical alterations in order to maximize the

probability of detecting neurotoxicity. The methods

used may differ with the objective of the study, the

age of the animal, and the species examined (123).

Potential neurotoxic risks are difficult to assess

because of the complexity of the nervous system.

Some of the problems in assessment are associated

with the wide variations in response that can occur.

Other problems are related to the examiner’s incomplete understanding of what is being measured by a

given test. Therefore, no single test can be used to

examine the total functional capacity of the nervous

system (123).

Animal Choice

In preliminary screening of known or suspected

toxic substances, numerous economic factors influence the design of the evaluation. It is useful if there

exist adequate anatomical, physiological, and toxicological databases on the species chosen for study

to allow meaningful interpretations of effects and

appropriate hypotheses about mechanisms and sites

of action (123).

Most routine toxicity testing is carried out with

only one or two species. For example, cancer

bioassays frequently involve the use of rats and

mice, and the monkey may be used for identifying

the effects of MPTP, a byproduct in the illicit

synthesis of a meperidine analog. Hens have been

used to evaluate the neurotoxic potential of organo-
Chapter 5-Testing and Monitoring ● 107

phosphorous pesticides. Most other neurotoxicity

screening studies use laboratory rats. Ideally, more

than one animal species should be tested—if only a

single species is tested, it is possible to conclude that

human exposure is acceptable when in fact it is not.

However, routine multispecies testing is a costly and

demanding enterprise. The facilities and services

needed for animal husbandry and the equipment and

technical expertise needed to carry out the research

make multispecies testing economically impractical

in many instances (59).

There are other variables besides species that

should be considered. For example, the sex of the

test animal may influence results of the study. Some

toxic substances may have a greater adverse effect

on females than males or vice versa. Consequently,

EPA testing guidelines require both male and female

rats for neurotoxicity testing.

Another important factor is the age of the animal.

The effects of a toxic substance may vary dramatically, depending on the stage of maturation of the

animal. For example, cell loss in the nervous system

due to natural aging processes may predispose an

animal to the adverse effects of toxic substances.

Most preliminary assessments are designed to provide information on the population with the greatest

potential for exposure, namely, adults. However,

aged populations or those undergoing rapid maturation are often especially vulnerable to environmental

exposures; thus, tests to assess the neurobehavioral

functioning of these populations are necessary for a

complete evaluation.

The ideal tests are those that permit longitudinal

assessment of animals of both sexes at any stage of

development (i.e., at young childhood, prepuberty,

and adulthood) (67). Whenever possible, the choice

of animal model should take into account such

factors as the differences in metabolism of substances between species, genetic composition of the

species, and the sensitivity of the test animals to the

toxic effects of the substances (50 FR 39458).

Dosing Regimen

Some compounds produce one kind of toxic effect

following a single exposure and other effects following prolonged or repeated exposure. In environmental

toxicology, a major objective is the detection of

cumulative toxicity following continued (or intermittent) exposure. Thus, a multiple-dosing regimen

is most commonly used. This is particularly important in neurobehavioral testing, since both quantitative and qualitative changes in the response to

environmental factors can occur with repeated

exposure, or at some later time following a single

exposure (67,123). Normally, assessments are made

for a period of time following termination of the

dosing regimen, both to determine the reversibility

of any observed effects and to see if any new effects

appear (123).

Substances are administered in varying doses, the

dose being a function of the concentration of the

substance and the duration and frequency of exposure. Significant differences in response may occur

when the same quantity of toxic material is administered over different exposure periods. Acute exposure to substances may produce both immediate and

delayed toxic effects (such is the case for some

organophosphorous pesticides). These effects may

differ from the effects following long-term exposure. Repeated exposure to certain solvents may

produce immediate effects after each dosing as well

as delayed adverse effects from long-term exposure

(47).

Acute toxic responses result when an animal is

subjected to high concentrations of a substance over

a short period of time. The acute response may be

sudden and severe, and usually lasts for a brief

period of time; in some cases, however, it is

permanent. If the dose is sufficiently high, death may

result. Lower doses (lower concentrations over

longer periods of time) may not immediately cause

death. As the dose decreases, the response is

generally less severe and may take longer to

develop. In chronic exposures, clinically adverse

effects may take years to develop (47).

Route of Exposure

The most common routes by which toxic substances enter the body are, in descending order,

inhalation (through the lungs), oral (through ingestion), and dermal (through the skin). Although

substances generally produce the greatest effect and

most rapid response when given intravenously, this

is an unlikely route of entry except in the case of

drug therapies or drug abuse. The manner in which

a potentially toxic agent enters the body can

influence the time of onset, intensity, and duration of

the toxic effects. The route of exposure may also

influence the degree of toxicity and the organs most

severely affected.
108 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Exposure to toxic chemicals in the atmosphere is

unavoidable unless devices are used to remove the

contaminants from the air before they enter the

respiratory tract. In order for any contaminant to

reach the alveoli of the lungs (where gas exchange

takes place), it must be either a gas or of a certain

particulate size (less than 10 microns in diameter) so

that it is not removed in the airway to the lungs. The

actual and potential’ hazards associated with exposure to toxic agents via inhalation are evident in

industrial workplaces and in urban areas with

polluted atmospheres (55,1 17).

Most episodes of acute toxicity result from

intentional or accidental ingestion of a chemical. For

instance, a person may deliberately take an overdose

of a psychoactive drug. Poisonous mushrooms may

be accidentally ingested. Sufficiently large particles

of inhaled toxic matter may collect in the throat and

be swallowed.

The simplest route of exposure for humans and

animals is accidental or intentional contact of the

chemical with the skin. The skin is the most readily

accessible organ to all forms of foreign chemicals,

yet it is also an efficient barrier to many toxic

substances. Many substances can be absorbed

through the skin, including substances in fragrances

(AETT), antidandruff shampoos (zinc pyridinethionine), and solvents (methyl n-butyl ketone) that have

proven to be neurotoxic in humans or animals, or

both (3,44,47). The degree of absorption is influenced by the type of compound(s) involved and the

condition of the skin. For example, cuts or abrasions

on the skin’s surface will allow the agent to bypass

the epidermis, the outer, protective layer of the skin.

Once through the epidermis, the substance can easily

pass into the circulatory system. Depending on the

concentration and duration of the exposure, some

substances, solvents, for example, can easily pass

through the epidermis.

Extent and Duration of Exposure

The exposure of animals to chemicals is often

divided into four categories: acute, subacute, subchronic, and chronic. Acute is defined as exposure

to a chemical for less than 24 hours. The purpose

of an acute test is to observe the evidence of toxicity

after administration of the compound and the degree

of lethality (55). While acute exposure usually refers

to a single administration, repeated or continuous

doses may be given within a 24-hour period for some

substances with limited acute toxicity. An example

is acute exposure by inhalation, which refers to

continuous exposure for less than 24 hours. Repeated exposures are divided into subacute, subchronic, and chronic categories. Subacute exposure

refers to repeated exposure to a chemical for 1

month or less, subchronic exposure occurs typically from 1 to 3 months, and chronic exposures

occur for more than 3 months (47).

As mentioned earlier, the toxic effects following

a single exposure to a substance may be quite

different from those produced by repeated exposure.

This may occur because of compensatory changes

elicited by repeated administration or because of

cumulative effects of mechanisms different from

those causing acute toxicity. For example, the

primary acute toxic effect of carbon disulfide is

depression of central nervous system activity; however, repeated exposures can result in peripheral

neuropathy or parkinsonism. Acute exposure to

rapidly absorbed substances is likely to produce

immediate toxic effects, but acute exposure can also

produce prolonged toxicity that may or may not be

similar to the toxic effects of chronic exposure.

Likewise, chronic exposures may produce some

immediate effects after each administration in addition to the chronic effects (47).

The extent of exposure is another important factor

in the characterization of exposure parameters.

Generally, but not always, fractionation of the dose

reduces the effect. A single dose of a compound that

produces an immediate, severe effect might produce

less than half the effect when given in two equal

doses and no effect when given in 10 doses over a

period of several hours or days. Chronic toxic effects

occur if the compound accumulates in the organism’s system, if it produces irreversible toxic effects,

or if there is insufficient time for the system to

recover from the toxic damage (47).

Other Considerations

Several additional factors are considered in designing neurotoxicological tests. One condition that

may affect toxicity is the nutritional state of the

animal. Changes attributed to exposure to toxicants

might be due to relatively nonspecific effects related

to inhibition of growth or decreases in food or water

consumption.

Another factor is the housing conditions of the

experimental animals. Sometimes animals are

housed individually in cages during toxicological
Chapter S--Testing and Monitoring ● 109

studies, an arrangement that may alter their responsiveness to the test compounds. For example, a

chemical that causes depletion of the neurotransmitters norepinephrine and dopamine produces less

depression of motor activity in isolated rats than in

grouped rats (125).

Temperature of the environment is another

important factor. Normally, the response of an

animal to a toxic compound decreases as the

environmental temperature is lowered, but the duration of the overall response may be delayed. Also,

some drugs are more toxic in certain environmental

temperatures than in others. For example, compounds affecting the neurotransmitter acetylcholine

may produce significantly greater toxicity in a warm

environment than in a colder one. Some substances

inhibit sweating. Eventually, the body temperature

becomes elevated because the absence of perspiration prevents cooling (38). In such a case, toxic

effects may result from hyperthermia, not directly

from the effect of the substance on the nervous

system.

Validation

Validation is a critical component of the test

development process because it ensures that data

generated as a result of testing will be useful in

evaluating the health risk posed by a particular

substance. The value of any toxicity test lies in its

ability to measure the endpoint it is designed to

detect. For neurotoxicity, the endpoints are adverse

changes in the structure or function of the nervous

system. General acceptance of a new toxicity test

usually requires demonstration that the test is

reliable, sensitive, and specific. For validation studies, chemicals with known neurotoxic potential and

those known not to be neurotoxic are studied to

determine the ability of the test to distinguish

between them. Because toxic substances can have

many different effects on the nervous system, known

neurotoxic substances with different effects on the

nervous system are chosen for validation studies.

Before test guidelines are proposed for national or

international use, validation studies commonly include a multilaboratory phase to test the reproducibility of the testing paradigm in different laboratories (58,81).

Evaluating Chemicals for Neurotoxicity

It is impossible to thoroughly examine the neurotoxicity of each of the chemicals in commerce.

However, it

Photo credit: U.S. Environmental Protection Agency

may be possible through a welldeveloped screening program to flag the substances

either currently in use or recently introduced that

have neurotoxic potential. Screening is conducted to

provide an initial evaluation of the effects of various

substances on the nervous system. The results of

screening may be used to reduce the number or

quantity of hazardous substances in commerce or to

aid in determining which additional studies should

be undertaken to further characterize their toxicological properties (67). An efficient screen should

evaluate a variety of neurological effects rather than

just one. Screens should also be sensitive, reproducible, and capable of being administered rapidly

(32,33),

Testing strategies often involve a tiered approach.

Tiered testing involves a stepwise progression of

more specific and sophisticated tests, beginning

with a general screen to determine if further testing

is necessary. In the initial screen of the tiered testing

approach, the outcomes of acute studies are interpreted. If acute effects are identified, then experiments involving repeated exposures are performed

in the second tier. The third tier is composed of

detailed studies of subtle effects or mechanisms of

toxicity. At each stage the examiner builds on the

data collected from the previous tier.
110 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Typically, 5 to 10 animals of the same species and

strain are used in the tests. It is important to select the

proper animal model initially because it is desirable

to use the same model in subsequent tiers. Using the

same animal is more efficient, costs less, and allows

consistent analysis of data. Some toxicity tests only

require the acute dosing regimen, and it is not

necessary to conduct repeated dosages. Box 5-A

illustrates one example of a tiered testing approach.

Other investigators have proposed slightly different

schemes (32-34,62).

As in vitro tests become available, tiered testing

schemes may be modified to take advantage of both

whole animal and tissue and cell culture testing

approaches. For example, a future scheme might call

for in vitro tests as a screen, followed by in vivo tests

(32,37). In vitro tests will be described later in this

chapter.

Types of Animal Tests

The EPA has taken the lead in devising neurotoxicity tests for use in regulatory programs. In 1985,

the Agency devised a final rule on general toxicity

testing guidelines under the Toxic Substances Control Act (50 FR 39398-39418). The guidelines are

dermal, inhalation, and oral exposure); subpart C

includes testing procedures for subchronic dermal,

inhalation, and oral exposure; and subpart D describes testing procedures for chronic exposure.

General toxicological tests evaluate a broad

spectrum of potential toxicological effects, including some effects on the nervous system; however,

these tests are not designed to examine comprehensively the possible neurotoxic properties of chemicals. In 1985, EPA proposed specific guidelines for

neurotoxicity testing (50 FR 39458-39470). EPA

has proposed guidelines for the functional observational battery (FOB) and specific tests to analyze

motor activity, schedule-controlled operant behavior (SCOB), developmental neurotoxicity, neuropathology, and the effects of organophosphorous

pesticides (1 12). When specific neurotoxicity testing is necessary, EPA currently plans to require the

FOB, together with motor activity and neuropathology tests. At the present time, these three tests are

referred to by EPA as the core test battery. EPA’s

Office of Toxic Substances and Office of Pesticides

Programs are currently considering a requirement to

use the core tests routinely in evaluating new and old

categorized into three subparts: subpart B describes chemicals and pesticide products. When approprithe procedures for general toxicity testing (i.e., acute ate, other tests may also be required.

Box 5-A—Tiered Animal Testing To Identify Adverse Neurobehavioral Effects of Substances

Tiered testing is an efficient and cost-effective approach to evaluate the toxicity of chemicals. In the first tier

of an experiment, the recommended strategy is to identify acute hazards of substances. The second tier is designed

to characterize the toxicity in repeated exposure, and the third is used to undertake detailed studies of special

impairments or of mechanisms of chemical injury. Each tier provides useful information for subsequent tiers.

First tier—Animals are exposed to the substance being evaluated. The exposure period is short and covers

a wide range of concentrations. The investigator seeks to identify any evidence of mortality, morbidity, or

morphological changes. The experimenter also observes behavior. The first tier helps establish the parameters of

exposure that are appropriate for the second tier. It may also suggest mechanisms by which the effect is produced,

which may assist in the design of more sensitive experiments in the third tier.

Second tier—Animals are repeatedly or continuously exposed to substances being evaluated. This tier

provides an opportunity to characterize delayed toxicity, to observe the development of tolerance, and to

characterize the reversibility of adverse effects.

Third tier—At this stage, highly focused studies are performed to fully characterize toxicity, using methods

dictated by the nature of the system. This tier can identify subtle sensory or perceptual impairments, affective

disorders, or cognitive and intellectual dysfunction. A detailed hazard characterization not only can facilitate the

identification of the most sensitive situation, but also may clarify the mechanism of action of the substance.

The above schemes may be modified in the future as in vitro tests become available.

SOURCES: A.M. Goldberg and J.M. Frazier, “Alternatives to Animals in Toxicity Testing,” Scientific American 261(2):24-30, 1989; R.W.

Wood, American Psychological Association, testimony before the Neurotoxicity Subpanel of the FIFRA Science Advisory Panel,

U.S. Environmental Protection Agency, Washington, DC, Oct. 15, 1987.
Chapter .5-Testing and Monitoring . 111

In August 1989, EPA sponsored a meeting of the

Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA) Scientific Advisory Panel to examine

various issues related to proposed guidelines for

neurotoxicity and mutagenicity testing under the Act

and to review the classification of several selected

compounds (54 FR 35387).

Unless otherwise specified, it is assumed that both

acute and subchronic testing will be conducted for

both FOB and motor activity. Although some

experts have recommended that neuropathological

examinations be conducted following acute exposures, at the present time EPA anticipates requiring

such analysis only after repeated exposures. These

neurotoxicity tests represent an initial approach to

identifying hazardous chemicals and are not specifically designed to develop the data necessary for

full-scale risk assessments (101). (See ch. 6.)

The EPA core battery does not represent a

complete screening assessment of the nervous system. For example, it does not adequately assess

cognitive function, neurophysiology, or neurochemistry. Some neurotoxicologists have challenged the

usefulness of the core battery, saying that it does not

go far enough. Nevertheless, EPA plans to require

just the core battery, with the option of using more

comprehensive tests for selected compounds. Additional tests that EPA might require in conjunction

with or in place of the core battery include SCOB,

developmental neurotoxicity, and neurotoxic esterase assay (101).

Which tests are most appropriate for routine use

in screening for neurotoxicity is the subject of

disagreement in the scientific community. Some

scientists believe that developmental and SCOB

should be part of the EPA core test battery because

they measure different aspects of neurotoxicity than

do the FOB, motor activity, and neuropathology

tests. Others believe that the motor activity and

SCOB tests should not be used as part of an initial

screen, because they may not be direct measures of

neurotoxicity. EPA believes that the initial screen

should include FOB, motor activity, and neuropathology assessments because these tests provide

adequate initial measures of neurotoxicity and

enable investigators to judge whether or not additional (second tier) testing is necessary. Descriptions

of various neurotoxicity tests follow.

Functional Observational Battery

An FOB is a collection of noninvasive tests to

evaluate sensory, motor, and autonomic dysfunction

in either animals exposed to substances or animals

having endured direct damage to the nervous system

(57). FOBS are generally used as screens to determine which substances require additional testing.

EPA published a test guideline for an FOB in

1985. The EPA guideline incorporates aspects of

tests developed and used in industry and academia

(32-34,42,79,80). The battery is designed to be used

in conjunction with general toxicity tests or neuropathological examinations, or both (50 FR 39458-

39460). It serves as a screening tool (thus, it is

considered a first tier test), indicating which substances should be further characterized using second

tier methods. It is not intended to provide an overall

evaluation of neurotoxicity. EPA is currently refining and validating its FOB.

The EPA test battery is administered to female

and male rats, usually 10 per dose group per sex.

Three doses of the test substances are used, with

doses chosen so that the highest dose produces

obvious signs of toxicity. The doses are selected on

the basis of values from previous literature and

experiments in order to ensure the detection of

neurobehavioral effects (69,70). The observer is not

aware of the dose identification. The observer

records each response subjectively, using established rating scores. After all data are collected, they

are entered into a computer, summarized, and

analyzed using statistical methods (17,68-70). Box

5-B summarizes the procedures for conducting the

EPA FOB.

The FOB is advantageous because it can be easily

administered and can provide some notion of the

possible functional changes produced by exposure

to neurotoxic substances. It also allows evaluation of

the dose-response and time course characteristics of

the neurological and behavioral changes produced

by exposure to a substance. Furthermore, the equipment used is relatively inexpensive, and the total

time to complete an entire evaluation is short

(68,69). Potential problems include difficulty in

defining certain measures, a tendency toward subjective biases in assessing behavior (123), and the

need for trained observers.
112 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 5-B-Conducting the EPA Functional Observational Battery

In conducting the EPA functional observational battery (FOB), the technician first observes and describes the

rat’s posture in the home cage, then closure of the rat’s eyelid and any convulsions or tremors that may be present.

Next, the animal is picked up and rated for ease of handling and removal from the cage. The rat is observed and

rated for signs, such as lacrimation and salivation, that the autonomic nervous system has been adversely affected.

The rat is then placed on a cart top for 3 minutes, during which time the number of rears are counted and the gait,

mobility, and level of arousal are rated. At the end of the 3 minutes, fecal and urine output are recorded.

Next, the technician rates the rat’s responses to several stimuli, such as the approach of a pencil, snap of a metal

clicker, touch of the pencil on the rat’s rump, and pinch of the tail with forceps. Using a pen flashlight, the observer

tests the rat for pupil constriction in response to light. The righting reflex is then measured by the ability of the rat

to flip over in midair and land on its feet. Using strain gauges, the rat’s forelimb and hindlimb grip strength are

measured. The rat’s hind feet are painted, and the technician then holds the rat a few inches above the cart top and

drops it in order to measure landing foot splay. Finally, the rat’s weight and rectal temperature are recorded. The

entire procedure takes approximately 6 to 8 minutes per animal.

SOURCES: V, Moser, Director, NSJ Tedmology Services Corp., Research Triangle Park, NC, personal communication, Nov. 16, 1988; V.

Moser, J. McCormick, J.P. Creason, et al., “Comparison of Chlordimeform and Carbaryl Using a Functional Observational

Battery,” Fundamental and Applied Toxicology 11:189-206, 1988.

Photo credit: John O’Donoghue

One component of the functional observational battery

(FOB) evaluates a rat’s response to an auditory stimulus.

Motor Activity

Motor activity is generally defined as any movement of the experimental animal, and it is most often

evaluated after acute and subchronic exposures. The

acute motor activity test is used to examine changes

in animal movement following the administration of

a range of acute doses. This test can also be used to

determine the potential of a substance for producing

acute neurotoxicity, and it may be used as a screen

to evaluate certain classes of substances for neurotoxicity. The subchronic motor activity test is used

to determine whether repeated dosing with suspected chemicals results in changes in activity, This

test may be used to determine a substance’s potential

for producing subchronic neurotoxicity (50 FR

39460) (60). There is disagreement as to whether

motor activity is a primary indicator of neurotoxicity. For example, the primary action of a toxicant

may be at some site other than the nervous system;

the changes in motor activity maybe secondary, that

is, a result of the primary effect.

Proposed EPA guidelines require that the test

substance be administered in different amounts to

groups of animals. Levels of exposure that result in

significant changes in motor activity are compared

to levels that produce toxic effects not originating in

the central nervous system (50 FR 39460). Observation measurements may be either quantitative or

qualitative. The quantitative approach measures the

frequency, duration, and sequencing of various

motor components of behavior. The qualitative

approach is used to gather data on the presence or

absence of certain components of activity (90).

The use of observational methods to detect subtle

changes in behavior has limitations. Many manhours are required to obtain and evaluate the data.

Some studies also require more than one observer.

Because of possible subjective influences on data

collection, a great deal of technical knowledge is

required to ensure reliability. Finally, subjectobserver interaction is an important consideration.
Chapter 5—Testing and Monitoring ● 113

For example, the presence of the observer may

modify the animal’s behavior (90).

The techniques of observational analysis have

included videotape recordings and computerized

pattern recognition. In most cases, videotaping has

minimized the problem of subject-observer interaction and has provided a permanent record of

behavior which can be used for standardizing

observations. The computer techniques have alleviated the problems of subjectivity (subject-observer

interaction and subjective bias) and laborious datacollection procedures (90).

Some of the automated techniques that have been

developed for motor activity testing include photocell devices, mechanical devices, field detectors, and

touch plates. Photocell devices provide direct measures of motor activity in which beams of light

traverse a cage and collide with photoreceptors. This

technique involves placing the rat in a figure-8 maze

and recording any movement of the experimental

animal that interrupts the beam of light. The number

of beam interruptions is counted and recorded by a

computer for a l-hour time period (60,68). The

figure-8 maze is only one of a variety of chambers

used for motor activity examinations. For example,

another device commonly employed for assessing

motor activity is the Motron Electronic Mobility

Meter, which differs from the figure-8 maze because

of its rectangular shape and the density and arrangements of the photodetectors that are used to record

motor activity (60). Automated motor activity measures may be used to generate dose-response data.

This is typically done by placing rats in a plexiglass

box, Two video cameras monitor the animal’s

behavior, and the video signals are transferred to

computers in order to identify common patterns in

movement and behavioral classification of the data

(71).

Toxic substances may have a variety of effects on

motor activity. To generate the data illustrated in

figure 5-1, motor activity was measured for 1 hour

in a group of rats in a figure-8 maze after administration of a toxic substance or placebo (P). The numbers

represent motor activity units for the entire hour.

Group FLT received the pesticide fenvalerate, which

depressed activity. Group TPT received the pesticide triphenyltin, which had no effect on activity.

Group TDM received the pesticide triadimeform,

which stimulated activity, Experiments are ordinarily conducted with many doses of a toxic substance

Figure 5-l—The Effects of Toxic Substances

on Motor Activity

Motor activity units

500 475

400-

300- 280 II

200-

100-

235

P FLT P TPT P TDM

Substance

P , Placebo FLT = Fenvalerate TPT . Triphenyltin TDM = Triad tmeform

SOURCES: K.M. Crofton and L.W. Reiter, “The Effects of Type I and II

Pyrethrolds on Motor Actiwty and the Acoustic Startle Response in the Rat,” Fundamental and A#ied Toxicology

10:624-634, 1988; K,M. Crofton, V.M. Boncek, and R.C.

MacPhail, “Evidence for Monoaminergic Involvement in Triadlmefon-induced Hyperactivity ,“ Psychopharmaco/ogy97 :326-

330, 1989; S, Padilla, R,C. MacPhail, and L.W. Reiter,

“Neurotoxic Potential of Pesticides: Age-related Effects of

Pesticides to Youth in Agriculture,” U.S. Environmental Protection Agency report, Health Effects Research Laboratory,

1985.

to determine how motor activity changes with level

of exposure (59).

Motor activities recorded with mechanical devices involve a vertical or horizontal displacement

of the chamber in response to the animal’s motions.

Some of the mechanical devices used include

stabilimeters and running wheels. Stabilimeters

record the movement of the animal when it causes

the chamber floor to be displaced from its resting

position. Running wheels are designed so that the

wheel is positioned on a horizontal axle and the

animal’s running causes the device to rotate. Running wheels have been used in behavioral toxicology

for over three-quarters of a century to study the

effects of food deprivation, water deprivation, estrus, lesions of the central nervous system, and

locomotor activity (90).

Field detectors are used to record the disturbances

that an animal creates in moving within a test cage.

Touch plates measure motor activity by recording

contacts of the animal with sections of the chamber

floor (90).
114 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

There are many advantages of motor activity tests.

These include the availability of automated test

equipment, ease of testing, and objectivity of data

(60). Additional factors include obtaining reproducible data that are sensitive to the effects of acute

exposure to various toxic substances. These methods

do not require any special training or surgical

preparations prior to testing.

Several organizations, including the National

Academy of Sciences, the World Health Organization, and the Federation of American Societies for

Experimental Biology, have recommended that

motor activity testing be included in evaluating the

toxicity of potential and known neurotoxic substances (30,64,74,123). However, further testing is

usually needed to provide more specific information

on the adverse health effects of the test substance.

Furthermore, the data collected may not provide

information on the origin of the problem or indicate

what subsequent tests should be administered (64).

There is general agreement within the scientific

community that questions remain concerning the

specificity of motor activity measures. For example,

sickness resulting from chemical exposure is not

always associated with changes in motor activity

(60).

Photo credit: V Moser and R.C. MacPhail

The figure-8 maze is used to evaluate changes in motor

activity after exposure to neurotoxic substances.

Photo credit: Julia Davis, NSI Technology Services Corp.,

Research Triangle Park, NC

The electron microscope is a useful tool in examining nerve

tissue damaged by toxic substances.

Neuropathology

Neuropathology is the third component of the

EPA core test battery (50 FR 39461). The neuropathological examination is designed to develop data

on structural and functional changes in the nervous

system as a result of exposure to toxic substances.

EPA’s guidelines recommend procedures to detect

pathological alterations produced by neurotoxic

substances. Morphological examination of animals

exposed to neurotoxic substances helps to distinguish between pharmacological and structural types

of adverse effects, describes the relative frequency

and severity of the lesions, establishes the location

of structural changes in the central nervous system,

serves as a basis for relating particular classes of

compounds to particular kinds of damage, and

reveals the cellular components that have been

damaged. Additional neuropathological techniques

are currently in use to determine NOAELs and to

examine the effects of toxic substances on the

nervous system (48,100).

There is general agreement that neuropathological

studies should be conducted in parallel with other

neurotoxicity tests. Neuropathological evaluations

may be performed following acute, subchronic, and
Chapter S-Testing and Monitoring ● 115

chronic exposures to toxic substances (50 FR

39461).

Developmental Neurotoxicology

Developmental neurotoxicology (behavioral teratology), an emerging discipline within the toxicological sciences, is concerned with behavioral and

related effects in the offspring of parents exposed to

neurotoxic substances prior to conception, during

gestation, during lactation, or any combination of

these times (45). Research efforts are under way to

understand the basic principles of behavioral neurotoxicity, the biological mechanisms involved, and

the appropriate methods for testing and obtaining

data to be used by regulatory agencies in setting

standards (45). In recent years, major advances have

been made in methods for detecting the adverse

behavioral effects of toxic substances on the developing organism. In 1979, the National Center for

Toxicological Research (NCTR) developed a battery of tests to be used for the Collaborative

Behavioral Teratology Study. NCTR served as the

pilot test facility for conducting the study, and five

other laboratories were involved in evaluating a

standard protocol. The study was designed to assess

the reliability of the test methods used and to detect

the sensitivity of each (1,14,45,114,115).

Regulatory efforts in behavioral teratology began

in 1975, when Great Britain and Japan produced

guidelines for testing pharmaceutical substances. In

1983, the European Economic Community developed similar guidelines. WHO proposed draft testing guidelines for drugs and other substances in

1986 (45). That same year, EPA proposed testing

guidelines for several glycol ethers (51 FR 17883;

51 FR 27880). A final test rule for diethylene glycol

butyl ethers (53 FR 5932) was set in 1988 and for

triethylene glycol monomethyl ethers (54 FR 13472)

in 1989. These were the first testing guidelines

directly related to developmental neurotoxicity to be

promulgated by a U.S. regulatory agency.

Developmental neurotoxicity tests are used to

characterize various aspects of damage to the

developing nervous system, including adverse structural and functional changes. This information

serves as a basis for relating particular classes of

compounds to particular kinds of damage; it can then

be used to predict what classes of compounds may

be neurotoxic. Developmental neurotoxicity tests

are also used in determining the magnitude of

damage resulting from particular exposure levels,

and they aid in establishing NOAELs (51 FR

17890). The guidelines for glycol ethers consist of

evaluations of morbidity and mortality, growth and

physical development, neurological and physical

abnormalities, auditory startle habituation, learning

and memory, developmental locomotor activity, and

neuropathology. Recently, a consent order for the

testing of 1,1,1 -trichloroethane was published (54

FR 34991); it includes developmental neurotoxicity

testing.

In 1987, FIFRA’s Science Advisory Panel approved the development of a generic testing guideline for developmental neurotoxicity testing (along

with a guideline for adult neurotoxicity testing).

Generic guidelines have also recently been proposed

for developmental and adult neurotoxicity testing of

pesticides. These tests are designed to determine the

effects of maternal exposure to pesticides on the

nervous systems of offspring. The proposed generic

test guidelines require administration of the test

substance to several groups of pregnant animals

during gestation and lactation. Selected offspring are

then tested for neurotoxicity. This evaluation is

designed to detect any effects on growth and

development, gross neurological effects, or behavioral abnormalities. These guidelines will be required for the testing of pesticides on a case-by-case

basis. Testing may be required for substances that

cause central nervous system malformations, substances already known to be neurotoxic in adults,

hormonally active substances, and substances that

are structurally related to known neurotoxicants

(46).

In April 1989, a workshop on the comparability of

human and animal developmental neurotoxicity was

sponsored by EPA and the National Institute on

Drug Abuse to evaluate and compare the effects of

known neurotoxic substances on the developing

nervous system. The workshop focused initially on

several agents known to adversely effect humans,

including selected abused substances (primarily

methadone and cocaine), alcohol, lead, polychlorinated biphenyls, diphenylhydantoin, methyl mercury, and X-irradiation. It is possible to make

qualitative comparisons of effects across species,

especially when major categories of function are

compared. Making quantitative comparisons in data

is more difficult (46).

Based on this information, work groups then

focused on the underlying basis for comparability of
116 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

effects across species, the appropriateness of current

testing approaches, alternative approaches to risk

assessment, and the considerations (triggers) that

should be used in determining when to require

testing. Participants agreed that the support for

cross-species comparability was great enough that a

reliable effect (including permanent and transient

effects) should be considered a potentially adverse

effect in humans. Also, developmental effects, in the

presence or absence of maternal toxicity, should be

considered adverse. Since no single category of

function was found to be routinely the most sensitive, it was agreed that a battery of functions should

be included in any developmental neurotoxicity

testing screen. Although limitations were identified,

workshop participants felt that a reference dose

should be established to identify a level below which

no increase in developmental neurotoxicity is expected, An abbreviated test battery was proposed for

screening purposes. Whether to use this abbreviated

battery or a full-scale testing protocol may depend

on the type of information already available. For

example, a substance that causes central nervous

system malformations should be thoroughly evaluated for developmental neurotoxicity, whereas a

substance that is structurally related to known

neurotoxic substances might be tested first using the

abbreviated battery (46).

EPA has published risk assessment guidelines for

developmental toxicity (51 FR 34028) and has

recently proposed amendments to these guidelines

(54 FR 9386). Developmental neurotoxicity data

may aid in evaluating the long-term consequences of

adverse effects discovered at the time of birth and the

relationship of the behaviorally effective dose to the

toxic dose. These data may also aid in identifying

effects that should be monitored in exposed populations (45). EPA is currently developing guidelines

for the use of data on adult and developmental

neurotoxicity in risk assessments.

Schedule-Controlled Operant Behavior

Changes in behavior are a useful indicator of

exposure to neurotoxic substances because behavior

involves the integration of motor, sensory, and

higher order nervous system activities (102). Regulatory officials increasingly recognize behavioral

change as an important endpoint of neurotoxicity.

Several organizations, including the National Academy of Sciences and WHO, have recommended that

operant behavior testing be included in evaluations

Photo credit: D. Cory-Slechta

Schedule-controlled operant behavior (SCOB) tests are

used to evaluate a rat’s learned behavior in

scheduled intervals.

of potential and known neurotoxic substances (74,75,

123). Operant behavior refers to “behavior that is

maintained by its own consequences’ (50). Schedulecontrolled operant behavior refers to reinforcing an

animal’s response to stimuli according to an explicit

schedule, thereby producing orderly patterns of

behavior (50).

There are several reasons why operant behavior

tests may be useful. Operant behavior is critical for

adaptation and long-term survival of animals. Tests

of this kind allow reliable and quantitative examination of the effects of substances on behavior, and the

extensive literature on operant behavior provides a

conceptual framework for analysis of effects. Finally, operant conditioning allows the researcher to

tailor the behavior to the needs of the experiment

(98). Disadvantages of using this type of test include

the cost of equipment and of data acquisition and

analysis systems, the time involved in training

animals to certain schedules, and the difficulties in

interpreting the toxicological significance of some

of the subtle endpoints used as indices of operant

performance.

In 1985, EPA established guidelines for evaluating the effects of toxic substances on simple learning

processes using SCOB tests. SCOB evaluates the

effects of acute and chronic exposures on the rate
Chapter S-Testing and Monitoring ● 117

and pattern of responses under schedules of reinforcement (50 FR 39465). Following testing for

behavioral effects, additional tests may be necessary. Operant behavior studies may be used in

conjunction with neuropathological examinations.

EPA’s approach to operant behavior testing involves placing the animal in an apparatus containing

a lever and a device to deliver a reinforcer, such as

milk. One method is to train the animal under a

fixed-ratio reinforcement schedule, in which a fixed

number of presses on the lever is followed by a

reward of milk. For example, if one rewards an

animal for exactly each third lever press that it

makes, the ratio between responses (lever presses)

and reward is fixed (50,68). Animals may also be

trained under variable-ratio reinforcement schedules. In other words, the technician varies the

schedules so that sometimes the third response

yields milk, sometimes the seventh, and sometimes

the hundredth. The animal never knows when the

next reward is coming (50). These schedules of

reinforcement may be used to generate moderate

response rates that may increase or decrease as a

function of exposure to toxic substances (50 FR

39466). Several kinds of SCOB tests are currently

used in industry (49,50,89,102).

A variety of other testing schemes are commonly

used to examine behavior. These include tests to

determine the effects of neurotoxic substances on

motor coordination, tremor, sensory processes, reflexes, and learning and memory (23,27,29,49,66,102).

There is some disagreement in the scientific community as to the optimal approach for evaluating

operant behavior.

Biochemical Markers

Various biochemical markers have been used to

assess the effects of toxic substances on adult and

developing nervous systems. EPA recently developed a proposed guideline for the assessment of

developmental neurotoxicity using a glial fibrillary

acidic protein (GFAP) radioimmunoassay (77). GFAPs

are proteins located in the glia, the non-neuron

satellite cells of the central nervous system. When

glial cells are damaged by toxic substances, they

substantially increase production of GFAP. The

proposed test is designed to develop data on changes

in the amount of GFAP in the developing nervous

system after postnatal exposure to a toxic substance.

Such an assay is a useful adjunct to developmental

neuropathological examinations (76,77), Assays of

A. Control

B. Rat exposed to trimethyltin.

Photo credit: J.P. O’Callaghan, U.S. Environmental Protection Agency

Trimethyltin increases levels of glial fibrillary acidic protein

(GFAP) in astrocytes of the rat brain, a sign of nervous

system damage.

proteins in neurons and glia can be used to detect and

characterize specific responses and alterations in

brain development due to toxic substances. While

not designed to uncover basic mechanisms underlying specific neurotoxic effects, this approach can aid

in defining neurochemical mechanisms underlying

altered brain development (78).

Specialized Tests for Organophosphorous

Pesticides

.

Exposure to some organophosphorous pesticides

produces delayed effects, including weakness of

limbs and improper function of certain motor
118 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

neurons. Evidence of toxicity first appears approximately 2 to 3 weeks after initial exposure. In 1985,

EPA established guidelines for neurotoxic esterase

assay for organophosphates (50 FR 39463). These

guidelines describe the procedure for measuring the

inhibition of an enzyme known as neurotoxic

esterase (NTE) in the brain or spinal cord of hens

exposed to organophosphorous substances (50 FR

39463). This assay is intended to serve as an adjunct

to behavioral and pathological examinations of hens

and is not intended to replace in vivo tests.

EPA also established guidelines in 1985 for a test

of acute delayed neurotoxicity of organophosphorous substances (50 FR 39466-39467). This test

involves administering a single dose of these substances orally to adult hens and observing them for

symptoms such as gait changes, lack of coordination, and paralysis. The animals are observed daily

for approximately 3 weeks until effects are determined. All signs of toxicity are recorded, as well as

the duration and extent of exposure. In addition, the

hens are evaluated for motor ability at least twice a

week, with various tests. If neurotoxic effects are not

seen immediately, the dosage may be repeated and

the observation period extended (50 FR 39466-

39467). Later, pathological examinations are also

conducted on the animals.

Subchronic delayed neurotoxicity refers to a

prolonged lack of coordination resulting from repeated exposure to a toxic substance over a limited

period of time. In 1985, EPA established guidelines

for a test of subchronic delayed neurotoxicity of

organophosphorous substances (50 FR 39467). This

test involves administering these substances orally

to hens for approximately 3 months. It is usually

conducted after obtaining information from acute

tests. Evaluators observe the hens daily for such

indicators as gait changes, lack of coordination, and

paralysis. Following the observation period, pathological tests of selected neural tissues are conducted using perfusion techniques and microscopic

evaluations. In addition to providing information on

the possible health effects of repeated exposures to

organophosphorous substances, this test may provide information on dose-response, thus aiding in

determining an estimate of a no-effect level.

Neurophysiology Techniques

Neurophysiological tests for assessing the health

effects of potential and known neurotoxic substances are usually adopted by neurotoxicologists

from testing techniques used in the basic neurosciences. These tests are designed to provide specific

types of information, and the technique or set of

techniques chosen for a given application will

depend on the nature of the scientific issues under

investigation (9).

In general, neurophysiological testing techniques

depend on the electrical properties of nerve cell

membranes. The firing of a single neuron involves

the movement of electrically charged ions across the

membrane. This movement of charged particles

creates electrical potentials which can be measured.

The measured potentials, in turn, reflect the functioning of the neuron or neurons that generated them.

Neuronal potentials are usually measured by placing

electrodes on or near the neural tissue of interest. In

many cases where the neural tissue is not directly

available, such as the human brain, the electrodes

can be placed at remote sites for detection of

electrical activity which is conducted through the

cranial tissues. The electrical signals recorded from

the electrodes are typically amplified, filtered, and

passed on to a data acquisition device such as a

computer (9).

It is convenient to categorize electrophysiological

testing techniques by the size of the recording

electrodes used. These range from a few microns to

several millimeters. The former, termed "microelec -

trodes," can be used to penetrate cell membranes

and measure the function of single neural cells or

parts of cells, such as membrane ion channels or

synaptic endings. Moving up in size, “multiunit

electrodes” can be placed in the vicinity of several

cells and can measure the activity of each neuron in

a cluster of neurons simultaneously. Still larger

‘‘macroelectrodes’ can measure the summed activity of many neurons, possibly thousands of cells.

With macroelectrodes, the activity of individual

cells is no longer detectable; instead, the activity of

neural systems can be monitored (9). Neurophysiological tests may be used to study neural function

either in vitro or in vivo, and they can measure

spontaneously emitted neural responses or those

evoked in response to some type of stimulation (9).

For neurotoxicological applications, microelectrode techniques and in vitro procedures are useful

for investigating mechanisms of action of known

neurotoxic substances because of the specificity of

the techniques. For investigating the potential neurotoxicity of compounds with unknown properties,
Chapter .5--Testing and Monitoring . 119

in vivo macroelectrode procedures are more useful

because of their generality. One set of macroelectrode techniques, sensory evoked potentials (EPs), is

being developed by EPA for potential use in

neurotoxicology testing paradigms. This approach

has been endorsed by several industrial organizations (9).

Sensory evoked potentials can be used to identify

which of the sensory systems in the nervous system

are affected by neurotoxic substances and to provide

information about the nature of these changes. In

addition, sensory systems are model systems for

studying ‘generic’ dysfunctions, since they include

all the components of other systems but can be

studied relatively noninvasively. Evoked potentials

are essentially electrical signals that are generated

by the nervous system in response to a stimulus.

Using neurophysiological techniques, these signals

can be measured and recorded. Various types of

evoked potential techniques are currently in use,

including brainstem auditory evoked responses,

flash evoked potentials, pattern reversal evoked

potentials, and somatosensory evoked potentials

(25,56,61).

The electroencephalograph (EEG) records spontaneous, ongoing electrical activity in the brain

(activity that, unlike EPs, is not associated with

presentation of a stimulus). Electrodes are surgically

implanted in a rat’s skull or pasted onto a human’s

scalp. The electric potential differences between the

electrodes are measured and the changes in the

potential difference are recorded. EEGs can provide

a detailed record of electrical activity at several brain

sites, allowing investigators to identify general

regions of the brain that may be adversely affected

by acute or long-term exposure to known or potential

neurotoxic substances. However, EEG data can be

difficult to interpret, and the technique provides

limited information on the mechanisms of action of

toxic substances (4,43,97). The limitations of EEGs

spurred the innovation of methods for measuring

evoked potentials.

Brainstem auditory evoked responses (BAERs)

can be used to detect specific losses in the auditory

system and thus to determine specific regions of the

rat’s nervous system that have been damaged (25).

This approach has been used to assess the effects on

hearing of various solvents, such as toluene (56,61,

82,83,88).

Photo credit: Julia Davis, NSI Technology Services Corp.,

Research Triangle Park, NC

Experimental neurophysiologist examines a visual evoked

potential recorded from a subject watching the

checkerboard stimulus seen at right.

Visual evoked potentials, which include flash

evoked potentials (FEPs) and pattern reversal

evoked potentials (PREPs), are used to evaluate the

effects of toxic substances on those components of

the nervous system responsible for vision (25,61).

The visual system is vulnerable to neurotoxic

substances, and acute and chronic exposure to such

substances can lead to damage of the retina and the

nerve cells in various areas of the brain that process

the information received from the retina. Visual

evoked potentials have been used to assess the

effects of various heavy metals, pesticides, and

solvents on visual function in rats. Potentials can be

generated using stimuli ranging from diffuse light

flashes to complex patterns of shapes and colors

(25,61,83).

FEPs in rats are altered by exposure to many

heavy metals, pesticides, and solvents. One technique for using FEPs in neurotoxicological studies

involves flashing a strobe light of high intensity

(turning on and off an intense stimulus) at the test

species followed by observing and analyzing the

effects on the visual system. One common technique

involves placing the rat in a chamber surrounded

with mirrors on three walls and on the fourth wall a

strobe light which flashes at various intensity levels.

Stimulus intensity, pupil diameter, and level of light
120 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

adaptation are the major parameters of concern in

recording FEPs (4,25,56,61,82,97). Following FEP

examinations, a neuropathological examination may

be conducted to identify any retinal or brain lesions

(damage or loss of retinal cells) caused by exposure

to the toxic substance.

PREPs are used in the diagnosis of optic neuritis,

multiple sclerosis, and other illnesses that affect the

visual system in humans. Visual evoked potentials

can be created by changing a pattern of bright and

dark areas on a screen in front of an animal without

altering the overall level of illumination. Patterns for

PREP testing are generated by reversing the checks

on a checkerboard display (black for white and vice

versa) or the bars in a horizontal or vertical

arrangement. One drawback of this technique is that

it is difficult to ensure that animals focus on the

patterns, especially without training (4,25,56,61 ,82,

83,97). On the other hand, PREPs can be recorded in

awake rats without concern for the focal point. When

the stimulus is in the rat’s visual field, the eyes will

be in focus (10).

Figure 5-2 indicates the results of testing the

chemical chlordimeform on the rat visual system. As

the dosage of the toxic substance is increased (from

O to 40 micrograms per kilogram), the amplitude

(size) of the PREPs increases (note, e.g., the distance

from points N1 to Pi), but the amplitude of the FEPs

is unchanged. The chlordimeform enhances the

response to high-contrast, but not to low-contrast,

stimuli (12).

Somatosensory evoked potentials (SEPs) are

commonly used to determine the effects of both

potential and known toxic substances on the nervous

system. The somatosensory nerves are the longest

cells in the body, extending from the limbs to the

head. In testing, an electric current is applied to the

sensory nerve of particular interest and the SEPs are

measured. Responses can be examined at many

points along the nerve. This approach has been used

to study the effects of acrylamide (4,25,26,56,61 ,82)

and sulfuryl fluoride on the rat’s somatosensory

system (63).

Figure 5-2-Pattern Reversal Evoked Potential (PREP) and Flash Evoked Potential (FEP)

After Treatment With Chlordimeform

A. Pattern reversal evoked potential B. Flash evoked potential

NI N1 N2

N3 N2 N3

N1 N2

o PI

P3

PI

N1 N3 N1

OY

x N2

F5 P1

6

0

c-a C/Y

s

g

N1 N1

N1

o

al

E 15

~

~

P1

-!=

c)

P2 P2

N3

N1 N1

40

-1

P1

25u V

+[

50 msec P2 50 msec

SOURCE W Boyes and R S Dyer, “Chlordimeform Produces Profound, SeIective, and Transient Changes in Visual

Evoked Potentials of Hooded Rats,” Experimenta/ Neurology 86434-447, 1984
Chapter S--Testing and Monitoring ● 121

SEPs have been used extensively in neurotoxicological studies because they provide rapid, effective,

and quantifiable methods for testing sensory functions (including the visual, auditory, and somatosensory systems). Another advantage is ease in surveying the entire sensory pathway to the brain. However, the equipment associated with this technique is

expensive, and special training is often required to

operate it. Another limitation is that, due to the large

variability among rats, many must be tested to obtain

statistically reliable results.

Animal Testing Issues

How Well Are Animal Test Results

Extrapolated to Humans?

An important goal of toxicology is to increase the

capability of predicting human responses from

animal toxicity tests and to understand the causes of

interspecies differences in susceptibility to toxic

substances. The greatest difficulty in extrapolating

animal data to humans is the difference in responses

between humans and animals to toxic substances.

Humans may be more sensitive to certain substances

than animals and vice versa. In addition, since the

human population is more heterogeneous than any

animal species, the range of doses producing an

effect on humans maybe larger than that for animals

(122).

Sex, age, health, nutritional state, and genetic

makeup may affect an animal’s response to toxic

substances and must be considered when selecting

an animal model. Also, similarity between animal

and human metabolism is an important consideration because it may influence the final determination

of whether a chemical will be therapeutic or toxic,

will be stored or excreted, or will cause acute or

chronic effects in humans (65).

When the risks of toxic substances are being

assessed, the potential exposure of humans is a

critical consideration. Toxicological data on experimental animals should be applied to the situations

and routes of exposure that are likely to occur for

humans. For example, data collected from the oral

administration of a substance to animals have less

relevance to a situation in which humans are

exposed by inhalation. In addition, an evaluator

should be cautious when applying data obtained on

young, healthy animals to a human population that

is diseased, malnourished, or diverse in its genetic

makeup. The data that are to be evaluated to

Illustrated by: Ray Driver

determine a potential risk should be obtained from

animal models that are as similar to humans as

possible (65). When assessing functional effects, the

measures taken in animals should relate to the

functions that are at risk in humans. Thus, if human

complaints are confusion, memory loss, or irritability, the animal data should be addressed, to the

extent possible, to changes in these functions.

ALTERNATIVES TO ANIMAL TESTS

Some individuals argue that more animals are

used for testing than are needed and that changes in

experimental design or improved methods of data

analysis could reduce the number of animals used.

Alternatives to animal tests, such as in vitro tests,
122 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

serve the same fundamental purpose as whole

animal tests: to establish the toxicological properties

of a chemical in order to protect and improve human

health and the environment. In vitro approaches use

animal, human, or plant cells, tissues, or explants

maintained in a nutritive medium for use as a model

system in toxicity testing.

Concern about the use of animals in testing seems

to be accelerating at the same time as concern about

product and drug safety. However, the need for more

experimental animals is an incentive for the development of new techniques, especially faster and less

expensive ones (105). While Federal regulatory

agencies currently rely on animal tests to predict

human toxicity, in vitro alternatives are likely to

play an increasingly important role in future toxicological evaluations.

In vitro tests are often used to complement animal

tests and reduce the number of animals being used

for routine toxicity testing. Methods for integrating

in vitro tests into routine toxicity testing are necessary to enhance understanding of the neurotoxic

potential of toxic substances (37).

Toxicologists have identified three major reasons

for developing in vitro techniques: scientificacademic, economic, and humane. There are many

scientific-academic reasons for developing in vitro

methods. There are more than 60,000 chemicals in

EPA’s inventory of toxic substances and thousands

more chemical formulations, many of which have

not been tested for toxicity. Current testing methods

are time-consuming; for example, it might take from

3 months to 2 years to complete a battery of chronic

studies. With the enormous number of substances

that have not been tested and with new substances

continually entering commerce, rapid, inexpensive

methods are needed for screening.

In vitro testing is already of critical importance in

academic scientific research. This approach is often

employed to determine the mechanism of action of

toxic agents because in vitro systems are less

complicated and can be manipulated easily. Tissue

culture methodologies have advanced rapidly, and

new equipment and facilities will ensure continued

progress (36). It has been estimated that more than

$70 million has been spent in the United States over

the past decade to develop in vitro testing (37). There

are numerous opportunities to apply the knowledge

that has been gained in basic research to the

development of methods of toxicity testing.

The cost of in vivo research and testing is

increasing. In vitro approaches are generally more

economical, being both less expensive and less

time-consuming. In addition, they are also more

humane because they reduce animal use and minimize animal suffering (36).

In Vitro Neurotoxicity Test Development

Interest in using in vitro testing approaches to

assess neurotoxicity has increased considerably in

recent years. In 1980, a symposium on the use of

tissue culture in toxicology, held in Sosterberg,

Holland, focused on the potential application of in

vitro approaches to the study of neurotoxic substances. Participants emphasized the need for improved methodologies and increased awareness in

the regulatory community of the utility of in vitro

techniques. Since that time, efforts to develop in

vitro tests have advanced rapidly (36,37,103).

In vitro tests do have some limitations. They

cannot mimic the complex biochemical and physiological interactions that take place in vivo. Also, the

supply of normal human cells available for toxicological testing is currently limited. In order for

human cells to be used routinely for toxicity testing,

some method of making them more readily available

must be devised. In addition, not all human cell types

can be cultured (103).

A number of companies in the United States are

currently developing in vitro toxicological tests. For

competitive reasons, industry initiatives are generally not made public. Consequently, they will not be

addressed in this report.

The Food and Drug Administration (FDA), the

National Institutes of Health (NIH), the Consumer

Product Safety Commission (CPSC), and EPA are

examining potential in vitro testing approaches

(116). In particular, the National Toxicology Program of the Department of Health and Human

Services is evaluating in vitro systems and has asked

for proposals on alternative test development (1 16).

The CPSC is attempting to make greater use of

existing chemical, biological, and human data in

order to avoid animal tests, to reduce the number of

animals used in tests, and to modify existing

methods so as to reduce pain and suffering (95). EPA

has also taken action to reduce the use of animals in

toxicity research and testing.
Chapter 5-Testing and Monitoring ● 123

Photograph by J.C. Owicki and K.M. Kereso

Photomicrograph of living cells in the wells of chambers

that allow monitoring of changes in cellular metabolism

following exposure to toxic substances.

Numerous in vitro techniques are currently in use.

Tissue culture involves maintaining or growing

organs, tissues, or cells in vitro for more than 24

hours. Tissue culture can be further subdivided into

cell culture and organ culture (22,105).

Tissue Culture

Many tissues from humans and animals can be

successfully maintained and studied in culture.

Roux originally used tissue culture in 1885 to

maintain chick embryos outside the egg (99).

Nervous tissue was among the first tissues to be

cultured. In 1907, R.G. Harrison developed a method

for maintaining frog neural tissues in vitro for weeks

(40). In the 1930s, advances were made in defining

the media required for maintaining cells and tissues

in culture, and by the 1950s, tissues could be

cultured in entirely synthetic media. At the same

time, scientists became aware of the importance of

adding antibiotics to culture systems. Before antibiotics, bacterial growth interfered with the developing cells, and all work had to be done in aseptic

conditions. It is now standard procedure to inhibit

bacterial growth with antibiotics (99,105).

Pure cultures of cells and mixtures of cells have

different properties. These differences may be used

to study various aspects of cell activity, such as

differentiation. In this process, one can distinguish

between cells that have a capacity to form other cells

(undifferentiated cells), and cells that have reached

their final stage of development and will not undergo

any further change (differentiated cells) (21,99).

In cell cultures, the colony consists of a mass of

differentiated or undifferentiated cells, and individual cell types are not easily identified. However,

where a number of different kinds of cells are

growing together, such as in organ cultures, the cells

retain their normal function and differentiated form;

thus, the different types of cells are easy to identify

(99). Tissues can be kept alive outside the living

animal for months or years in cell cultures; however,

whole organs can be sustained in cultures for only a

few days to a few weeks.

Assessing toxicity using tissue culture approaches

generally involves adding a test substance to the

culture, observing the viability of the cells, and

identifying any structural or functional changes.

Applications of In Vitro Techniques to

Neurotoxicity Testing

Various types of in vitro techniques are being

developed to evaluate the effects of potential and

known neurotoxic substances. These approaches can

be grouped into three general categories: primary

cultures, cell lines, and cloned cells.

Primary Cultures

Primary culture refers to the removal and maintenance of cells, tissues, and organs in vitro. Embryo

culture, for example, has proven to be very useful in

neurotoxicological studies. Recently, the Chemical

Industry Institute of Toxicology (CIIT) in Research

Triangle Park, North Carolina, developed a rodent

fetal cell culture system for in vitro testing. This

approach involves removing certain regions of the

brain from mouse embryos and culturing them in a

chemically defined environment. After the culture is

exposed to various known and potential neurotoxic

substances, the tissues and cells can be examined for

morphological and biochemical changes (20). This

technique is useful because neuronal tissues undergo

normal or near-normal development, and cellular

and tissue interactions can be analyzed.
124 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

CIIT scientists are using a class of substances

known as monohalomethanes to validate this test

system. Animal and human exposure to monohalomethanes may result in a variety of neurological

symptoms, such as tremors, lack of coordination,

epileptic seizures, and coma. The results from in

vitro studies using monohalomethanes are compared

with documented animal studies to determine correlations between in vitro and in vivo methods.

Development of a database to compare results from

in vitro and whole animal studies, human studies,

and epidemiological studies may aid in validating

this system (20). A similar embryo culture approach

was used successfully by others to demonstrate that

ethyl alcohol can retard the growth and differentiation of fetal tissues (13).

Retinal neurons may also be employed to

evaluate the effects of toxic substances on the

nervous system. This approach involves dispersion

and culture of retinal cells removed from chick

embryos. Culture methods have recently been improved, allowing growth of low-density, clump, and

flat cell-free cultures of chick embryo neurons.

These cultures can be used to analyze the effects of

toxic substances on cell differentiation using timelapse video recordings. In addition, various biological techniques may be used to define and characterize observed effects (2).

Techniques for culturing neonatal mouse retinal

neurons and photoreceptors have also been developed recently. Cells from the retinas of 2-day-old

mice can be cultured in serum-free, completely

chemically defined environments. They serve as

useful models for evaluating the survival and

differentiation of photoreceptor cells, which are

critical to visual processes (87).

A “monolayer” culture system has been developed to allow the survival and differentiation of

chick embryo retinal neurons and photoreceptors

without contamination. Photoreceptor cells can be

purified with kainic acid and B-bungarotoxin, which,

when added to the culture medium, destroy many

retinal neurons without affecting the photoreceptors

(86). The technique of selectively destroying cells is

a recognized means of cell separation in tissue

culture. Once purified photoreceptors are available,

the effects of various toxic substances can be

determined without the complicating factors introduced by multiple cell types.

Muscle cells can also be cultured, allowing

investigators to analyze the effects of toxic substances on the neuromuscular system. Cultured

muscle cells from rats and chicks have been used in

electrophysiological studies to examine the sensitivity of acetylcholine receptors. Toxic substances have

also been used to aid in characterizing the structure

and function of acetylcholine receptors (91). This

type of system could be adapted to assess the effects

of toxic substances on the neuromuscular junction.

Another useful testing method involves organotypic cultures, cultures that preserve the connections and spatial relationships between neurons and

glia (126). One such culture used in neurotoxicity

studies is of the ganglion (a collection of nerve cells

external to the brain or spinal cord) (96). In addition,

the mouse embryo spinal cord has been used to study

the effects of various neurotoxic substances, including organophosphorous pesticides (35). Organotypic cultures have also been used to examine the

mechanisms of action of a wide range of neurotoxic

substances, including such metals as mercury and

thallium and such organic compounds as chloroquine (a drug used to treat rheumatic fever) and

2,5-hexanediol, a metabolize of n-hexane (126).

Explant cultures are also useful in evaluating

neurotoxicity. They involve placing a small piece of

nerve tissue in a culture medium and maintaining it

for several weeks or months at a time. Explants have

been used to evaluate the effects of chemicals on the

myelin sheath surrounding nerve cells and on the

synaptic connections between these cells (96).

Cell Lines

Cell lines take advantage of the immortal properties of certain types of malignant nervous system

cells. For example, the neuroblastoma C-1300 and

the rat glioma C-6 cell lines have been used in

neurochemical and morphological studies for evaluating the effects of a variety of neurotoxic substances

(22,35). One group of investigators recently fused

rat retinal cells with mouse neuroblastoma cells to

create a hybrid cell line that proved to be very useful

in evaluating the neurotoxic effects of the amino

acid glutamate and related compounds (73). Cell

lines are especially useful because a large quantity of

single cell types are available for biochemical

analysis, the cells can be easily examined microscopically, and electrophysiological evaluations may

be undertaken (96).
Chapter .5-Testing and Monitoring ● 125

Advantages and Limitations of

In Vitro Testing

In vitro tests are advantageous for several reasons.

They involve simpler procedures and consequently

take less time to complete than animal tests. For

example, technicians can conduct morphological,

biochemical, and physiological studies on the same

preparation (93). Furthermore, cultures can be transferred from one region of the country to another,

allowing evaluation of the same culture in various

laboratories specializing in particular tests. Cultures

can be made of human cells, hence the difficulty of

species variation and of extrapolation of data is

minimized. Substances may be studied in isolation,

and responses by selected cell populations can be

examined. Also, the cellular environment can be

controlled through modification of the concentration

and nature of specific nutrients, which is difficult

using animals (21,99,20).

On the other hand, in vitro tests normally do not

account for the route of exposure to a substance, its

distribution throughout the body, or its complete

metabolism. Also, because in vitro systems generally do not duplicate the neural circuitry of the entire

animal, toxic endpoints (e.g., behavioral changes,

motor disorders, sensory and perceptual disorders,

and lack of coordination) may be difficult to define

(93). Other concerns are that substances added to the

culture to keep it viable (e.g., antibiotics) might

interact with the tested substance, that cell lines of

cancerous cells may respond to toxic substances

differently than normal cells, and that it may not be

possible to perform chronic toxicity studies due to

the relatively short lifespan of many cultures (cell

lines using immortal cells are a possible exception).

Nevertheless, all test systems have limitations, and

there is general agreement that the many advantages

of in vitro testing present a strong incentive for

continued development and increased utilization

(21,99,20).

HUMAN TESTING

Millions of U.S. workers are exposed full- or

part-time to general toxic or neurotoxic substances

(3). Nearly 400,000 cases of occupational diseases

are recognized annually (111). Preventing the adverse health effects of chemicals is largely dependent on understanding the toxicological properties of

new and existing chemicals. Various standardized

human tests are available to assess the adverse

effects of toxic substances on the nervous system;

however, because of the ethical issues inherent in

performing some human tests and the difficulty of

obtaining trained staff and expensive equipment,

there have been relatively few human studies

conducted (24).

Overview of Human Tests

Human testing may occur in response to occupational, environmental, or laboratory exposures. The

methods used to assess the toxicity of substances

vary from one setting to another, since some

approaches are appropriate in one situation but not

in others. For example, when determining early

symptoms of chronic exposure, subjects exposed

occupationally are better test groups than groups

exposed environmentally. On the other hand, in

certain epidemiological studies, subjects exposed

environmentally may be helpful because of the large

diversity of individuals and wide range of ages (74).

In the occupational setting, workers are often

exposed unintentionally to toxic substances. In the

general environment, exposure groups may include

individuals and families living near sources of

industrial pollution, people living in large industrial

cities where they are exposed to vehicle exhaust and

fuel additives, and farmers and agricultural workers

exposed to pesticides in the field (74). Epidemiological studies of these individuals are required to

determine the extent to which neurotoxic substances

are affecting human health.

Neurobehavioral Tests

Neurobehavioral tests can provide objective evaluations of nervous system and neurobehavioral

functions. Test methods have been utilized both in

evaluation of groups of workers exposed to substances and in laboratory examinations of individuals suspected of having occupational illnesses. In the

evaluation of a group of workers, neurobehavioral

tests are used to assess exposure-effect relationships

and, in some cases, to serve as guides for establishing standards for workplace exposures. In the

laboratory setting, neurobehavioral methods are

useful in quantifying the degree of functional

disability and in making a diagnosis (44).

Several considerations are involved in the selection of testing techniques to determine the effects of

neurotoxic substances on workers’ health. It is very

important to consider the purpose of the examina-
126 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

tion. For example, the study may be designed to

identify effects on individual workers who are

exposed or on a population of workers exposed as a

group. Furthermore, the frequency and duration of

exposure must be determined: a study of acute

effects may require tests measuring different functions and properties than a study of chronic effects.

Finally, in some tests a certain time period must

elapse before effects become apparent (44,67).

Researched most commonly select tests that are

known to measure functions affected by several

neurotoxic substances; provide a complete analysis

of nervous system effects, ranging from reflexes to

complex behaviors; are known to measure one or

more well-defined functions, whether psychological

or neurophysiological; and are cost-effective in

terms of the information they provide (44,67).

Neurobehavioral test results are influenced by

many factors. These can be divided into three

general classes: subject, examiner, and environmental. Subject factors include the individual’s age,

sex, education, socioeconomic status, health and

drug history, and motivation. Table 5-1 summarizes

the subject factors influencing neurobehavioral test

results. Examiner factors are another important

consideration. In order to ensure the cooperation of

subjects and to maximize the reliability of the data,

Table S-l-Subject Factors Influencing

Neurobehavioral Test Results

Age: The performance on neurobehavioral tests varies with age.

When comparing exposed groups, subjects should be

matched by age as closely as possible.

Sex: There are biological and social differences that must be

considered when designing tests that include male and female

workers.

Years of school education: Amount of education also influences

the performance on neurobehavioral tests.

Socioeconomic status: Socioeconomic status includes a combination of educational, cultural, and occupational factors that

may affect test results. This factor takes into account the years

of school education, regular income, and special occupational

training.

Health and drug history: Any disease that affects neurological

functions will affect neurobehavioral studies. Some of these

diseases include epilepsy, diabetes, and arthritis. If an

individual has any of these health problems, the evaluator may

want to exclude the individual from the study. Drugs must also

be considered. Psychoactive drugs, in particular, can alter

performance on the study. In addition, certain consumed foods

and beverages may alter the individual’s alertness and

performance. These include coffee, colas, and chocolate, all

of which contain caffeine.

Motivation: The attitude of the participants must also be taken

into account.

SOURCE: B.L. Johnson (cd.), Prevention of Neurotoxic Illness in Working

Populations (New York, NY: John Wiley& Sons, 1987).

it is important to establish a good working relationship between examiner and participants. It is also

important that a well-trained examiner speak and

interact with all subjects in a consistent and standardized manner (44). Environmental factors that

influence neurobehavioral studies include the test

surroundings, subject-experimenter interaction, and

season of the year.

Finland’s Institute of Occupational Health

Approach

During the 1950s, the first neurotoxicity test

battery for occupational exposure was developed at

Finland’s Institute of Occupational Health (FIOH).

The battery was designed to study the effects of

various substances, especially solvents, on workers.

The 14 neurobehavioral tests listed in table 5-2 are

typical methods used at FIOH to evaluate effects on

intelligence, short- and long-term memory, learning

ability, perception, motor performance, and personality. The battery is now used routinely in Finland

(39).

Psychological testing is usually conducted at the

Institute, although sometimes it is conducted at an

industrial facility. The tests are usually performed on

an individual basis. Before the tests are administered, the patient is interviewed. The tests are

presented in a fixed order, as indicated in table 5-2.

The examination takes 1 to 3 hours, depending on

the tests used and the time available

(39).

World Health Organization’s

Recommended Approach

During a meeting cosponsored by

for- interviews

WHO and the

National Institute for Occupational Safety and

Health in 1983, neurotoxicologists recommended a

core set of tests, known as the Neurobehavioral Core

Test Battery, that could be used in screening for

neurotoxic effects. This test battery is particularly

useful in developing countries or in places where

there are limitations in the setting or the literacy of

the test population (3).

Table 5-3 lists the tests used in this battery. They

were chosen to allow development of uniform,

consistent data from a variety of occupations and

neurotoxic exposure situations (3). Most of the core

tests require the use of paper and pencil in order to

minimize the need for mechanical instruments (a

concern for developing countries). These tests generally require minimal training to administer; how-
Chapter 5-Testing and Monitoring . 127

Table 5-2-Behavioral Test Battery for

Toxicopsychological Studies Used at the

Institute of Occupational Health in Helsinki

Test method+Test description

Wechsler Adult Intelligence:

-determining similarities between items;

measures verbal ability

-determining synonyms of words;

measures general intelligence and verbal ability

—reproducing patterns of design using blocks;

measures visual ability

-determining the missing parts of pictures;

measures perception

—associating symbols and digits;

measures memory and speed

—recalling digits in series;

measures verbal memory

Wechsler Memory Scale:

–logical memory, visual reproduction, and associative learning

Benton Visual Retention Test:

—recalling and reproducing figures;

tests memory and visual retention ability

Kuhnburg Figure Matching Test:

—recalling various figures on cards;

measures speed and memory

Bourdon Wiersma Vigilance Test:

—strike over all groups of 4 dots as printed on the test sheet

(50 rows); each row contains 25 groups of 3,4, or 5 dots;

performed as accurately and quickly as possible;

measures speed and perception

Figure Identification:

—identifying figures; measures speed and perception

Symmetry Drawing Test:

-drawing the other symmetric half of figures;

measures perception and motor speed

● Santa Ana Dexterity Test:

—test for manual dexterity; hand-eye coordination;

measures the ability to perform skillful movements with hands

and arms

Flnger Tapping Test:

—taps a counter with thumb rapidly;

measures motor speed

Reaction Time:

—reactions of hands or feet from visual and auditory signals;

measures simple reaction time to respond to stimulus

MIra Test:

-draw simple, straight, and broken lines without seeing the paper

and pencil;

measures psychomotor behavior and psychomotor ability

Rorschach Inkblot Test:

—variables: adaptability, emotionality, spontaneity v. inhibition,

rational self-control, originality of the perception;

measures personality, nonintellectual personality disturbances,

changes in mood, readiness for affective reactions

Eysenck Personality Inventory:

—measures two dimensions of personality: neuroticism and extroversion-introversion

Questionnaire:

—measures changes in mood, emotionality, and subjective wellbeing; two forms used: 1) measures sleep disturbances, fatigue,

neurotoxic behavior; and 2) measures disturbances in control of

mood, emotions, attention, fatigue

SOURCE: H. Hanninen and K. Lindstrom, Behavioral Test Battery for

Toxicopsychological Studies Used at the Institute of Occupational Health in Helsinki (Helsinki: Institute of Occupational

Health, 1979), pp. 1-58.

Table 5-3—WHO Neurobehavioral Core Test Battery

Functional domain Core test

Motor speed, motor

steadiness

Attention, response speed

Perceptual-motor speed

Manual dexterity

Visual perception,

memory

Auditory memory

Aiming (Pursuit Aiming ii):

assess the control and precision of

hand movements; individual is required to follow a pattern of small

circles, placing a dot in each circle

around the pattern; subject’s score

is the number of taps in the circle

within 1 minute

Simple reaction time; see table 5-2

for description

Wechsler Adult Inteiiigence Scale:

a sheet contains a list of numbers

that are associated with certain simple symbols and a list of random

digits with blank spaces below them;

subject asked to write correct symbols in blank spaces as fast as

possible

Santa Aria: see table 5-2 for description

Benton Visual Retention: see table

5-2 for description

Wechsler Adult intelligence Scale:

recall digits in series forwards and

backwards immediately after hearing them

SOURCE: B.L. Johnson, (cd.), Prevention of Neurotoxic Illness in Working

Populations (New York, NY: John Wiley & -Sons, 1987).

ever, the reaction time test requires the use of an

electrical instrument that necessitates some training.

The total amount of time necessary to complete the

core test battery is approximately 45 minutes (44).

Computer-Based Testing

Computer-based neurobehavioral tests have recently been developed in response to the need for

standardized testing methods that objectively and

efficiently collect data on various neurotoxic effects

seen in exposed workers. Computer testing has been

used to study acute exposures of workers in laboratory (experimental) studies and to study chronic

effects on workers in epidemiological studies. Some

computer-based tests are reliable for conducting

comparative studies of workers, but methods appropriate for clinical studies have not been developed

(52).

The most extensively used computer-based test

battery is the Neurobehavioral Evaluation System.

The tests selected analyze a broad range of central

nervous system functions, including psychomotor

performance, memory, perceptual ability, vocabulary ability, and mood (53,7).

Various computer-based tests have been developed for epidemiological applications, including the
128 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

MicroTox System (27); Swedish Performance Evaluation System (41); Milan Automated Neurobehavioral System, a computer implementation of many of

the tests in the WHO Neurobehavioral Core Test

Battery (15); and the Cognitive Scanner, developed

in Denmark (51).

Computerized techniques have several advantages and limitations. Some of the primary advantages are reproducibility of testing conditions, ease

of scoring, immediate reporting of results to the

subjects, and storage of data in the computer’s

memory for future use. In addition, highly trained

staff are not required (52,7). The limitations of these

techniques center on the cost and availability of

equipment. In addition, computer techniques usually

emphasize speed of response; thus, other behavioral

responses may not be adequately measured.

Neurophysiological Techniques

As is the case for animal testing, a variety of

neurophysiological techniques can be used to assess

the health effects of potential and known neurotoxic

substances on humans. Many of the same techniques

used in animal studies can be employed for evaluating worker exposure to various neurotoxic substances. These include the sensory evoked potentials, electromyograph, and electroneurograph. Sensory evoked potentials include brainstem auditory

evoked responses, flash evoked potentials, pattern

reversal evoked potentials, and somatosensory evoked

potentials. Most of these techniques have been

summarized earlier in this chapter; they will not be

readdressed here. (See the section on neurophysiological techniques of animal testing.) EPA summarized several situations in which analysis of sensory

evoked potentials would be useful (82), including

determining the sensory effects of injured workers

who are unconscious, immobile, or unable to respond verbally; sensory testing of workers claiming

compensation when malingering is suspected; sensory testing of workers whose complaints do not

correspond to clinically significant deficits in routine clinical examination; distinguishing peripheral

from central nervous system damage in sensory

pathways; and monitoring of workers chronically

exposed to chemicals known to be neurotoxic.

Electromyography (EMG) and electroneurography (ENG) are established testing techniques

well-suited to studies of various neuromuscular

disorders. They are also often used in clinical

examinations in neurology, orthopedics, and neurosurgery. EMG records electrical activities using a

needle electrode inserted into the muscle. Researchers note several characteristics, including electrical

activity in the muscle when the needle is inserted,

electrical activity of the resting muscle, and electrical activity of motor conduction velocity during

voluntary muscle contraction (43). ENG measures

the electrical signals generated by the nerves. The

electromyograph has not been used extensively for

evaluating the health effects of neurotoxic substances on test animals, because few toxicologists

are trained in EMG procedures. Interpretation of the

results requires special training, and it can be

difficult to control the degree of muscle contraction

in test animals (97,43).

Human Exposure Studies

Information collected in human neurotoxicity

studies may have several important uses, including:

providing indications of toxic effects that can

serve as early warnings of chronic disease

processes;

testing the adequacy of existing or proposed

exposure limits;

identifying human performance capacities that

may be impaired by short-term exposure to

toxic chemicals; and

providing data on the neurotoxic effects of

exposure to more than one chemical or other

workplace conditions (e.g., physical agents,

work level, drugs) that may interact to modify

the neurotoxicity of single substances (44).

Fundamental components of this type of study are

controlled exposure to the substances being studied,

methods for estimating the body burden of the

substances, appropriate tests and experimental design to reflect the neurobehavioral response of the

subjects to the substance, and control groups or

control conditions. However, human exposure studies are among the most difficult and expensive

controlled laboratory experiments to conduct. Because humans have complex personalities, each

individual brings to the experiment several attributes

that may be difficult for an investigator to control.

Such variables include age, sex, education, motivation, and work history (24).

Human studies typically require more examinersubject interaction than other types of tests. A certain

amount of controlled and consistent interaction is

necessary to reduce the anxiety caused by the test
Chapter S-Testing and Monitoring ● 129

situation. Several factors may affect the interaction,

including the presence of more than one examiner,

and the personality, experience, and sex of the

examiner. Interaction effects occur when subjects

are tested in groups in large exposure chambers. The

results of a study may change if the subjects are

tested in groups of two or more rather than singly, in

groups of both sexes rather than one sex, or in groups

in which the subjects are friends rather than strangers

(24).

Selection of Study Populations

The success of any human toxicity test depends on

a well-designed study that has a clearly defined

purpose. Two major reasons for conducting a study

in the industrial setting are: 1) an awareness that a

group of people collectively has similar health

complaints and that a potential occupational health

problem exists, or 2) a potential hazard has been

identified and more information is needed to define

the extent of the hazard. When undertaking human

studies, it is important to select a well-defined group.

If the purpose of the study is a potential health

problem, the study population may have been

identified by a formal complaint from an individual

or company to a Federal agency. Usually, the source

of the complaint appears to be limited to a work site

or a plant. In this circumstance, a preliminary

screening questionnaire may be conducted to determine the study group (125).

Steps in Conducting Workplace Research

There are several fundamental steps in conducting

a workplace research study, and there are several

significant dangers to be avoided. The identification

of a suitable work group is the first, difficult step.

The evaluator should consider the willingness of a

company to allow worker participation. Prior to

beginning the test, the evaluator must seek out the

companies involved and convince them of the value

of the test in order to ensure participation. Most

employees will cooperate as long as they are

convinced that data on them will be kept confidential

(3).

Testing conditions are determined by the industry

involved and past experience with the test selection.

Testing sites are usually clinics, hospitals, laboratories, and conference centers. It is standard practice to

describe the purpose and the benefit of the study to

test subjects, what unpleasant tests they will encounter, who is responsible for the study, and whom to

contact if they have questions or experience difficulties. They should also be informed that they may

withdraw from the study at any time if they feel that

it is unsatisfactory in any way (3).

Records should be kept on file for each research

project. They should contain information on the

day-to-day decisions regarding the study and any

unusual events that take place. In addition, there

should be a comprehensive report containing information on worker characteristics such as age, sex,

race, and education; the number of years that the

worker has been at his or her profession; the

measurements or pattern of exposure over the years;

the methods used to obtain the measurements;

complete descriptions of all tests; descriptions of

statistical tests used; and any adverse effects and

diseases that were determined (3).

Epidemiological Studies

Epidemiological studies play a very important

role in evaluating the effects of neurotoxic substances on workers and in developing strategies for

the prevention of occupational diseases affecting the

nervous system (44). The advantage of such studies

over animal testing is that they provide direct

evidence of effects on human health. However,

human studies are difficult to conduct and evaluate.

One limitation is that if the exposure results only in

acute effects, epidemiological studies must be performed shortly after exposure occurred.

Another limitation is the complex relationship

that exists between toxic exposures and human

disease. Humans vary greatly not only in their

exposure to substances, but also in their physiological response to exposure. Despite these difficulties,

extensive techniques for evaluating data from human

studies have been developed. Epidemiology has

proved to be a reliable means of evaluating qualitative and quantitative relationships between exposure

to toxic substances and human disease (16). Because

epidemiological studies generally identify correlations between exposures and effects, it is often

necessary to undertake animal studies to identify

cause and effect relationships.

Occupational epidemiology is the study of the

distribution of a disease among a working population and the factors that influence this distribution.

This field attempts to identify relationships between

diseases and occupational exposures to chemicals.

The value of such epidemiological studies is in-
130 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

creased when they are used with toxicological

studies on humans or animals. They are important in

identifying possible associations that can be tested

in laboratory environments. Furthermore, they can

be used to evaluate human health risks suggested by

laboratory exposures (16).

Legal and Ethical Considerations in

Neurotoxicity Testing and Monitoring

Deliberate exposure of humans to neurotoxic

substances in the course of research calls for all of

the basic protections afforded research subjects

under existing Federal law. Department of Health

and Human Services regulations require institutions

performing research on human subjects to create and

use Institutional Review Boards to check proposed

projects for compliance with regulations if those

projects are funded by the Department or its

constituent agencies (45 CFR 46.103(b)). Although

these regulations are legally binding only on institutions receiving Federal funds, they are usually

considered minimum standards for other institutions

and research situations as well.

After there has been an appropriate evaluation of

the value, scientific merit, probability of generating

knowledge, and risk-benefit ratio of a proposed

study, subjects can be selected and their consent

solicited. Federal law requires that specific information be disclosed before valid consent can be

obtained. Under Federal regulations (45 CFR 46.116)

and some State statutes, all reasonably foreseeable

risks and discomforts that subjects might experience

must be disclosed.

Risk information is not the only type of information that requires greater elaboration in the research

setting. Federal law also mandates disclosure regarding the nature and purpose of the research;

anticipated length of the subject’s participation in

the study; procedures to be followed; identification

of experimental procedures; benefits that may reasonably be expected to accrue to the subject or others

from the study; steps to be taken, if any, to maintain

confidentiality of records identifying participants;

whether compensation and treatment are available

for injury arising from a study where more than

minimal risk is involved; and who should be

contacted if subjects have questions regarding the

research or their rights, as well as the contact person

in the event of research-related injury (45 CFR

46.1 16(a)).

Workplace exposures to neurotoxic substances

may be accidental or nonaccidental. The primary

ethical obligation in the case of an accidental

exposure to a neurotoxic substance is prevention.

Box 5-C illustrates the important ethical issues that

arise from chronic workplace exposure to neurotoxic

substances such as mercury, A continuing issue in

both types of workplace exposure is whether it is

appropriate to notify workers about past exposures

to hazardous substances, including neurotoxic substances. Many persons believe that groups of workers who have been exposed to hazardous substances

in the past should be informed of this whenever

possible. However, the possibility that some workers will be mistakenly identified and informed has to

be weighed against the value of a retrospective

notice procedure.

Prevention of Human Exposure to

Neurotoxic Substances

Some of the disorders caused by neurotoxic

substances can require extensive therapy and medical care. In addition, a significant number of these

may be irreversible if exposure levels are high. The

severity of these effects is an excellent reason for

implementing methods of preventing exposure to

neurotoxic substances.

Several approaches are used. One method is to

increase awareness of the effects of neurotoxic

substances through educational programs (6). These

programs are designed to educate supervisors and

workers about the signs and symptoms associated

with exposure to certain toxic substances in the

workplace. Managers may reduce risk of exposure to

substances by substituting a less hazardous substance for the substance of concern, using adequate

engineering controls, developing improved working

conditions, and providing proper protective equipment, such as respirators, gloves, eye shields, and

boots (6,125).

All occupational safety and health programs

should be directed toward recognizing and preventing problems early. This includes communication

among Federal agencies, manufacturers, and users

of potentially neurotoxic substances.

Medical controls are another important aspect of

an exposure prevention program. The extent of the

controls will depend on the hazards and seriousness

of the risks involved. Preemployment physical

examinations, including detailed histories of previ-
Chapter S--Testing and Monitoring . 131

Box 5-C—Ethical Issues Associated With Chronic Exposure to a Neurotoxic Agent

One example of an occupational exposure to a neurotoxic agent is the case of workers assigned the task of

recovering mercury from old or broken thermometers.

On October 16, 1986, two executives and a supervisor of the Pymm Thermometer Company were indicted on

charges of assault for allegedly endangering the lives of workers by knowingly and continually exposing them to

mercury, conspiracy for hiding the existence of a cellar workshop from the Occupational Safety and Health

Administration (OSHA) inspectors, and falsifying records in an attempt to conceal the cellar operation. According

to the brief filed on behalf of the workers:

Already aware of the dangerous conditions on their main manufacturing floor, defendants created and

maintained even worse conditions in a cellar mercury-reclamation operation. In order to salvage some of the valuable

mercury that was being wasted in its main manufacturing process, Pymm constructed a crushing machine that ground

up broken and defective thermometers, spewing mercury-laden dust into the face of the machine operator. The

machine was housed in a windowless, underventilated cellar, where defendants stored boxes leaking mercury from

the broken and faulty thermometers to be processed (85).

One worker who was employed in this area for approximately 11 months suffered permanent brain damage

from mercury poisoning (85). Exposure to mercury can cause tremors, headaches, and nausea, and more severe cases

of mercury poisoning have been linked to brain damage, kidney disease, loss of vision and hearing, and motor

impairment. Humans can absorb mercury by inhaling the vapors in the air. Mercury passes from the lungs into the

bloodstream, which transports and deposits it first in the brain and then in other parts of the body, including the

spinal cord and peripheral nervous system. Once in the body, mercury binds to proteins in the central nervous

system. As long as mercury circulates and remains in the body’s soft tissue, some of it can be returned to blood and

plasma, to be extracted and excreted through the kidneys and intestines. In this way, the body rids itself of about

half of one day’s intake over a period of 40 to 70 days. When, however, a person takes in mercury faster than it be

can excreted, the body begins to store mercury in bones and teeth (47). OSHA’s limit for exposure during an 8-hour

day is 0.1 milligram per cubic meter of air.

Chronic exposure of workers to a known neurotoxic agent like mercury raises ethical arguments about the

duties of employers not to knowingly inflict harm on workers, the use of coercion in exposure to neurotoxic agents,

the right of an employee to know that he or she is working in a harmful area, and the right of the employee to

experience the full benefit of Federal efforts to ensure a safe workplace through OSHA inspectors and accurate

record keeping. The employers in a case such as this could make an ethical argument that the greatest good for the

greatest number entails recovery of mercury, but they are not ethically or legally free to pursue this objective when

it clearly inflicts a known hazard on workers. The ethical dilemma in a case such as this would be an arguable ethical

right of the worker to assume the risks of exposure to a known neurotoxic agent, such as mercury, in order to pursue

some other value, such as increased pay. In order to explore whether the worker would have such a right it would

be necessary to ensure that the worker was freely and knowingly opting to take such a risk. In addition, it would

be important that the individual not impose unnecessary risk on others, for example, by exposing family members

to mercury by bringing it home on work clothes. In the Pymm case, it is alleged that when the workers asked about

any possible dangers of working with mercury, the employer lied and provided no training, protective clothing, or

other safety equipment (85). Although the company officers were convicted by the jury on the assault charges, the

trial court judge overturned the verdict. The State appealed to the appellate division of the Supreme Court of the

State of New York. The case is continuing.

SOURCES: C.D. Klaassen, M.O. Amdur, and J. Doull (eds.), Casarett and Doull’s Toxicology (New York, NY: Macmillan, 1986); People of

the State of New York v. William Pymm, Edward A. Pymm, Pym Thermometer, Inc., and Pak Glass Machinery Corp., Brief for the

Appellant, Mar. 21, 1988.

ous exposures to substances and relevant preexisting the effectiveness of engineering controls. Symptoms

conditions, are often very useful. Such examinations of a high level of exposure to a substance in a-group

can identify persons who are likely to be susceptible of workers may indicate a failure that must be

to specific toxic substances. In addition, they allow corrected. Consequently, more stringent engineering

the occupational physician to take necessary steps to controls may be implemented to improve the worklimit employee exposure to certain hazards. Routine ing environment. A variety of engineering controls

medical examinations also aid in monitoring the may be used to minimize exposure to neurotoxic

effectiveness of worker safety programs and verify substances. Because OTA described these in detail
132 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

in a previous report (104), they will not be addressed

here.

MONITORING OF TOXIC

SUBSTANCES

Numerous methods are currently being used to

monitor exposure to and adverse health effects of

toxic substances, including substances that may

affect the nervous system. These methods include

specimen banking (long-term storage of biological

specimens for toxicological analysis), monitoring of

animal tissues (e.g., marine mammal tissues and

mussel tissues), and biological monitoring. Monitoring studies are used to develop baseline data, to

determine whether and to what extent humans and

other organisms are exposed, and to assess exposure

trends. The following discussion summarizes some

of the current domestic and international monitoring

programs.

Specimen Banking

Domestic and International Programs

To Monitor Toxic Substances

The purpose of specimen banking programs is to

track the concentrations of contaminants in tissues

over time. Data from programs of this kind are very

useful to public health and regulatory officials, who

must ensure that human exposure to toxic substances

is limited. These data are also critical to epidemiological and other scientific investigations designed

to link adverse health effects with particular toxic

substances. Human tissue monitoring was first

undertaken in the Federal Republic of Germany and

the United States. Other countries now have plans to

collect and store human tissues, including Canada,

Japan, and Sweden. In 1980 and 1981, the West

German Specimen Banking Program began collecting and storing human specimens at the University

of Munster and at the central bank at the Atomic

Research Center in Julich (54). Three types of

human material were collected: whole blood, adipose tissue (fat tissue), and liver tissue. Biological

specimens from terrestrial, freshwater, and marine

environments were also collected (54).

In 1973, EPA, in collaboration with the National

Bureau of Standards (NBS),l proposed the establishment of a National Environmental Specimen

Bank, a systematic approach to specimen banking

and monitoring for effects of toxic substances. Since

1975, EPA and NBS have been involved in researchrelated programs for specimen sampling, analysis,

and storage (118,120,1 19). Furthermore, in 1975,

the Federal Republic of Germany and EPA agreed to

cooperate in general activities of specimen banking

(120). A workshop was sponsored by EPA and NBS

in 1976 to design a pilot National Environmental

Specimen Bank program and to evaluate the longterm storage of samples. The primary goals of this

program are the collection, processing, storage, and

analysis of specimens (120).

In addition, EPA has established two monitoring

programs to assess exposure to pesticides and to

identify changes in exposure levels. The first program analyzes pesticides in urine and blood serum;

the second monitors and stores adipose tissue (54).

From 1976 to 1980, the National Center for

Health Statistics (NCHS) sponsored the National

Health and Nutritional Examination Survey II

(NHANES II) to establish base-line data on public

exposure to various classes of pesticides, including

the organophosphate, carbamate, chlorophenoxy,

and organochlorine classes (54,72). Researchers set

out to obtain health and nutritional information by

conducting direct physical examinations and tests

(including blood, serum, and urine specimens) for

pesticide exposure in the general population in

various regions of the United States. The program

has provided estimates of the total prevalence of

selected illnesses, impairments of health and nutritional status, and the distribution of many conditions

in the population by sex, age, income levels, race,

and region (72). Technicians have developed systematic methods of collecting, analyzing, and interpreting the data for the studies in order to detect

potentially toxic substances. In addition, from 1982

to 1984, the Hispanic Health and Nutrition Examination Survey (HHANES) was conducted by NCHS to

provide data on the health and nutritional status of

the Hispanic population of the United States (31).

In 1985, NCHS began planning NHANES III (a

survey to be conducted between 1988 to 1994) to

assess nutrition status, osteoporosis (abnormal decrease in density and loss of calcium in the bone),

arthritis, lung disease, heart disease, diabetes, AIDS,

kidney disease, growth and development of children,

and health and disability of older citizens (54,109).

l

In 1988, the National Bureau of Standards became a component of the National Institute of Standards and Technology.
Chapter 5-Testing and Monitoring ● 133

Currently, all data are collected by computerized

methods in mobile examination centers, which

increases the quality and availability of the data for

analysis.

The current goals of NHANES III include examining the national prevalence of various diseases and

risk factors, documenting and investigating reasons

for trends, understanding disease etiology, and

investigating the natural history of selected diseases

(109),

Another type of program was established by EPA

some years ago to monitor toxic substances in

human adipose tissue. In 1970, the Agency initiated

and sponsored a National Human Adipose Tissue

Survey to determine incidence, levels, and other

indicators of exposure to pesticides in the general

population of the United States (54). This program

monitors the levels of various pesticides in adipose

tissue collected from cadavers during autopsies (54).

WHO is conducting a multinational specimen

banking program for human tissues. Specimens

from the heart, brachial artery, aorta, and diaphragm

of cadavers are being evaluated. This program is

designed to compare exposure to trace metals with

the development of cardiovascular diseases (54).

Additional human monitoring programs include a

serum program conducted by the Centers for Disease

Control and collection of preserved human tissues in

formaldehyde at the EPA Pesticide Research Laboratory (54)0

Monitoring of Nonhuman Tissues

In 1987, the Alaskan Marine Mammal Tissue

Archival Project was established by the Minerals

Management Service to collect and store Alaskan

marine mammal tissues in order to monitor toxic

substances. To reach this goal, three objectives were

set: to collect marine mammal tissues that are

suitable for determining levels of organic and

inorganic substances; to transport and archive tissues in a condition that is ideal for long-term storage

and analysis; and to determine the most appropriate

collection protocols for long-term storage of marine

mammal tissues (8,1 11).

In 1984, the National Oceanic and Atmospheric

Administration within the U.S. Department of Commerce conducted studies through its National Status

and Trends Program for Marine Environment Quality to determine the environmental quality of the

coastal and estuarine regions of the United States.

The objectives of this program are to determine

concentrations of substances in biological tissues

and sediments and to examine and record changes in

these concentrations. Since 1984 and 1986, respectively, samples have been collected at approximately

50 benthic surveillance sites and 150 Mussel Watch

sites. Benthic (bottom-dwelling) fishes are collected

at the Benthic Surveillance sites and their livers are

removed and stored for further chemical evaluation.

At the Mussel Watch sites, molluscs are collected for

chemical analysis. Commonly assayed substances

include polyaromatic hydrocarbons, polychlorinated

biphenyls, pesticides, and the elements arsenic,

cadmium, chromium, lead, mercury, silver, and tin

(106,107,108).

Biological Monitoring

Monitoring programs are designed to observe,

measure, and judge on a continuous basis the

potential health effects of substances and make

proper decisions on the adequacy of control measures. Monitoring is more than just sampling the air

where workers are being exposed or conducting

medical examinations of workers. It is an entire

series of activities that are undertaken to make

proper judgments on the protective controls needed

or the adequacy of the control measures in place, or

both. One approach commonly used in occupational

health is biological monitoring. This makes it

possible to determine both the occurrence of exposure and the presence of particular substance(s) in

body fluids (i.e., blood or urine) or organs in order

to evaluate health risk (5).

Biological monitoring programs are designed to

detect the presence in the body of substances from

all routes of exposure. The appropriate frequency of

monitoring may be influenced by several factors,

including intensity and duration of exposure and

toxicity of the substances. Monitoring is generally

done more often when the toxic substances being

evaluated are expected to produce irreversible changes.

One limitation of biological monitoring is that it

is sometimes difficult to establish whether exposure

to toxic substances is responsible for observed

changes in the biological parameters. Individuals are

often exposed to several substances simultaneously,

and one must consider whether a different substance

or a combination of substances caused the observed

toxic effects. Variability in individual responses

may be another limitation to monitoring. Multiple
134 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

factors may cause variability in response among

workers exposed to the same substance. Thus, it may

be difficult to determine the normal response for a

given individual (5).

Internationally, the Global Environment Monitoring System created a biological monitoring system to evaluate the health risks from exposure to

lead, cadmium, and pesticides. The study of lead

exposures was conducted between 1979 and 1981

and involved 10 countries. In 1984, a follow-up

study was conducted in four countries. Blood

samples from volunteers were taken and analyzed

for lead and cadmium content. In 1981, a study of

selected organochlorine pesticides, including DDT

and PCBs in human milk, was conducted in 10

countries to assess the population’s exposure to

these substances (124).

Other Monitoring Programs

As part of the Federal Emergency Planning and

Community Right-to-Know Act of 1986, EPA was

Photo credit: U.S. Environmental Protection Agency

required to generate a database on toxic substances

released into the environment from industrial sites

throughout the country. Commonly known as the

Toxics Release Inventory (TRI), the database contains information on approximately 328 toxic substances (see box 5-D). Results of the inventory

indicate that in 1987, approximately 18 billion

pounds of toxic substances were released directly

into the air, surface waters, land, or underground

injection wells in the United States. In addition, 4.6

billion pounds were transported offsite for disposal

or treatment. TRI will enable regulatory and public

health officials, researchers, and the public to

monitor what quantities of particular chemicals are

being released from sites around the country. The

first data were published in 1989, and the inventory

will be updated annually. The database pertains only

to manufacturing industries; Federal facilities are

not accounted for (94,1 13). Figure 5-3 illustrates the

neurotoxic substances among the TRI’s top 25

chemicals emitted into the air.
Chapter 5-Testing and Monitoring . 135

Box 5-D-Neurotoxicants Released Into the Environment by Industry:

The Toxics Release Inventory Supplies New Evidence

Until recently, regulators had no comprehensive answer to a basic question underlying toxic substances

regulation: What amounts of toxic substances are we actually dealing within the United States? Despite dozens of

databases devoted to toxic chemical regulation, such as data on air pollution permits, surface water discharges

controlled under Federal water pollution control regulations, and hazardous wastes regulated under the Resource

Conservation and Recovery Act, no single compendium contained estimates of the overall amounts of chemicals

released into the environment. The Toxics Release Inventory, which grew out of reporting requirements mandated

in the 1986 Superfund amendments (Superfund Amendments and Reauthorization Act sec. 313), provides a

preliminary answer—at least for the 327 chemicals covered by the statute that are discharged into air or water or

dumped on land by manufacturers in 20 specified industries.

Inventory data show, for example, that manufacturing facilities emitted significant amounts of neurotoxicants

to the air in 1987. Overall, facilities released 2.6 billion pounds of the 327 toxic chemicals on the Inventory list.

A brief review of the scientific literature reveals that 17 of the top 25 chemicals, accounting for 1.8 billion

pounds (77 percent) of the total for the top 25, have documented neurotoxic effects ranging from narcotic

effects (drowsiness or fatigue) to more permanent and debilitating effects, such as hearing impairment and

blindness. Of these 17 neurotoxicants, only benzene, which is a known human carcinogen, has been regulated

as a hazardous pollutant under the Clean Air Act. The neurotoxic effects of two additional chemicals-l,l,l -

trichloroethane and glycol ethers, which account for another 189 million pounds (8 percent) of the top 25-are being

investigated under the Toxic Substances Control Act section 4 test rules. In sum, manufacturers released a total of

nearly 2 billion pounds of potential or known neurotoxicants (85 percent of the top 25) in 1987. Figures on 1988

releases, which will become available in 1990, should give some indication as to whether emissions of these

neurotoxicants are increasing or decreasing.

The Inventory data do not cover many sources of toxic chemicals in the environment, notably consumer

products and agricultural chemicals, nor do they address the chemical releases and exposures in the occupational

setting. Furthermore, the data do not reveal the amounts to which people are actually exposed (chemicals may break

down or be transported rapidly through the environment after being released, or they may accumulate in the

environment) or the probable risks from exposure. The Inventory data do, however, suggest that significant amounts

of identified neurotoxicants are finding their way out of factories and into the environment; these releases are

plausible candidates for further study or control.

SOURCES: U.S. Environmental Protection Agency, Office of Pesticides and Toxic Substances, The Toxics Release Inventory: A National

Perspective, 1987, EPA 560/4-89-006 (Washington, DC: 1989); W.K. Anger and B.L. Johnson, “Chemicals Affecting Behavior,”

Neurotoxicity of lndustrial and Commercial Chemicals, vol. 1, J.L. O’Donoghue (cd.) (Boca Raton, FL: CRC Press, 1985), pp.

51-148.

A wide variety of additional monitoring programs assayed for were less than 1 percent of acceptable

has been undertaken by several Federal agencies.

For example, in 1978, the U.S. Department of

Agriculture (USDA) and the Human Nutrition

Information Service devised a survey called the

Nationwide Food Consumption Survey to measure

the food and nutrient content of the U.S. diet, the

dollar value of food used in the average U.S.

household, and food and nutrient intakes of individuals at home and away from home. In addition, since

1965, FDA has conducted a survey known as the

Total Diet Study to collect and analyze diet samples

from retail markets to assess concentrations of

metals, pesticide residues, and other substances

commonly found in the diet. In 1987, FDA analyzed

936 food samples in the diets of U.S. consumers and

found that the levels of intake of the pesticides

levels set by WHO and the United Nation’s Food

and Agriculture Organization (110). Also, the National Residue Program is conducted by USDA to

evaluate pesticide residue levels and other potentially hazardous substances present in meat and

poultry. In 1984, EPA’s Office of Pesticide Programs developed a Tolerance Assessment System in

order to estimate potential human exposure to

pesticides in the diet and analyze the risks that could

result from exposure (31).

The Agency for Toxic Substances and Disease

Registry of the Department of Health and Human

Services recently set up a registry of persons

exposed to toxic substances at hazardous waste sites

and at emergency chemical spills. The registry will
136 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Figure 5-3-Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s Top 25

Chemicals Emitted Into the Air in 1987

Millions of pounds

350 I

I

Listed as a neurotoxic substance by

_ Anger and J ohnson (1985), or

subject to TSCA Sect ion 4 test ruIe

for neurotoxic S Ubstances

O Not I i s ted as a neurotoxic substsance

AM TO ME AC 1T MK XY CD DI CH AO) ET F R HA TR PR GE NA TE ST BE Ml CL CS SA

AM - Ammonl a MK - MethYI E t hv I Ke lone F R - F reon 113 ST - St y rene

- -

TO - To I u e n e X V - Xy I e n~ ( m I xi d Isomers ) H A - H yd rOC h I Or iC AC I d b t - Benzene

ME - Methanol CD - Car bon Dlsu I tid e T R - Tr Ich Ioroel hy Ie ne M I - Met hyl Isobu t y I Ketone

DI - Dlch Ioromet hane P R - Propylene

AC - Ace tone

CL - Ch Iorofor m

CH - Ch I or Ine

IT - 1,1, l-Tr 1-

G E - G I YCOI Ethers

AO - A I u m I n u m Ox I d e

CS - Car bonyl Su I f Ide

NA - N - BU t y I Alcohol SA - Su I f u r i c Ac, d

chloroethane ET - Ethylene T E - Te 1 rac h I o ro e t h y I e ne

SOURCES: Data obtained from W.K. Anger and B.L, Johnson, “Chemicals Affecting Behavior,” Neurotoxicity of industrial and

Commercial Chemicals, vol. 1, J.L. O’Donoghue (ad.) (Boca Raton, FL: CRC Press, 1985), tables 1 and 2, pp. 70-141;

TSCA sec.4,52FR31445; TSCA seC. 4,53 FR 5932; 54 FR 13470; 54 FR 13473; U.S. Environmental Protection Agency,

Office of Pesticides and Toxic Substances, The Toxics Release Inventory: A National Perspective, 1987, EPA

560/4-89-006 (Washington, DC: 1989).

provide information needed by researchers to assess

the long-term health effects of both low-level

chronic exposures and high-level acute exposures

(108).

SUMMARY AND CONCLUSIONS

The adverse effects of toxic substances on the

nervous system may be evaluated through three

categories of toxicological tests: whole animal,

tissue and cell culture, and human subjects. Each

approach has both advantages and limitations, and in

practice combinations of these tests may be used in

a complete toxicological evaluation. The best means

of predicting human health effects is to evaluate the

effects of potentially toxic substances directly on

human subjects. However, this approach is difficult

and frequently presents ethical dilemmas. Consequently, it is often necessary to rely on animal tests

in making predictions of human health effects. In

some cases, in vitro tests can be used to detect the

neurotoxic potential of toxic substances. As more in

vitro testing techniques become available and are

validated, they will be useful in initial screening, as

complements to various animal tests, or both.

Several industrial and Federal organizations have

developed animal tests to evaluate the effects of

known and potential neurotoxic substances. In

industry, various testing approaches are currently in

use and protocols are continually being revised and

improved. In the Federal arena, EPA has developed

guidelines under the Federal Insecticide, Fungicide,

and Rodenticide Act and the Toxic Substances

Control Act specifically for determining neurotoxic

properties of toxic substances. The guidelines are

composed of a core set of tests consisting of the

functional observational battery (a series of tests

designed to screen rapidly for neurotoxic potential),

tests of motor activity, and neuropathological examinations. For regulatory purposes, EPA plans to

utilize the core tests and supplement them with

additional neurotoxicity tests when appropriate.

These may include schedule-controlled operant
Chapter S-Testing and Monitoring ● 137

behavior, neurotoxic esterase assay for organophosphorous substances, acute and subchronic delayed neurotoxicity of organophosphorous substances, and developmental examinations. Neurophysiological evaluations are also used in identifying neurotoxic substances and in evaluating their

adverse effects; however, EPA currently has not

developed guidelines for using these tests in regulatory activities.

Several human tests are in use to determine the

neurotoxic potential of suspected and known toxic

substances. These include neurobehavioral evaluations and various neurophysiological tests. In addition, computerized techniques are rapidly advancing

to aid in studies of neurotoxicity.

Monitoring of toxic substances is critical because

it enables investigators to systematically trace toxic

pollutants and their sources that are contaminating

the air, land, and water. Monitoring programs

include human and animal specimen banking, biological monitoring, and related efforts. Toxicity

monitoring programs now under way in Federal

agencies address neurotoxicological concerns in

varying degrees. However, much more could be

done in this area.

Until recently, Federal agencies have devoted

little attention to neurotoxicity testing. EPA is the

leader in developing test guidelines to evaluate

neurotoxicity. The regulatory programs of other

agencies would benefit from joint test development,

and more active involvement of industry and academia in test development and validation programs

would help ensure the optimal design of neurotoxicity tests for general use in regulatory programs,

EPA is continuing to examine the testing guidelines already produced to determine whether a wider

range of tests is needed to evaluate the neurotoxic

properties of toxic substances, For example, the

schedule-controlled operant behavior and developmental tests provide additional information about

certain effects that cannot be determined by the

FOB, motor activity, and neuropathology examinations.

The Federal Government is encouraging the

development of in vitro neurotoxicological tests. As

these tests become available, testing schemes may

be modified to take advantage of both in vivo and in

vitro approaches. Finally, monitoring programs

under way at various organizations and Federal

agencies would benefit by giving greater attention to

substances with neurotoxic potential and by incorporating a wider range of neurological and behavioral

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

effects into monitoring schemes.

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802.
Chapter 6

Assessing and Managing Risk

‘The alternative to not performing risk assessment is to adopt a policy of either reducing all potentially toxic

emissions to the greatest degree technology allows or banning all substances for which there is any evidence

of harmful effect, a policy that no technological society could long survive. ”

William D. Ruckelshaus

Issues in Science and Technology

Spring 1985

“Risk assessment has become a central focus of environmental policy in the past couple years. In part, this

is a matter of fashion. But it also arises from the real need to compare the relative importance of the vast

number of environmental threats, because it has become obvious that not all threats can receive maximum

attention.’

William K. Reilly

The Conservation Foundation

1985

“Over the past decade increasingly sophisticated methods have been developed to identify health hazards and

assess risks quantitatively. But society has yet to agree on the most critical step in risk management:

identifying risk goals and translating them into practical regulations. Does society seek to eliminate all risks,

eliminate all nontrivial risks, all significant risks, or only those risks that are not outweighed by benefits?”

Daniel Byrd and Lester B. Lave

Issues in Science and Technology

Summer 1987
RISK ASSESSMENT .

Hazard Identification

CONTENTS

Page

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Dose-Response Assessment . .. .. ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... .+....

Exposure Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Risk Characterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

RISK MANAGEMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

RISK ASSESSMENT AND NEUROTOXIC SUBSTANCES . . . . . . . . . . . . . . . . . . . . . . .

Examples of Regulatory Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Limitations occurrent Approaches, ...,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147

147

147

148

148

149

150

150

151

154

156

Box

Box Page

6-A. Individual v. Social Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Figures

Figure Page

6-1. The Relationship Between Risk Assessment and Risk Management . . . . . . . . . . . . . .

6-2. Hypothetical Placement of a No Observed Effect Level (NOEL) and

No Observed Adverse Effect Level (NOAEL) for a Single Chemical on a

Dose-Response Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6-3. Use of Safety Factors in Deriving preference Dose . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6-4. Postulated Decline in Brain Functional Capacity With Age and Exposureto

Neurotoxic

Table

Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...:..... . . . . . . . . .

Table

145

148

149

152

Page

6-1. Estimated Risk of Death to an Individual From Various Human-Caused and

Natural Accidents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Chapter 6

Assessing and Managing Risk

Risk assessment is the analytical process by

which the nature and magnitude of risks are identified. Risk, as it pertains to the health effects of toxic

substances, is the probability of injury, disease, or

death for individuals or populations undertaking

certain activities or exposed to hazardous substances. It is sometimes expressed numerically (e.g.,

1 in 1 million); however, quantification is not always

possible, and risk may sometimes be expressed in

qualitative terms such as high, medium, or low risk.

Risk management, a process guided by risk

assessment, and by political, social, ethical, economic, and technological factors as well, involves

developing and evaluating possible regulatory actions and choosing among them (15). The four

components of risk assessment and the process of

risk management are summarized in figure 6-1 and

are discussed in more detail below. In practice, risk

assessment and risk management frequently overlap

and become difficult to distinguish (27). This is

partly because definitions such as “adverse,’ “harmful,” and “toxic” involve both scientific and social

judgments.

Some degree of risk is associated with almost

every aspect of modern living. For example, traveling in an automobile involves a risk of accidental

death of 1 in 4,000, a relatively high risk. In contrast,

the risk of being killed by lightning is 1 in 2 million.

Whether a risk is acceptable or not depends on many

factors, including benefits. Defining acceptable risk

is the task not only of scientists and regulatory

officials, but of society in general. Everyone evaluates risks on a daily basis and makes individual

choices depending on experience and numerous

other factors. At times, one’s perception of risk may

not be entirely logical. For example, some people are

reluctant to travel by air, even though the risk of

death associated with automobile travel is 25 times

greater (table 6-1) (13). People tend to overestimate

the number of deaths from rare, dramatic risks and

Table 6-l-Estimated Risk of Death to an individual

From Various Human-Caused and Natural Accidents

Accident Risk

Automobile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 4,000

Drowning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 30,000

Air travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 in 100,000

Lightning . . . . . . . . . . . . . . . . . . . . . . . . . . ........1 in 2.000.000

SOURCE: C.D. Klaassen, “Principles of Toxicology,” Casarett and Doull’s

Toxicology, C.D. Klaassen, M.O. Amdur, and J. Doull (ads.)

(New York, NY: Macmillan, 1986).

Figure 6-l-The Relationship Between Risk Assessment and Risk Management

Research Risk Assessment Risk Management

Laboratory and field

observation of adverse

health effects and

exposures to particular

agents

-F

I

I Field measurements, ~ ! t ExDosure assessment I =tm

\

>

/

I

;

/

I

I

7

Risk characterization

(What is the estimated ~

incidence of the adverse I

effect in a given I

population?) I

I I I

I Development of

I regulatory options

II I

I

Evaluation of public

health, economic,

social, political

consequences of

regulatory options

i Agency decisions

and actions

SOURCE: National Research Council, Risk Assessment in the Federal Government: Managing the Process (Washington, DC: National Academy Press,

1983).

-145-
146 ● Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

underestimate the number from common, undramatic

causes (6). For example, public perception of the

annual death rates from floods or tornadoes are

typically overestimated, while the risk from smoking or drinking alcoholic beverages is typically

underestimated (6).

Risk assessment practices are the subject of

ongoing debate within the regulatory and scientific

communities, and in the last two decades strategies

for regulating toxic substances have changed considerably. In the early 1970s, environmental legislation focused on regulating a relatively small number

of pollutants of known toxicity. Today, concern is

focused on thousands of toxic substances, for many

of which little information is available. Consequently, regulatory strategies have changed. This

change has been forced in part by improved methods

of detecting toxic substances in the environment,

improved capability of identifying the adverse

effects of those substances, and difficulty in determining threshold levels below which no adverse

effects occur. A major question facing both regulators and the public is how much risk is acceptable.

A wide variety of views has been expressed on the

topic of acceptable risk (4,6). A risk of death of less

than 1 in 100,000 (10-5) to 1 in 1 million (10-6) is

sometimes considered an acceptable risk for exposure to a chemical (13).

Policies regarding risk assessment have been

controversial. Some people believe that Federal

agencies overestimate risk by making overly conservative assumptions in developing risk assessments.

Others feel that risk assessment practices do not take

into account the complex interactions of multiple

pollutants that often occur in the environment. Still

others point out that risk assessments focus primarily on adverse effects on human health and devote

little attention to other organisms and the environment in general. Critics of established risk assessment procedures believe that too little attention is

being paid to the potential effects of toxic substances

on children, infants, and the unborn, and efforts to

address these concerns are under way at regulatory

agencies. Regardless of the various viewpoints, risk

assessment has become an integral component of

regulatory strategies, and it is important to appreciate the scientific issues underlying this process in

order to understand how toxic substances are controlled (6).

illustrated by: Ray Driver

In this chapter, the basic principles of risk

assessment as they relate to the neurotoxicity of

industrial chemicals are described. The risks posed

by pharmaceuticals, for example, are typically

evaluated through other approaches. The Environmental Protection Agency (EPA) has actively pursued regulatory strategies based on risk assessment

(17), and the National Research Council (NRC) of

the National Academy of Sciences has examined the

issue of evaluating the risk posed by neurotoxic
Chapter 6-Assessing and Managing Risk ● 147

substances. The reader may wish to refer to the NRC

report for further information on this subject (16).

RISK ASSESSMENT

A complete risk assessment comprises four steps:

hazard identification, dose-response assessment,

exposure assessment, and risk characterization (15).

Each of these is discussed in the sections that follow.

Hazard Identification

Hazard identification involves gathering and evaluating toxicity data on the types of injury or disease

that may be produced by a substance and on the

conditions of exposure under which the injury or

disease may be produced. Toxicity data typically

derive from epidemiological and experimental animal studies. Hazard identification involves judgments about the quality and relevance of these data.

Of special importance is the question of whether

specific toxic effects observed in one human population or in a particular experimental setting are likely

to be produced in populations for which such data

have not been or cannot be collected.

The most relevant toxicity data for identifying

human hazards are usually derived from studies in

humans. However, such information is often unavailable or limited and can be obtained only after

human exposure has occurred. Consequently, it has

become common practice to rely on data from

animal studies to assess the toxic properties of

chemicals. As discussed in chapter 5, a substantial

body of evidence indicates that results from animal

studies, with appropriate adjustments and qualifications, can be used to infer human hazard (1 3). There

are important exceptions to this generalization, but

unless existing data on human toxicity convincingly

contradict a specific finding in animals, or there are

other physiological reasons to consider certain types

of animal data irrelevant to humans, the assumption

is generally made that animal toxicity data can be

used to identify potential human hazards (8).

The hazard identification section of a risk assessment report typically includes an evaluation of all

available toxicity data to identify those adverse

effects that are best documented and those that are

most relevant to human health. In most cases, the

toxic effects causing greatest concern are those

that are most severe, occur at lowest exposures,

and persist after exposure ceases.

A complete hazard identification also includes a

discussion of the limitations of the available data.

The absence of relevant data cannot, of course, be

taken as evidence that a particular substance does

not pose a hazard.

Dose-Response Assessment

In the second step of risk assessment, assessors

derive the quantitative relationship between exposure to a substance, usually expressed as a dose, and

the extent of toxic injury or disease. There may be

more than one relationship per substance, because

several different kinds of responses may be elicited.

For any given chemical and exposure route, the

severity and frequency of an effect generally increase with dose. Because humans are typically

exposed at lower doses than those used in toxicity

studies, it is necessary to extrapolate dose-response

relations. At present, there are differences between

dose-response extrapolations for noncarcinogenic

types of toxicity, such as neurotoxicity, and for

carcinogenicity. Noncarcinogenic effects are generally assumed to occur only when a certain level of

exposure has been exceeded. This level is referred to

as the threshold. It is frequently assumed that most

carcinogens pose some risk at any level of exposure.

However, the assumption that there is a threshold for

all neurotoxic substances is questioned by some

scientists (21).

The dose-response evaluation for noncarcinogens

is derived from observations of a no observed effect

level (NOEL) or no observed adverse effect level

(NOAEL) in exposed people or experimental animals (figure 6-2). The NOAEL or NOEL represents

an approximate threshold for the group that has been

studied. The NOEL is that dose at or below which no

biological effects of any type are noted (a determination that is influenced by the sensitivity of analytical

techniques), and the NOAEL is that dose at or below

which no harmful effects are seen. As noted earlier,

definitions of “harmful” effects are influenced by

social norms and values. If more than one effect is

seen in animal tests, the effect occurring at the

lowest dose in the most sensitive animal species and

sex is generally used as the basis for estimating a

NOEL or NOAEL. The NOAEL is most commonly

used in current neurotoxicological evaluations.

Experimental studies are often conducted using

relatively high doses of a chemical to increase the

probability of observing effects in small groups of
148 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Figure &2—Hypothetical Placement of a No Observed

Effect Level (NOEL) and No Observed Adverse Effect

Level (NOAEL) for a Single Chemical on a

Dose-Response Curve

Percent responding

I I

i Effects, but biological “

relevance unknown

Adverse effects

I

I

NOEL Dose NOAEL

SOURCE: Office of Technology Assessment, 1990.

animals. Human exposures tend to be in low doses,

where responses are not generally directly observable. Therefore, in moving from laboratory exposures

to human exposures, it is usually necessary to

extrapolate from high dose-responses to low doseresponses. Extrapolations are also necessary to

adjust for differences between animals and humans

with regard to conditions of exposure and certain

physiological factors, such as size, lifespan, metabolism, brain maturation rate, and absorption. Adjustments are also made for variations in sensitivity

among individuals in a population (intraspecies

differences) (15). Some of these extrapolations and

adjustments take the form of safety factors; these are

discussed in more detail in the risk characterization

section of this chapter.

Exposure Assessment

The next step in risk assessment is determination

of the extent and nature of human exposure (including source, route, dose, and duration). An assessment of subgroups in the population expected to

experience unusual exposures is also appropriate

(15).

Exposure can occur from many sources (e.g., soil,

food, air, or water) and may enter the body by several

routes, including ingestion, inhalation, or contact

with skin. It is important to note that an individual

may incur exposures from more than one source or

route. Determination of environmental concentrations and means of human exposure, route of entry,

site of the exposed population, and uncertainties in

exposure estimates are important factors in exposure

assessment. The degree of exposure to some toxic

substances is strongly influenced by occupation. For

example, industrial workers may be exposed to high

concentrations of some chemicals that the public

may encounter at much lower levels.

Duration refers to the period of time over which

individuals are exposed. An acute exposure is

generally a single exposure that occurs over a short

period of time. An exposure is considered chronic

when it occurs over extended periods of time or a

substantial portion of a person’s lifetime (see ch. 5).

Exposures of intermediate duration are called subchronic. Chronic and subchronic exposures may be

episodic (occurring at various intervals) or continuous (occurring over extended periods).

The pattern of exposure-the dose, duration,

frequency, and route—is an important determinant

of risk. Other concerns include knowledge of the

age, sex, health status, and presence or absence of

other environmental exposures for a given population. Obtaining such information requires a comprehensive monitoring program; however, data of this

kind for a given toxic substance are often not

available.

Risk Characterization

The final step of risk assessment combines the

results of hazard identification, dose-response assessment, and exposure assessment to produce a

characterization of risk. The NOAEL (or, less

frequently, the NOEL) derived in the assessment of

dose-response is divided by a safety factor, or

uncertainty factor, yielding what is called the

reference dose (RfD) (2). At the present time, risk

characterization for noncarcinogenic forms of

toxicity, including neurotoxicity, is based on the

NOAEL (or NOEL) safety factor approach. The

RfD (also called the acceptable daily intake)l is used

to characterize risk. If human exposure is consistently below the RfD, risk assessors assume there is

little health risk. If exposures exceed the RfD, it is

assumed a significant risk exists. Generally, no
Chapter 6-Assessing and Managing Risk ● 149

attempt is made to describe the magnitude of the

risk.

Three safety factors are commonly used to develop an RfD. The NOAEL or NOEL is divided by

10 when epidemiological or human experimental

data are used to predict human risk. This safety

factor is applied in order to protect sensitive

members of the population when data have been

obtained from average, healthy persons. Another

factor of 10 is applied to the NOAEL or NOEL when

extrapolating from animals to humans. To develop

a chronic RfD when only subchronic animal studies

are available, another factor of 10 is added, for a total

safety factor of 1,000. Sometimes a factor is added

for an incomplete database. The magnitude of the

safety factor employed can vary from chemical to

chemical. Scientific judgment may be exercised in

evaluating species differences, the nature and extent

of human exposure, the types of toxic effects, and the

relative doses at which toxicity occurs in test species

(see, e.g., 51 FR 34040). The application of safety

factors is diagramed in figure 6-3.

A variation on the safety factor approach is the

margin of safety (MOS), or margin of exposure

(MOE). This involves dividing the NOAEL (or

NOEL) by the current, desired, or most feasible

human exposure level. This margin is sometimes

compared with the safety factors mentioned above in

order to judge its adequacy. Risk assessors generally

employ the MOS approach to make judgments about

the safety of existing or proposed exposure levels.

They use the safety factor approach in circumstances

where guidelines or regulations specify maximum

allowable or safe exposure limits (3).

For substances that produce carcinogenic effects,

the NOAEL (or NOEL) safety factor approach is not

used. Instead, various extrapolation models are

applied to develop estimates of risk (typically, the

probability of developing cancer over a lifetime)

associated with various levels of exposure. There is

little scientific literature on the application of this

type of extrapolation to noncarcinogenic effects.

Currently, cancer risks and RfDs are expressed

numerically, but these quantitative figures may be

qualified with factors such as the strength of the

evidence of toxicity on which the risk or RfD is

based. The uncertainties and assumptions inherent in

any risk assessment should also be stated. This

information is as essential as the quantitative deFigure 6-3-Use of Safety Factors in Deriving a

Reference Dose

Animal Dose-Response Data

1

NOEL or NOAEL

1

Divide by 10

(for short- to long-term extrapolation)

1

Divide by 10

(for animal to human extrapolation)

i

Divide by 10

(for homogeneous to heterogeneous population extrapolation)

1

Reference dose (RfD)

(or acceptable daily intake, ADI)

SOURCE: Office of Technology Assessment, 1990.

scription of risk associated with exposure to a toxic

substance.

RISK MANAGEMENT

The purpose of risk management is to determine

whether an assessed risk should be reduced and to

identify the degree of risk reduction that is appropriate to a given situation. Risk management depends

on information derived from the risk assessment, but

it may also depend on political, social, ethical,

economic, and technological factors. NRC has

recommended that regulatory agencies take steps to

establish and maintain a clear conceptual distinction

between risk assessment and risk management (15).

Different risk management approaches are taken by

different regulatory agencies, depending largely on

the kind of exposure being evaluated and the

agency’s statutory authority. The three most common risk management approaches mandated by the

various environmental and public health laws are

risk only, risk balancing (risk-benefit), and technological control (25), Public perceptions may also

influence risk management decisions.

A regulatory decision using the risk only approach

takes into account only the level of risk that is

considered necessary to protect public health. However, the risk balancing approach may consider
150 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

social, economic, and technological factors as well.

This approach involves developing a consensus

among interest groups and making trade-offs for the

public well-being. The third risk management approach, technological control, involves reducing

risk by applying the best available, most feasible

technologies.

RISK ASSESSMENT AND

NEUROTOXIC SUBSTANCES

The risk assessment approaches outlined above

have been discussed extensively in various Federal

and State regulations and guidance documents (see,

e.g., 51 FR 33992-34003; 50 FR 10372-10442) (5),

as well as in the scientific literature (50 FR

10372-10442) (15). Practical applications of these

methods of risk assessment can be found in hundreds

of regulations promulgated by EPA, the Food and

Drug Administration, the Occupational Safety and

Health Administration (OSHA), and the Consumer

Product Safety Commission, as well as in the

scientific literature. A representative sampling of the

latter, and references to many more assessments, can

be found in the National Academy of Sciences’

series Drinking Water and Health (8 volumes

through 1988). While legitimate scientific differences exist regarding many issues in risk assessment, particularly those concerning extrapolation,

consensus exists regarding the need for some type of

analysis of the risk posed by toxic substances.

Differences in approaches to risk assessment can

result in different conclusions with respect to the

degree of risk posed by a toxic substance and how

much of society’s resources should be used to

address toxicological concerns.

To date, most risk assessments have been devoted

to carcinogenic substances. As mentioned above,

some basis has been found for development of

explicit descriptions of noncarcinogenic risk, and

most of the guidance documents mentioned above

deal with this issue. There is some discussion of

noncarcinogenic effects in the Drinking Water and

Health series cited above, in EPA’s Toxic Substances Control Act Test Guidelines (50 FR 39398-

39418; 50 FR 39458-39470), and in various documents issued by the World Health Organization (28).

EPA’s “Guidelines for the Health Assessment of

Suspected Developmental Toxicants,” issued in

1986 (51 FR 34040), were the first noncancer risk

assessment guidelines produced.

Risk assessment strategies were originally developed for evaluating carcinogens, which have often

been viewed as exerting “all-or-none” effects

(although this view is changing for some carcinogens). Neurotoxic substances differ from carcinogens in that adverse effects are strongly dependent

on dose—severe effects may result from exposure to

large concentrations of a substance, but little effect

may result from exposure to low concentrations.

Also, cancer is a relatively well-defined, discrete

endpoint. Neurotoxicity may result in multiple

endpoints (e.g., seizures, memory loss, hearing loss),

thus complicating risk assessment strategies. In

most of these cases, and in many specific regulatory

applications, the RfD approach to risk characterization (or its equivalent in occupational settings) is

accepted.

Examples of Regulatory Approaches

Federal regulatory agencies have not developed

uniform risk assessment approaches to neurotoxic

substances, although EPA has been particularly

active in developing risk assessment guidelines (1 2).

To illustrate how various agencies have used risk

assessment, one may focus on four widely recognized neurotoxic substances: lead, ethyl-p-nitrophenyl phosphonothionate (EPN, an organophosphorous pesticide), acrylamide (a chemical often

used because of its ability to polymerize), and

n-hexane (a commonly used industrial solvent) (9).

Each of these substances is representative of a major

category of environmental exposure: lead (general

exposure), EPN (pesticide), and acrylamide and

n-hexane (occupational exposures).

Two of the four chemicals examined, EPN and

n-hexane, are regulated primarily on the basis of

neurotoxic concerns. Risk assessments for the two

focus on histopathologica1 analyses, as opposed to

examinations of functional effects. Lead is regulated

because of its neurotoxic properties, especially

prenatally and in early life, and its effects on the

blood-forming system. Acrylamide is regulated

because of both its carcinogenic and its neurotoxic

potentials (box 7-E).

The methodological approaches used by EPA (for

lead and EPN) and OSHA (for acrylamide and

n-hexane) were generally the same. In identifying

hazards, the agencies placed greatest reliance on

human data, when they were available, but also

relied on animal data. Principal emphasis was placed
Chapter 6--Assessing and Managing Risk ● 151

Photo credit: National Arhives, EPA Documerica Collection

on identifying NOAELs and determining the appropriate margin of exposure for humans.

In determining the bases for the occupational

standards, OSHA adopted the American Conference

of Governmental Industrial Hygienists’ (ACGIH)

threshold limit values (TLVs) for the n-hexane and

acrylamide standards. ACGIH documented its derivation of each TLV (l), but the relationships

between the TLVs and the underlying documentation were not explicitly stated. EPA’s standards were

stated more clearly.

A detailed evaluation of the risk assessment

information used in the development of the standards for lead, EPN, acrylamide, and n-hexane

confirmed that the safety factor approach has been

used for neurotoxicity risk assessment in diverse

circumstances. The safety factor approach (based on

a NOAEL) is commonly used in the U.S. pharmaceutical industry, where neurotoxic effects sometimes limit the dose (10).

To date, there have been few instances in which

neurotoxicity was the principal basis for regulation.

There are perhaps three reasons for this. First,

toxicity tests currently used by regulatory agencies

are generally not specifically designed to identify

neurotoxic agents. Histopathological analyses may

identify some neurotoxic agents, but pathological

analyses alone are of limited use in identifying

adverse effects on the function of the nervous system

(e.g., behavioral effects). Second, the risk assessment methodologies currently in use for carcinogenesis assume the absence of a threshold, whereas

those used for other toxic effects assume a threshold.

The practical consequence of this dichotomous

system is that whenever a toxic agent exhibits both

carcinogenic and other-than-carcinogenic effects,

concerns about the carcinogenic risks tend to override concerns about other risks that may be associated with the agent at low doses. As indicated earlier,

however, these assumptions regarding thresholds for

carcinogenic and other toxic chemicals are the

subject of debate. Third, in some cases other,

noncancer health effects may occur at lower levels

than neurotoxic effects, and regulations may have

been based on these concerns.

Concerns about carcinogenicity have dominated

discussions about the risks posed by toxic substances. However, the adverse effects on organs and

organ systems (the nervous system, liver, immune

system, cardiovascular system, and so on) may pose

an equal or greater threat to public health. Consequently, it is important to devise risk assessment

strategies to address noncancer health risks.

Limitations of Current Approaches

The nervous system is perhaps the most complex

organ system of the body. Consequently, evaluating

the neurotoxic potential of environmental agents is

a particular challenge. For example, testing for a

toxic effect on one component of the nervous system

(e.g., hearing) may or may not reveal a toxic effect

on another component (e.g., vision); furthermore, an

effect on one nervous system function is not

necessarily predictive of an effect on another nervous system function. Other factors that complicate

risk assessment of neurotoxic substances include the

apparent reversibility of many neurotoxic effects

and the possibility of “silent,” or latent, adverse
152 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

effects, which become apparent only late in life (27)

(see box 7-G).

An important difference between neurotoxicity

and carcinogenicity is the extent to which the effects

are reversible. The endpoint of carcinogenicity is

considered to be irreversible (although some persons

argue that, strictly speaking, a “cure” would render

the effect reversible), whereas the endpoints of

neurotoxicity may be either reversible or irreversible, depending on the specific effect, the duration

and frequency of exposure, and the toxicity of the

substance (see box 7-G). Reversibility requires the

introduction of a new variable into the risk assessment equation. Consequently, it has been proposed

that it may be useful to specify a reversible effect

level (27). Yet, determining whether or not an effect

is truly reversible can be difficult. For example,

exposure to a neurotoxic substance early in life

could appear to give rise to a short-term, reversible

effect, but later in life an irreversible effect (e.g., a

neurological disease) could become apparent.

The age at which neurotoxic effects are evaluated

can strongly influence the outcome of a risk analysis.

For example, mice exposed to methylmercury during prenatal development may not exhibit adverse

effects until late in their lives (23). Similarly,

humans exposed to a toxic substance early in life

may not suffer adverse effects until decades later.

With age, the functional capacity of the brain

declines significantly, and chronic exposure to some

neurotoxic substances is thought to accelerate this

process (27). As indicated in the hypothetical

example in figure 6-4, a small acceleration in the loss

of functional capacity may, with time, have very

significant effects. For example, in this model, the

postulated functional capacity of the brain that has

not been chronically exposed to neurotoxic substances through age 65 is more than 80 percent of the

capacity at age 65 (see figure 6-4, point A).

However, even a modest acceleration of 0.5 percent

per year results in a functional capacity of 65 percent

(see point B), a more than 15-point reduction in this

theoretical example. As figure 6-4 suggests, an

acceleration of 1.0 percent per year could result in a

large reduction in functional capacity over time.

Hence, many scientists and regulatory officials

believe that risk analyses should consider adverse

effects over a range of ages and should take into

account possible latent effects (27). More research is

needed to understand the actual relationship beFigure 6-4-Postulated Decline in Brain

Functional Capacity With Age and Exposure

to Neurotoxic Substances

90.

\

~ Normal decline wilh age

80- -

70 \

0.5% 0.1 %

1% Excess per year Excess per year

Excess per year #

60.

25 35 45 55 65 75 85 95

Chronological age

The heavy line (top) shows the rate posited to occur without added

variables. The lighter lines show accelerations of 0.1 percent, 0.5

percent, and 1.0 percent annually, as might be produced by

chronic exposure to neurotoxic substances.

SOURCE: B. Weiss and W, Simon, “Quantitative Perspectives on the

Long-Term Toxicity of Methyl Mercury and Similar Poisons,”

Behavioral Toxicology, B. Weiss and V. Laties (eds.) (New York,

NY: Plenum Press, 1975).

tween decline in functional capacity and the impact

of toxic substances on the nervous system.

Issues in Hazard Identification

Neurotoxicological assessment of environmental

agents is not uniform among Federal regulatory

agencies (1 1,20,24). Although hazard identification

through general toxicity testing (described inch. 5)

can identify substances with obvious neurotoxic

properties, substances producing more subtle effects

are generally not detected. One exception is EPA’s

Office of Toxic Substances, which has included a

battery of more sophisticated neurotoxicity tests in

its regulatory requirements (see ch. 7). Until recently, however, EPA has not imposed these specific

test requirements on many substances.

As discussed in chapter 5, neurotoxicity tests (and

toxicity tests in general) should meet certain criteria

such as sensitivity, specificity, and reproducibility

before being adopted for routine use in hazard

identification or dose-response assessment. Currently, there is a consensus among scientists that

several neurotoxicological tests meet the necessary

criteria and could be used for routine testing of

potentially neurotoxic substances (14,18,22). A

question that remains is precisely how EPA will use

test data in the regulatory decisionmaking process.
Chapter 6-Assessing and Managing Risk ● 153

Issues in Dose-Response Assessment

Thresholds and the RfD Approach-Toxic agents

are conventionally classified into two groups: those

that exert adverse effects only after a threshold dose

is exceeded and those that theoretically increase risk

at all doses greater than zero (no-threshold agents).

This classification system, which has important

consequences for risk assessment, has the practical

effect of grouping all carcinogens into the nothreshold category and all other forms of toxicity

into the threshold category. As indicated earlier,

there is uncertainty about whether all carcinogens

belong in the no-threshold group and all noncarcinogens, including neurotoxic agents, belong in the

threshold group (19).

One consequence of this dichotomous system is

that different models for risk assessment are used for

the two groups. Typically, noncarcinogenic risk is

modeled under the assumption that risk declines

with dose and that the mathematical model that

describes this relationship applies even below the

region of observed effects. The model used for

carcinogens yields zero risk (zero probability of

developing cancer) only when the dose becomes

zero. On the other hand, the consequence of assuming a threshold model is the development of RfDs by

applying safety factors to NOELs or NOAELs.

NOAEL v. NOEL-The objective of using a

NOAEL as opposed to a NOEL, as described above,

is to establish a threshold dose such that no adverse

effect would be likely to occur at exposures at or

below this dose. Implicit in the establishment of a

NOAEL is the understanding that any effects that

occur below this dose would have no known

biological relevance, whereas effects occurring above

this dose would be harmful. A NOEL, on the other

hand, reflects a dose below which no observable

effect of any type occurs. An effect might be

measurable, yet not be deleterious to human health;

in fact, the effect might be beneficial or might not be

biologically meaningful.

Due to limits in scientific understanding of the

biological relevance of measurable effects, regulatory standards are often based on NOELs and not

NOAELs. This reflects the intent to err on the side

of caution and to be overprotective rather than

underprotective of public health. When regulating

pharmaceuticals, NOAELs are used because adverse

effects must be distinguished from positive pharmaPhoto credit: United Automobile, Aerospace, and Agricultural

Implement Workers of America-U4VPublic Relations Department

cological effects. Also, recent draft developmental

toxicity testing guidelines (54 FR 13472; 53 FR

5932; 51 FR 17890) are based on the NOAEL.

Developmental testing is discussed in chapter 5.

Safety Factors—A safety factor, as described

above, is generally applied to the NOEL or NOAEL

to estimate the RfD. However, the use of such factors

creates an uncertainty in itself. Safety factors are

generally derived not from chemical-specific data,

but from a priori estimations of the ranges of

variation in extrapolations used to determine an RfD

(from animals to humans and within the human

population). The limited research done on the topic

of safety factors needed to account for intraspecies

variability indicates that the tenfold factor used for

this purpose tends to be more rather than less

protective of a diverse human population (7,26).

What is unclear at the present time is the actual

degree of protection against toxic effects that is

associated with the RfD. It is likely that different

safety factors are necessary for different chemicals;

thus the RfD may be highly protective for one

neurotoxic substance (i.e., one associated with an

extremely low risk) but insufficiently protective for

another.
154 ● Neurotoxicity: [dentifying and Controlling Poisons of the Nervous System

Issues in Risk Characterization

Uncertainty-An important component of risk

characterization that often receives inadequate attention is the delineation of uncertainties in the various

stages of the assessment. The greater the total

uncertainty, the less likely it is that the calculated

risk represents the true risk. Every risk characterization should include a thorough discussion of all the

uncertainties (50 FR 10372-10442, 51 FR 33992-

34003).

There are uncertainties inherent in every risk

assessment. Some are fundamental scientific questions common to all risk assessments. Questions that

often arise include:

. How useful are animals as predictors of human

toxicity?

. HOW well do responses at high doses predict

responses at low doses?

● What is the relative importance of individual v.

social risk? (See box 6-A.)

These questions are often difficult to answer; indeed,

at times they cannot be answered. In the meantime,

assumptions must be made and mathematical and

interpretational conventions must be devised. In

some areas, such as high to low dose extrapolation,

there is no consensus among scientists. Regulatory

agencies deal with such situations by adopting

science policy assumptions (15). These assumptions

tend to favor overstatement of risk, a practice that

agencies justify on public health grounds.

Other types of uncertainties arise because the data

available for any given risk assessment are incomplete or imperfect. Examples of these kinds of

uncertainties include the following questions: Are

toxic responses resulting from different experimental exposure routes comparable? What environmental concentrations of a contaminant are people

actually exposed to? Is the toxic substance chemically modified in the environment or metabolized in

the body to a more or less active form? What

quantity of the chemical actually reaches and causes

the toxic effect in the target organ?

Assumptions must be made to fill these gaps in

information. The risk assessor usually tries to be

conservative by making a worst probable case

assumption. This results in a final risk number that,

although uncertain, is highly likely to overestimate

the true risk.

SUMMARY AND CONCLUSIONS

Toxicology and risk assessment have traditionally

dealt with effects that can be characterized by

physical changes, including morphological or biochemical abnormalities. Functional impairment of

the organism, such as a chemically induced change

in behavior, is now also considered a direct and

measurable consequence of these types of abnormalities. The relationship between pathological changes

and functional impairment needs to be further

correlated, however.

Determining the biological mechanisms underlying behavior is a frontier of basic research. Research

aimed at defining adverse effects at the cellular and

systems levels is being actively pursued in tandem

with the development of toxicity testing methods.

Several tests already developed in the academic,

regulatory, and private sectors can be used in routine

preliminary or secondary screening of neurotoxic

substances. Regulatory agencies will most likely

adopt a tiered testing approach2 whenever specific

neurotoxicity tests as well as general toxicity tests

are required.

With respect to identifying neurotoxic hazards

and developing standardized methods of predicting

them, several approaches might be pursued simultaneously. Research to improve the utility of structureactivity relationships in predicting neurotoxicity is

critically needed. Strong, continuing research programs are needed to further refine and validate

neurotoxicity tests. To guide the direction of this

research, specific epidemiological surveillance programs could be developed to follow subpopulations

that are exposed to high concentrations of neurotoxic substances (e.g., certain occupational groups).

Also, weight-of-evidence approaches for classifying

neurotoxic hazards, similar to EPA’s weight-ofevidence classification scheme for carcinogens,

might help guide regulatory decisionmaking. EPA

has recently proposed such a scheme for neurotoxicity.

Further exploration of the scientific basis for the

threshold assumption now adopted for all noncarcinogens is needed. The desirability of adopting nonthreshold dose-response relationships for some agents

Zne tle~ test~g approach is described iI’I ch. 5.
Chapter 6---Assessing and Managing Risk ● 155

Box 6-A—Individual v. Social Risks

Risk, particularly as it relates to carcinogenicity, is typically evaluated in the context of the individual,

but evaluations of this kind may underestimate the overall risk to society. A useful example is levels of lead

in children. A recent analysis of lead levels in newborns grouped concentrations of lead in the umbilical cord

into three categories: low (1.8 micrograms of lead per deciliter of blood, ug/dl), medium (6.5 ug/dl), and high

(14.5 ug/dl). Even though children in the high exposure group fell just below the 15 ug/dl level considered

to be hazardous (according to the Centers for Disease Control), at age 2 these children score 8 percent lower

than nonexposed children on a standard mental development index (the Mental Development Index of the

Bayley Scales of Infant Development).

Although individual children do not display adverse neurotoxic effects, the impacts on society can be

very significant. As shown in the figure below, a 5 percent reduction in the mean scores can result in a

significantly different distribution of IQ scores.

Probability Probability 0.03- 0.03-

0.02- 0.02-

0.01- 0.01-

0,00 0.00 1 , I I 1 I 1 I I I I I I I ! I I I 1 (

50 70 90 110 130 150 50 70 90 110 130 150

IQ Score IQ Score

Distributions of intelligence test scores. Left: standardized mean 100; standard deviation 15. Right: mean 95.

The graph on the left indicates a typical distribution, in which the mean IQ score is 100 (the standardized

average). In a population of 100 million, 2.3 million individuals would be expected to score above 130. In

the distribution on the right, based on a mean score of 95, about 1 million individuals score above 130, a

reduction of 1.3 million individuals. Clearly, what may appear to be small differences in lead

leve1-differences that are not apparent in individual evaluations-can translate into a major social problem,

detectable only through statistical analysis of data from exposed and unexposed children.

SOURCE: Adapted from B. Weiss, ‘‘Neurobehavioral Toxicity as a Basis for Risk Assessment, ”Trends in Pharmacological Sciences

9:59-62, 1988.

producing delayed, irreversible neurotoxic effects needed to identify relatively weak neurotoxic chemmight be considered. Alternative means of modeling icals that can cause adverse effects in humans after

dose-response relationships for neurotoxic agents low-level exposures over long periods of time.

need to be investigated and developed into practical Facilitating and maintaining coordination among

tools. If the safety factor approach is to be main- researchers and scientists in the various regulatory

tained, empirical verifications of its adequacy are programs will be crucial to ensure efficient and

desirable, not only for neurotoxic agents but for consistent integration of research findings into

other toxic agents as well. In addition, methods are regulatory decisionmaking.
156 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

1.

2.

3.

4.

5.

6.

-7.

8.

9.

10.

11.

12.

13.

14.

CHAPTER 6 REFERENCES

American Conference of Governmental Industrial

Hygienists, Documentation of the Threshold Limit

Values and Biological Exposure indices, Acrylamide

and Hexane (Cincinnati, OH: 1986).

Barnes, D. G., and Dourson, M., “Reference Dose

(RfD): Description and Use in Health Assessments,”

Regulatory Toxicology and Pharmacology 8:471-

486, 1988.

Bass, B. F., and Muir, W. R., Summary of Federal

Actions and Risk Assessment Methods Relating to

Neurotoxicity, EPA Contract No. 68-02-4228 (Arlington, VA: Hampshire Research Associates, Inc.,

1986).

Byrd, D., and Lave, L., “Narrowing the Range: A

Framework for Risk Regulators, ” Issues in Science

and Technology (Summer) :92-100, 1987.

California Department of Health Services, “A Policy

for Chemical Carcinogens: Guidelines on Risk Assessment and Their Scientific Rationale, ” draft

Berkeley, CA, 1984.

Conservation Foundation, Risk Assessment and Risk

Control (Washington, DC: 1985).

Dourson, M. L., and Stara, J. F., “Regulatory History

and Experimental Support of Uncertainty (Safety)

Factors,” Regulatory Toxicology and Pharmacology

3:238-244, 1983.

ENVIRON Corp., Elements of Toxicology and Chemical Risk Assessment (Washington, DC: 1988).

ENVIRON Corp., “Assessing Human Risks Posed

by Neurotoxic Substances, ” prepared for the Office

of Technology Assessment, December 1988.

Gad, S., Searle Research & Development, personal

communication, May 23, 1989.

Hampshire Research Associates, Inc., Expert Neurotoxicity Assessment Report: Neurotoxicity Risk Assessment Guidelines (Arlington, VA: 1985).

Kimmel, C. A., “Regulatory Issues and Risk Assessment for Neurotoxicology, ” Neurotoxicology, Feb.

27, 1989.

Klaassen, C. D., “Principles of Toxicology,” Casarett and Doull’s Toxicology, C.D. Klaassen, M.O.

Amdur, and J. Doull (eds.) (New York, NY: Macmillan, 1986), p. 25.

McMillan, D. E., “Risk Assessment for Neurobehavioral Toxicity, ’ Environmental Health Perspectives

76:155-161, 1987.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

National Research Council, Risk Assessment in the

Federal Government: Managing the Process (Washington, DC: National Academy Press, 1983).

National Research Council, Neurotoxicology and

Models for Assessing Risk (Washington, DC: National Academy Press, in preparation).

Preuss, P. W., and Ehrlich, A. M., “The Environmental Protection Agency’s Risk Assessment Guidelines,” JAPCA 37(7):784-791, 1987.

Reiter, L. W., “Neurotoxicology in Regulation and

Risk Assessment,” Developmental Pharmacology

and Therapeutics 10:354-368, 1987.

Rodricks, J. V., Frankos, V., Turnbull, D., et al.,

“Risk Assessment for Effects Other Than Cancer, ”

Food Protection Technology, C.W. Felix (cd.) (Chelsea, MI: Lewis Publishers, 1987).

Sette, W. F., “Complexity of Neurotoxicological

Assessment” Neurotoxicology and Teratology 9:411-

416, 1989.

Silbergeld, E.K., “Developing Formal Risk Assessment Methods for Neurotoxins, ” Neurobehavioral

Methods in Occupational and Environmental Health

(Washington, DC: Pan American Health Organization, 1988).

Spencer, P. S., and Schaumburg, H.H. (eds.), Experimental and Clinical Neurotoxicology (Baltimore,

MD: Williams & Wilkins, 1980).

Spyker, J. M., Behavioral Toxicology, B. Weiss and

V.G. Laties (eds.) (New York, NY: Plenum Press,

1975), pp. 311-375.

Tilson, H. A., “Symposium: Screening for Neurotoxicity: Principles and Practices, ” Journal of the

American College of Toxicology 8(1):13-17, 1989.

U.S. Congress, General Accounting Office, Health

Risk Analysis: Technical Adequacy in Three Selected

Cases, GAO/PEMD-87-14 (Washington, DC: 1987).

Weil, C. S., “Statistics v. Safety Factors and Scientific Judgment in the Evaluation of Safety for Man, ”

Toxicology and Applied Pharmacology 21:454-463,

1972.

Weiss, B., ‘‘Neurobehavioral Toxicity as a Basis for

Risk Assessment, ” Trends in Pharmacological Sciences 9:59-62, 1988.

World Health Organization, Principles and Methods

for the Assessment of Neurotoxicity Associated With

Exposure to Chemicals, Environmental Health Criteria 60 (Geneva: 1986).
Chapter 7

The Federal Regulatory Response

“The workplace should not be a test tube and company employees should not be guinea pigs. We cannot

tolerate stone-age protections for space-age dangers. ”

Senator Harry Reid

Committee on Environment and Public Works

March 6, 1989

“There are substances commonly used in the home that make our lives easier. We use these substances in

good faith, seldom questioning the fact that they could cause peripheral nerve or brain damage. Consumers

rely on the Government’s and industries’ judgment on health dangers associated with the use of chemicals

and pesticides.

Representative Harold L. Volkmer

Committee on Science and Technology

October 8, 1989

“The industrial laboratory will always outpace the regulatory agency in providing substitutes for banned

chemicals, and some of those substitutes in field use may prove as troublesome as the ones they replace. ”

William D. Ruckelshaus

Issues in Science and Technology

Spring 1985
CONTENTS

Page

LICENSING AND REGISTRATION LEGISLATION AND REGULATIONS . . . . . . . 161

Federal Food, Drug, and Cosmetic Act . +... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163

Federal Insecticide, Fungicide, and Rodenticide Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168

Toxic Substances Control Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

STANDARD-SETTING LEGISLATION AND REGULATIONS . . . . . . . . . . + . . . . . . . . 179

Clean Air Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

Federal Water Pollution Control Act and Clean Water Act . . . . . . . . . . . . . . . . . . . . . . . . 182

Safe Drinking Water Act . . . . . . . . . ● . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183

Consumer Product Safety Act and Federal Hazardous Substances Act . . . . . . . . . . . . . 184

Federal Mine Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

Occupational Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185

CONTROL-ORIENTED LEGISLATION AND REGULATIONS . . . . . . . . . . . . . . . . . . 187

Cornprehensive Environmental Response, Compensation, and Liability Act. . . . . . . . 187

Controlled Substances Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 188

Marine Protection, Research, and Sanctuaries Act.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

Lead-Based Paint Poisoning Prevention Act and Poison Prevention Packaging Act . 189

Resource Conservation and Recovery Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191

NEW INITIATIVES IN REGULATING NEUROTOXIC SUBSTANCES . . . . . . . . . . . 191

Revision of EPA’s Neurotoxicity Test Guidelines for Pesticides . . . . . . . . . . . . . . . . . . . 191

Revision of the FDA’s Red Book for Food and Color Additives . . . . . . . . . . . . . . . . . . 192

Suggested Revisions of OECD Toxicity Testing Guidelines . . . . . . . . . . . . . . . . . . . . . . 194

CONSISTENCY OF FEDERAL REGULATION OF NEUROTOXIC SUBSTANCES . 194

General Toxicological Considerations . . . +.. ....., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

Specific Neurotoxicological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199

ADEQUACY OF THE FEDERAL REGULATORY FRAMEWORK . . . . . . . . . . . . + . . . 201

Measurements of Effectiveness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Expected and Detected Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

Monitoring Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

CHAPTER 7 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .205

Boxes

Box Page

7-A. Toxic Substances Laws Go To Court: The Judicial Role in Interpreting Legislative

Language and Regulatory Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . +.. 162

7-B. Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:

Halcion, A Case Study . . . . . . . . . . . . . . . . . . . . .., , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169

7-C. Regulatory Requirements for Labeling: How Effective Are They? . . . . . . . . . . . . . . . 172

7-D. Confidential Business Information Under TSCA: Does It Influence Regulatory

Effectiveness? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

7-E. Regulating for Neurotoxicity v. Other Toxic Effects: The Case of Acrylamide . . . 178

7-F. The American Conference of Governmental Industrial Hygienists . . . . . . . . . . . . . . . 186

7-G. Flexibility in Neurotoxicological Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193

7-H. TSCA’s Premanufacture Notice Program: Is More Toxicity Testing Feasible? .,. 197

Tables

Table Page

7-1. Key Features of Federal Laws Regulating Toxic Substances . .......... .......+. 160

7-2. Chemicals Subject to Neurotoxicity Evaluation Under Section 4 of TSCA . . . . . . . 179
Chapter 7

The Federal Regulatory Response

Over the years, Congress has enacted many

statutes that apply directly or indirectly to the

regulation of neurotoxic substances. Some of these

statutes are framed in broad terms to protect human

health in general; others address specific adverse

health effects, such as carcinogenicity, teratogenicity, and in rare cases behavioral changes and

neurotoxicity (25). Some statutes provide broad

authority for requiring that substances be tested for

potential toxic effects; others require the implementing agency to prove that substances may be harmful

before any regulatory action can be taken. Some

statutes call for absolute protection of health and

safety; others allow for balancing risks, costs, and

benefits.

Not surprisingly, Federal agencies have promulgated equally diverse regulations. Some regulatory

programs require substantial testing of chemicals to

screen for toxic effects; others are not empowered to

require any such testing. Some call for screening

substances before they are allowed to enter the

marketplace; others are reactive, taking effect only

when evidence indicates that an existing chemical

can, or does, cause harm.

Federal laws governing toxic substances can be

divided into three general categories:

1.

2.

3.

licensing and registration laws for new and

existing chemicals, which entail an explicit

review process and may include a requirement

for toxicity testing;

standard-setting laws for chemicals used in

specific situations, under which regulatory

agencies determine recommended or required

limits on toxic substances in various environmental media (air, water, or soil) or emitted by

a given source, or dictate appropriate labeling

of products that contain toxic substances; and

control-oriented measures for dealing with

chemicals, groups of chemicals, or chemical

processes that are explicitly identified in the

laws. 1

Distinctions among the three categories are not

absolute—there is more of a continuum than a

discrete grouping in the legislative language—but

this classification indicates the basic types of

approaches that have been developed to protect the

public and the environment from the adverse effects

of toxic substances. Table 7-1 presents key features

of 18 Federal laws regulating the use of toxic

substances (14).

The approach to regulation embodied in a statute

largely determines the Federal response. Licensing

programs are externally driven and must respond to

petitions or applications from manufacturers or other

outside parties; standard-setting and controloriented programs may have to respond to deadlines

set by Congress (for control-oriented programs,

however, these deadlines generally affect regulation

of sites rather than specific chemicals). Application

and notification procedures under the licensing

statutes require the regulatory agencies to review

however many chemicals per year are submitted,

whereas agencies charged with setting standards can

control the scheduling and priorities of review to a

greater degree.

Although some of the standard-setting and controloriented programs have the ability to pursue research

into the adverse effects of chemical substances, it is

the licensing statutes that generally grant authority

to require that chemicals be tested for toxic effects.

As a consequence of these and other differences,

implementation of licensing statutes has tended to be

more active and, accordingly, more controversial

than that of standard-setting or control-oriented

statutes.

It is necessary to keep in mind that regulatory

activities may be curtailed, expanded, or otherwise

affected by various nonregulatory factors. The

appropriations process determines the resources

available to an agency to carry out its regulatory

activities. Oversight by the Office of Management

and Budget may require an agency to restrict or

modify regulatory implementation. Abundant litigation challenging environmental laws and regulations

has created a large body of court decisions that

further interpret and clarify agencies’ regulatory

rights and responsibilities (see box 7-A); product

l~hers have clmsifi~ the regulatory response differently; one environmental law treatise, for example, suggests o~j’ two categofies+roduct

controls and pollution emission controls. The scheme proposed here is not definitive but is meant to emphasize how chemicals are singled out for attention

and review in the legislative and regulatory processes.

-159-
160 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table 7-l—Key Features of Federal Laws Regulating Toxic Substances

Regulatory authority Toxic substance or

Statute (regulatory agency)a

effect of concern Approach to risk

Part1-Licensing Laws

Federal Food, Drug, and Control levels of added subCosmetic Act stances (FDA)

Control levels of natural components of food (FDA)

Control levels of environmental

contaminants (FDA)

Set (EPA) and enforce (FDA,

USDA) tolerances on pesticide residues for food and

feed crops

Regulate introduction of new

drugs and biologics (FDA)

Report on adverse reactions to

drugs (FDA)

Label cosmetics (FDA)

Federal Insecticide, Fungicide, Register pesticides (EPA)

and Rodenticide Act

Toxic Substances Control Act Require testing of existing chemicals where data are inadequate to assess risk (sec.

4); prohibit introduction into

commerce of chemicals that

will present an unreasonable risk (sec. 5); restrict or

prevent production, use, or

disposal of existing chemicals that present unreasonable risk (sec. 6) (EPA)

Part II-Standard-Setting Laws

Clean Air Act

Federal Water Pollution

Control Act; Clean Water

Act

Safe Drinking Water Act

Consumer Product Safety Act

Federal Hazardous Substances

Act

Conduct research on air pollution (EPA)

Set air quality standards; regulate emissions of hazardous

air pollutants; set standards

for vehicle emissions, fuels,

and fuel additives (EPA)

Set effluent standards for water;

establish water quality criteria (EPA)

Set MCLs and MCLGs for public drinking water supplies

(EPA)

Promulgate consumer product

safety standards (CPSC)

Ban hazardous substances for

household use (CPSC)

“any poisonous or deleterious

substance which may render it injurious to health”

“poisonous or deleterious . . .

does not ordinarily render it

injurious to health”

“poisonous or deleterious . . .

does not ordinarily render it

injurious to health”

“poisonous or deleterious . . .

not generally recognized as

safe for use . . . to the

extent necessary to protect

the public health”

“substantial evidence that safe

and effective”; no “imminent hazard to public

health”

“any adverse experience ., .

includes any side effect, injury, toxicity, or sensitivity

reaction”

“poisonous or deleterious . . .

may render it injurious”

“will not generally cause any

unreasonable risk to man

or the environment”

“unreasonable risk of injury to

human health or the environment. . . including] carcinogenesis, mutagenesis, teratogenesis, behavioral disorders, cumulative or synergistic effects, and any other

effect. . .“

“adverse effects on health, including, but not limited to,

behavioral physiological, toxicological, and biochemical

effects”

“endanger public health”

“identifiable effects on health

and welfare”

“may have an adverse effect

on the health of persons”

“an unreasonable risk of injury”

“toxic. . . may cause substantial

personal injury or substantial illness”

No explicit consideration of benefits

Balance risk against need for

plentiful and affordable food

Balance risk against whether

required, unavoidable, or not

measurable

Ensure adequate, wholesome,

economical food supply; other

ways pesticide affects consumers; usefulness

Balance risks against efficacy

and need

Balance risks against drug benefits

No explicit consideration of benefits

Pesticide must not only be safe

under conditions of use, but

also effective

Risks posed by chemical must

be balanced against benefits it provides (i.e., risk must

be unreasonable)

NA

“Adequate margin of safety”

Water quality criteria do not

consider economic or technological feasibility

MCLGs do not consider feasibility, but MCLs do

Balance risks against product

utility, cost, and availability

“the public health and safety

can be adequately served”
Chapter 7—The Federal Regulatory Response ● 161

Table 7-l—Key Features of Federal Laws Regulating Toxic Substance-Continue d

Regulatory authority Toxic substance or

Statute (regulatory agency)a

effect of concern Approach to risk

Federal Mine Safety and Set standards for airborne conHealth Act taminants in mines (MSHA)

Occupational Safety and Set standards for airborne conHealth Act taminants in the workplace

(OSHA)

Part III-Control-Oriented Laws

Comprehensive Environmental Fund cleanup of hazardous waste

Response, Compensation, sites; designate reportable

and Liability Act; Superfund quantities for environmental

Amendments and Reauthor- release; report on community

ization Act preparedness and release;

prepare toxicity profiles on

contaminants (EPA)

Controlled Substances Act Control drugs that have potential fo rabuse (USDJ, FDA)

Lead-Based Paint Poisoning Determine, if possible, a safe

Prevention Act level of lead in paint (CPSC)

Marine Protection, Research, Regulate ocean dumping (EPA)

and Sanctuaries Act

Poison Prevention Promulgate standards for packPackaging Act aging substances that could

produce effects of concern

(CPSC)

Resource Conservation and Regulate the handling of hazRecovery Act ardous wastes; list hazardous wastes on basis of constituents (EPA)

“protection of Iife and prevention

of injuries. . . material impairment of health or functional

capacity”

“material impairment of health

or functional capacity”

“substantial danger to the public health or welfare”

“substantial and detrimental effect”

Poisoning of children by leadbased paint

“adversely affect human

health, welfare or amenities”

“serious personal injury or serious illness”

“protect human health . . . serious irreversible or incapacitating reversible illness

substantial present or

potential hazard”

Attain highest degree of health

and safety protection; latest

available scientific data; feasibility; and experience

gained with health and safety

laws

Attain highest degree of health

and safety protection; latest

available scientific data; feasibility; and experience

gained with health and safety

laws

Focus on highest-risk chemicals

Define list of substances to be

controlled

Determine whether any safe

level could be established

above 0.06°/0

Consider appropriate alternative

locations

Determine degree and nature

of hazard to children

Control handling to minimize

risks

aList of acronyms is given in app. F.

SOURCE: Office of Technology Assessment, 1990.

litigation may further modify the regulatory process.

Furthermore, regulations may incorporate direct or

indirect economic incentives in attempting to motivate industry to control pollutants (see ch. 9), adding

another dimension to regulatory implementation.

Clearly, the regulatory processes described herein

are not rigidly circumscribed but are part of a larger

regulatory dynamic (14).

LICENSING AND REGISTRATION

LEGISLATION AND

REGULATIONS

Three statutes govern most aspects of the licensing and registration of drugs, food additives, pesticides, and industrial chemicals: the Federal Food,

Drug, and Cosmetic Act; the Federal Insecticide,

Fungicide, and Rodenticide Act; and the Toxic

Substances Control Act. All of these statutes require

submission of applications for use of, or notification

of intent to use, new chemical substances; they also

authorize reviews of previously registered chemicals. The review processes followed under these acts

have

1.

2.

3.

4.

four basic steps:

manufacturer’s submission of data;

evaluation of data by the responsible regulatory agency;

requests for additional data (if necessary); and

agency determination (which may or may not

involve a formal rule-making procedure).

The extent to which neurotoxicity is addressed in the

process varies among and within statutes according
162 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 7-A—Toxic Substances Laws Go To Court: The Judicial Role in Interpreting Legislative

Language and Regulatory Implementation

The passage of a statute by Congress establishes overarching boundaries for regulatory implementation, but

translating Congress’ goals, as stated in the legislative language, into regulatory action is by no means a simple

process. Environmental laws abound with general phrases calling for protection of “public health and the

environment’ or for protection from ‘adverse effects’ some laws require that standards incorporate a‘ ‘margin

of safety. ” The definition of these phrases often depends on the ever-changing forefront of scientific research

into what levels of toxic substances may cause adverse effects—what, indeed, should be defined as an adverse

effect—and, based on the often uncertain conclusions of preliminary research, what constitutes a margin of

safety. Congress leaves the interpretation of its mandates to the discretion of the Federal regulatory agencies.

Thus, regulatory agencies get the first opportunity to interpret what Congress meant, but their responses are

modified by many factors: the appropriations process; oversight by the Office of Management and Budget;

requirements of the Administrative Procedures Act that the agency notify and obtain comments from the public

on any proposed regulations and that it respond to all significant comments; recommendations of scientific or

technical advisory panels; recognition that standards and regulations may have a profound effect on product

litigation; and other internal and external pressures and requirements. It typically takes from 2 to 8 years for an

agency to promulgate a rule, and the rule is then subject to further examination and interpretation through court

challenges and interpretive rulings.

Administrative and procedural complexities have made environmental statutes the most frequently litigated

of all fields of administrative law (Grad, 1985). During litigation, courts must evaluate agencies’ interpretations

of congressional intent, and they must often evaluate the complex underlying technical issues as well—including

the definitions of adverse effects or margins of safety. The judicial interpretation may have a considerable impact

on how the legislative language can be interpreted and how the regulations can be implemented.

In at least one case, the Federal district courts have upheld the use of neurotoxic effects in the setting of

standards. In 1980, the Lead Industries Association, Inc., brought suit against the Environmental Protection

Agency (EPA), charging that the Administrator went beyond the scope of his authority in setting standards for

lead under the Clean Air Act. EPA had issued a rule setting the primary national ambient air quality standard

for lead on the basis of its effects on the blood and on the nervous system (43 FR 46254). After considerable

study, EPA had determined that lead’s effects on the nervous system begin to appear at the level of 50 micrograms

of lead per deciliter of blood (ug/dl), that anemia and other effects appear at 40 ug/dl, and that identifiable changes

in the blood (though not easily diagnosed through clinical examination) begin at 30 ug/dl. To provide an adequate

margin of safety, EPA set a target for the population of 15 ug/dl.

Among other arguments, the Lead Industries Association contended that the EPA’s rule was not adequately

supported by the finding that neurotoxic effects begin to appear at 50 ug/dl and that basing the standard on

subclinical effects at 30 ug/dl went beyond the Agency’s statutory authority. The courts upheld EPA’s finding

on neurotoxicity, stating that the record revealed ample support for the Administrator’s determination of when

central nervous system effects begin to occur. The decision noted that it was not the function of the court ‘‘to

resolve disagreement among the experts or to judge the merits of competing expert views. ’ (“ [C]hoice among

scientific test data is precisely the type of judgment that must be made by EPA, not this court. That evidence in

the record may also support other conclusions, even those that are inconsistent with the Administrator’s, does

not prevent us from concluding that his decisions were rational and supported by the record. ’ The court further

upheld EPA’s justification for the margin of safety, noting that the legislative history of the Clean Air Act shows

that margins of safety were considered essential for protecting against hazards that had not yet been identified.

Judicial interpretation is one of many factors influencing the implementation of regulations; as this case

shows, it may strengthen an agency’s regulatory decisions. As for neurotoxic effects, which have rarely been

explicitly mentioned in statutes, the courts may play an important role in ensuring that they are considered in

the process of protecting public health and the environment.

SOURCES: F.P. Grad, “A Brief Account of the Beginnings of Modern Environmental Law,” Treatise on Environmental Law, sec. 1.01 (St.

Paul, MN: Matthew Bender, 1985); “kid Industries Association, Inc. v, U.S. Environmental Protection Agency, ” Federal

Reporter (2d series) 647:1130-1189, 1980.
Chapter 7—The Federal Regulatory Response ● 163

, @‘L-/

Illustrated by: Ray Driver

to the type of substance being reviewed and whether

it is a new or existing substance.2

Federal Food, Drug, and Cosmetic Act

The earliest Federal statute governing food safety

was the Food and Drugs Act of 1906 (19), which

prohibited the marketing or transport of “adulterated food,” that is, any food that contained “any

added poison or other added deleterious ingredient

which may render such article injurious to health. ”

The Federal Food, Drug, and Cosmetic Act (FFDCA)

(21 U.S.C. 301-392),3 which replaced the original

Act in 1938, expanded controls to include naturally

occurring as well as added toxic substances. However, it did not delineate specific toxic effects. The

Act is based on a broad concept of safety as absence

of injury:

A food shall be deemed to be adulterated-if it

bears or contains any poisons or deleterious substances which may render it injurious to health; but

in case the substance is not an added substance, such

food shall not be considered adulterated under this

clause if the quantity of such substance in such food

does not ordinarily render it injurious to health . . .

[sec. 402(a)(l)] [emphasis added].

Thus, added substances are governed by a stricter

standard than naturally occurring substances. Since

its passage, FFDCA has been clarified and expanded

by various amendments, but the language referring

to toxic effects remains the same.

The Act grants the Food and Drug Administration

(FDA) authority to regulate foods, drugs, and

cosmetics in the following categories:

. food and general safety (sec. 402),

. environmental contaminants (sec. 406),

. pesticide residues (sec. 408),

. food additives (sec. 409),

. drugs and biologics (sec. 505),

● cosmetics (sec. 601), and

. color additives (sec. 706).

FDA can use this authority to require premarket

submission of specific toxicity test data. It could

incorporate neurotoxicity tests in the guidelines for

recommended testing or require neurotoxicity testing during the application process if there is

evidence of potential neurotoxic effects.

Environmental Contaminants of Food

FDA is authorized to regulate unavoidable contaminants of raw agricultural commodities under”

either the general food safety provisions (sec. 402)

or the specific provisions of section 406, which calls

for FDA to:

2~e information in t~s section is draW pnm~]y from person~ comm~ica~ion wi~ offlci~s al the respective agenCieS.

3A11 Unitd States Code (U. S. C.) citations refer to the 1982 edition, unless otherwise noted.
164 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

. . . promulgate regulations limiting the quantity

therein or thereon to such extent as. . . [is] necessary

for the protection of public health, and any quantity

exceeding the limits so fixed shall also be deemed

unsafe . . . (21 U.S.C. 346).

In setting the limits, FDA must consider whether the

substance is required or unavoidable in the production or processing of the food item and the potential

effects of the substance on health. Though not

included in the statute, the extent to which the

substance can be detected in foods is also considered, since it would be impossible to enforce limits

that could not be detected (19).

FDA asserts that it is not always appropriate to set

formal tolerance levels for contaminants-e.g., when

new toxicity data are being developed for a substance that previously had little or none (39 FR

42745). In addition, the formal rule-making procedure demanded for setting tolerances is elaborate

and time-consuming. Given these circumstances,

FDA has chosen to rely primarily on a regulatory

option not explicitly established by statute—that of

setting informal tolerances, called action levels. An

“action level is based on the same criteria as a

tolerance, except that an action level is temporary

until the appearance of more stable circumstances

makes a formal tolerance appropriate” (39 FR

42745 ).4 Action levels are not binding, nor do they

have the legal force of tolerance levels, but they can

be used to “prohibit any detectable amount of the

substance in food” (21 CFR part 109.4). Any food

that contains more than the action level dictates may

be declared adulterated and be subject to further

regulatory action.

In establishing either an action level or a tolerance, FDA uses available information on health

effects to determine a dosage at which risk of

exposure to a contaminant is acceptable. Once the

action level or tolerance is established, FDA may

take appropriate action to restrict food that does not

meet these standards.

Pesticide Residues

The 1954 amendments to FFDCA empowered

FDA to set and enforce standards for pesticide

residues on raw, unprocessed agricultural commodities. More recent amendments bestowed the standardsetting responsibility on the Administrator of the

Environmental Protection Agency (EPA):

The Administrator [of EPA] shall promulgate

regulations establishing tolerances with respect to

the use in or on raw agricultural commodities of

poisonous or deleterious pesticide chemicals and of

pesticide chemicals which are not generally recognized . . . as safe for use, to the extent necessary to

protect the public health [sec. 408(b), 21 U.S.C.

346a, 1976)].

Pesticides that are expected to become more

concentrated during processing require separate

tolerances. EPA may revoke or change tolerances if

new evidence or further review indicates that a

change is necessary (29).

The establishment of tolerances takes place concurrently with pesticide registration under the Federal Insecticide, Fungicide, and Rodenticide Act,

described below. The manufacturer petitions EPA to

set a tolerance for the pesticide residue; the pesticide

cannot be registered for use on a food or feed crop

until a tolerance has been set or an exemption

granted (48). The FFDCA specifies that a pesticide

tolerance petition include “full reports of investigations made with respect to the safety of the pesticide

chemical” [sec. 408(d)(l)(C)], thus placing the

burden of proof of the safety of a pesticide on the

manufacturer.

Food and Color Additives

The Food Additives Amendment of 1954 (Public

Law 85-929) sought to “prohibit the use in food of

additives which have not been adequately tested to

establish their safety. ” The amendment initiated an

application process for the approval of food additives that, like the pesticide tolerance provisions,

shifted the burden of proof from the FDA to the

producer.

Manufacturers must file a written petition before

a potential food additive can be approved for use.

The petition must contain “scientific data adequate

to support safety” (15) and “. . . full reports of

investigations made with respect to the safety for use

of such additive, including full information as to the

methods and controls used in conducting such

investigations’ [sec. 409(b)(2)(E)].

4RWent ~o~ ~h~lenge~, however, have ~e+u]t~ in ~ dwision rquifig ~A to subj~t propos~ action ]evels to public notification ad COIIIIWXlt;

FDA incorporated the decision in a proposed rule in April 1989 (54 FR 16128-30). It remains to be seen whether action levels will continue to offer a

streamlined alternative to the setting of tolerances.
Chapter 7—The Federal Regulatory Response ● 165

w

FDA decides whether, and in what amounts, a

food additive may be used on the basis of the data

submitted with the application. It has drawn its

interpretation of safety from the legislative history

of the Act, which used the phrase “reasonable

certainty of no harm,” and has incorporated that

standard into its regulations regarding toxicity

testing (15).

Color additives to food are regulated under the

Color Additive Amendments of 1960. These regulations are essentially the same as those for food

additives, including a process of premarketing

approval. In addition, color additives to drugs and

cosmetics are regulated. A color additive may be

approved for general or restricted use if it is found

that “it is suitable and may be safely employed”

[sec. 706(b)(2)].

Petitions for approval of food and color additives

are handled by FDA’s Center for Food Safety and

Photo credit: U.S. Environmental Protection Agency

Applied Nutrition (CFSAN). These include direct

food additives (e.g., preservatives) and color additives, as well as indirect additives, such as constituents of packaging materials that might migrate into

food. Although the application process officially

begins with submission of the petition and supporting data, CFSAN may, and frequently does, hold

informal preapplication meetings with petitioners to

clarify data needs.

Each application must contain all data relevant to

assessing safety. The tests required are determined

on the basis of predicted exposure. For direct food

additives, CFSAN test guidelines, known as the Red

Book, list particular exposure levels and characteristics of chemical structure that require certain types

of tests (30). Most substances must be subjected to

subchronic studies in mammals as well as reproductive tests. No specific neurotoxicity tests are required, but the protocols do call for observation of
166 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

effects on animal behavior, so some prediction of

adult or developmental neurotoxicity, or both, may

be provided. The test requirements are negotiable,

but the petitioner must present sufficient data to

ensure a reasonable certainty that no harm will result

from the use of the additive.

The Red Book is currently being revised, and the

new version may contain specific tests for neurotoxicity. The precise nature of these tests is still under

review. In order for FDA to impose any additional

testing requirements, it must show that further tests

are necessary.

Petitions must be reviewed within 90 days of

submission, although FFDCA permits extensions to

180 days. Each petition is evaluated by senior

scientists from CFSAN’s Division of Toxicological

Review and Evaluation. Most reviewers are general

toxicologists; the division has had neurotoxicologists directly involved in reviewing petitions in the

past, but few in 1988 or 1989. If the data indicate

neurotoxic effects, the division may call on the

Neurobehavioral Toxicology Team-neurotoxicologists who are not generally members of the review

team-for further research. This team has been

asked to review three chemicals in the last 5 years;

the total number of chemicals reviewed by CFSAN

during that period is uncertain, but the center

annually reviews approximately 60 indirect food

additives, 10 direct food additives, and 10 color

additives.

If the toxicological data submitted with a petition

are insufficient for reaching a conclusion on whether

a substance poses unreasonable risks, CFSAN negotiates with the petitioner to conduct additional tests.

New data must be submitted within 180 days,

although extensions may be given for reasonable

cause. (Time spent on developing new data is not

counted in the time limit by which FDA must act on

the application, and if the necessity for new information is a result of the petitioner’s failure to submit all

data that were clearly required, the FDA may reset

the clock to day 1 when the additional data are

submitted.)

If CFSAN determines, on the basis of toxicological data and potential exposure patterns, that a

substance may be harmful, the food or color additive

petition may be denied. Alternatively, FDA may

impose limits on the amount of additives that will be

allowed in foods. If the petition does not contain

enough evidence for CFSAN to make a determia

nation on the safety of a substance, and if the

petitioner is unable or unwilling to develop the

necessary data, CFSAN requests that the petition be

withdrawn or the petition is denied approval.

To date, CFSAN has reviewed the neurotoxic

potential of a variety of direct food additives,

indirect food additives, and color additives, including:

●

●

●

●

●

●

●

●

●

acrylamide (as a contaminant of polymer food

contact surfaces),

acrylonitrile (as a contaminant of polymer food

contact surfaces),

aspartame (artificial sweetener),

chlorofluorocarbons (Freon 12),

cyclamates (artificial sweeteners),

erythrosin (FD&C Red No. 3),

methyl chloride (as solvent for hop extract),

methyl tin compounds (as stabilizers for plastics),

organophosphites (antioxidants in food packaging):

-di-tert-butylphenyl phosphite,

--octadecyl phosphite, and

—Tris phosphite.

As noted above, the Neurobehavioral Toxicology

Team does not regularly participate in such reviews.

Drugs and Biologics

Drugs are regulated under various categories,

including new drugs (for humans), biologics (biological products such as vaccines), and animal

drugs. The statute requires submission of a new drug

application (NDA) before a drug can be approved for

market. The NDA must contain “substantial evidence” that the drug is both safe and effective:

. . . evidence consisting of adequate and wellcontrolled investigations, including clinical investigations, by experts qualified by scientific training

and experience to evaluate the effectiveness of the

drug involved, on the basis of which it could fairly

and responsibly be concluded by such experts that

the drug will have the effect it purports or is

represented to have under the conditions of use

prescribed . . . [sec. 505(d)(7)].

This is generally considered to be the highest

standard for drug approval in the world.

The statute also provides that FDA shall not

approve a drug if it finds deficiencies in the safety

tests conducted or if the test data indicate a lack of
Chapter 7—The Federal Regulatory Response ● 167

safety. If clinical investigations “do not include

adequate tests by all methods reasonably applicable

to show whether or not such drug is safe for use

under the conditions prescribed, recommended, or

suggested in the proposed labeling thereof or if

“the results of such tests show that such drug is

unsafe for use under such conditions or do not show

that such drug is safe for use under such conditions,’

FDA is directed to refuse the application [sec. 505

(d)(1) and (2)].

FDA may deny approval of a new drug on the

finding of “an imminent hazard to the public

health” [sec. 505(e)]. If the application is approved,

FDA specifies how the drug is to be packaged,

labeled, and so on. New drugs that are identical to

previously approved drugs are subject to an abbreviated application process.

Biologics, including “any virus, therapeutic serum,

toxin, antitoxin, vaccine, blood, blood component,

allergenic product, or analogous product” (42 U.S.C.

262), are under the purview of a complex regulatory

mechanism combining provisions of both FFDCA

and the Public Health Service Act. Because they are

also defined as drugs, most biologics must be tested

and approved by the same process FDA uses for new

drugs (29).

Animal drugs are approved under essentially the

same process as human drugs, with the additional

provisos that FDA must consider “the probable

consumption of such drug and of any substance

formed in or on food because of the use of such

drug’ and the ‘cumulative effect on manor animal

of such drug” [WC. 512(d)(2)(A)].

FFDCA also requires reporting of adverse drug

reactions, both during the application process [sec.

505(i)] and after a drug has been approved [sec.

505@]. “Adverse reactions” are defined by FDA as

"

. . . any adverse experience associated with the use

of a drug, whether or not considered drug-related,

and includes any side-effect, injury, toxicity, or

sensitivity reaction, or significant failure of expected

pharmacological action” (21 CFR 310.301). This

requirement for reporting adverse reactions could be

used to gauge the effectiveness of the drug approval

process.

Applications for approval of new or investigational prescription drugs are handled by FDA’s

Center for Drug Evaluation and Research; biological

products are handled by the Center for Biologics

Evaluation and Research. The approval process for

a new drug generally takes about 3 years, but it can

take up to 7 years. (The shortest approval time to

date, for azidothymidine (AZT), used to treat AIDS,

was 7 months.)

An NDA must contain data from all prior preclinical (animal) and clinical (human) studies. Clinical

studies are conducted in three phases. Phase 1

consists of short-term tests designed to elucidate

how the drug is metabolized in humans, to obtain

basic pharmacological and toxicological data in

humans, and, if possible, to find evidence that the

drug is effective in humans. Phase 2 tests are the

initial controlled clinical trials and studies of shortterm side-effects. Phase 3 generally consists of

controlled and uncontrolled clinical trials in a larger

group of subjects. These trials are intended to

provide the additional information on safety and

effectiveness needed to determine the risk-benefit

ratio of the drug and to draft appropriate labeling.

All drugs that have not been previously tested in

humans, or for which additional clinical data are

required before NDA submission, must submit an

investigational new drug (IND) application before

the sponsor can initiate clinical trials. New drugs

that have previously undergone clinical trials, such

as drugs that have been approved in other countries,

may skip the IND application (if they have already

been subjected to adequate, well-controlled clinical

trials).

FDA has developed guidelines for the types of

nonclinical studies that are needed to support

approval of different types of clinical trials. The

guidelines do not, for the most part, call for specific

tests for toxic effects (the prevailing view at the

Center for Drug Evaluation and Research is that

rigid test guidelines rapidly become obsolete and

may lead to false assurance of the safety of a drug).

Instead, the guidelines allow for considerable latitude in the selection of test protocol. The final

selection of test protocols requires that the petitioner

convince FDA that the data are adequate and that

FDA convince the petitioner that its requirements

are not unreasonable.

An IND is reviewed by a general toxicologist.

Drugs that are not designed to cause neuropharmacological effects are not necessarily reviewed separately for neurotoxicity, although behavioral effects

are evaluated in animal reproduction studies and

neuropathology is conducted as part of the sub-
168 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

chronic studies required for the IND. A specific

review for neurotoxicity is initiated only if there is

cause for suspicion. Outside experts may be called

in for such reviews through mechanisms such as

standing committees and special review committees.

Drugs that are designed to act on the nervous

system—i.e., neuroeffective substances—are reviewed separately by neurotoxicology specialists

from the Division of Neuropharmacological Drug

Products of the Center for Drug Evaluation and

Research’s Office of Drug Evaluation I.

After the phase I tests have been concluded, the

applicant must conduct appropriate additional nonclinical toxicity tests. The data required hinge on the

particular clinical trial under consideration. A l-year

animal study incorporating ophthalmological examinations and behavioral observations is required for

all drugs. (For a drug to be prescribed to women of

childbearing age, reproductive toxicity studies are

routinely conducted; the reproductive studies may

provide some evidence regarding the potential

teratological effects of the drug.)

Positive evidence of toxic effects can lead to

termination or modification of the clinical trials,

depending on the nature of the evidence, the seventy

of the effects, and the disease that the drug is

intended to treat. If the animal data included in either

the IND application or NDA are inadequate, FDA

will issue a “clinical hold” order to delay further

clinical testing until the appropriate preclinical data

are developed.

Postmarked monitoring of drugs occurs through

FDA’s spontaneous adverse report monitoring system. Any person observing an adverse reaction

associated with the use of a drug may submit a Drug

Experience Report (form FDA-1639) directly to

FDA or to the drug’s manufacturer, who, in turn, is

required to report the information to FDA (21 CFR

1989 ed. 314.80). About 90 percent of the adverse

reports FDA now receives are obtained through

manufacturers and 10 percent through direct reports.

Analysis of these reports constitutes FDA’s device

for monitoring the adverse effects of prescription

drugs, including effects not noted during premarket

tests or clinical trials. However, as described in box

7-B, the system is limited in many respects.

No specific neurotoxicity tests are required for

drugs that are not expected to be neuroeffective.

Some FDA scientists believe that it is more appropriate to conduct general preclinical toxicological

tests than to focus on specific tests. FDA scientists

do not appear to have reached a consensus

regarding the validity of preclinical neurotoxicity

tests as predictors of clinical effects. They argue

that it is difficult to design clinical trials that test

specifically for neurotoxic effects.

Cosmetics

Substances used in cosmetics are subject only to

the “may render it injurious” clause (sec. 601 of

FFDCA). FDA cannot require any toxicity testing. It

can, however, require that any cosmetic product that

has not been adequately tested be packaged with a

warning label stating that ‘the safety of this product

has not been determined” (21 CFR ed. 740.10).

FDA has restricted or prohibited the use of fewer

than 20 ingredients on the finding that they were

“poisonous or deleterious” (21 CFR ed. 700.11,21

CFR ed. 250.220) (29).

Proposed Amendments

Among the proposed amendments to the FFDCA

that have been introduced during the 10lst Congress, the Food Safety Amendments of 1989 (identical versions were introduced in the House and

Senate as H.R. 1725 and S. 722, respectively) are

potentially relevant to toxic substances regulation. A

key provision of these bills is an attempt to define a

standard of “negligible risk” that would apply to

pesticide residues on food without regard to balancing costs and benefits. This definition would replace

the current approach, under which pesticide tolerances for both raw commodities and processed foods

are set at a level to protect the public’s health unless

the pesticide is a carcinogen, in which case no

detectable amount is allowed in processed foods.

Hearings have been held on the bills, but neither has

been voted on by the full assembly.5 If passed, the

negligible risk provisions—and the absence of

authority for cost-benefit analyses-could have

far-reaching consequences in the regulation of

pesticide residues.

Federal Insecticide, Fungicide, and

Rodenticide Act

FIFRA was enacted in 1947 to replace the 1910

Federal Insecticide Act. FIFRA expanded the con5AS of February 1990.
Chapter 7—The Federal Regulatory Response ● 169

Box 7-B—Limitations of FDA’s Postmarked Monitoring System for Adverse Drug Reactions:

Halcion, A Case Study

Halcion, the most widely prescribed sleeping medication in the United States, was first approved for use in late

1982 with a recommended usual adult dose of 0.25 to 0.50 mg. Its package insert included mentions of amnesia,

confusion, agitation, and hallucinations as possible side-effects. Over the next few years, FDA’s adverse reaction

monitoring system recorded an excess of adverse reports for Halcion in comparison to other benzodiazepine

hypnotics-even after correcting for market share of the drug. In 1987, as a result of the reports and the apparent

dose-relatedness of some adverse effects, several labeling and marketing changes were made. The usual adult dose

was changed to 0.25 mg, two paragraphs mentioning the apparent dose-relatedness of some side-effects were added

to the package insert and a “Dear Doctor” letter was issued detailing the labeling changes. In early 1988, Upjohn,

the manufacturer, discontinued the 0.50 mg tablet.

Following these changes, public concern about possible problems associated with Halcion use increased,

largely because of a September 1988 article in California Magazine and a story on the ABC television program

20/20 in February 1989. The number of adverse reports received, which was expected to decline as a result of the

labeling changes and Halcion’s status as an “older” drug (the number of adverse reports associated with a drug

normally decreases over time), rose. In September 1989, FDA convened an expert panel to review the reporting data

on Halcion and to discuss whether further changes should be made in the labeling or marketing of the drug.

Discussion at that meeting illustrates the difficulties of drawing conclusions from the spontaneous adverse

reporting process. In a comparison of adverse reports for Halcion (45 million prescriptions written since 1982) with

adverse reports for Restoril (35 million prescriptions written since 1980), a drug prescribed to patients with similar

sleeping problems, the following data were presented:

Total number of reports received by FDA

Adverse event Halcion Restoril

Amnestic events 267 4

Hallucinations, paranoid behavior 241 12

Confusion and delirium 304 17

Hostility and intentional injury 48 2

Overall, an average of 38 adverse reports per million prescriptions was received for Halcion, while 7.5 adverse

reports per million prescriptions were received for Restoril.

These seemingly dramatic results, however, were tempered by myriad complicating variables, The influence

of publicity, differences in reporting rates by manufacturers, lack of dosage information in about one-half of the

adverse reports for Halcion, and “new drug” v. ‘‘older drug’ effects all obscured the significance of differences

between the sets of data, The 4-week period following the 20/20 episode, for example, produced twice as many

adverse reports for Halcion as the 4-week period preceding the show. The FDA panel finally concurred that the data

were too unreliable to warrant action, except possibly in the case of amnesia.

The unreliable data generated by the postmarketing monitoring system now in place effectively limit FDA

review to premarket trials. Unexpected interactions with other medications or long-term side-effects may easily be

missed. This is particularly disturbing from the standpoint of neurotoxicity, since drugs not expected to have

neuropharmacological effects are not necessarily subjected to specific neurotoxicity testing. Changes which could

improve the present system might include a requirement that all adverse report forms be sent directly to FDA as

well as a requirement that physicians submit reports for all ‘‘serious” adverse reactions observed.

Because of the inherent limitations in FDA’s drug approval and adverse reaction monitoring systems, it is

important that physicians and patients be aware of the possible adverse effects of the medications they prescribe

and consume. Drugs are approved for use under certain conditions and at certain doses, and complicating factors

such as age, other medications, or illness may significantly alter the effects of these drugs. In most cases, the decision

to take any medication is a personal choice for the patient; an individual cannot make an informed decision without

access to information about potential adverse effects.

SOURCES: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Psychopharmacological

Drugs Advisory Committee, Transcript of Proceedings, Thirty-First Meeting (Rockville, MD: September 1989); “When Sleep

Becomes a Nightmare,” 20/20, ABC, Feb. 17, 1989; Pharmaceutical Data Services, ‘‘Top 200 Drugs of 1989,’ American Druggist,

in press.
170 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

sumer protection aspects of the earlier statute by

instituting a premarket registration procedure for all

pesticides in interstate commerce. The 1972 amendments—the Federal Environmental Pesticide Control Act (Public Law 92-516)—shifted the emphasis

from consumer protection to the protection of public

health and the environment (47). Amendments in

1975 (Public Law 94-140), 1978 (Public Law

95-396), 1980, and 1988 refined the regulatory

procedures embodied in the legislation but maintained the focus, namely, to govern pesticide use to

prevent “unreasonable adverse effects. ” FIFRA

uses a broad standard for adverse effects:

. . . any unreasonable risk to man or the environment, taking into account the economic, social, and

environmental costs and benefits of the use of any

pesticide [sec. 2(bb)] [emphasis added].

The statute prohibits the sale or distribution of any

pesticide in the United States unless it is registered

or exempt from registration under FIFRA. It gives

EPA considerable authority to require submission of

data, including neurotoxicity tests, as part of the

registration process for new and existing chemicals.

The statute places the burden of proof of safety on

the manufacturer, although in the case of existing

pesticides, EPA may have to go to considerable

lengths to prove the inadequacy of data before it can

call for further data or regulatory action.

New Pesticide Registrations

FIFRA calls for premarket review and registration

of both new pesticides and pesticides with new

active ingredients.6 A pesticide may be registered if

EPA determines that, when considered with any

restrictions on use:

●

●

●

●

its composition is such as to warrant the

proposed claim for it;

its labeling and other material required to be

submitted comply with the requirements of the

Act;

it will perform its intended function without

unreasonable adverse effects on the environment; and

when used in accordance with widespread and

commonly recognized practice, it will not

generally cause unreasonable adverse effects

IthB

Photo credit: National Archives

on the environment [sec. 3(c)(5)] [emphasis

added].

The 1972 amendments enabled EPA to require

that manufacturers submit whatever data EPA specifies for approval or continuation of the registration:

The Administrator shall publish guidelines specifying the kinds of information which will be required

to support the registration of a pesticide . . . [sec.

3(c)(2)(A)].

Applications for pesticide registration are submitted to EPA’s Office of Pesticide Programs (OPP).

The applicant must demonstrate that anew pesticide

will be both safe and effective under the proposed

conditions of use. In order to demonstrate efficacy,

applicants must obtain an Experimental Use Permit

(EUP) to conduct field studies. (An EUP application

bIne~ ~~~ents+me parts of tie ~sticide formulation not claimed to have any pesticidal activity-have not traditionally kn included in tie

registration process. EPA has recently begun to review and evatuate them, however. Although EPA believes that FIFRA provides the authority to require

testing of inert ingredients of known toxicity, it is not clear how inert ingredients of unknown toxicity should be handled (l).
Chapter 7—The Federal Regulatory Response ● 171

requires less extensive toxicity data than the registration application, but the applicant must provide

enough information to establish that the field test

itself is safe.) EUPs are also obtained for new uses

of a pesticide, such as application on a new crop. If

the pesticide is intended to be used on food or feed

crops, the applicant submits a petition for the setting

of tolerances, which is done in tandem with the

registration process.

The toxicity data in each application are reviewed

initially by a toxicologist from OPP’s Hazard

Evaluation Division. The division has a neurotoxicologist on its staff who may be consulted if

necessary, but the neurotoxicologist does not automatically participate in application reviews. Under

division procedures, a single toxicologist is responsible for reviewing each application. The review is

conducted in accordance with procedures codified in

OPP’s Standard Evaluation Procedures or Risk

Assessment Guidelines, or both. Limited neurotoxicity testing is required only for organophosphorous

pesticides, but subchronic tests include a limited

evaluation of behavioral and pathological effects on

the nervous system.

If data provided with an application are determined by EPA to be inadequate for a reasonable

evaluation of potential hazards, the Agency will

require additional toxicity testing. EPA may require

tests in addition to those specified in the test

guidelines, if necessary, to clarify issues raised by

the data presented.

If OPP finds that a new pesticide presents an

unreasonable risk of adverse effects, EPA may deny

the registration altogether, restrict use of the pesticide to certain crops or to certain geographical areas,

or require that it be applied under the supervision of

certified applicators or that protective equipment be

worn during application. In addition, EPA may

impose specific labeling requirements (see box 7-C).

The FIFRA test guidelines (40 CFR ed. 158)

contain very limited recommendations for neurotoxicity testing. At the present time, only organophosphates must be tested for neurotoxic effects, and

they are subject to just a single type of test—a hen

test for delayed neuropathy (see ch. 5 for more

information on test procedures). Current guidelines

require limited neuropathological examinations and

observations for behavioral effects as part of acute

and subchronic toxicity studies. However, the test

guidelines are now under revision, and new neurotoxicity test requirements are likely to be added (the

development of new guidelines is described below

in the section on “new initiatives”). A review of

new active ingredients registered in the past 5 fiscal

years revealed that out of 54 pesticides, including 20

insecticides, only 3 were organophosphates.

Reregistration of Existing Pesticides

Because many pesticides were registered on the

basis of toxicity data that might now be considered

inadequate, EPA is reexamining the safety of

registered pesticides. EPA may call for the registrant

to develop new data for evaluating toxic effects of

the pesticide. Section 3(c)(2)(B) of FIFRA states:

. . . If the Administrator determines that additional

data are required to maintain in effect an existing

registration of a pesticide, the Administrator shall

notify all existing registrants.

In conjunction with the FIFRA reregistration

process, EPA is also mandated by FFDCA to set

tolerances for the maximum pesticide residues

allowed in or on various food and animal feed crops.

EPA may periodically review previously set tolerances, which are enforced by FDA and the U.S.

Department of Agriculture (USDA) (48 FR 39499).

As pesticides go through the reregistration process,

EPA may decide that the tolerance levels need to be

reassessed.

Reregistration of existing pesticides does not

require the submission of applications or data.

Rather, OPP initiates the process by reviewing

available data from its internal files and, on rare

occasions, from the published literature. In the past,

EPA has selected and scheduled reviews of chemicals with few restrictions, producing approximately

25 registration standards (the document which

specifies the conditions that a registrant must meet

to maintain the registration of a pesticide) per year.

The 1988 amendments to FIFRA mandated that

EPA review 600 active ingredients of existing

pesticides by 1997 (i.e., more than 60 registration

standards per year-a considerably faster rate than

current operating procedures have fostered). EPA,

therefore, is developing procedures for conducting

reregistration reviews more quickly and is determining whether additional personnel will be required.

The evaluation process is similar to that for new

chemicals and the test guidelines for re-registration

are the same as those for registration. OPP may

consult with outside experts about what kinds of
172 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 7-C—Regulatory Requirements for Labeling: How Effective Are They?

Labeling requirements are a common regulatory tool for dealing with toxic but useful substances. Pesticides,

prescription and over-the-counter drugs, household substances, and all commercial poisons are subject to labeling

provisions incorporated in statutes such as the Federal Insecticide, Fungicide, and Rodenticide Act; the Federal

Food, Drug, and Cosmetic Act; the Federal Hazardous Substances Act and the Consumer Product Safety Act.

Labels are intended to reduce the risks of exposure to, or harm from, toxic substances by alerting consumers

to the dangers of a substance and providing instructions for its safe and proper use. When regulators make decisions

contingent on specific labeling requirements, they rely on at least three tacit assumptions: 1) that consumers will

read the label; 2) that they will understand and believe it; and 3) that they will obey its instructions. Clearly, all three

must happen in order for labels to be effective in preventing dangerous exposures. But is it realistic to rely on labels?

Increasing evidence suggests that it is not. An Environmental Protection Agency (EPA) draft report on the

effectiveness of pesticide labeling finds several weaknesses in current schemes. The report which includes a survey

of representatives from the pesticide industry, State regulatory agencies, environmental organizations, and

household users, found that few people read an entire label and that many people may not even read the parts of

the label that relate specifically to their intended use of the chemical. Labels maybe redundant and too technical;

the information is often crowded and difficult to read; and the instructions may be vague or contradictory. (For

example, the label on one rat poison instructed users to keep the poison away from wildlife.) Furthermore, there

are few guidelines on how to label for specific toxic effects, such as neurotoxicity, EPA concluded that many labels

are not well designed for their audiences and must be improved if they are to have any real effect.

What is the solution? EPA suggests measures such as greater use of hazard symbols, more readable and perhaps

standardized formats, and a uniform system of designating hazards so that consumers can recognize them more

easily. EPA is developing criteria for the labeling of specific categories of toxic effects, including neurotoxicity;

guidelines may be issued by early 1990.

Labeling requirements have often been central in product litigation cases. Court decisions have stressed the

need for labeling to protect humans from injury, and one State court ruled that even ‘‘compliance with Federal

labeling requirements will not prevent the finding that the manufacturer had not fully disclosed the risks of a

product” (Grad, 1985), It appears, then, that industry also stands to benefit by working with regulators to develop

adequate and effective labels.

SOURCES: U.S. Environmental Protection Agency, “Pesticide Label Utility Project Report, ” unpublished draft, April 1986; F.P. Grad,

‘‘Pesticide Pollution-Labeling and Misbranding,’ Treatise on Environmental Law, sec. 8.03.4 (St. Paul, MN: Matthew Bender,

1985).

additional data should be developed. If additional EPA has requested specific neurotoxicity test data

data are needed, EPA issues a data call-in, either

through publication in the Federal Register or by

sending letters to affected registrants. FIFRA grants

EPA the authority to request any additional data that

are determined to be necessary.

If EPA determines during the reregistration process that an existing pesticide ingredient may pose an

unreasonable risk, the chemical may undergo a

special review as described below. If registrants do

not respond to the data call-in (as is generally the

case for pesticides that are no longer being manufactured), the registration is canceled. If, in the course

of reregistering a pesticide, EPA finds that it poses

an unreasonable risk, the Agency may cancel or

suspend the chemical without initiating a special

review.

in a number of cases. While the Agency’s database

on registration standards does not enable investigators to determine all chemicals for which neurotoxicity data call-ins have been issued, it does include a

data call-in (under consideration) to evaluate nervous system lesions that may be induced by thiocarbamates and a developmental neurotoxicity study

protocol on N, N-diethyl-m-toluamide (Deet), the

active ingredient in many mosquito repellents.

Active ingredients of existing pesticides undergo

special review if EPA finds that they may pose an

unreasonable risk of adverse effects. The special

review is a formal procedure; accordingly, a notice

of the initiation of the review and of each subsequent

step in the process must be published in the Federal

Register.
Chapter 7—The Federal Regulatory Response ● 173

The review begins with an evaluation by EPA

staff similar to that conducted for the registration of

a new pesticide. In addition, EPA’s independent

Science Advisory Panel examines each case, and the

Agency seeks public comment as part of the

rule-making process. If a data call-in has not already

been issued, EPA may issue one at this time. EPA

can request all data relevant to the question of

whether a chemical poses unreasonable risks of

adverse effects.

If EPA determines that the risks of a pesticide

outweigh the benefits of its continued use, it may

cancel or suspend registration of the pesticide or

impose restrictions on its registration. Registration

may be suspended during the time it takes to

complete the cancellation proceedings if EPA determines that the risks of use during that time outweigh

the benefits. A suspension may be appealed and

public hearings requested. EPA may also issue an

emergency suspension, which is immediate and

Photo credit: U.S. Environmental Protection Agency

absolute and cannot be appealed. Other potential

restrictions are the same as listed above for new

pesticide registrations. Until 1988, EPA was required to indemnify all manufacturers and consumers for any amounts of the pesticide they possessed,

which made cancellation proceedings extremely

costly for pesticides that were being marketed in

significant quantities. Now, however, EPA must

reimburse only endusers (usually farmers).

About 14 special review decisions are made each

year, one-third of which are final decisions to initiate

special review. Five active ingredients are known to

have been reviewed for neurotoxicity. On further

review, three of these, dichlorvos, tributyl phosphorotrithioate, and S, S, S-tributyl phosphorotrithioate,

were returned to the registration process and two,

acrylonitrile and EPN (phenylphosphonothioic acid,

o-ethyl, o-p-nitrophenyl ester), were not (9). Registration of acrylonitrile was voluntarily canceled;

EPA imposed restrictions (protective clothing and

new labeling requirements) on the use of EPN

(phenylphosphonothioic acid, o-ethyl, o-p-nitrophenyl

ester), and subsequently all registrations were voluntarily canceled. Aldicarb, which has welldocumented neurotoxic effects, is subject to special

review, but the principal focus of the special review

is the potential of Aldicarb to contaminate groundwater. No chemical has undergone full special

review for neurotoxicity.

Approximately 75 active pesticide ingredients are

on EPA’s restricted use list (i.e., they may only be

used under the supervision of a certified applicator),

some of which are restricted because of concern

about their neurotoxic effects. While there are

certainly active ingredients whose use is restricted

based on their neurotoxic effects (48 FR 39496),

determining which ones was not feasible within the

limits of this survey.

Toxic Substances Control Act

The Toxic Substances Control Act (TSCA) (Public Law 94-469) was enacted in 1976 to “regulate

commerce and protect human health and the environment by requiring testing and necessary use

restrictions on certain chemicals. ” Congress intended to create “adequate authority” to test and

regulate chemicals in commerce that are not subject

to other statutes:

[A]dequate authority should exist to regulate

chemical substances and mixtures which present an
174 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

unreasonable risk of injury to health or the environment, and to take action with respect to chemical

substances and mixtures which are imminent hazards. . . [sec. l(b)(2)] [emphasis added].

TSCA defines several health and environmental

effects of concern, including neurotoxic effects that

are exhibited as behavioral disorders:

The health and environmental effects for which

standards for the development of test data may be

prescribed include carcinogenesis, mutagenesis, teratogenesis, behavioral disorders, cumulative or

synergistic effects, and any other effect which may

present an unreasonable risk of injury to health or the

environment [sec. 4(b)(2)(A)] [emphasis added].

The statute, which is one of the most procedurally

complex pieces of legislation in the area of human

health and the environment, sets forth a framework

that authorizes EPA to review the safety of existing

chemicals, to receive premanufacture notices (PMNs)

for new chemicals, to regulate hazardous substances,

and to call for the reporting of data on health and

environmental effects and substantial risks. EPA

may, in some cases, require that manufacturers

conduct health and safety studies, but the burden of

Photo credit: U.S. Environmental Protection Agency

proof is on the Agency to find that a chemical

substance or mixture may or will present an unreasonable risk to public health or the environment.

New Chemicals

TSCA requires manufacturers to notify EPA in

advance of the intended introduction into commerce

of a new chemical (through PMNs) or the intended

manufacture or processing of any chemical for a

significant new use. (The Act does not require PMNs

for the production of small quantities of chemicals

for the purpose of research and development.)

Submitters are required to present all test data that

indicate whether “the manufacture, processing,

distribution in commerce, use, and disposal of the

chemical substance or any combination of such

activities will not represent an unreasonable risk of

injury to health or the environment” [sec. 5(b)(2)(B)(i)].

EPA has 90 days (extendable under certain

circumstances to 180 days) to review the PMN. If

EPA determines that the chemical may present an

unreasonable risk, it may prohibit or limit the use of

the chemical in commerce until data are developed

to permit a further evaluation of the chemical’s

effects. If EPA decides that a substance “presents or

will present” an unreasonable risk, it may restrict or

prohibit the production, use, or disposal of the

substance.

The PMN contains data on a chemical’s identity

and structure, proposed use, byproducts, and impurities and is submitted to EPA’s Office of Toxic

Substances (OTS). Certain chemicals are also subject to reporting under a significant new use rule

(SNUR); EPA must be notified if such a chemical is

to be used in a way that differs significantly from

that proposed in the original PMN (usually because

the evaluation of the PMN depended on a specific

pattern of use).

Because TSCA does not require that manufacturers carry out any specific program of toxicity testing

in order for new chemicals to be approved, PMNs are

rarely submitted with toxicity data—fewer than 50

percent of all PMNs and fewer than 65 percent of

PMNs for nonpolymers contain any toxicity data(5).

PMNs that do include toxicity data generally provide results from a minimal set of studies, perhaps

two or three acute tests and maybe a test for irritation

(see ch. 5 for details on testing). The requirement

for manufacturers to submit all data in their

possession may act as a disincentive to testing, in
Chapter 7—The Federal Regulatory Response ● 175

that evidence of toxicity could lead EPA to

conclude that there may bean unreasonable risk,

whereas the absence of data will not do so.

Because the PMN generally provides few data,

most evaluation is performed on the basis of the

structural analogues of the new chemical to existing

chemicals and extrapolations from known properties

of well-characterized chemical classes. Thus, the

first stage of the PMN review is a computer-assisted

search for structural analogues with known toxicity

(or lack of toxicity). Senior OTS toxicologists with

expertise in various specialty fields then review the

chemical’s potential toxicity. Their review is based

on the structure-activity relationships revealed by

the computer search and conducted by members of

the review team. Until recently, neurotoxicologists

were not routinely present at the initial structureactivity meetings but were called on afterward if

concerns about neurotoxicity were raised. Under

current OTS procedures, a neurotoxicologist is

present at the initial structure-activity review and all

appropriate meetings thereafter.

Unlike the public regulatory process for reviewing existing chemicals, the PMN process rarely calls

on reviewers outside of OTS. In addition, because of

the high proportion of confidential business information that accompanies PMNs, little of the review

process is open to the public (see box 7-D).

If toxicity is predicted on the basis of structural

analogues, a chemical may be submitted to standard

review, a detailed examination that consumes much

of the time allotted for the PMN review. From fiscal

year 1984 through fiscal year 1987, approximately

20 percent of the 6,120 PMN chemicals received a

detailed review. Based on the standard review, EPA

has concluded that approximately 10 percent of all

PMN chemicals may or will present unreasonable

risks of adverse effects on human health or the

environment.

EPA cannot require additional toxicity data unless

it finds that a chemical mayor will present unreasonable risks. However, EPA can sometimes induce

manufacturers to develop the additional data that

EPA considers necessary by offering to suspend the

PMN process in the meantime. In negotiating with

manufacturers, EPA may request tests listed in the

guidelines for testing existing chemicals or additional tests. If EPA finds that the chemical may

present an unreasonable risk, it can halt the use of the

chemical pending development of adequate data to

resolve the issue of risk. If EPA finds positive

evidence that a chemical presents or will present

unreasonable risks, it can ban or limit the use of the

chemical.

A neurotoxicologist is present from the early

stages of a PMN review for all chemicals except

polymers, which, because of their low reactivity and

low potential for absorption, generally present lower

toxicity hazards and are thus evaluated separately.

EPA has identified at least six classes of chemicals

(acrylamide derivatives, acrylates, carbamates,

phosphines and phosphates, pyridine derivatives,

and imidazoles) that should alert reviewers to the

potential for neurotoxicity during the structureactivity review. Other chemicals likely to cause

concern include quaternary ammonium compounds,

glycol ethers, and miscellaneous halogenated solvents. OTS is developing a more explicit set of

classification criteria for neurotoxicity in order to

standardize the procedures; even so, EPA neurotoxicologists have expressed concern that accurate

structure-activity predictions may not be possible

without information on mechanisms of action,

which is available for only a few classes of

chemicals (including quaternary ammonium, organophosphate compounds, and some solvents).

Neurotoxicity concerns are one of the triggers for

placing a chemical into the standard review process.

However, most chemicals identified as being potentially neurotoxic do not enter that process, for a

variety of reasons, including lack of adequate data to

support a case, lack of a strong structure-activity

relationship, data indicating that human exposure

would be minimal (or inadequate data on exposure),

or lack of appreciation by individuals analyzing the

data of certain neurobehavioral effects.

Some 220 of the approximately 1,200 chemicals

(out of 6,120 PMNs submitted) that underwent

standard review during fiscal years 1984 through

1987 were identified as being potentially neurotoxic.

However, neurotoxicity was not the basis for most

regulatory actions taken by EPA. EPA was not able

to provide precise information on the extent to which

concerns about neurotoxicity did influence regulatory decisionmaking, although such an analysis is

now pending (5,24).

Regulation of Existing Chemicals

Existing chemicals are regulated under several

sections of TSCA. Section 4 allows EPA to rule that
176 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 7-D-Confidential Business Information Under TSCA: Does It Influence

Regulatory Effectiveness?

In order to assess accurately the toxic risks posed by a chemical, a considerable amount of information must

be reviewed, including the identity, properties, and intended uses of the chemical. Depending on the particular

chemical and its application, some of this information may represent trade secrets that, if known to a competitor,

would place the manufacturer or importer of a chemical at a competitive disadvantage.

The approach taken under the Toxic Substances Control Act (TSCA) toward the protection of trade secrets

has been to allow nearly all information submitted to the Environmental Protection Agency (EPA) on a

premanufacture notice (PMN) for a chemical to be claimed as confidential business information (CBI).

Information covered by such a claim is divulged only to EPA employees who have been granted a special CBI

clearance, primarily selected staff from and contractors for the Office of Toxic Substances (OTS). CBI may be

released only if the Administrator determines that it is necessary to do so to protect against an unreasonable risk,

and submitters must be given 30 days’ advance notice of CBI releases. EPA officials or officials of other Federal

agencies may obtain access to needed CBI materials, but given the breadth of information covered by CBI claims,

these officials are not in a position to know what CBI information in OTS files is relevant to the performance

of their duties.

The protection of CBI offered by TSCA is considerably greater than that offered by the confidentiality

provisions of some other laws. For example, under Title III of the Superfund Amendments and Reauthorization

Act, only the specific identity of a chemical covered by the reporting provisions of the Act can be claimed to be

confidential. Further, under TSCA, the burden of challenging CBI claims falls on EPA; PMN submitters are not

required to substantiate CBI claims unless challenged.

Toxicity data per se cannot be claimed as CBI under TSCA, but much of the other information relevant to

assessing toxic risks can be—including the identity of the chemical for which toxicity data are presented, its

physical-chemical properties, and its intended uses. These provisions of TSCA present significant obstacles to

effective regulation, not only with respect to the PMN program, but also with respect to other regulatory

programs, both inside and outside EPA. Three general types of obstacles can be identified: added administrative

burdens on OTS, interference with effective cooperation among regulatory programs, and prevention of public

oversight of the regulatory process.

Within the PMN program, CBI requirements have required OTS not only to maintain duplicate sets of

records (CBI and non-CBI), but also duplicate computer databases and even duplicate computers. Public interest

groups and other interested members of the public have no access to information that would allow them to

questioner to accept—EPA’s actions on PMNs, Neither can members of the public take any action for

self-protection, as they are frequently kept from information regarding the identity of toxic chemicals or the

products that might contain them. TSCA CBI provisions also pose a serious obstacle to the involvement of

regulatory, academic, and industrial scientists who could assist OTS in assessing the risks of PMN chemicals.

Because CBI has the capability to “contaminate” information systems (any document or information

system that contains CBI becomes CBI itself), the impediments to regulatory effectiveness posed by CBI have

spread from the PMN program to programs dealing with other aspects of TSCA. Rule-making on asbestos is a

particularly egregious example, where much of EPA’s supporting analysis could not be made available for public

review because it was based on CBI.

Persons involved in other regulatory programs, whether inside or outside of government, are not in a

position to obtain information that could make important differences in the implementation of regulations. A

Resource Conservation and Recovery Act permit writer in an EPA regional office, for example, will not have

access to information that might significantly influence decisions regarding the disposal of TSCA chemicals; and

the Consumer Product Safety Commission may not be made aware of information regarding chemicals in

consumer products.

Few persons would dispute the principle of protecting true trade secrets. There is good reason, however,

to question whether the burden imposed by the liberal confidentiality provisions of TSCA on the government,

the public, and even industry is justifiable. Industry has managed to adapt to the less protective provisions of

other laws, and alternative strategies for protecting proprietary information (e.g., patents) are available.

SOURCE: Office of Technology Assessment, 1990.
Chapter 7—The Federal Regulatory Response 177

chemicals or mixtures be tested for health and

environmental effects if the Agency determines that:

(A)(i) the manufacture, distribution in commerce,

processing, use, or disposal of a chemical substance

or mixture, or that any combination of such activities, may present an unreasonable risk of injury to

health or the environment (ii) there are insufficient

data and experience on which the effects of. . . such

activities on health or the environment can reasonably be predicted, and (iii) testing of such substance

or mixture with respect to such effects is necessary

to develop such data; or (B)(i) a chemical substance

or mixture is or will be produced in substantial

quantities, and (I) it enters or may reasonably be

anticipated to enter the environment in substantial

quantities or (II) there is or may be significant or

substantial human exposure to such substance or

mixture [sec. 4 (a)(l)].

If EPA can show that there is inadequate information on the effects of a compound and that testing is

necessary to obtain such information, it is required

to write a test rule that defines what is to be tested

and what particular tests are to be performed. OTS

has developed guidelines that describe the general

procedures for the conduct of toxicity tests (40 CFR

796), although each test rule contains specific

requirements for the individual chemical involved.

In contrast to FIFRA, TSCA has mandated an

explicit means of identifying chemicals that must be

tested by EPA for their effects on health and the

environment-namely, the Interagency Testing Committee (ITC). The ITC is a multidisciplinary advisory panel composed of one member each from

EPA, the Occupational Safety and Health Administration, the Council on Environmental Quality, the

National Institute for Occupational Safety and

Health, the National Institute of Environmental

Health Sciences, the National Cancer Institute, the

National Science Foundation, and the Department of

Commerce. ITC conducts an ongoing, independent

review of chemicals in commerce, based on recommendations from members as well as external

nominations, in order to select chemicals for testing.

(ITC reviews data from the published literature and

solicits information from the public and from

manufacturers.) The committee recommends testing

priorities based on the finding that there are insufficient data to assess the hazards posed by a substance

or the finding that potential human exposures are

significant. (ITC has no overarching responsibility

to coordinate agency testing; it simply suggests

high-priority chemicals for EPA to investigate.)

ITC publishes its findings in the Federal Register

and submits to EPA all data located on the substance, as well as important gaps in data, by means

of a priority list which is updated every 6 months.

The committee may indicate particular effects for

which it believes that a substance should be tested,

or it may simply point to high exposure and a general

lack of data as justification for including a chemical

on the priority list.

Chemicals selected for review and testing are

subjected to an extensive evaluation by ITC members, experts called onto review documents, and any

persons who nominate chemicals for review. EPA

then conducts its internal review, which involves a

multidisciplinary team, including neurotoxicologists if indicated. The group may also request

assistance from EPA research personnel.

EPA examines the concerns raised by ITC and

decides whether or not to issue a test rule for a

substance. EPA is not limited to the issues raised by

ITC; it may decide that some concerns are unjustified, or it may identify additional issues that were

not mentioned in ITC’s recommendations. The main

reasons for which EPA may decide not to test a

chemical are the determination that adequate data for

a risk decision are available or that the chemical is

no longer used in commerce. In three cases, EPA has

issued test rules on chemicals that were not nominated by the ITC. If EPA decides to pursue testing,

it may require tests on the basis of hazard concerns

raised in the review or a high volume of production.

EPA has developed guidelines for the types of tests

that may be required; these are published in the Code

of Federal Regulations (40 CFR 795; 40 CFR 798).

EPA can seek additional data under section 4 of

TSCA by negotiating a consent decree, which is a

legally binding mutual agreement that industry will

conduct specified tests and that EPA will not make

additional requests. The process of negotiating a

consent decree can be faster and more efficient than

formal rule-making, and EPA generally prefers this

option. In either case, the manufacturer must conduct additional tests and submit the data to EPA in

a timely manner. Once the test data have been

developed and submitted, section 6 of TSCA authorizes EPA to restrict or prohibit the production, use,

and disposal of the substance if the data indicate an

unreasonable risk.
178 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 7-E—Regulating for Neurotoxicity v. Other Toxic Effects: The Case of Acrylamide

One of the first chemicals that the Interagency Testing Committee (ITC) considered, shortly after it began

operations in 1977, was acrylamide, a chemical with a variety of commercial uses. Acrylamide was already known

to cause severe neurotoxic effects, but its ability to cause other chronic effects had not been well characterized. ITC

noted this state of research and recommended that acrylamide be tested for effects other than neurotoxicity. The

Environmental Protection Agency (EPA) had to decide whether the known neurotoxicity of this chemical was

sufficient for regulatory purposes or whether additional data documenting its effects on health were necessary.

In its response to the ITC, EPA chose not to require testing of acrylamide, for two reasons. First, EPA believed

that acrylamide was so neurotoxic that regulatory restrictions would be imposed to the maximum degree possible

on the basis of known effects, and additional test information would be of little regulatory significance. Second, EPA

noted that a chemical company was already in the midst of performing a long-term bioassay for other effects, so

if additional data were, in fact, necessary, they were already forthcoming.

When the chemical company in question learned that EPA was not going to require testing, it decided to

suspend its test for toxic effects other than neurotoxicity. EPA then had to decide whether neurotoxicity would be

considered the driving effect or whether to impose new testing requirements. EPA retreated from its earlier position

that the neurotoxicity data were sufficient and decided that data on other effects were needed. As a result, EPA

persuaded the company to resume its testing and withheld assessments and final regulatory decisions pending those

additional data.

SOURCE: W.R. Muir, former director, Office of Toxic Substances, U.S. Environmental Protection Agency, and President, Hampshire Research

Associates, personal communication, 1988.

Neurotoxicity is one of the specific concerns that It may be necessary to examine other endpoints

may be identified by ITC in recommending that a for specific chemicals, depending on their structure

substance be tested, in which case EPA must

respond either by including a requirement for

neurotoxicity testing in its test rule or by justifying

the exclusion of neurotoxicity tests. In the 24 ITC

reports to the EPA Administrator issued between

October 1977 and May 1989, the ITC proposed 100

chemicals or chemical classes7 for inclusion in the

TSCA section 4 priority list for testing. Of these

proposals, one-third included an expression of

concern regarding possible neurotoxicity (box 7-E).

Current EPA policy is to specify neurotoxicity

testing both when a chemical “may present an

unreasonable risk” of neurotoxicity and when there

may be substantial human exposure. Under an ‘A’

finding (an unreasonable risk finding), a core test

battery for neurotoxicity is recommended; the core

battery includes a functional observational battery

(FOB), motor activity tests, and neuropathological

evaluations. When appropriate, these tests can be

combined with other toxicity studies. Unless otherwise specified, it is assumed that both acute and

subchronic testing will be conducted using the FOB

and motor activity protocols, with neuropathological tests following subchronic exposures.

or the nature of existing data. Among the additional

tests specified in EPA guidelines are schedulecontrolled operant behavior (SCOB), developmental

neurotoxicity, peripheral nerve function, and neurotoxic esterase (NTE). For organophosphates and

related compounds, study design would include a

28-day repeated exposure period (e.g., 5 days per

week) and NTE, ataxia, and neuropathological tests.

Because of the wide variety of production levels

and exposure patterns among chemicals, EPA has

developed a three-level approach to testing under a

“B” finding (significant quantity finding). Testing

of level 1 chemicals (low production, low exposure)

generally includes the three core tests. FOB and

neuropathology are considered a minimum requirement, although a 28-day subchronic study may be

used in place of the usual 90-day study. For

organophosphorous compounds, acute NTE and

acute delayed hen tests are required. For level 2

chemicals (medium production and exposure, consumer exposure), the core battery is required; when

appropriate, these tests may be combined with other

toxicity studies. Level 3 chemicals (high production,

high exposure) also require the core battery, and

TThe ac~~ n~ber depends on the breadth of the class designation U*.
Chapter 7—The Federal Regulatory Response ● 179

Table 7-2-Chemicals Subject to Neurotoxicity Evaluation Under Section 4 of TSCA

Chemical Current status Neurotoxicity test; notes

Aniline and substituted anilines

Aryl phosphates

Cresols

Cumene

Cyclohexane’

Cydohexanone’

1,2-Dichloropropane

Diethylene glycol butyl ether

(and corresponding acetate)

Diisodecyl phenyl phosphite (PDDP)

Ethyltoluenes, trimethylbenzenes,

and C9 aromatic fraction

Commercial hexane

Hydroquinone and quinone

Isopropanol

2-Mercaptobenzothiazole

Methyl ethyl ketoxime

Methyl-tert-butyl ether (MTBE)

Oleylamine

Unsubstituted phenylenediamines (o,m,p)

Tributyl phosphate

1,1,1 -Trichloroethane

Triethylene glycol ethers

Urea-formaldehyde resins

Enforceable consent agreement announced

8/88 (53 FR 31 804)

Advanced notice of proposed rule-making

12/83 (48 FR 57452)

Notice of final rule-making 5/87

(52 FR 19082)

Final rule 7/88 (53 FR 28195)

Proposed rule 5/87 (52 FR 19096)

Negotiated testing agreement 1/84

(49 FR 136)

Final rule 9/86 (51 FR 32079); test standard

10/87 (52 FR 37138)

Final rule 2/88 (53 FR 5932)

Consent order, 2/89 (54 FR 81 12)

Final rule 5/85 (50 FR 20662); test standard

1/87 (52 FR 2522)

Final rule 2/88 (53 FR 3382)

Final rule 12/85 (50 FR 53145);

5/87 (52 FR 19865)

Proposed rule 3/88 (53 FR 8638)

Final rule 9/88 (53 FR 34514)

Proposed rule 9/88 (53 FR 35838)

Consent order 3/88 (53 FR 10391)

Final rule 8/87 (52 FR 31962)

Extension of comment period 1/88

(53 FR 913)

Proposed rule 11/87 (52 FR 43346)

Consent order in preparation 8/87

(52 FR 31445)

Consent order 4/89 (54 FR 13470); final

rule for DN (54 FR 13473)

Advanced notice of proposed rule-making

Not being pursued for neurotoxicity; originally proposed on basis of ability to

induce anoxia

Proposed rule under development

FOB, MA, and NP (subchronic) added to

ongoing studies by Office of Drinking

Water

FOB, MA, NP (subschronic)

FOB, MA, NP, (subchronic); SCOB (subchronic and acute); DN if warranted

after other studies completed

DN

FOB, MA, NP (subchronic)

FOB, MA, NP (subchronic)

NTE, delayed neurotoxicity (subchronic)

FOB, MA, NP (subchronic)

SCOB (acute), FOB (subchronic), MA, NP

FOB, NP (subchronic); existing data on

motor activity

FOB, MA, (acute); FOB, MA, NP (subchronic); DN

FOB, MA, NP (subchronic)

FOB, MA (acute and subchronic); NP (subchronic)

FOB, MA, (acute and subchronic); NP

(subchronic) testing begun

No neurotoxicity testing in final rule, although was in proposed rule

Revised notice includes FOB, MA (acute,

all three isomers, subchronic triggered

from acute)

FOB, MA (acute and subchronic); NP (subchronic)

FOB, electrophysiology (acute and subchronic)

FOB, MA (acute and subchronic); NP (subchronic); DN

No rule issued

KEY:

DN-developmental neurotoxicity tests

FOB-functional observational battery

MA-motor activity test

NP-directed neuropathological studies

NTE-neurotoxic esterase

SCOB-schedule-controlled operant behavior

Rule-making began prior to issuance of neurotoxicity test guidelines.

SOURCE: Office of Technology Assessment, 1990.

developmental neurotoxicity tests may be required event that other tests indicated neurotoxic effects in

in the near future. EPA neurotoxicologists may add adults.

tests to any of the above requirements if existing data In the event that testing conducted under TSCA indicate the need. section 4 indicates that a chemical poses an unreaTo date, test rules or consent decrees for 19 sonable risk, section 6 gives EPA the authority to

chemicals or chemical classes have included neuro- regulate production, distribution, use, or disposal of

toxicity testing (table 7-2). In four cases, a test chemicals in commerce, if there is “a reasonable

protocol for developmental neurotoxicity was also basis’ to conclude that any of these activities

considered, either as a definite requirement or in the “presents or will present an unreasonable risk of
180 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

injury to health or the environment” [sec. 6(a)]. In

order to take a regulatory action, the burden of proof

again falls on EPA to show that the listed activities

“will present” a risk. EPA may then promulgate

rules “to the extent necessary to protect adequately

against such risk using the least burdensome requirements” [sec. 6(a)]. This provision has been used for

the regulation of a very limited number of chemicals,

among them PCBs, dioxin, and, most recently,

asbestos.

Finally, TSCA authorizes EPA to require that new

information regarding harmful effects of chemical

substances be reported:

. . . any person who manufactures, [imports,] processes, or distributes in commerce a chemical substance or mixture and who obtains information

which reasonably supports the conclusion that such

substance or mixture presents a substantial risk of

injury to health or the environment shall immediately inform the [EPA] Administrator of such

information . . . [sec. 8(e)].

STANDARD-SETTING

LEGISLATION AND REGULATIONS

These statutes authorize regulatory agencies to set

standards for chemicals in specific situations or

environments. Emissions from smokestacks, automobile exhaust, and sewage pipes, as well as

chemicals found in the workplace and in consumer

products, are subject to restrictions mandated by

various standard-setting statutes. Some of the major

standard-setting statutes—the Clean Air Act, the

Federal Water Pollution Control Act as amended by

the Clean Water Act, and the Safe Drinking Water

Act-are pollution control measures. Others focus

on the safety, labeling, and packaging of consumer

and household products, including the Consumer

Product Safety Act, the Federal Hazardous Substances Act, and the Poison Prevention Packaging

Act. A third type of standard-setting statute, characterized by the Federal Mine Safety and Health Act

and the Occupational Safety and Health Act, addresses issues of workplace safety. (See table 7-1 for

key features of these statutes.)

In contrast to the regulatory activity mandated by

licensing statutes, regulatory programs charged with

setting standards cannot require that chemical substances be tested for toxicity. For the most part,

standard-setting programs must base their decisions

on reviews of existing literature on toxicology,

Photo credit: National Archives

although some of them have limited research capabilities as well (see ch. 4). Once a standard is set, the

primary regulatory activity is enforcement—making

sure that standards are not exceeded.

Clean Air Act

The Clean Air Act (CAA) (Public Law 159) was

passed in 1955 “to provide research and technical

assistance relating to air pollution control. The Act

cited “dangers to the public health and welfare” as

an adverse effect of concern. The 1970 amendments

(Public Law 91-604) defined more specific effects

and authorized an accelerated research program:

. . . to improve knowledge of the contribution of air

pollutants to the occurrence of adverse effects on

health, including, but not limited to, behavioral,

physiological, toxicological, and biochemical effects . . . and the short- and long-term effects of air

pollutants on welfare [sec. 2(f) (l)] [emphasis

added].

The 1970 amendments also called for EPA to set

standards limiting hazardous air pollutants based on

their effects on the public health and welfare. Recent

amendments have refined the standard-setting procedures further and have revised the schedule for

meeting standards. The air pollution control framework set forth by the Clean Air Act calls for EPA to

establish standards for ambient air, emissions of

hazardous substances, and emissions from automobiles, including fuel and fuel additives.

EPA regulates air pollutants by setting National

Primary and Secondary Ambient Air Quality Standards as necessary to protect public health, with ‘an

adequate margin of safety” [sec. lo]. EPA
Chapter 7—The Federal Regulatory Response ● 181

has interpreted the requirement for “an adequate

margin of safety’ as intending:

. . . to address uncertainties associated with inconclusive scientific and technical information available

at the time of standard setting. It is also intended to

provide a reasonable degree of protection against

hazards that research has not yet identified (50 FR

37484).

The primary standard is to be based solely on

health concerns (50 FR 37484). However, a regulatory impact analysis is conducted to obtain information and provide a cost-benefit analysis for various

alternative standards (22).

The Act defines a hazardous air pollutant as:

. . . an air pollutant to which no ambient air quality

standard is applicable and which in the judgment of

the Administrator causes, or contributes to, air

pollution which may reasonably be anticipated to

result in an increase in mortality or an increase in

serious irreversible, or incapacitating reversible

illness [sec. 1 12(a)(l)].

It directs EPA to set emissions standards for such

pollutants at a level that will provide “an ample

margin of safety to protect the public health” [sec.

1 lo]. In its promulgation of National Emissions Standards for Hazardous Air Pollutants, EPA

has interpreted “ample margin of safety” as not

requiring the total elimination of risk (40 CFR 19 ed.

61).

The Act specifically prescribes that EPA set

standards for vehicle emissions, fuel, and fuel

additives. A fuel or fuel additive may be regulated

only on the basis of endangerment of the public

health or welfare and then only”. . . after consideration of all relevant medical and scientific evidence

. . . including consideration of other technologically

or economically feasible means of achieving emission standards . . .“ [WC. 21 l(c)(2)(A)].

EPA has promulgated Primary National Ambient

Air Quality Standards for the following six pollutants: sulfur oxides, particulate matter, carbon monoxide, ozone, nitrogen dioxide, and lead (40 CFR

50). Standards for carbon monoxide (36 FR 8186)

and lead (43 FR 46254) were set in response to

neurotoxic effects caused by these compounds.

The original carbon monoxide standards were

based on evidence that the ability to discriminate

time intervals was impaired in humans when 2 to 3

percent of the body’s hemoglobin—the oxygenbinding component of red blood cells—was bound

to carbon monoxide (forming carboxyhemoglobin,

COHb) and was therefore unable to bind to and carry

oxygen (28). The impairment of time discrimination,

a neurotoxic effect, was considered the most sensitive effect. The study from which these data were

derived, however, has been discredited (45 FR

55066). On August 18, 1980, after reviewing the

literature, including that published since the original

standards were promulgated, EPA proposed retention of the 8-hour primary standard [9 parts of carbon

monoxide per million parts of air (ppm)] and

revision of the l-hour standard (from 35 ppm to 25

ppm), based on cardiotoxic rather than neurotoxic

effects (45 FR 55066). In order to set an ambient air

standard, the Agency used an equation to estimate

the concentrations of carbon monoxide in ambient

air that were likely to result in COHb levels of

concern (45 FR 5506).

Since that time, an expert committee convened by

EPA has determined that EPA should not rely on

these data (50 FR 37484). After further review of the

scientific literature, however, EPA decided to let

stand the current primary carbon monoxide standards, which are based on concern for central nervous

system and cardiovascular effects, the latter being

considered to be the more sensitive (50 FR 37484).

Effects on the central nervous system of low levels

of COHb include “impairment of vigilance, visual

perception, manual dexterity, learning ability, and

performance of complex tasks” (50 FR 37484). The

population most sensitive to the cardiovascular

effects included persons with angina and other

cardiovascular diseases. The standard was set at a

level which was estimated to keep more than 99.9

percent of this sensitive population below 2.1

percent COHb (50 FR 37484).

The primary lead standard was based on impaired

heme synthesis (heme is a nonprotein iron compound that gives hemoglobin its characteristic color

and oxygen-carrying properties) and nervous system

deficits, which included cognitive deficits, encephalopathy, and peripheral neuropathy (43 FR 46254).

Children were considered to be the most sensitive

population, and the standard was set at a level

estimated to keep 99.5 percent of children below

what was considered to be the maximum safe level

of 30 micrograms of lead per deciliter of blood (43

FR 46254). The actual standard was calculated

based on 20 percent of lead in the blood being
182 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

contributed from the air and 80 percent from other

sources.

8 The lead standard is presently under

review by EPA, and nervous system disturbances are

still one of the most sensitive categories of effects

(9).

National Emission Standards for Hazardous Air

Pollutants have been promulgated by EPA for the

following: benzene arsenic, beryllium, mercury,

vinyl chloride, asbestos, and radionuclides. Only the

standard for mercury was based on concerns about

neurotoxic effects (38 FR 8820). The endpoint that

was the driving force behind this standard was

paresthesia (tingling, burning sensations) (45).

Automobile and other vehicle emissions are

regulated by the Office of Mobile Sources. To date,

carbon monoxide, nitrogen oxides, hydrocarbons,

and particulate have been regulated. Of these four

pollutants, carbon monoxide was regulated in part

on the basis of neurotoxic concerns, the same

concerns on which the Primary National Ambient

Air Quality Standard for carbon monoxide was

based. The standard itself varies, depending on the

vehicle class and model year.

EPA regulates the lead content of gasoline on the

basis of the same neurotoxic effects cited in the

primary national ambient air quality standard for

lead (50 FR 9386). A standard of 0.1 gram of lead per

gallon of leaded gasoline became effective January

1, 1986. EPA was particularly concerned about the

impact of lead on the health of preschool children

and has clearly stated that its long-term objective is

to eliminate the use of lead in gasoline (50 FR 9386).

Proposed Amendments

Efforts to amend the CAA during the IOOth

Congress were not successful. More than 30 different bills proposing amendments to CAA, including

an Administration proposal, have been introduced in

the House and Senate during the 10lst Congress, and

hearings have been held on many of them. Although

the issue is being actively debated and the CAA will

almost certainly be amended, it is too early to tell

what form the amendments will take and what direct

effect, if any, the amendments will have on the

regulation of neurotoxic substances.

Federal Water Pollution Control Act and

Clean Waler Act

The Federal Water Pollution Control Act (FWPCA)

(33 U.S.C. 466) and amendments to it, including the

Clean Water Act (CWA), established a framework

for the control of water pollution based on human

health and environmental concerns. The 1972 amendments (Public Law 92-500), which completely

revised earlier versions of FWPCA, authorized EPA

to set effluent standards for a designated list of

hazardous substances (40 CFR 116). Further amendments to the FWPCA, including the 1977 Clean

Water Act, authorized EPA to develop and periodically review water quality criteria that accurately

reflect ‘‘the latest scientific knowledge” on “the

kind and extent of all identifiable effects on health

and welfare’ [sec. 304(a)(l)] [emphasis added]. The

criteria are not regulations and, as such, carry no

enforcement authority. However, they provide guidance for the derivation of regulatory standards,

including general effluent limitations and toxic

pollutant effluent limitations authorized by the

FWPCA (45 FR 79319).

EPA is authorized to establish water quality

criteria to protect human health and the environment. The criteria to protect human health are

“based solely on data and scientific judgments on

the relationship between pollutant concentrations

and environmental and human health effects. . . and

do not reflect considerations of economic or technological feasibility” (45 FR 79319).

EPA’s Office of Water Regulations and Standards

has established three types of water quality criteria

for pollutants where sufficient data are available: 1)

to protect freshwater aquatic life, 2) to protect

saltwater aquatic life, and 3) to protect human

health. Derivation of criteria to protect human health

was based on three endpoints: carcinogenicity,

adverse noncarcinogenic effects, and organoleptic

effects (45 FR 79347). (Organoleptic effects refer to

taste or odor characteristics of a compound and have

no demonstrated adverse effects on human health.)

Criteria were based on organoleptic effects when the

organoleptic threshold was lower than that calcug~e had ~dus~es Association, Inc., challenged the standard in court, arguing that EPA could only regulate based on “clearly adverse effwts’

and that the nervous system effects had not been adequately documented at the levels cited by EPA (17). The court upheld EPA’s standard, however,

noting that the EPA Administrator’s actions were reasonable, that EPA did, in fact, have sufficient evidence suggesting nervous system effects, that the

statute allows the EPA Administrator considerable discretion to determine adverse effects, and that in any event the standard was based in part on

providing an “adequate margin of safety,’ which is required by the Clean Air Act.
Chapter 7—The Federal Regulatory Response ● 183

lated from toxicity data or when there were insufficient toxicity data.

Water quality standards set to protect human

health and based on toxicological data have been

established for 86 compounds (45 FR 7931 8; 49 FR

5831). For four of these, lead, mercury, thallium, and

toluene, neurotoxic effects were of major concern

(34-44). A brief survey of the water quality criteria

documents (34-44) indicates that at least eight other

chemicals are noted as causing neurotoxic effects,

even though the standards for these chemicals were

based on other endpoints (9).

Safe Drinking Water Act

The Safe Drinking Water Act (SDWA) of 1974

amended the Public Health Service Act ‘‘to assure

that the public is provided with safe drinking water”

(Public Law 93-523). SDWA and its amendments

instituted a framework of primary and secondary

water regulations designed to control contaminants

in public drinking water supplies that EPA determines ‘may have any adverse effect on the health of

persons” [sec. 1401(1)(B)].

Under the Act, EPA was to establish Revised

National Primary Drinking Water Regulations, using

a two-stage process. First, EPA was to establish

recommended maximum contaminant levels (RMCLs),

which are nonenforceable health goals. RMCLs

were to be set “at a level [at] which. . . no known or

anticipated adverse effects on the health of persons

occur and which allows an adequate margin of

safety” [sec. 1412(b)(l)(B)]. For carcinogenic pollutants, the RMCL was to be set at zero. Once an

RMCL had been promulgated, EPA was to establish

a maximum contaminant level (MCL) for that

pollutant. An MCL was an enforceable standard and

is to be set:

. . . as close to the recommended maximum contaminant levels. . . as is feasible. . . [i.e.], with the use of

the best technology, treatment techniques, and other

means, which the Administrator finds are generally

available taking costs into consideration [sec. 1412

(b)(3)].

A treatment technique maybe established instead

of an MCL if “it is not economically or technologically feasible to . . . ascertain the level of . . . [a]

contaminant [in drinking water]” [sec. 1401 (C)(ii)].

When the Act was amended in 1986, the two-step

process was retained, with EPA to specify nonenforceable goals [RMCLs were renamed maximum

contaminant level goals (MCLGs)], on which MCLS

were to be based. EPA was required to propose and

promulgate MCLGs and MCLs simultaneously for

any chemical. Another key feature of the amendments, from a neurotoxicological perspective, was

the imposition of a ban on the use of lead pipe,

solder, or flux in plumbing for drinking water after

June 19, 1986.

The Office of Drinking Water of EPA has set

MCLGs for carcinogenic pollutants at zero. MCLGs

for noncarcinogenic agents are set by establishing

the dose at which harmful effects may be observed

and then compensating for uncertainties in the

process (50 FR 46946). EPA then predicts exposures

from food and air sources and sets the MCLGs

accordingly (50 FR 46946).

Since the revision of the Act, MCLGs have been

set for fewer than 15 inorganic chemicals under the

National Primary Drinking Water Regulations (48

FR 45502). Of the 10 MCLs issued, three were based

partly or entirely on nervous system effects: 1)

barium, 2) lead, and 3) mercury. For one, arsenic, the

nervous system was mentioned as one of several

organ systems affected with more severe intoxication, but the MCL was not based on this (33).

The National Primary Drinking Water Regulations also contain MCLs for 10 organic chemicals:

four pesticides, two herbicides, and four trihalomethanes. It is difficult to ascertain the effects of

concern for the four pesticide and two herbicide

MCLs. According to one EPA document, the

severity of the symptoms of the pesticides (endrin,

lindane, methoxychlor, and toxaphene) is related to

the concentrations of the compounds in the nervous

system (33). Specific effects of concern for the two

herbicides [2,4-D and 2,4,5-TP (Silvex)] are not

mentioned (33). The standard for the four trihalomethanes was based on chronic low-level effects

(primarily cancer), although these compounds do

have an acute effect on the nervous system.

In addition to setting drinking water standards, the

Office of Drinking Water publishes health advisories describing levels of contaminants. These advisories cover l-day, 10-day, long-term (approximately 7 years, or 10 percent of an individual’s

lifetime), and lifetime exposures. The advisories are

not federally enforceable but describe levels of

contaminants in drinking water that are associated

with adverse health effects. The advisories do not
I&f ● Neurotoxicity : Identifying and Controlling Poisons of the Nervous System

clearly indicate the effects that are of primary

concern, but one or more of the advisories for seven

contaminants appear to have been based on neurotoxic effects (50 FR 46936).

Consumer Product Safety Act and

Federal Hazardous Substances Act

The Consumer Product Safety Act (Public Law

92-573) of 1972 established the Consumer Product

Safety Commission (CPSC) as an independent

regulatory commission charged with protecting the

public from “unreasonable risks of injury associated

with consumer products” [sec. 2(a)(3)]. Risk of

injury is defined as “risk of death, personal injury,

or serious or frequent illness” [sec. 3(a)(3)].

The Act authorizes CPSC to promulgate consumer product safety standards, including performance requirements and warning or instructional

labels, necessary to ‘prevent or reduce an unreasonable risk of injury associated with such product”

[sec. 7(a)]. The determination of whether or not a

particular risk of injury is unreasonable involves

balancing “. . . the probability that the risk will

result in harm and the gravity of the harm against a

rule’s effects on the product’s utility, cost, and

availability to the consumer” (42 FR 44198). The

Consumer Product Safety Act’s broad authority

could cover products with neurotoxic effects, but

toxic substances in general are more likely to be

regulated under the Federal Hazardous Substances

Act because the former prohibits the regulation of a

risk that can be adequately regulated under the latter

[sec. 30(d)].

The Federal Hazardous Substances Act (Public

Law 86-613) was passed in 1960 to protect the

public health by requiring that hazardous substances

be labeled with various warnings, according to the

nature of the hazard. The Act defines a ‘‘hazardous

substance’ as:

Any substance or mixture of substances which (i)

is toxic, (ii) is corrosive, (iii) is an irritant. . . if such

substance or mixture of substances may cause

substantial personal injury or substantial illness

during or as a proximate result of any customary or

reasonably foreseeable handling or use, including

reasonably foreseeable ingestion by children [sec.

2(f)(l)] [emphasis added].

A toxic substance is defined as “any substance

(other than a radioactive substance) which has the

capacity to produce personal injury or illness to man

through ingestion, inhalation, or absorption through

any body surface” [sec. 2(g)].

The Act directs CPSC to issue regulations clarifying which categories of substances fit the various

definitions of hazardous, if there is any uncertainty

[sec. 3(a)(l)], and to ban substances through a

formal rule-making procedure:

. . . on the basis of the finding that, notwithstanding

such cautionary labeling as is or may be required

under this Act for that substance, the degree or nature

of the hazard involved in the presence or use of such

substance in households is such that the objective of

the public health and safety can be adequately served

only by keeping such substance . . . out of the

channels of interstate commerce . . . [sec. 2(q)(l)].

The Act calls for banning substances that are too

dangerous for household use.

Because of the interrelatedness of concerns embodied in the Consumer Product Safety Act and the

Federal Hazardous Substances Act and because both

are administered by CPSC, regulatory actions under

the two statutes have been closely intertwined.

CPSC has responded to its mandate by setting

standards for various consumer products. Its actions

based on neurotoxicity concerns have been to ban

products with paint or other surface material containing lead in excess of 0.06 percent (42 FR 44199).

This standard was designed “to reduce or eliminate

the unreasonable risk of injury associated with lead

poisoning in children’ (42 FR 44198) and addressed

consumer products that bear lead-containing paint,

including toys and other items used by children and

furniture used by consumers (42 FR 44199). The

Commission cited the following as adverse effects

of lead on the nervous system: hyperactivity, slowed

learning ability, withdrawal, and blindness (42 FR

44200).

CPSC has been involved in working out a

voluntary consensus on the labeling of various

consumer products containing organic solvents such

as n-hexane. Concern about these compounds was

based on the association between repeated exposure

to solvents and permanent neurological damage.

CPSC recently hired a staff neurotoxicologist but

has not undertaken any specific neurotoxicity product evaluations lately. The Commission does, however, plan to draft criteria for classifying, evaluating,

and labeling products that warrant concern for

neurotoxic effects (under the authority of both Acts).
Chapter 7—The Federal Regulatory Response ● 185

Federal Mine Safety and Health Act

The Federal Mine Health and Safety Act of 1969

(Public Law 91-173), as amended in 1977 (Public

Law 95-173), grew out of congressional concern

over the:

. . . urgent need to provide more effective means and

measures for improving the working conditions and

practices in the Nation’s coal or other mines in order

to prevent death and serious physical harm, and in

order to prevent occupational diseases originating in

such mines [sec. 2(a)] [emphasis added].

Although no specific toxic effects are singled out for

consideration, the concern about physical harm and

occupational diseases could encompass neurotoxic

effects.

The Act established the Mine Safety and Health

Administration (MSHA) in the Department of Labor

and authorized it to “develop, promulgate, and

revise, as may be appropriate, improved mandatory

health or safety standards for the protection of life

and prevention of injuries in coal or other mines’

[sec. 10l(a)] [emphasis added]. MSHA is to ensure

that miners will not ‘‘suffer material impairment of

health or functional capacity even if such miner has

regular exposure to the hazards dealt with by such

standard for the period of his working life” [sec.

lo] .

MSHA initially fulfilled its standard-setting mandate by adopting standards for airborne contaminants recommended by the American Conference of

Governmental Industrial Hygienists (ACGIH) (box

7-F), and the American National Standards Institute

(30 CFR 57.5). In 1981, MSHA began a comprehensive review of its safety standards, including those

for air (46 FR 57253,46 FR 10190); since then, it has

moved to update its regulations by incorporating

more recent threshold limit values (see ch. 6).

Occupational Safety and Health Act

The Occupational Safety and Health Act (OSH

Act) was enacted in 1970 to improve workplace

safety. The Act established the Occupational Safety

and Health Administration (OSHA) in the Department of Labor and directed it to promulgate health

and safety standards, defined in the Act as:

. . . conditions, or the adoption or use of one or more

practices, means, methods, operations, or processes,

reasonably necessary or appropriate to provide safe

or healthful employment and places of employment

[sec. 3(8)].

The Act also authorizes OSHA to promulgate new

standards for toxic materials and to modify or revoke

existing ones, to ensure “. . . that no employee will

suffer material impairment of health or fictional

capacity even if such employee has regular exposure

to the hazard dealt with by such standard for the

period of his working life” [sec. 6(b)(5)] [emphasis

added].

In 1971, OSHA adopted existing Federal standards, most of which had been adopted under the

Walsh-Healy Act, and approximately 20 consensus

standards of the American National Standards Institute as permissible exposure limits (PELs) (39 FR

23540).

In addition to initiating a standard-setting framework, the OSH Act established the National Institute

for Occupational Safety and Health (NIOSH) as a

research agency “authorized to develop and establish recommended occupational safety and health

standards” [sec. 22(c)(l)] and to set criteria for such

standards. Although the Act directed that the standards and criteria be used by OSHA in the promulgation of new or revised health and safety standards,

OSHA has acted on few of NIOSH’s recommendations. NIOSH is also responsible for assessing

work-related diseases and injuries, including those

caused by toxic substances.

Since the adoption of initial standards, OSHA has

issued complete health standards for 25 substances

(27). Of these, the one concerning lead was based, in

part, on nervous system effects (43 FR 52952). Four

other compounds, inorganic arsenic, acrylonitrile,

ethylene oxide, and 1,2-dibromo-3-chloropropane,

were cited as causing various disturbances in the

nervous system, but the standards for these were

driven by concerns about carcinogenic effects (29

FR 1910).

OSHA recently published a far-reaching revision

and update of existing standards (54 FR 2332). The

rule affects standards for 428 chemical substances:

it lowers PELs for 212 substances, establishes them

for 164 substances that were not formerly regulated,

and maintains unchanged the existing levels for 52

substances. The regulation addressed only chemicals that were covered by the most recent ACGIH

recommendations and whose threshold limit values

(TLVs) differed from current PELs. No new stand-
186 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 7-F—The American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a professional society organized

in 1938 by a group of governmental industrial hygienists. Its recommendations have played a major role in setting

standards under both the Occupational Safety and Health Act and the Federal Mine Safety and Health Act. ACGIH

membership consists of government or industrial hygienists involved in occupational safety and health programs

who seek to establish a consensus among industrial toxicologists on the levels of chemicals that might reasonably

be considered safe in the workplace.

Over the years, ACGIH has set threshold limit values (TLVs) for hundreds of occupational substances and

publishes its recommendations annually. These values refer to airborne concentrations of substances that the

majority of workers maybe repeatedly exposed to on a daily basis without adverse effect (ACGIH, 1985).

ACGIH sets three types of TLVs for chemical compounds: time-weighted average concentrations, which are

for an 8-hour workday and a 40-hour workweek; short-term exposure limits, which are 15-minute time-weighted

average exposures not be exceeded at any time; and ceiling limits, which are not to be exceeded even for an instant

(ACGIH, 1985).

There are no set guidelines for the establishment of TLVs. Rather, the values are based on the TLV committee’s

professional judgment, after they have reviewed information from industrial experience, from experimental human

and animal studies, and, when possible, from a combination of all three. The basis on which the values are

established may differ from substance to substance: protection against impairment of health maybe a guiding factor

for some, whereas reasonable freedom from irritation, narcosis, nuisance, or other forms of stress may form the basis

for others (ACGIH, 1985).

The TLVs are not legally enforceable but are meant to be used as guidelines. The 1968 ACGIH chemical

substance TLVs and the 1969 noise TLV, however, were adopted as Federal standards under the Walsh-Healy Act

prior to enactment of the Occupational Safety and Health Act. In the early 1970s, these standards were adopted as

permissible exposure limits by the Occupational Safety and Health Administration, as mandated by the Act (OTA,

1985).

As of 1985, ACGIH had set 605 TLVs covering a wide range of compounds (ACGIH, 1985); TLVs for 202

of these substances were set in whole or in part to protect individuals from nervous system effects ranging from

drowsiness to nerve damage. (This number does not include effects such as eye, nose, and throat irritation, although

these effects might be broadly construed as neurotoxic.)

OSHA recently published a revised standard that increased the protection of workers by implementing new

or revised PELs for 428 toxic substances (53 FR 20960-20991). The final standard was published in January 1989.

The new rule established lower exposure limits for approximately 212 substances already regulated by OSHA. PELs

would be established for the first time for another 164 substances. A large number of these are established to prevent

adverse effects on the nervous system. The regulation addressed only chemicals that were covered by the most recent

ACGIH recommendations and whose TLVs differed from current PELs. No new standards were promulgated for

chemicals for which NIOSH had specified recommended exposure levels, unless those chemicals were also on the

ACGIH list.

Critics of ACGIH argue that the TLVs are essentially industry consensus standards arrived at through a limited

review of available toxicological information. Nevertheless, TLVs are widely used by both industry and government

officials.

SOURCES: American Conference of Governmental Industrial Hygienists, Threshold Limit Values for Chemical Substances in the Work

Environment Adopted by ACGIH for 1985-1986 (Cincinnati, OH: 1985); U.S. Congress, Office of Technology Assessment,

Preventing Illness and Injury in the Workplace, OTA-H-256 (Washington, DC: U.S. Government Printing Office, 1985).

ards were promulgated for chemicals for which behind 410 of the standards. Of those, PELs for 20

NIOSH had specified recommended exposure lev- compounds were based on the avoidance of direct

els, unless those chemicals were also on the ACGIH neuropathic effects. An additional 19 were based on

list. This issue is discussed in more detail in chapter the avoidance of narcosis. A total of 79 chemicals

10. were regulated to prevent irritation, an effect that

does not necessarily imply neurotoxicity but may

Tables in the Federal Register notice announcing include some neurotoxic effects. Methanol, a chemithe rule listed the explicit toxicological concerns cal that adversely affects the optic nerve, was one of
Chapter 7—The Federal Regulatory Response ● 187

the five substances listed because of ocular concerns. Finally, 26 chemicals were listed under the

category of avoidance of metabolic effects. This

category contained several substances that cause

neurotoxic effects, including carbon monoxide and

some types of cholinesterase inhibitors (cholinesterase inhibition is discussed in chs. 3 and 10).

The rule sets standards for an additional 73

chemicals on the basis of structural analogies to

other compounds with known effects. Of the 73, 18

were selected because they are analogous to compounds that induce neurological effects, narcosis, or

cholinesterase inhibition. PELs for 26 chemicals

were based on no observed adverse effect levels

(NOAELs). For six of these, the adverse effects

noted in the rule were neurological.

Although the chemicals discussed above have

been regulated explicitly on the basis of neurological

concerns, it should be remembered that other neurotoxic chemicals may have been regulated on the

basis of other undesirable effects they induce. For

example, the PEL for carbon disulfide, a well-known

neurotoxicant, is based on avoidance of cardiovascular effects.

In addition to specifying PELs, OSHA has issued,

and subsequently expanded, a hazard communication standard (52 FR 3 1852). This requires manufacturers and importers to assess the hazards of the

chemicals they produce or import, requires employers to provide information to their employees

concerning hazardous chemicals (using training,

labels, material safety data sheets, and access to

written records), and requires distributors of hazardous chemicals to provide information to their

customers (via proper labels and Material Safety

Data Sheets). It should be noted that many such data

sheets contain very limited information on toxic

hazards.

CONTROL-ORIENTED

LEGISLATION AND REGULATIONS

Hazardous chemical substances in the environment and in consumer products are the subject of

control-oriented statutes such as the Comprehensive

Environmental Response, Compensation, and Liability Act, the Controlled Substances Act, the

Lead-Based Paint Poisoning Prevention Act, the

Marine Protection, Research, and Sanctuaries Act,

the Poisoning Prevention Packaging Act, and the

Resource Conservation and Recovery Act. These

statutes, which are founded on a recognition of the

problems caused by predetermined or specified sets

of hazardous chemicals, are focused on developing

procedures to control existing situations (see table

7-l). Regulatory implementation under these laws

consists primarily of setting allowable levels or

reporting requirements and enforcing the limits that

have been set.

Comprehensive Environmental Response,

Compensation, and Liability Act

The Comprehensive Environmental Response,

Compensation, and Liability Act (CERCLA), also

known as Superfund, was enacted in 1980 to provide

authority for EPA to clean up hazardous waste sites.

CERCLA defined hazardous substances as either

compounds that have already been designated under

other Acts or compounds designated by EPA” which,

when released into the environment may present

substantial danger to the public health or welfare or

the environment” [sec. 102(a)] [emphasis added]. In

addition to identifying hazardous substances,

CERCLA directs EPA to “promulgate regulations

establishing that quantity of any hazardous substance the release of which shall be reported” [sec.

102(a)], essentially supplanting a similar process

established under the Clean Water Act. These

reportable quantities (RQs) are used to trigger the

appropriate response “necessary to protect the

public health or welfare or the environment” [sec.

lo] .

Initially, all RQs were set at 1 pound, unless other

RQs were assigned under section 311 of the Clean

Water Act. As authorized under section 102 of

CERCLA, EPA has adjusted RQs for approximately

440 of the 717 substances on the list (40 CFR 302;

51 FR 34534), based on “scientific and technical

criteria which correlate with the possibility of hazard

or harm on the release of a substance in a reportable

quantity” (48 FR 23560). The criteria EPA used

were aquatic toxicity, mammalian toxicity, ignitability, reactivity, chronic toxicity, and potential

carcinogenicity. Of the 245 hazardous substances

evaluated by EPA’s Environment Criteria and Assessment Office, 64 were reviewed for chronic

toxicity. Of those 64, 22 could not be ranked due to

insufficient data. Of the 42 that were ranked, 5 were

ranked on the basis of effects on the nervous system

(11).

20-812 - 90 - 5 : QL 3
188 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Photo credit: U.S. Environmental Protection Agency

The Superfund Amendments and Reauthorization

Act (SARA) (Public Law 99-499) passed in 1986

called for the development of a list of 100 high-risk

chemicals from the chemicals on the Superfund list

for which available data were inadequate. SARA

established a research program at the Agency for

Toxic Substances and Disease Registry to conduct

the necessary research and to develop toxicology

data profiles on the 100 chemicals. Thus, although

CERCLA as amended is not a testing program, it

does sponsor research. The toxicological profiles

being prepared under SARA provide an explicit

discussion of health effects for various routes of

exposure to a chemical (oral, inhalation, dermal).

The specific effects considered include systemic

effects, immunological effects, neurological effects,

developmental effects, reproductive effects, genotoxic effects, cancer, and death.

Controlled Substances Act

Congress passed the Controlled Substances Act in

1970 as Title II of the Comprehensive Drug Abuse

Prevention and Control Act (Public Law 91-513).

Finding that “. . . the illegal importation, manufacture, distribution, and possession and improper use

of controlled substances have a substantial and

detrimental effect on the health and general welfare

of the American people’ [sec. 101(2)], Congress set

forth a framework for restricting a defined list of

substances, many of which are drugs with beneficial

as well as harmful uses.

The Act established five categories, or schedules,

of controlled substances based on potential for

abuse, severity of possible harmful effects, likelihood of dependence, and accepted medical uses [sec.

202; 28 CFR]. The Act grants the Attorney General

and the Department of Justice authority to regulate

and enforce the control of scheduled substances and

to add to, remove from, or amend the schedules as

appropriate.

The Controlled Substances Act calls for cooperation between FDA and the Justice Department in

determining which drugs should be controlled. In

addition, FDA is directed to notify the Justice

Department whenever “a new drug application is

submitted . . . for any drug having a stimulant,

depressant, or hallucinogenic effect on the central

nervous system, [and] it appears that such drug has

abuse potential” [sec. 201(f)]. Thus, the primary

scientific and pharmacological investigations, including evaluations of toxicity or of effects on the

central nervous system, are handled under the FDA

procedures described under FFDCA.

Marine Protection, Research, and

Sanctuaries Act

Finding that “unregulated dumping of material

into ocean waters endangers human health, welfare,

and amenities, and the marine environment” [sec.

2(a)], Congress enacted the Marine Protection,

Research, and Sanctuaries Act (MPRSA) (Public

Law 92-532) in 1972 to:

. . . regulate the dumping of all types of materials into

ocean waters and to prevent or strictly limit the

dumping into ocean waters of any material which

would adversely affect human health, welfare, or

amenities, or the marine environment, ecological

systems, or economical potentialities [sec. 2(B)]

[emphasis added].

Materials are defined as:

. . . matter of any kind or description, including, but

not limited to, dredged material, solid waste, incinerator residue, garbage, sewage, sewage sludge, munitions, radiological, chemical, and biological warfare

agents, radioactive materials, chemicals, biological

and laboratory waste, wreck or discarded equipment
Chapter 7—The Federal Regulatory Response . 189

Photo credit: U.S. Environmental Protection Agency

rock, sand, excavation debris, and industrial, municipal, agricultural, and other waste [sec. 3(c)].

The Act prohibits dumping of the defined materials

in U.S. territorial waters and 12 miles beyond U.S.

boundaries unless the dumper obtains a permit.

MPRSA does not establish any program or

requirement for ascertaining the toxic effects of

materials nor any mechanism by which specific,

newly identified toxic materials may be added to the

list. EPA has restricted or prohibited the dumping of

several categories of substances because of toxic or

radioactive effects or persistence. Mercury and

mercury compounds—known neurotoxicants—are

among the compounds specifically restricted (40

CFR 227.6), although the regulations do not mention

neurotoxic effects in particular.

. EPA’s primary regulatory responsibility under

MPRSA has been control of ocean dumping sites

through the permitting process (40 CFR 220-31).

EPA has delegated this authority to regional EPA

administrators (52 FR 25009). EPA considers the

impact of the proposed dumping on ‘‘aesthetic,

recreational, and economic values, ” including the

“[presence in the material of toxic chemical constituents released in volumes which may affect

humans directly” (40 CFR 227.18). Apart from

restrictions on mercury, however, there is no clear

record of how or whether specific neurotoxic effects

have been regulated under MPRSA.

Lead-Based Paint Poisoning Prevention Act

and Poison Prevention Packaging Act

The Lead-Based Paint Poisoning Prevention Act

(LBPPPA) (Public Law 91-695) is the only statute

based primarily on concerns for neurotoxic effects

(see ch. 10). The purpose of the Act-to eliminate

lead-based paint poisoning—was to be accomplished by screening and testing children, removing

lead-based paint from buildings, and banning the use

of lead-based paint in Federal construction or

rehabilitation of residential housing. The 1973

amendments (Public Law 93-151) defined leadbased paint as any paint which contains 0.06 percent

lead. That 0.06 percentage was based on studies

indicating the permissible daily intake of lead to be

300 micrograms, which the U.S. Public Health

Service and the American Academy of Pediatrics
Household substances

then calculated to be a limit

percent lead by weight.

Photo credit: U.S. Environmental Protection Agency

that pose a risk to children are regulated under the Poison Prevention Packaging Act.

of no more than 0.06

The Act was amended again in 1976 by the

National Consumer Health Information and Health

Promotion Act, which instructed the CPSC:

. . . to determine, by December 23, 1976, whether a

level of lead in excess of 0.06 percent but not over

0.50 percent, was safe. If the Commission were

unable to determine a safe level of lead in this range,

paint manufactured after June 22, 1977, containing

more than 0.06 percent would be considered ‘‘leadbased paint” (42 FR 44193).

The CPSC later ruled that available data did not

support the establishment of a level in this range as

being safe (42 FR 44193), so the 0.06 percent level

remained in effect.

The Poison Prevention Packaging Act (PPPA)

(Public Law 91-601) was enacted in 1970 to prevent

inadvertent poisoning of small children by hazardous household substances. Packaging of these substances was to be done in such a way as to make it

“significantly difficult for children under 5 years of

age to open or obtain a toxic or harmful amount of

the substance therein within a reasonable time’ [sec.

2(4)]. The Act authorizes the CPSC to promulgate

standard-setting rules for special packaging if the

Commission determines that:

. . . the degree or nature of the hazard to children in

the availability of such substance, by reason of its

packaging, is such that special packaging is required

to protect children from serious personal injury or

serious illness resulting from handling, using, or

ingesting such substance [sec. 3(a)(l)] [emphasis

added].

The Act encompasses hazardous substances as

defined in the Federal Hazardous Substances Act;

foods, drugs, and cosmetics as defined in the

FFDCA; and fuels packaged for household use.

Because LBPPPA and PPPA are designed to

control acknowledged problems, most regulatory

actions undertaken by the CPSC under these two

statutes are aimed at enforcement. Under LBPPPA,

the Commission may conduct periodic measure-
Chapter 7—The Federal Regulatory Response . 191

ments to ensure that lead in paints does not exceed

the mandated level. Under PPPA, the only regulatory option is for CPSC to require protective

packaging of hazardous household substances that

are identified or designated as toxic by other statutes

or agencies; PPPA has little impact on the substantive regulation of toxic substances.

Resource Conservation and Recovery Act

The Resource Conservation and Recovery Act

(RCRA) directs EPA to identify and list hazardous

wastes. Generators, transporters, and facilities that

treat, store, or dispose of such wastes are then subject

to regulations promulgated by the Administrator as

necessary to protect human health and the environment” [sec. 3002(a)] [emphasis added]. A hazardous waste is defined as a:

. . . solid waste, or combination of solid wastes,

which because of its quantity, concentration, or

physical, chemical, or infectious characteristics may:

(A) cause, or significantly contribute to, an increase

in serious irreversible, or incapacitating reversible, illness; or

(B) pose a substantial present or potential hazard to

human health or the environment when improperly treated, stored, transported, or disposed of,

or otherwise managed [sec. 1004(5)] [emphasis

added].

EPA classifies a solid waste as hazardous based

on ignitability, corrosivity, and reactivity, as well as

on various toxicity criteria, including fatality at low

doses or the capability of “causing or significantly

contributing to an increase in serious irreversible, or

incapacitating reversible, illness’ (40 CFR 261).

Toxic wastes are designated on the basis of the

nature of the toxicity of the constituent, its concentration, and its persistence (40 CFR 261.1 1). The

statute allows for direct measurement of waste

toxicity in some cases.

EPA has adopted standards based on the chronic

health limits defined under the National Primary

Drinking Water Standards; consequently, the same

eight chemicals that were identified for neurotoxic

concerns under the SDWA are regulated under the

Resource Conservation and Recovery Act.

NEW INITIATIVES IN

REGULATING NEUROTOXIC

SUBSTANCES

A primary issue in regulating potentially neurotoxic substances is the adequacy of the data on which

evaluations are based. Representatives of Federal

regulatory agencies disagree on whether or how well

current toxicity tests predict neurotoxic effects of

chemicals on humans. Consequently, new initiatives

for regulating neurotoxic substances have emerged

in agencies dissatisfied with existing approaches.

The first tangible result of attempts to improve

regulatory testing for neurotoxic effects was the

publication in 1985 of a set of neurotoxicity test

guidelines by EPA’s Office of Toxic Substances.

The primary purpose of these guidelines was to aid

development of test rules under section 4 of TSCA

(50 FR 39458). The significance of the guidelines is

demonstrated by the fact that, since they were

introduced, experimental protocols based on them

have been incorporated into a substantial number of

test rules and consent agreements. Studies to validate the scientific utility of the guidelines are now

under way.

The two most notable ongoing regulatory initiatives concerning neurotoxicants are also centered on

development of test guidelines. These initiatives,

one by EPA and one by FDA, are discussed in the

sections that follow. A third new initiative, which is

less a change in neurotoxicity regulation than an

attempt to obtain international consensus on changes

already made by EPA, is an EPA proposal to the

United Nations Organization for Economic Cooperation and Development (OECD) to add a mammalian neurotoxicity screening battery to OECD’s test

guidelines.

Revision of EPA’s Neurotoxicity Test

Guidelines for Pesticides

Recent efforts at EPA to coordinate evaluations of

neurotoxicity under TSCA and FIFRA highlight

some of the differences that have existed between

the regulatory programs of the Office of Toxic

Substances and those of the Office of Pesticide

Programs (OPP). When OTS published its neurotoxicity guidelines in 1985, its Health and Environmental Review Division had been employing neurotoxicologists for several years, reflecting OTS’s

approach of having chemicals reviewed by several
192 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

scientists with different areas of toxicological expertise. In contrast, OPP’s Hazard Evaluation Division

has traditionally assumed equivalency of training

among its toxicologists, which may have fostered

some reluctance on OPP’s part to focus on specific

organ system tests, including neurotoxicity tests, in

its evaluations. Since 1986, OPP has consulted OTS

neurotoxicity test guidelines when requesting data

on the neurotoxicity potential of pesticides. In that

year, OPP also hired two neurotoxicologists previously employed by OTS.

Adoption of neurotoxicity testing guidelines by

OPP was delayed by uncertainties regarding revision of FIFRA by Congress in late 1986, but plans

to add neurotoxicity guidelines to those specified in

40 CFR 158 continued in 1987. Work on the

guidelines received further impetus in February

1987, when a coalition including the Center for

Science in the Public Interest (CSPI) and 11 other

groups and individuals petitioned EPA to develop

methods for assessing neurotoxic effects of active

and inert ingredients in pesticides (10). OPP submitted its response to a subpanel of the FIFRA Science

Advisory Panel (SAP) for review in October 1987,

but SAP’s approval of those guidelines was superseded by a decision to revise all of the part 158

guidelines, eliminating tests that are outmoded or

uninformative and adding tests in several areas,

including neurotoxicity and immunotoxicity.

In May 1988, the director of OPP met with

representatives of CSPI and other groups who had

signed the petition. In August 1988, CSPI sent a

letter to EPA’s administrator for pesticides and toxic

substances suggesting several modifications of the

revised guidelines approved by SAP. CSPI called for

routine conduct of chronic neurotoxicity studies

(rather than just when acute and subchronic studies

indicated neurotoxic effects) and for inclusion of

schedule-controlled operant behavior and developmental neurotoxicity tests on a regular basis (see ch.

5 for descriptions of these tests). CSPI also pressed

for revision of the pesticide assessment guidelines

(46) rather than promulgation of a regulation to add

new data requirements to 40 CFR 158.

EPA responded with a letter to CSPI in November

1988, stating that the Agency intended to adhere to

the guidelines recommended by the SAP subpanel

and that it was still considering appropriate criteria

for initiating tests beyond the base set of tests. EPA

agreed to modify the pesticide test guidelines but

stressed the need to coordinate OPP and OTS

guideline revisions through an intra-agency work

group. Draft EPA guidelines were supposed to be

completed by February 1990 and made available for

public comment in May 1990.

Meanwhile, efforts to improve neurotoxicity testing requirements through the 1988 amendments to

FIFRA resulted in changes in the principal report

accompanying these amendments. Section 219 of S.

1516 (reported by the Senate Agriculture Committee

in May 1988) would have required the EPA Administrator to “develop methods for testing to accurately detect neurotoxic and behavioral effects of

pesticides, and their ingredients,” and “as such

methods are developed, require to the extent appropriate and necessary that data from such testing be

submitted by persons seeking to obtain or maintain

pesticide registrations.” This provision was not

included in the amendments finally enacted, but the

House Agriculture Committee’s report on the bill

that became law noted the deficiencies of EPA’s

current neurotoxicity testing and called for improvements:

In light of recommendations made by a number of

scientific and public health organizations urging

expanded neurotoxic and behavioral testing, the

Committee requests that EPA intensify the degree of

such testing in its pesticide program, including

testing related to chronic exposure, prenatal, and

neonatal effects (26).

At present, scientists in OPP and OTS are working

together to produce a set of revised neurotoxicity test

guidelines (see ch. 5). The test guidelines will be

accompanied by risk assessment guidelines to direct

the scientific review of the data they provide (box

7-G).

Revision of the FDA’s Red Book for

Food and Color Additives

FDA’s Center for Food Safety and Applied

Nutrition has been considering the utility of specific

tests for neurotoxic effects for several years. In

9The co-petitioners were the State of New York, the Wisconsin Public Intervener’s Office, the Natural Resources Defense Council, the National

Coalition Against Misuse of Pesticides, the Northwest Coalition for Alternatives to Pesticides, the American Psychological Association, the American

Public Health Association, the Association of Children and Adults with Learning Disabilities, the U.S. Public Interest Research Group, and Drs. Philip

J. Landrigan and Richard E. Letz, Mount Sinai School of Medicine.
Chapter 7—The Federal Regulatory Response ● 193

Box 7-G-Flexibility in Neurotoxicological Testing

One controversy that has arisen with the introduction of neurotoxicity test guidelines by the Environmental

Protection Agency (EPA) is the assertion by some scientists that test guidelines impose excessively rigid limitations

on toxicological testing. These scientists, both inside and outside regulatory agencies, have stated that test

guidelines result in testing that may ignore important parameters influencing a chemical’s toxicity, preclude the

effective use of expert scientific judgment, and stifle innovation in testing.

While acknowledging the validity of some of these objections, scientists favoring test guidelines have observed

that the purpose of most toxicological testing in the regulatory context is not elucidation of mechanisms of toxicity,

but rather clarification of the relative toxic hazards posed by various chemicals. (FDA’s preclinical studies of drugs

represent an exception to this generalization.) If toxicity test protocols are designed independently for each chemical

under review, it becomes nearly impossible to compare chemicals.

Scientists with opposing views on this issue have also advanced arguments on practical grounds. Those

opposed to test guidelines have stated that few contract laboratories have the capabilities to perform all of the

neurotoxicological tests specified in the current EPA Office of Toxic Substances’ guidelines. (However, scientists

at contract testing laboratories have stated that they can implement any test procedures that are supported by an

adequate market.) Opponents of test guidelines have also noted that the laboratories frequently lack an adequate set

of control data to demonstrate the validity and reliability of tests. Regulatory scientists have noted that the

requirements of Federal rule-making procedures would make designing new studies for each chemical of concern

an extremely protracted process. (In practice, regulatory agencies have sometimes negotiated the performance of

tests that differ substantially from those specified in the guidelines.)

One compromise (which has received extensive discussion but apparently little effort toward implementation)

is the specification of test guidelines in terms of sensitivity. Sensitivity could be defined as the detection of effects

of known toxicants (positive control studies) or as the detection of a specific decrease in neurological function (e.g.,

a 30-degree narrowing of the visual field). Such a specification would provide for both scientific judgment and

consistency across tests of different agents.

In some areas of neurotoxicity testing, either form of sensitivity specification appears to be workable. This is

the case for tests of basic sensory functions, because there is wide agreement among scientists on functional

definitions, and probably also for various tests of motor function. It may also be possible to achieve consensus on

the sensitivity of various approaches to neuropathological examinations. Tests of more complex neural function,

such as learning, while amenable to specification in terms of positive control studies, provide much greater

challenges to other forms of validation. There is still considerable debate concerning the validity of various

measures of complex neural function (see ch. 5), and debates over the relative merits of test strategies are likely to

persist for some time.

SOURCE: J.S. Young and W.R. Muir, ‘‘Survey of Major Toxicology Testing Laboratories on the Use of Organ Function Tests in Toxicology,’

prepared for the U.S. Environmental Protection Agency, EPA contract No. 68-024228, work assignment No. 121415, Washington,

DC, September 1986.

September 1985, it sponsored a conference on effects during any of the fret-tier tests. (These tests

‘‘Predicting Neurotoxicity and Behavioral Dysfunction from Preclinical Toxicologic Data, ” administered by the Life Sciences Research Office of the

Federation of American Societies for Experimental

Biology. At this conference, a panel of scientists

from academia, industry, and government recommended a two-tiered approach to neurotoxicological

evaluations: the first was a screening test, which

included either a functional observational battery or

a motor activity test, or both, with the use of

structure-activity information as appropriate; the

second contained more detailed tests, to be conducted on substances that produced neurotoxic

are described in more detail inch. 5.) This approach

is comparable to the screening required by EPA’s

OTS guidelines, although the FDA panel did not

request direct neuropathological examination.

Since the 1985 meeting, CFSAN has continued to

consider revision of the Red Book guidelines for

testing of food and color additives. CFSAN scientists considered including some neurotoxicity tests

but perhaps not the full range of tests specified in the

OTS guidelines. FDA believes that, in order to

impose additional testing requirements on industry,

it must demonstrate that the tests would increase the
194 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

ability to detect neurotoxicants. CFSAN is seeking

to demonstrate the utility of proposed neurotoxicity

tests by supporting extramural research efforts that

focus on neurochemical measures, animal behavior,

and measurements of human performance.

The proposed CFSAN guidelines differ from the

OTS guidelines in several respects. For example,

FDA is reluctant to recommend screening tests that

require specific instrumentation, because agency

officials believe that requiring industry to procure

potentially expensive new instruments would be

difficult to justify if less expensive methods would

produce adequate data. FDA is also reluctant to

require specific neuropathological examinations as

screening tests, instead reserving such studies, and

behavioral studies requiring instrumentation, as

second-tier tests for compounds that give indications

of being neurotoxic. Finally, CFSAN is unlikely to

include any structure-activity considerations in its

proposed neurotoxicity guidelines. CFSAN has yet

to develop a specific proposal for a set of neurotoxicity tests or for indicators requiring the performance

of such tests.

Suggested Revisions of OECD Toxicity

Testing Guidelines

In 1986, EPA, as the designated U.S. representative to the OECD committee for updating toxicity

testing guidelines, suggested adding a mammalian

neurotoxicity screening battery, which includes

elements of the OTS functional observational battery, motor activity test, and neuropathology evaluation (see ch. 5). The new battery would be more

generally used, while the OECD’s current neurotoxicity guidelines, which specify hen tests, would be

used for delayed organophosphate toxicity. In accordance with OECD updating procedures, the proposal

was circulated to member countries for review. EPA

subsequently revised the guidelines, and the complex OECD procedure for convening expert panels

was begun.

CONSISTENCY OF FEDERAL

REGULATION OF NEUROTOXIC

SUBSTANCES

General Toxicological Considerations

There are numerous differences in regulatory

practice under different laws, even within the group

of licensing laws (FFDCA, FIFRA, and TSCA). For

the most part, these differences do not apply

specifically to the regulation of neurotoxic effects,

but rather to regulation of all toxic effects. Thus,

consistency of regulation for specific neurotoxic

effects hinges on consistency of regulation in

general (14).

Consistency of Regulatory Requirements

Statutory requirements for chemical regulatory

programs differ in several important respects, among

them the number of chemicals evaluated, the time

available for review, the amount and type of data

available at the beginning of the review process, the

ability of the reviewer to acquire additional data

after review has begun, and the burden of proof

regarding safety. For example, the premanufacture

notice process under TSCA necessitates review of

hundreds of chemicals every year; each review is

allotted only 90 days (although an extension is

possible), and substantive toxicity data are rarely

submitted. EPA can obtain additional data or impose

controls on chemicals only if it finds that there may

be an unreasonable risk associated with use of the

chemical. Indeed, critics charge that the procedural

complexities of TSCA incorporated in the statute

impose a considerable administrative burden on

EPA and render any action under the law difficult. In

contrast, under FIFRA, applicants for registration of

a pesticide must submit extensive toxicological data

and follow specified test protocols, the review

process extends over a period of years, the applicant

is required to submit additional data if the basic data

set raises concerns, and the applicant must establish

that the pesticide will be both safe and effective

under the proposed conditions of use. Thus, legislation is the root of some regulatory inconsistency,

although there is little in legislative language that

would preclude a significant increase in intra- and

interagency cooperation and coordination.

Consistency of Protection

That there are differences in the degree of scrutiny

under different regulatory programs is widely acknowledged. What is less certain is that these

differences correspond to differences in the degree

of protection offered by the laws and regulations.

Often, these disparate requirements reflect real

differences in the potential risks posed by the

chemicals each program regulates. It maybe that the

more intense scrutiny reserved for some types of

chemicals is an appropriate reflection of the likeli-
Chapter 7—The Federal Regulatory Response . 195

hood that they will harm human health or the

environment.

Current laws are generally based on the premise

that chemicals for which there is a greater probability of exposure should meet a higher standard of

safety. This is most clearly illustrated by explicit

prohibition of carcinogenic substances as direct food

additives and of pesticides that become concentrated

in foods [FFDCA Delaney clause, sec. 409(c)(3),

706(b)(5)(B)]. No such blanket prohibition applies

to general industrial or commercial chemicals (regulated under the OSH Act and TSCA), in part because

there is less certainty concerning the likelihood of

human exposure to many of these chemicals. Some

critics of the mechanisms by which industrial and

commercial chemicals are regulated argue that these

laws do not adequately protect the public’s health.

The case is similar for chemicals causing noncarcinogenic toxic effects, which can be divided into

chemical classes on the basis of both inherent hazard

and expected level of exposure. Chemicals in

commerce make up a vast universe—more than

60,000 identifiable chemicals are in EPA’s invenPhoto credit: U.S. Environmental Protection Agency

tory. Many of these chemicals may be present in

industrial settings, and a large subset of them is

present in consumer products. Pesticides, broadly

defined, form a slightly smaller universe, but the

number of active ingredients used on foods is much

smaller (approximately 600). These differences in

the size of chemical classes are reflected in the

number of new members of each class introduced

each year.

The stringency of the evaluation process for new

chemicals under the various laws generally matches

the presumption of risk-the combination of hazard

and exposure potential-posed by each class and the

number of new class members introduced each year.

Thus, drugs are not to be permitted to enter the

market until proven safe and effective in clinical

trials. New pesticides and food additives are evaluated nearly as stringently; however, human trials are

not performed. Commercial chemicals, whether

intended for industrial or consumer use, receive the

least scrutiny.

There are two exceptions to these trends, one

minor and one significant. Consumer chemicals
196 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

have not received any procedurally different scrutiny than those intended for industrial use, despite

the fact that larger numbers of persons may be

exposed as consumers than as industrial workers.

(EPA does take exposure patterns into account in

evaluating chemicals in commerce.) Of much greater

potential importance is the fact that cosmetics are

not required to undergo premarket toxicity testing.

Industry voluntarily tests cosmetics and cosmetic

ingredients for acute toxic effects, but few are

examined for chronic toxicity. Some have been

found to have acute and chronic neurotoxic effects

on laboratory animals.

While many scientists find some comfort in the

observation that the stringency of review of a

chemical matches its presumptive risk (except for

cosmetics), public interest groups and others have

voiced concerns over such odds playing. The transition of chemical regulation in general from “assurance of safety” to “acceptable risk” remains a

source of contention (16). A less comforting observation, even to scientists, is that the stringency of

review of a chemical is often inversely proportional

to the size of the class of chemicals to be reviewed.

For example, chemicals under TSCA make up the

largest chemical class, yet they receive relatively

little scrutiny under the normal premanufacture

notice process. Critics of EPA argue that regulatory

resource considerations and a desire not to burden

industry, rather than presumptive risk, are in fact

driving chemical review criteria. (Economic considerations in regulating toxic substances are discussed

in ch. 8.) They raise the question of whether the

minimal screening given the majority of chemicals

is adequate to deal with high-risk chemicals that are

not members of known risk categories (see box 7-H).

Regulation of New v. Existing Chemicals

Existing chemicals in each of the classes considered above are subject to varying degrees of review

and reevaluation. In contrast to procedures for

reviewing new chemicals, however, procedures for

reexamining existing chemicals do not reflect the

inherent risks of the chemical classes involved.

Photo credit: U.S. Environmental Protection Agency
Chapter 7—The Federal Regulatory Response ● 197

EPA attempts to ensure the adequacy of data

supporting continued pesticide registration through

a regular review process. The registration standards

program, which examines 25 chemicals per year, has

thus far addressed only a small portion of the active

ingredients of registered pesticides. At the present

rate, active pesticide ingredients would be reviewed

on an average of only once every 12 years. The 1988

FIFRA amendments mandated that the review schedule be accelerated so that all active ingredients are

reviewed by 1997. To meet this goal, EPA will need

to streamline its existing review process. Pesticides

suspected of being associated with unusually high

risks are examined through a separate special review

program. EPA conducts special reviews of 12 to 15

chemicals per year, reaching final decisions on a

Under section 4 of TSCA, existing chemicals are

ranked for probable risk or high exposures before

they enter the test rule or consent decree process. In

the period from 1977 to 1988, final rules were issued

on only 25 chemicals or related sets of chemicals,

and consent decrees were reached on three, with nine

proposed rules pending. Clearly, these rules address

only a very small fraction of the 60,000 chemicals in

the TSCA inventory. Evidence that a chemical poses

a significant risk must be reported to EPA under

section 8(e), but no data need be developed to

evaluate the risks of most chemicals. Further evidence comes from sections 8(c) and 8(d) provisions,

which require that manufacturers maintain and make

available to EPA records of adverse reactions and

third of them. Thus, it addresses only a small fraction the results of unpublished toxicological investigaof the (presumably) high-risk pesticides. tions.

Box 7-H—TSCA’s Premanufacture Notice Program: Is More Toxicity Testing Feasible?

The thousands of new industrial and consumer chemicals manufactured each year are typically subjected to

far less toxicity testing and evaluation under the Toxic Substances Control Act (TSCA) than the smaller number

of new pesticide, food additive, and pharmaceutical chemicals registered under other Federal laws. Although TSCA

does require a premanufacture notice (PMN) process—all manufactures must notify the Environmental Protection

Agency (EPA) before they can begin the commercial manufacture or importation of a new chemical-the statute

does not demand that toxicity tests be conducted prior to notification. Consequently, few PMNs include any toxicity

information, much less data from specific tests for neurotoxicity. EPA must review PMNs for nearly 2,000 new

chemicals each year, and notwithstanding a paucity of data, EPA has only 90 or 180 days (depending on the type

of chemical) to examine each PMN and determine whether the new chemical presents a significant risk.

TSCA does grant EPA the authority to require additional testing or to impose restrictions on the use of a new

chemical if the Agency determines that the chemical will present an unreasonable risk. EPA has intervened in 10

to 20 percent of the PMNs reviewed annually to restrict the use of the chemicals; most of these actions have been

aimed at lowering potential human exposure. In some cases, chemicals were withdrawn from consideration. In other

cases, EPA has been successful in requiring manufacturers to conduct significant additional testing.

Critics have decried the lack of more comprehensive testing for this large set of chemicals. They argue that

the public health cannot be adequately protected by the minimal testing conducted under TSCA. Why, they ask,

doesn’t EPA require more testing for toxic effects? It is not because the statute has proven defective: whenever EPA

has intervened during PMN review, the Agency has prevailed. Nor is it because scientists in the Office of Toxic

Substances (OTS)—the scientists responsible for reviewing PMNs—have substantially different views than their

counterparts in other regulatory programs of what constitutes adequate testing.

Testing policies under TSCA are defended on the basis of practical reality: TSCA program officials rebut the

charge of insufficient toxicity testing by arguing that the amount of testing being pursued under TSCA is all that

can reasonably be required under the circumstances. They note that most new industrial and consumer chemicals

have small, uncertain markets and that significant additional testing would cost more than the market for the

chemical could cover—in effect banning the chemical based solely on a lack of information about it rather than

on any concern or even suspicion about it. Furthermore, OTS scientists point out that EPA does take action against

chemicals with high anticipated production volumes (and thus with substantial potential for human exposure) and

chemicals suspected of causing adverse effects. Thus, they view the amount of testing of new chemicals being

sought under TSCA to be the only feasible amount unless (or until) less expensive, reliable testing methods are

developed that could reasonably be sought for a wider number of chemicals.

SOURCE: Office of Technology Assessment, 1990.
198 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

FDA’s procedures for reviewing existing drugs

and food and color additives are less formal than

those for pesticides or toxic substances. The Center

for Drug Evaluation and Research tracks physicians’

reports of adverse drug reactions and relays them to

the original evaluators of the drugs. Food and color

additives have been notable exceptions to the review

of existing chemicals. Until recently, there was no

formal monitoring of adverse reactions after an

additive was registered. For aspartame, CFSAN

established voluntary reporting programs and subsequently requested that physicians and other health

professionals inform it of any severe, welldocumented reactions associated with foods, food

additives, or dietary practices.

Although CFSAN does not require reporting on

the use of approved food and color additives, it could

track such information and use it to assess the risks

associated with approved uses. Under the PriorityBased Assessment of Food Additives Program, a

database on uses, levels in food, toxic effects, and

chemical structure was created. This system should

enable CFSAN personnel to compare new toxicity

data to current use patterns or proposed changes in

use and to search for predictive trends (e.g., correlations of particular functional groups with toxic

effects). Without the ability to actively update

information, however, this system may be of limited

use for regulatory purposes.

Redundancy of Effort Among Agencies

The definitions of the classes of chemicals addressed in the various statutes have minimized

redundancy of regulatory effort. While some chemicals have multiple uses and may be regulated under

two or more different laws-e. g., pesticide compounds that also have industrial applications—the

different uses dictate different risk evaluations.

Under standard-setting and control-oriented laws,

toxicity and risk evaluation are usually driven by

considerations of probability of exposure; and differences in exposure potential probably preclude

redundancy in the evaluation process. Although

greater coordination among the standard-setting and

control-oriented programs might be worthwhile,

available evidence suggests that these programs

devote relatively little effort to evaluating toxic

hazards and much more to evaluating the risks posed

by particular patterns of exposure.

Integration of Effort

EPA is the only regulatory agency discussed in

this chapter responsible for implementing a number

of very different laws. Other agencies considered in

this chapter address only one law or a few closely

related laws. The division of labor among regulatory

agencies raises the question of how well regulatory

efforts are being integrated within and between

agencies.

EPA, which is charged with implementing seven

regulatory programs under eight of the laws reviewed, does appear to be actively engaged in

integrating regulation. Although some integration

efforts have been initiated by legislation, the Agency

has undertaken a number of initiatives on its own in

the recent past. For example, OTS issued a section

4 test rule on chemicals referred by the Office of

Solid Waste Management under CERCLA; MCLGs

and MCLs have been issued for hazardous waste

chemicals that might affect drinking water, even if

they have rarely been detected in drinking water; and

the drinking water priority list for regulation explicitly includes both pesticides and chemicals listed for

priority review under SARA, Another example of

recent efforts in regulatory integration is the attempt

to produce consistent neurotoxicity test guidelines

for both pesticides and toxic substances. Also, EPA

is working to consolidate all its risk assessment

information into the Integrated Risk Information

System (IRIS). Finally, the creation of a discrete

Regulatory Integration Division in EPA’s Office of

Program Planning and Evaluation suggests a commitment to consistent regulation. The creation of a

formal neurotoxicity working group, which would

indicate an EPA commitment to regulatory integration for the specific concern of neurotoxicity, has

been proposed.

There is less evidence of attempts at regulatory

integration across Federal agencies than within

EPA. There is some collaboration on research but

little coordination of regulatory efforts (see app. B).

This may be due, in part, to the different-and

sometimes conflicting-statutes. Legal requirements

for dealing with confidential business information

pose barriers to sharing data in some cases; more

important is the focus of agency personnel on

internal priorities, which does not foster interagency

cooperation. The apparent lack of coordination is

sometimes quite striking. For example, NIOSH is

required by Congress to recommend exposure limits
Chapter 7—The Federal Regulatory Response . 199

for OSHA, but OSHA has rarely acted on those

recommendations. In its recent rule, OSHA showed

a decided preference for values recommended by the

ACGIH, despite the fact that NIOSH had established

recommended exposure levels (RELs) for 5 of the 20

compounds listed as neuropathic and that four of the

five were lower than ACGIH’s TLVs. OSHA would

be expected, in some cases, to set PELs that were

higher than NIOSH’s RELs, based on technological

and economic feasibility. ACGIH TLVs, however,

are derived by a completely different process. OSHA

appears to be giving equal or greater weight to the

views of a private organization than to those of the

agency created to supply it with health assessments.

Specific Neurotoxicological Considerations

Regulatory differences in general strategies for

evaluating toxicity entail corresponding differences

in the evaluation of neurotoxic effects. Thus for

human therapeutic drugs, preclinical toxicity tests

are used only to guide observations on clinical trials

and to elucidate possible mechanisms of toxicity

rather than to assess toxic potential directly. For

pesticides and food and color additives, in contrast,

animal toxicity data are used directly in predicting

human risk. However, even within programs that

have essentially similar approaches to assessing

toxic risks, there are differences with respect to

consideration of neurotoxic risks.

Consistency of Protection

Regulatory programs have adopted one of three

basic approaches to toxicity evaluation, depending

on which of three underlying assumptions they hold.

One approach is based on the assumption that

general toxicity tests using high doses are adequate

to detect neurotoxic potential and that specific

neurotoxicological evaluations are needed only if

general tests, data on structural analogs, or other

specific knowledge about a chemical indicates a

potential for neurotoxicity. Among these are FDA’s

preclinical testing program for drugs and its current

program for approving food additives. The second

approach, represented by the pesticide registration

program under FIFRA, accepts more general structural information in guiding neurotoxicity testing.

All organophosphorous compounds are evaluated

for their potential to induce delayed neuropathy, but

nonorganophosphorous compounds are not specifically evaluated for neurotoxic potential. All pesticides undergo a general toxicity screen; however,

specific neurotoxicity tests are not conducted. Finally, under section 4 of TSCA, specific neurotoxicity testing is required for any chemical with high

exposure potential, as well as for chemicals specifically suspected of being neurotoxic. Such testing

presumes that standard toxicity tests are not adequate to evaluate neurotoxic effects.

OTA found that Federal efforts to control neurotoxic substances vary considerably between agencies and between programs within agencies. Improving the Federal response will require increased

neurotoxicity testing, improved monitoring programs, and more aggressive regulatory efforts.

Whether these different testing procedures correspond to different levels of protection depends

entirely on which assumption regarding the sensitivity of standard toxicological tests is correct. Scientists inside and outside of Federal regulatory agencies have expressed a range of opinions regarding

the desirability of singling out neurotoxicity as an

effect of concern. Many argue that neurotoxic effects

cannot be identified without undertaking specific

tests. Others argue that there is no more justification

for including neurotoxicity tests than for including

immunotoxicity (immune system), cardiotoxicity

(heart), hepatotoxicity (liver), nephrotoxicity (kidney), or other organ system tests as part of a standard

test battery. These scientists believe that general test

protocols in which high doses are used will be

sensitive detectors, if not elucidators, of neurotoxicity. Other scientists argue that potential noncancer

health effects in general receive too little scientific

and regulatory attention and believe that greater

emphasis should be placed on all noncancer health

risks.

There is a correlation between the opinions

expressed and the actual testing approach of the

program in which a particular scientist works. The

wide diversity of opinions expressed by knowledgeable scientists reflects individual views on the extent

to which existing regulatory programs are protecting

public health and the environment from noncancer

health risks.

In principle, a study to evaluate whether neurotoxicity testing detects effects that would be missed by

conventional toxicity tests is easy to design. However, to be truly predictive for regulatory purposes,

such a study would have to address a large number

of toxicologically dissimilar compounds. No such

study has yet been designed. FDA did sponsor a
200 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

review of whether conventional toxicity testing was

adequate for the prediction of neurotoxic potential

(18). This review consisted of the deliberations of an

ad hoc expert panel and a symposium. The panel

concluded that explicit neurotoxicological evaluations should be incorporated into toxicity testing,

using a tiered-testing scheme. However, its report

did not present objective evidence of improvements

in test sensitivity as a result of neurotoxicological

testing.

As part of its effort to develop neurotoxicity test

guidelines, OTS sponsored a retrospective comparison of neurotoxicity tests with standard toxicity tests

for chemicals inducing narcosis, as well as a

comparison of acute and chronic neurotoxicity tests

that addressed a somewhat broader range of chemicals (7,8). The choice of chemicals that induce

narcosis tends to bias the comparison in favor of

conventional tests, because this effect is relatively

easy to detect.

The OTS-sponsored studies found greater sensitivity in acute tests when specific neurotoxicological

evaluations were performed-i. e., the lowest observed effect levels were lower for a majority of the

25 compounds evaluated (effects in humans were

reported at even lower levels). Considerably greater

sensitivity was shown by repeated-dose studies.

Some compounds produced qualitatively different

neurotoxic effects after repeated dosing, and others

showed irreversible effects after repeated, but not

acute, tests. Quantitative extrapolation from acute

tests was found to underpredict toxicity from repeated exposures. The OTS studies suggest that

conventional toxicity tests, especially acute highdose tests, are not an adequate substitute for

neurotoxicological evaluations. The validity of this

conclusion for a broader range of compounds has not

yet been established.

Coordination Among Agencies

Interviews with toxicologists and neurotoxicologists in various Federal agencies indicated that there

has been, until recently, little formal coordination

among agencies (see app. B). Regulatory scientists

are generally aware of the views of their colleagues

in other agencies. There are also several coordinated

research efforts mediated by interagency agreements

and by personal contact.

Contact among neurotoxicologists at different

Federal agencies has not, however, fostered any

Photo credit: U.S. Environmental Protection Agency

unanimity of opinion on the best approach to

regulating neurotoxic hazards. Real differences of

scientific opinion remain, and data that would

resolve these differences have not been developed

by the agencies involved. Moreover, even within

agencies, neurotoxicologists and other toxicologists

sometimes disagree on the proper role of neurotoxic -

ity in safety evaluations.

An agency’s approach to evaluating neurotoxicity

often corresponds to the presence or absence of

neurotoxicologists on its staff. Although this presumably reflects personnel considerations-if an

agency is not evaluating neurotoxicological data, it

does not require people trained to do so-it does

raise the question of whether persons who evaluate

general toxicological data understand the contributions of directed testing to the prediction of neurotoxic effects. General toxicologists are essential to

the review process, but individuals with specialized

expertise are often necessary to ensure a comprehensive evaluation. Variations in the perceived need for

staff neurotoxicologists reflect a more general problem of toxicological assessment, that of determining

the appropriate degree of specialization required to
Chapter 7—The Federal Regulatory Response ● 201

evaluate the many organ systems potentially affected by a toxic substance.

The Federal regulatory response to neurotoxicity

is fragmented not only by differences in scientific

judgment, but also by differences in regulatory

responsibility. The decision to evaluate drugs, pesticides, and food additives by stricter standards than

are applied to commercial chemicals is not based on

the views of scientists in regulatory agencies, but on

national consensus, as expressed through Congress.

The Value of Establishing a Minimal Data Set

The most striking difference in regulatory programs is between those that require routine testing of

all chemicals submitted for review and those that

must establish some probability of unacceptable risk

in order to require the manufacturer to submit data.

These differences tend to reflect both a legislative

consensus regarding the hazards posed by different

classes of chemicals and the sheer number of

chemicals in each class that require review. If

neurotoxic effects of chemicals are difficult to

predict, it might follow that any regulatory scheme

that does not routinely test for neurotoxicity offers

diminished or insufficient protection.

If no changes are made in the laws with respect to

which kinds of chemicals do and do not require

premarket testing, the issue becomes one of whether

there is a sound reason to require comparable tests in

the several programs that already require premarket

testing. Scientists charged with reviewing toxic

hazard data in the various programs disagree over

the desirability of standardized test guidelines in

general, and standardized neurotoxicity evaluations

in particular. EPA scientists have argued that

standardization provides a distinct advantage for

comparing the hazards posed by disparate chemicals, while FDA scientists counter that it is more

appropriate to design specific tests to assess expected toxic effects.

These arguments reflect real differences between

programs and the power to compel extensive testing.

FDA’s Center for Drug Evaluation and Research has

perhaps the broadest power to compel testing, both

preclinical and clinical, and is one of the strongest

advocates for flexibility in testing. On the other

hand, OTS must undertake arduous rule-making

procedures to issue test rules and must carry out

protracted negotiations to obtain consent decrees; it

is, perhaps, not surprising that OTS was the first

regulatory program to issue extensive neurotoxicity

testing guidelines. The presence of established

guidelines diminishes the number of testing issues

that have to be argued in each rule-making or

negotiation. The legal constraints on OTS—

companies need not conduct any testing beyond

what OTS explicitly rules-have favored a more

rigid and explicit approach to testing requirements.

There seems to be general, if not complete,

agreement among regulatory toxicologists that specific neurotoxicological evaluation is valuable, once

evidence of neurotoxicity has been detected. There

is also general agreement that such detailed evaluation should not be specified too rigidly but should

allow for flexibility in designing tests to fit particular

chemicals and to address particular questions.

ADEQUACY OF THE FEDERAL

REGULATORY FRAMEWORK

It is important to bear in mind that regulations

have implications reaching far beyond the letter of

the law. Thus, measuring regulatory effectiveness is

only one aspect of gauging the broader set of

regulatory impacts. For example, regulations impose direct or indirect costs on industry that affect

how industry conducts its business. These considerations are addressed in more detail in chapter 8.

Measurements of Effectiveness

Any attempt to measure the success of Federal

regulatory agencies in evaluating and controlling the

neurotoxic risks posed by chemicals depends on

having an independent measure of neurotoxic risks.

Finding such a measure is difficult. Two alternatives

are considered here. The frost is to compare the

proportion of chemicals detected and controlled as

neurotoxic substances by Federal regulatory programs to estimates of the proportion of chemicals

likely to have neurotoxic effects. The second is to

examine evidence of regulatory failures-i. e., misses

and false positives.

Expected and Detected Neurotoxicity

It is possible, for at least some regulatory programs, to estimate how many of the chemicals

evaluated were reviewed for neurotoxic potential or

identified as posing neurotoxic risks. Thus, in the

premanufacture notice program under TSCA, approximately 220 chemicals (4 percent of the approximately 5,500 chemicals reviewed during the life-
202 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

time of the law) have raised sufficient concern

regarding neurotoxicity to merit standard review. Of

the 220 chemicals receiving this detailed evaluation,

180 were judged to pose neurotoxic hazards, although in many cases other hazards were judged to

be more significant. Due to exposure limitations,

only 120 were judged to pose neurotoxic risks. Of

these, neurotoxicity was the driving concern in

approximately 12 cases.

It is difficult to establish whether the PMN

process is truly effective in assessing neurotoxic

risk. Generally, toxicity data to confirm the PMN

predictions are not available. Reports of significant

risk submitted under section 8(e) could be used to

identify regulatory failures resulting from inadequate review, but because chemical identities are

often claimed to be confidential business information, they are open only to internal scrutiny (see box

7-D).

Of the high-hazard or high-exposure chemicals

reviewed under section 4 of TSCA, 19 have been

considered for neurotoxicity evaluation since the

neurotoxicity test guidelines were issued; three of

these were judged not to require neurotoxicity

testing during the rule-making or consent decree

process. Three additional chemicals were proposed

for neurotoxicity testing prior to publication of the

test guidelines; one was the subject of negotiated

testing, a second was the subject of testing by

another program office, and a proposed test rule is

under development for the third. Of the chemicals

for which the Interagency Testing Committee recommended neurotoxicological evaluation, EPA disagreed on the need for such testing in only two cases;

in eight other cases, either testing was in progress or

potential exposures were determined to be minimal.

The chemicals evaluated for neurotoxic effects

represent a substantial fraction of the total number of

chemicals tested under section 4 of TSCA. There are

25 final test rules, seven of which include neurotoxicity testing; nine pending proposed rules, five of
Chapter 7—The Federal Regulatory Response ● 203

which include neurotoxicity; and three consent

decrees, two of which include neurotoxicity.

It is more difficult to gauge the extent of

neurotoxicity testing conducted under FIFRA.While

annual registration totals are available, OPP tracking

systems are not yet able to determine the number of

chemicals evaluated for adequacy of neurotoxicological data. Only EPN and acrylonitrile could be

identified as chemicals for which regulatory action

was taken on the basis of neurotoxicity. Other

pesticides are being evaluated for neurotoxicity, and

data call-ins have been issued, but EPA does not

have any accessible record of such data call-ins.

Applications for approximately 330 commercial

investigational new drugs are presented to FDA

every year; approximately 20 percent of these are

eventually approved. In recent years, perhaps 16

percent of the applications submitted have involved

neuropharmacological agents. Of the 54 neuropharmacological agents for which FDA reviewed IND

applications in 1988, nine were put on hold, two of

these because of concerns regarding their toxicity.

Only one of these was judged to be neurotoxic.

The FDA annually reviews approximately 60

indirect food additives, 10 direct food additives, and

10 color additives. Many of these involve potential

exposures sufficiently low that only the most basic

toxicity studies are performed. In the past 5 years,

only three chemicals have raised sufficient concern

regarding neurotoxic effects to be reviewed by the

neurobehavioral toxicity team; this represents less

than 1 percent of all applications received.

Under standard-setting or control-oriented legislation, it is not always possible to estimate accurately the proportion of chemicals regulated for

neurotoxic concerns, both because the number of

chemicals regulated is small and because these laws

address chemicals already determined to pose excessive risks. The latest rule proposed by OSHA on

permissible exposure limits clearly considers a large

number of chemicals (more than 400). Of the

approximately 300 for which a basis for a limit was

explicitly stated, 20 were indicated as causing nerve

damage and 19 as inducing drowsiness. Some

neurotoxic chemicals (e.g., methanol) are included

in lists for ocular effects, and the list of chemicals

regulated for biochemical or metabolic effects includes eight chemicals (out of 26) that inhibit, either

directly or indirectly, the production or activity of

cholinesterase.

Interpretation of these percentages depends on the

proportion of chemicals that would be expected to

have neurotoxic effects. Estimates of this proportion

have been made by several authors, and they vary

widely. For example, Anger and Johnson estimate

that there are more than 850 known neurotoxic

chemicals (4). Anger (3) reported that 167 of the 588

TLVs promulgated by the ACGIH in 1982 were

based at least in part on neurotoxic effects, while

Bass and Muir (9) determined that 202 of the 605

TLVs promulgated in 1984-1985 met a similar

criterion. In contrast, O’Donoghue (21), summarizing basic toxicity data obtained from Kodak for 448

high-volume chemicals, found only 12 to have

primarily neurotoxic effects. Of the 167 chemicals

listed by Anger, O’Donoghue found only 28 to have

neurodegenerative effects. Differences such as these

are also due in part to differing views regarding the

definition of neurotoxicity. The estimates given

above are not necessarily incompatible. For one

thing, they reflect different starting sets of chemicals. For example, ACGIH lists all chemicals for

which some toxic effect has been noted at or near

potential levels of exposure.

Monitoring Mechanisms

An alternative approach to assessing the effectiveness of regulatory programs in controlling neurotoxic hazards is to evaluate the rate of regulatory

failure. Unfortunately, while several of the licensing

programs have procedures that enable them to track

chemicals after approval, these programs have not

generally been used to assess the adequacy of the

original decisionmaking process.

The registration standards program under FIFRA

is aimed at identifying deficiencies in data that

resulted from earlier regulatory practice and assumes that current registration practices are appropriate. Reports of adverse reactions to drugs under

FFDCA consider a wide range of adverse effects but

are generally used on a chemical-specific basis.

Under TSCA, EPA receives and evaluates reports

that may indicate significant risks of chemicals in

commerce, some of which have been subject to

PMN review. These data have not been regularly

used to assess the adequacy of the PMN process.

EPA has, however, acknowledged the need to

review this process. Because EPA is forced to rely

substantially on structure-activity analysis, rather

than experimental data, in predicting the risks posed
204 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

by new chemicals, it has a particularly active interest

in assessing the accuracy of its efforts. In 1984, a

study was designed to obtain data on a small sample

of PMN chemicals that would be representative of

chemicals with the highest expected risk (those with

intrinsic hazard and high exposure); of these data

would be compared with the results of PMN risk

assessments to yield an estimate of the accuracy of

the PMN process. Unfortunately, although the study

was proposed in five versions spanning a wide range

of costs, not even the least expensive variant of the

study was funded.

Many other statutes, including FFDCA, FIFRA,

OSH Act, and the Consumer Product Safety Act,

contain similar provisions for reporting adverse

effects of chemicals. Any of these reporting requirements could potentially be used to track regulatory

effectiveness.

Because EPA is testing chemicals with high

production levels (100,000 kilograms in the third

year of production) and expectations of significant

human exposure, it will be obtaining some data with

which to evaluate the accuracy of PMN assessments.

These tests will include a functional observational

battery and neuropathological measurements, but

they will only be carried out for a long enough period

of time to measure subchronic effects. This set of

tests, taken together, may indicate how the structureactivity predictions used in PMN assessments compare to assessments that have at least a minimal data

set.

SUMMARY AND CONCLUSIONS

It is the task of regulatory agencies to limit public

exposure to toxic chemicals through programs

mandated by law. Because of the great diversity of

toxic substances, many statutes exist to control their

use. These laws are administered by various Federal

agencies, but primarily by EPA, FDA, and OSHA.

New and existing industrial chemicals are regulated by TSCA. Pesticides are controlled by FIFRA,

and toxic substances in the workplace are regulated

by the OSH Act. The FFDCA regulates food and

food additives, drugs, and cosmetics. These laws

address the vast majority of toxic substances, and

more than a dozen other acts focus on other

substances and sources of exposure. Although neurotoxicity is generally not explicitly mentioned in

legislation mandating the regulation of toxic substances, it is implicitly included as a toxicity

concern.

Regulatory differences in general strategies for

evaluating toxicity entail corresponding differences

in the evaluation of neurotoxic effects. Thus for

human drugs, preclinical toxicity tests are only used

to guide observations on clinical trials and to

elucidate possible mechanisms of toxicity, rather

than to directly assess toxic potential. For pesticides

and food and color additives, in contrast, animal

toxicity data are used directly in predicting human

risk,

Regulatory programs have adopted one of three

basic approaches to neurotoxicity evaluation, depending on which of three underlying assumptions

they hold. One approach is based on the assumption

that general toxicity tests using high doses are

adequate to detect neurotoxic potential and that

neurotoxicological evaluations are needed only if

general tests, data on structural analogues, or other

specific knowledge about a chemical indicate a

potential for neurotoxicity. Among these are FDA’s

preclinical testing program for drugs and its current

program for approving food additives. The second

approach, represented by the pesticide registration

program under FIFRA, accepts more general structural information in guiding neurotoxicity testing.

All organophosphorous compounds are evaluated

for the potential to induce delayed neuropathy, but

nonorganophosphorous compounds are not specifically evaluated for neurotoxic potential. All pesticides undergo a general toxicity screen; however,

specific neurotoxicity tests are not conducted. Finally, under section 4 of TSCA, specific neurotoxicity testing is required for any chemical with high

exposure potential, as well as for chemicals specifically suspected of being neurotoxic. Such testing

presumes that standard toxicity tests are not adequate to evaluate neurotoxic effects.

Critics of the regulatory framework voice concern

over the odds playing they see in the current process.

For example, the chemicals regulated under TSCA

make up the largest classes of chemicals, yet they

receive relatively little scrutiny by EPA. TSCA does

offer options for selecting high-risk chemicals for

further scrutiny, but the vast majority of chemicals

receive only a limited review. Without significant

toxicity data, predicting risk is difficult and must

rely on hypothetical relations between chemical

structure and biological activity. However, little is
Chapter 7—The Federal Regulatory Response ● 205

known about structure-activity relationships with

respect to neurotoxicity. Critics of EPA raise the

question of whether the minimal screening given to

the majority of chemicals is adequate to deal with

high-risk chemicals that are not members of wellunderstood risk categories.

OTA found that Federal efforts to control neurotoxic substances varied considerably between agencies and between programs within agencies. This

response is fragmented not only by differences in

scientific judgment, but also by differences in

regulatory responsibility. Moreover, the decision to

evaluate drugs, pesticides, and food additives by

stricter standards than are applied to commercial

chemicals is based not only on the views of

scientists, but also on national consensus. Thus,

improving the effectiveness of Federal programs

depends on many factors, including more public

awareness, greater involvement by neurotoxicologists in regulatory program offices, increased neurotoxicity testing, and improved monitoring programs.

1.

2.

3.

4.

5.

6.

7.

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v. Repeated Exposure Tests, ” prepared for the U.S.

Environmental Protection Agency, EPA contract No.

68-01-6554, work assignment No. 40127, Washington, DC, February 1985.

Bass, B. F., and Muir, W. R., “Summary of Federal

Actions and Risk Assessment Methods Relating to

Neurotoxicity," prepared for the U.S. Environmental

Protection Agency, EPA contract No. 68-02-4228,

Washington, DC, March 1986.

Center for Science in the Public Interest, ‘Petition for

Neurobehavioral Teratology Testing of Neuroactive

Drugs, ” draft of petition prepared for possible

submission to the Food and Drug Administration,

Washington, DC, September 1987.

Environmental Monitoring and Services, ‘‘Technical

Background Document to Support Rulemaking Pursuant to CERCLA, Sec. 102, Volume I,’ prepared

for the U.S. Environmental Protection Agency, EPA

contract No. 68-03-3182, March 1985.

Grad, F.P., “A Brief Account of the Beginnings of

Modern Environmental Law, ’ Treatise On Environmental Law, sec. 1.01 (St. Paul, MN: Matthew

Bender, 1985).

Grad, F. P., “Pesticide Pollution-Labeling and Misbranding, Treatise On Environmental Law, sec.

8.03.4 (St. Paul, MN: Matthew Bender, 1985).

Hampshire Research Associates, Inc., “The Federal

Regulatory Response to the Problem of Neurotoxicity, ’ prepared for the Office of Technology Assessment, Washington, DC, Dec. 1, 1988.

Hattan, D. G., Henry, S. H., Montgomery, S. B., et al.,

“Role of the Food and Drug Administration in

Regulation of Neuroeffective Food Additives, ” Nutrition and the Brain 6:31-99, 1983.

Hutt, P. B., “Risk Assessment: The First Fifteen

Years and the Next Fifteen Years, ” lecture at The

Brookings Institution, Washington, DC, Nov. 22,

1988.

“Lead Industries Association, Inc. v. The U.S.

Environmental Protection Agency,” Federal Reporter (2d series) 647:1130-1189, 1980.

Life Sciences Research Office, Predicting Neurotoxicity and Behavioral Dysfunction From Preclinical

Toxicologic Data (Bethesda, MD: Federation of

American Societies for Experimental Biology, 1986).

Merrill, R. A., and Schewel, M., “FDA Regulation of

Environmental Contaminants of Food, ” Virginia

Law Review 66:1357-1441, 1980.

Muir, W. R., former director, Office of Toxic Substances, U.S. Environmental Protection Agency, and

President, Hampshire Research Associates, personal

communication, December 1988.
206 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

21.

22.

23.

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25.

26.

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28.

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30.

31.

32.

33.

34,

35.

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and Commercial Chemicals (Boca Raton, FL: CRC

PRESS, 1986), vol. 2, pp. 7-92.

Padgett, J., and Richmond, H., “The Process of

Establishing and Revising National Ambient Air

Quality Standards,” Journal of the Air Pollution

Control Association 33:13-16, 1983.

Pharmaceutical Data Services, “Top 200 Drugs of

1989,” American Druggist, in press.

Rees, C., U.S. Environmental Protection Agency,

personal communication, Mar. 30, 1989.

Reiter, L.W., “Neurotoxicology in Regulation and

Risk Assessment” Developmental Pharmacology

and Therapeutics 10:354-368, 1987.

U.S. Congress, House of Representatives, Committee on Agriculture, “Report on H.R. 939,” 100th

Cong., 2d sess., 1988, p. 33.

U.S. Congress, Office of Technology Assessment,

Preventing Illness and Injury in the Workplace,

OTA-H-256 (Washington, DC: U.S. Government

Printing Office, 1985).

U.S. Department of Health, Education, and Welfare,

Air Quality Criteria for Carbon Monoxide, AP-62

(Washington, DC: 1980).

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, Requirements of Laws and Regulations Enforced by the U.S. Food and Drug Administration,

DHHS Pub. No. (FDA) 85-1115 (Washington, DC:

U.S. Government Printing Office, 1984).

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, Center for Food Safety and Applied Nutrition,

Toxicological Principles for the Safety Assessment of

Direct Food Additives and Color Additives Used in

Food (Washington, DC: 1982).

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, Center for Food Safety and Applied Nutrition,

Daily Operating Guide, HFF-2440.9 (Washington,

DC: 1980).

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, Psychopharmacological Drugs Advisory Committee, Transcript of Proceedings, Thirty-First Meeting (Rockville, MD: September 1989).

U.S. Environmental Protection Agency, “National

Interim Primary Drinking Water Regulations,” EPA

No. 570/9-76-003, app. A (Washington, DC: Office

of Water Supplies, 1976).

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Chlorinated Benzenes,

EPA 440/5-80-028, Office of Water Regulations and

Standards, Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Endosulfam, EPA 440/5-80-

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

046, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Dichlorobenzenes, EPA

440/5-80-039, Office of Water Regulations and

Standards, Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Halomethanes, EPA 440/5-

80-051, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Heptachlor, EPA440/5-80-

052, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality criteria for lead, EPA 440/5-80-057,

Office of Water Regulations and Standards, Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Mercury, EPA 440/5-80-

058, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Toluene, EPA 440/5-80-

075, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Tetrachloroethylene, EPA

440/5-80-073, Office of Water Regulations and

Standards, Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for Thallium, EPA 440/5-80-

074, Office of Water Regulations and Standards,

Washington, DC, October 1980.

U.S. Environmental Protection Agency, Ambient

Water Quality Criteria for 2,3,7,8-Tetrachlorodibenzop-dioxin, EPA 440/5-84-007, Office of Water Regulations and Standards, Washington, DC, February

1984.

U.S. Environmental Protection Agency, Mercury

Health Effect Update: Health Issue Assessment, EPA

600/8 -84-019F (Research Triangle Park, NC: Office

of Research and Development, August 1984).

U.S. Environmental Protection Agency, Office of

Pesticide Programs, Pesticide Assessment Guidelines, Subdivision F--Hazard Evaluation: Human

and Domestic Animals, EPA Pub. No. 540/9-82-025

(Washington, DC: 1982),

U.S. Environmental Protection Agency, Office of

Pesticide Programs, ‘‘Pesticide Label Utility Project

Report,” unpublished draft, April 1986.

U.S. Environmental Protection Agency, Office of

Public Affairs, Pesticides Fact Book, EPA Pub. No.

A-107/86-003 (Washington, DC: 1986).

‘‘When Sleep Becomes A Nightmare,’ 20/20, ABC,

Feb. 17, 1989.
Chapter 7—The Federal Regulatory Response ● 207

50. Young, J. S., and Muir, W. R., “Survey of Major Environmental Protection Agency, EPA contract No.

Toxicology Testing Laboratories on the Use of Organ 68-024228, work assignment No. 121415, WashFunction Tests in Toxicology, ’ prepared for the U.S. ington, DC, September 1986.
Chapter 8

Economic Considerations in

Regulating Neurotoxic Substances

‘The higher environmental issues rise on the national agenda the more important it is that we have the best

possible knowledge of the economic costs of undertaking particular environmental programs and the costs

associated with not undertaking them. ”

Russell E. Train

Remarks at the Library of Congress

October 18, 1989

“Although conventional regulatory policies have often worked well, they have also tended to pit economic

and environmental goals against each other. These goals should complement one another in the long run if

either of them is to be achieved. ’

Robert N. Stavins

Environment, vol. 31, No. 1

February 1989

“One of the problems in relating economic health and environmental health is that the nation has not

developed a quality of life index that measures both. Environmental health factors such as morbidity and

mortality, crop and forest damage, soil erosion, air and water pollution, and aesthetic degradation are given

little attention compared to such economic health factors as Gross National Product (GNP) and

unemployment. Much work needs to be done to develop and use more comprehensive measurements of

quality of life. ”

An Environmental Agenda for the Future, Island Press, 1985
CONTENTS

Page

ECONOMIC ANALYSIS OF REGULATIONS AFFECTING TOXIC

SUBSTANCES, PESTICIDES, AND DRUGS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

Costs, Benefits, and Economic Efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

Risks and Benefits . .. .. .+, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

Impacts on Market Prices and Industry Profits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

Regulation and Incentives for Innovation.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Utility of Regulatory Analyses in Devising Environmental Regulatory Policy . . . . . . 220

Economic Principles of Cost-Benefit and Cost-Effectiveness Analyses . . . . . . . . . . . . . 221

THE COSTS OF NEUROTOXICITY TESTING .. .. .. .. ... .+. . . . . . . . ...4. . . . . . . . . . 221

Determinants of the Costs of Toxicity Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

Cost Estimates for Neurotoxicity Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224

NEUROTOXICITY TEST COSTS AND INNOVATION . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Drug and Pesticide Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Neurotoxicity Tests and Innovation in Drugs and Pesticides . . . . . . . . . . . . . . . . . . . . . . . 226

Neurotoxicity Tests and Innovation in Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

ECONOMIC BENEFITS OF REGULATING NEUROTOXIC SUBSTANCES . . . . . . 228

Knowledge Requirements for Estimating Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

The Health Costs of Neurotoxicity ..,..,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .228

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232

Boxes

Box Page

8-A. Economic Balancing Provisions of FFDCA, FIFRA, and TSCA . . . . . . . . . . . . . . . . 212

8-13. Requirements of Executive Order 12291 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214

Tables

Table Page

8-1.

8-2.

8-3.

8-4.

8-5.

8-6.

8-7.

The Institutionalization of Regulatory Analysis, 1971-81 . . . . . . . . . . . . . . . . . . . . . . . . 215

Comparison of Licensing and Notification Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . 218

Protocols for Which Cost Estimates Were Solicited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Ranges in Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity

Evaluations for 1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .......,..............+.. . . . 225

Median Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity

Evaluations for 1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,....,.0. . . . . . . . . ,...,..+ 225

Personal Health-Care Expenditures for the 10 Most Expensive Medical Conditions

in the United States in 1980 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Estimates of the Health Benefits of Reducing the Neurotoxic Effects of Lead

in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Chapter 8

Economic Considerations in Regulating Neurotoxic Substances

The fundamental economic consideration in regulating neurotoxic substances involves balancing the

economic benefits of utilizing these substances

commercially against their actual or potential risks

to human health and the environment. The economic

benefits include the reduced cost and increased

productivity brought about by drugs, pesticides, and

chemicals in health care, agriculture, and industry.

The risks are the probabilities of increased morbidity, mortality, and environmental contamination

stemming from uncontrolled or excessive uses of

these substances (35).

Regulations designed to reduce or prevent neurotoxic risks can benefit society by improving public

health and the environment. Inmost cases, however,

government and the private sector incur costs in

order to achieve these ends. The costs of regulatory

compliance may give rise to a number of additional

economic impacts, such as increases in market

prices, reductions in industry profits, and declines in

new product innovation. The problem of balancing

benefits, costs, and risks of regulation is not unique

to the control of neurotoxic substances; it arises in all

forms of health, safety, and environmental regulation.

Many of the key Federal laws under which

neurotoxic substances are regulated require agencies

to ascertain the positive and negative economic

consequences of regulation (see box 8-A). In implementing these laws, Congress has generally intended

that agencies prepare regulatory analysesl and

document the balancing of benefits, costs, and risks

of proposed alternatives. It is important to note,

however, that Congress typically has not set priorities for the various economic issues arising from

regulation, nor has it specified the analytical criteria

or procedures that agencies must follow in evaluating the economic impacts of regulation.

The preparation of regulatory analyses of proposals to control neurotoxic substances is a two-step

process. The first step, risk assessment, involves

assessing the health and environmental risks posed

by various levels of exposure to these substances.

Risk assessment provides a scientific basis for

regulatory analyses. The second step, risk management, is the end for which risk assessment is

conducted (see ch. 6).

One economic consideration in conducting risk

assessments is the costs and benefits of acquiring the

reliable scientific and technical data needed to

regulate neurotoxic substances. Many of these data

must be obtained through animal toxicity tests. Two

recent evaluations of Federal efforts to regulate

neurotoxic substances concluded that there is a need

for more neurotoxicity testing of existing and new

chemicals (30,43). To date, the Environmental

Protection Agency (EPA), Food and Drug Administration (FDA), and other Federal agencies with

authority to regulate toxic substances have not

widely adopted or applied neurotoxicity test protocols (43). Consequently, available neurotoxicity

data are insufficient to determine reasonably or to

predict the health or environmental effects of all but

a few of the substances in commerce that have

neurotoxic potential, whether they be pesticides,

industrial chemicals, food additives, or drugs.2

More testing of suspected neurotoxic substances

will increase the chances of avoiding adverse health

and environmental effects. It will also increase

development and regulatory compliance costs. Industry and government incur costs in expanding the

knowledge base that is essential in regulating toxic

substances, but development of this knowledge

theoretically improves the precision with which the

benefits of regulation can be ascertained. Therefore,

the question arises: What is the appropriate economic balance between the costs of neurotoxicity

testing and the benefits of the resulting test data in

developing regulations?

As discussed in chapter 7, the Federal Government can regulate neurotoxic substances under at

least 16 laws. With the exception of regulations to

lk his chapter, the term “regulatory analysis” refers to analysis used in judging the desirability of a regulation. The term “regulatory impact

analysis” (RIA) refers specifically to analysis performed under Executive Order 12291 (46 FR 13191-13196).

2A Nation~ ~~emy of Sciences (NAS) s~udy examined toxicity test~gresults for a sample of substances that included chemicals in COInInerCe

(manufactured in both small and large volumes), pesticides, cosmetics, drugs, and food additives. From a list of 53,500 chemicals, NAS selected a

ramdom sample of 675. A random subsample of 100 chemicals with at least minimal toxicity test information was examined in great detail, and

conclusions were extrapolated from the review of test data on these 100 substances (30).

–21 1-
212 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 8-A—Economic Balancing Provisions of FFDCA, FIFRA, and TSCA

The Federal Food, Drug, and Cosmetic Act (FFDCA), the Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA), and the Toxic Substances Control Act (TSCA) are the primary laws under which neurotoxic substances

are regulated. Each contains provisions to encourage increased testing for neurotoxicity and to control the

production, distribution, and use of substances that present unreasonable risks of neurotoxicity. The following

requirements for economic balancing relate to the control provisions in each of these laws.

Federal Food, Drug, and Cosmetic Act—The economic balancing provisions of FFDCA are less explicit than

those of the other two Acts. The various sections of the law reflect Congress’ intent both to provide for the safety

of food (including substances added to food) and to maintain an economically affordable and abundant food supply.

Whether regulatory analyses are undertaken depends on which section of the law is being applied and the type of

regulatory action being considered. Because of amendments to FFDCA over the years, the regulation of chemicals

in food is quite complex (18). Food-related substances addressed under the Act may fall into one or more categories,

namely, food, direct or indirect food additives, color additives, naturally occurring environmental contaminants,

inherent constituents of raw agricultural commodities, pesticide residues, and animal drug residues.

Finally, procedural considerations are important. The Bureau of Foods does not consider the process of

approving and publishing a regulation that permits the safe use of a new food or color additive as formal rule-making

subject to the cost-benefit analysis requirements of Executive Order 12291. Proposals to ban or limit the use of food

additives that are already approved, however, are regarded as formal rule-making and are subject to the order’s

requirements, A proposal to establish a formal tolerance for environmental contaminants, a procedure that is rarely

undertaken, is also regarded as formal rule-making and would require a cost-benefit analysis.

Federal Insecticide, Fungicide, and Rodenticide Act—In order to register a new pesticide under FIFRA, EPA

must ascertain whether it will ‘‘cause unreasonable adverse effects on the environment. ’ FIFRA defines these

effects very broadly, to include ‘‘any unreasonable risk to man or the environment, taking into account the

economic, social, and environmental costs and benefits of the use of any pesticide” (7 U.S.C. 136(bb)).

Under section 6 of FIFRA, EPA may cancel, restrict, or suspend the current registration of a pesticide if the

Agency determines that the pesticide causes unreasonable adverse effects on the environment when used according

to commonly recognized practice. In proposing such action, EPA must take into account the impact it will have on

the prices of agricultural commodities, retail food prices, and the agricultural economy.

Toxic Substances Control Act—Section 6 of TSCA gives EPA broad authority to regulate manufacturing,

processing, distribution, use, and disposal of chemical substances that present an unreasonable risk of injury to

health or the environment. Section 6 states that in proposing any such regulation, EPA must consider and document:

the effects of such substance or mixture on health and the magnitude of the exposure of human beings to such

substance or mixture; the effects of such substance or mixture on the environment and the magnitude of the exposure

of the environment to such substance or mixture; the benefits of such substance or mixture for various uses and the

availability of substitutes for such uses; and the reasonably ascertainable economic consequences of the rule, after

consideration of the effect on the national economy, small business, technological innovation, the environment and

public health.

Congress (42) intentionally did not define “unreasonable risk,” but indicated that determining whether a

chemical posed such a risk should involve:

. . . balancing of the probability that harm will occur and the magnitude and severity of that harm against the effect

of proposed regulatory action on the availability to society of the benefits of the substance or mixture, taking into

account the availability of substitutes for the substance or mixture which do not require regulation, and other adverse

effects which such proposed action may have on society.

Congress further elaborated on the extent to which economic analysis was needed in the balancing process:

The balancing process described above does not require a formal benefit-cost analysis under which a monetary

value is assigned to the risks associated with a substance and to the cost to society of proposed regulatory action on

the availability of such benefits. Because a monetary value often cannot be assigned to benefit or cost, such an analysis

would not be very useful.

Congress cited the National Academy of Sciences (27) as support for the last statement.

SOURCES: Office of Technology Assessment, 1990; U.S. Congress, 1976; Hattan, 1983; National Academy of Sciences, 1975.
Chapter Economic Considerations in Regulating Neurotoxic Substances . 213

reduce human exposures to lead, 3 the greatest

amount of regulatory activity specifically directed

toward neurotoxic concerns has occurred under

three laws: the Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA), as amended by the

Federal Environmental Pesticide Control Act (FEPCA)

(7 U.S.C. 135-136y); the Toxic Substances Control

Act (TSCA) (15 U.S.C. 2601-2629), as amended;

and the Federal Food, Drug, and Cosmetic Act

(FFDCA) (21 U.S.C. 301-392). Each of these laws

provides authority to obtain scientific and other data

on which to assess risks and to control the use of

toxic substances.

As with their assessments of health risks, agencies

differ greatly in their approaches to evaluating and

balancing the economic impacts of regulation. EPA,

for example, has developed rigorous guidelines for

evaluating the costs, benefits, and alternatives of

regulations having major economic consequences

(19). At the other end of the spectrum, FDA, in

regulating food additives, carries out balancing in a

less formal, more qualitative manner (22,25 ),4 These

differences reflect differences in legislative requirements for balancing benefits, costs, and risks (see

box 8-A), as well as differences in agency views on

the applicability of Executive Order 12291 (46 FR

13191), which defines current policies and requirements for the executive branch in evaluating regulatory proposals (see box 8-B).

The purpose of this chapter is to examine and

evaluate several salient economic issues involved in

regulating neurotoxic substances. Economic issues

that arise from requirements to test for neurotoxicity

as well as from restrictions on production and use of

neurotoxic substances are discussed. Also discussed

are the different forms of regulatory analysis that

agencies have applied in addressing these issues.

Economic issues are common in the regulation of

all toxic substances, regardless of the health endpoints of concern. However, since (with the exception of lead) the regulatory record for neurotoxic

substances is limited, the present discussion is

general in scope. No attempt has been made to

present a comprehensive economic evaluation of the

costs and benefits of a test rule or use regulation for

a specific neurotoxic substance. Nor has an attempt

Ff__l?7 Wplw<

.——. .—— —.——— —

—

Illustrated by: Ray Driver

been made to conduct a technology assessment of

the impacts of regulating a class of neurotoxic

chemicals.

ECONOMIC ANALYSIS OF

REGULATIONS AFFECTING TOXIC

SUBSTANCES, PESTICIDES,

AND DRUGS

As noted above, current laws for controlling

neurotoxic substances do not specify which analytical procedures Federal agencies must use in evalu3Re@ations t. r~uce occupational and environmental exposures to lead have been promulgated under at least 10 different Federal statutes (28).

4h exception OCCWS in the regulation of food additives that are known or suspeeted carcinogens. Under the 1962 Delaney amendment to ~CA

(21 U.S.C. 348(c)(3)(A)), the use of these substances in any quantity is prohibited, regardless of the impact on food costs or supply or any offsetting

benefits of use (25).
214 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 8-B—Requirements of Executive Order 12291

President Ronald Reagan signed Executive Order 12291 in 1981 (46 FR 13191) to increase agency accountability

for regulatory actions. To achieve this goal, the order specifies that, in promulgating, reviewing, or developing

regulations, all agencies, to the extent permitted by law, adhere to the following requirements:

Administrative decisions shall be based on adequate information concerning the need for and consequences

of proposed government action.

Regulatory action shall not be undertaken unless the regulation’s potential benefits to society outweigh its

potential costs to society.

Regulatory objectives shall be chosen to maximize the net benefits to society.

Among alternative approaches to any given regulatory objectives, the alternative involving the least net cost

to society shall be chosen.

Agencies shall set regulatory priorities with the aim of maximizing the aggregate net benefits to society,

taking into account the condition of the particular industries affected by the-regulations, the condition of the

national economy, and other regulatory actions contemplated for the future.

The regulatory impact analysis (RIA) is the means for ensuring that agencies meet these requirements. The

Order requires that agencies submit RIAs to the director of the Office of Management and Budget at least 10 days

before publication in the Federal Register of a notice of proposed rule-making or final rule. For major rules, a

preliminary RIA must be prepared and submitted at least 60 days before publication of a notice of proposed

rule-making, and a final RIA must be submitted at least 30 days prior to publication of a final rule. A major rule

is any regulation that is likely to have an annual effect on the economy of $100 million or more, to result in a major

increase in costs or prices, or to have significant adverse effects on competition, employment investment,

productivity, innovation, or the competitiveness of domestic firms relative to foreign counterparts.

SOURCE: Office of Technology Assessment, 1990.

ating the economic impacts of regulatory decisions.

Regulatory agencies have not interpreted statutory

requirements to evaluate proposed regulatory alternatives as imposing certain limits on the scope or

approach of analyses that are undertaken. Instead,

agencies like EPA have adapted various evaluative

approaches, depending on the regulatory and economic issues involved.

The executive branch, through the Office of

Management and Budget (OMB), has independently

developed and implemented a requirement that

agencies produce specific kinds of economic evaluations for regulatory actions that have major economic impacts. The current OMB requirement for

regulatory impact analysis of such actions has

evolved through a series of executive orders, and the

OMB has incorporated the Regulatory Impact Analysis (RIA) requirement into its executive oversight

function (see table 8-l).

This section examines four economic issues and

the analytical approaches agencies have applied in

addressing these issues as they have emerged in

decisions to regulate toxic substances.

Costs, Benefits, and Economic Efficiency

Thus far, the terms “costs” and “benefits” have

been used in a generic sense to indicate negative and

positive economic impacts of regulation. Although

this usage is correct, it is important to recognize that,

for the purposes of analysis, these terms are narrowly

defined to have specialized meanings. The precise

operational definitions depend on the type and scope

of analysis and the economic issue being assessed.

Accordingly, cost-benefit analysis (CBA) and

cost-effectiveness analysis (CEA) have come to

refer to analytical techniques in which macroeconomic analysis serves as the basis for evaluating the

positive and negative economic consequences of a

program or decision. For both techniques, costs refer

to the resource inputs required to implement a

program. Benefits and effectiveness refer to program

outputs. Costs are computed in dollars, using values

that the resource inputs would have had in alternative uses—their opportunity cost. In cost-benefit

analysis, program consequences are also evaluated

in dollar terms. In cost-effectiveness analysis, program consequences are measured in natural or

physical units.
Chapter Economic Considerations in Regulating Neurotoxic Substances . 215

Table 8-l—The Institutionalization of Regulatory Analysis, 1971-81

Act. Executive Order Year Title Type of analysis

OMB memo 10/5/71 1971 Quality of Life Review Costs, benefits

Executive Order 11821 1974 Inflation Impacts Statement Costs, benefits, inflationary impacts

Executive Order 11949 1976 ~ Economic Impact Statement Costs, benefits, economic impacts

Executive Order 12044 1978 Regulatory Analysis Costs, economic consequences

Regulatory Flexibility Act 1980 Regulatory Flexibility Analysis Impacts on small businesses

Executive Order 12291 1981 Regulatory Impact Analysis Costs, benefits, net benefits

SOURCE: Office of Technology Assessment, 1990.

In the application of cost-benefit and costeffectiveness techniques to evaluate health and

safety regulations, costs and benefits are generally

defined and measured from the perspective of

achieving intended regulatory objectives of risk

reduction. Cost-benefit or cost-effectiveness analysis is employed to evaluate whether the benefits of

a regulation exceed its costs, or whether a regulation

is cost-effective. That is, are the resources required

to implement regulations being utilized in an efficient manner? The concept of economic efficiency

refers to gains derived from resources allocated to

achieve stated objectives.

In cost-benefit and cost-effectiveness analyses of

toxic substances regulations (e.g., premanufacturing

approvals, test rules, and use restrictions), the costs

consist of those resources expended for the purposes

of regulatory development, implementation, and

compliance. They include expenditures by both

government and the private sector. Government

incurs expenses in: 1) developing regulatory procedures, including toxicity test methods, test rules, and

chemical production, distribution, and use restrictions; 2) reviewing premanufacture notices (PMN),

registration, and other requests by industry to

produce and sell new chemical substances; and 3)

carrying out necessary monitoring, inspection, and

enforcement responsibilities.5 The private sector

usually bears compliance costs, which consist of

labor, materials, equipment, and other expenses for:

1) obtaining premanufacturing approvals; 2) conducting animal toxicity tests,6 keeping records, and

submitting reports on chemicals of concern; and 3)

altering production processes and products to conform with production, distribution, and use restrictions.

Evaluation of the benefits of controlling toxic

substances involves first assessing the effectiveness

of regulation in achieving risk reductions. Risk

reduction is measured as reductions in mortality,

morbidity, and ecological dysfunction that would

occur as a consequence of changes in exposure to

toxic chemicals. In cost-effectiveness analysis, benefits are measured in natural units, such as years of

life saved, incidence of disease averted, and days of

work loss avoided. In cost-benefit analysis, risk

reductions are evaluated in monetary units.

Net efficiency refers to the difference between

benefits and direct costs, or the difference between

the value of reductions in health, safety, and

environmental risks achieved through regulation

and the value of the resources employed to achieve

those reductions. It is important to note that the

efficiency criterion of cost-benefit and costeffectiveness analyses does not encompass any

positive or negative impacts that regulation may

have on industry employment, profits, or new

product innovation. Other forms of economic analysis, some of which are discussed below, are utilized

in assessing these so-called secondary economic

impacts of regulation.

Under sections 4 and 5 of TSCA (15 U.S.C. 2604

and 2605), EPA typically has not conducted costbenefit or cost-effectiveness analyses in implementing test rules or reviewing PMNs. The economic

costs of complying with individual test rules for

existing chemicals or production prohibitions for

new chemicals are generally relatively small;7 they

are not likely to reach the $100 million per year

specified by Executive Order 12291 for a major rule.

Furthermore, analysis of the health and environmental benefits achieved by these actions can be

51n practice, it is difficult t. appofion tic g~vernrnent’s program costs to individual proposals. Consequently they are ofien omit~ from an~YSis.

6Estimates of tie costs of conducting anim~ ~oxlcity tests hat include ce~in neurolqjc~ evacuations are present~ later in t.hls Chapter.

TEven when tie total costs of comp]yi~g Writh test ~]es are sm~l, hey may represent a S@ifiCant potion of tie s~es revenues fOr IOW-VOILlme,

specialty chemicals. As discussed below, EPA recognizes the distributive effects of test rule costs in an analysis of impacts on market prices and profits.
216 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

speculative. To quantify these benefits, many assumptions must be made about a chemical’s rate of

market penetration, projected sales volume, types of

uses, and likely disposal practices.

Under section 6 of TSCA (15 U.S.C. 2605), EPA

considers all aspects of formal cost-benefit analysis

in evaluating the impacts of a proposed regulation

(48). The balancing language of section 6 (box 8-A)

encourages cost-benefit analysis whether or not a

regulation is likely to have major economic impacts.

Since the enactment of TSCA, however, EPA has

promulgated only a handful of regulations under

section 6 (41).8

EPA’s Office of Toxic Substances recently completed a preliminary risk assessment for environmental and occupational exposures to acrylamide, in

which risks for carcinogenic reproductive effects

and neurotoxic effects were evaluated (49). Although this assessment may lead to use restrictions

that are based on neurotoxicity, further action by

EPA under section 6 is contingent on reviews of the

acrylamide risk assessment by the Occupational

Safety and Health Administration and other agencies having potentially applicable regulatory authorities.

Under FIFRA, EPA’s decisions to approve new

pesticide registrations or to cancel, suspend, or alter

existing registrations are not regarded as rulemaking that is subject to the cost-benefit requirements of Executive Order 12291 (48). However,

because of the specific balancing language of

sections 3(c) and 6(b) of FIFRA (box 8-A), EPA has

developed a methodology for evaluating the economic impacts of registration decisions. This procedure is discussed in the next section.

For pesticides that are applied in the production,

storage, or distribution of raw agricultural commodities, part of the registration process may include an

EPA review to establish a tolerance under FFDCA

[21 U.S.C. 346a(b)]. EPA’s granting of such a

tolerance is considered rule-making, but cost-benefit

analyses of these decisions are not developed,

because all of the economic consequences of a

tolerance are regarded as positive. Finally, the

revocation of a pesticide tolerance by EPA is also

considered rule-making. Although cost-benefit evaluations are developed for these decisions, they have

been of limited utility in the regulatory development

process.

Although few WA’S to control neurotoxic substances have been conducted, EPA has conducted

cost-benefit studies of regulatory proposals to reduce human exposures to lead under other environmental statutes. Under the provisions of the Clean

Air Act for regulating fuel additives [42 U.S.C.

7545(c)], EPA developed a cost-benefit analysis of

several options for phasing out the use of lead

additives in gasoline (39). In addition, EPA has

evaluated the economic benefits of options for

reducing lead in community water supplies under

the Safe Drinking Water Act (42 U.S.C. 300f-j) (23).

Both studies estimated the health benefits of reducing lead’s neurotoxic effects in children.

Risks and Benefits

A second economic issue that arises in regulating

chemicals, pesticides, and drugs concerns balancing

the economic benefits of a substance that are lost

through a restriction or ban on its use against the

risks of continued use at unregulated levels (27,29).

Risk-benefit analysis is used to address this issue.

As noted above, in a cost-benefit analysis of

chemical regulation, the benefits consist of improvements in public health and environmental quality

that would result from restricting the use of toxic

substances. However, in risk-benefit analysis of

licensing and approval regulations, in particular

under FIFRA and FFDCA, the term “benefit” has

acquired a different meaning. In this instance,

benefits are defined in terms of the opportunity cost

of switching to substitutes for the chemical in

question. In registration decisions for agricultural

pesticides, for example, EPA’s Office of Pesticide

Programs assesses benefits in terms of changes in

the value of crop yields and pest control costs (29).

Similarly, in approving new drugs, FDA assesses

benefits in terms of therapeutic efficacy.

Risk-benefit analysis recognizes that, on the one

hand, chemicals, pesticides, and drugs generate

economic benefits that manifest themselves in the

form of increased output and lower product prices.

On the other hand, the increased use of toxic

8@e ~emon fm limit~ ~ew]atog ~ctlvity ~der ~W 6 is hat EpA reg~ds TSCA as tie re@ato~ authori~ of 1~t resort. Under TSCA sec, 9 (15

U.S.C. 2608(b)), for example, EPA must provide other appropriate Federal agencies with the fust opportunity to regulate substances that present

unreasonable risks.
Chapter 8--Economic Considerations in Regulating Neurotoxic Substances ● 217

chemicals may introduce more of these substances

into the environment, at the time of initial use or

subsequently in waste disposal. The risks to health

and the environment from increased exposures to

toxic chemicals, therefore, may also increase.

Risk-benefit analysis can also be used to compare

the change in environmental and health risks to the

change in economic benefits resulting from regulation. If the use of an existing chemical is increased,

the analysis compares the potential increase in risks

with the anticipated increase in benefits. If the use of

a chemical is reduced, the analysis compares the

expected reduction in risks with reduction in benefits.

EPA initiates risk-benefit analysis for proposed

restrictions on pesticide use when it receives toxicity

data that trigger questions about potential risks to

human health. Although these analyses may be done

when new compounds are preregistered, they are

typically undertaken in response to toxicity data

generated through the special review process for

existing pesticides (see ch. 7). When special review

leads to proposed use restrictions or suspension or

cancellation of a registration for an agricultural

pesticide, for example, analysts estimate the health

risks and net values of crop production for projected

uncontrolled and the proposed controlled applications of the pesticide. The risk-benefit ratios for

these scenarios are then compared in assessing the

economic impact of the proposed regulation.

The 1988 amendments to FIFRA call for an

accelerated review of pesticides that were first

registered under the pre-1972 FIFRA guidelines (1).

Because this group includes a number of widely

used agricultural insecticides that function by attacking the nervous systems of target organisms, it

is likely that special reviews will trigger some

risk-benefit evaluations for neurotoxicity.

In conducting risk-benefit analysis of new drugs,

FDA is more qualitative in its approach. In ascertaining the benefits, FDA distinguishes between the

efficacy and the effectiveness of the candidate

chemical. Efficacy refers to the ability of the

substance to alter the symptoms or pathological

condition for which it was developed. Effectiveness

refers to the degree of reduction in disease or death,

and hence in health-care expenditures, a drug might

achieve when optimally prescribed and taken. FDA

weighs test evidence of adverse reactions to the drug

(risks) against its demonstrated therapeutic properties (benefits). The 1962 amendments to FFDCA

(Public Law 87-781) require that manufacturers

submit sufficient data to demonstrate a new drug’s

efficacy but not its effectiveness.

Impacts on Market Prices and Industry Profits

A third issue of economic importance that arises

in the regulation of toxic substances concerns the

impact of the direct costs of regulation on market

prices and industry profits. Although industry initially pays the compliance costs of regulation, it

attempts to pass these increases on to customers in

the form of higher product prices. Higher prices

may, in turn, discourage sales and reduce industry

profits. If there is a major expansion of regulations

covering abroad range of industrial and commercial

activities, as there was in the 1970s, the costs of

regulation may contribute to the Nation’s rate of

inflation.9

TSCA stipulates that EPA consider “the relative

costs of the various test protocols and methodologies” when implementing chemical test rules [section 4(b)(l); 15 U.S.C. 2603(b)(l)]. In 1980, with the

first test rule issued under section 4 (45 FR

48524-48566), EPA outlined procedures for estimating the relative costs of test protocols and the

projected impact of these costs on the marketability

of the chemicals to be tested. These procedures

remain in use today (24,40). EPA evaluates the

impact of anticipated testing costs for each manufacturer or processor by estimating unit10 test costs and

then comparing these unit values to the market price

of the chemical. A market analysis may be conducted to assess four key features of the market for

the chemical being tested: 1) responsiveness of

demand to changes in price; 2) expectations for

market expansion or decline; 3) industry cost

characteristics; and 4) industry structure (40).

90MB and tie f&gm Administration ernphasl~ed the cumulative inflationary effects of regulation in implementing Executive Order 12291.

l~nlt test ~05ts me estimated by fir5t computing he annualized v~ue of total direct test costs and then dividing by theWdSUpply (i.e., pK)dUCtiOIl

and imports) of the chemical. In annualizing test costs, EPA uses the expected product lifetime for the annualization period and the estimated cost of

capital in the chemical industry for the annualization rate. If available, sales volume information is used in estimating expected product lifetimes. Product

lifetimes are longer for commodity chemicaIs (i.e., chemicals with multiple uses and large-volume sales) than for specialty chemicals. lf sales volume

data are unavailable, EPA uses a 15-year annualization period. The Agency currently uses 7 percent as the annualization rate (1 1).
218 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table 8-2-Comparison of Licensing and Notification Mechanisms

Factor affecting incentives to innovate Licensing (FIFRA or FFDCA) Notification (TSCA)

Burden of proof Fails on innovating firm Initial burden falls on regulatory agency

Agency’s authority to compel testing of Withhold approval until desired informa- Requires agency finding that a product

new products tion is submitted may pose an unreasonable risk

Burden of delay Fails on innovating firm Falls on public

SOURCE: Office of Technology Assessment, 1990.

EPA uses an informal rule of thumb to determine adverse economic impacts of testing. If the

unit costs of testing a chemical are less than 1

percent of the price of the chemical, then the

potential for adverse economic impact due to the

test rule may be low. Conversely, if the unit test

costs exceed 1 percent of price, then the potential

for adverse economic impact may be high (24).

Regulation and Incentives for Innovation

An issue that is related to the impact of compliance costs on profitability is the effect of regulation

on incentives for innovation. The development and

introduction of new chemicals, pesticides, and drugs

have produced benefits in virtually every area of

human need: food, health, shelter, clothing, transportation, communication, and energy. On the other

hand, extensive use or misuse of these substances

has increased risks to public health and the environment. Hence the question, ‘‘Does regulation to

protect health and the environment alter industry’s

incentives to develop new drugs and chemicals?’ ’11

Companies develop and introduce new products

as a means of competing in a given market and

making a profit. Profitability depends on sales

volumes and the cost and time required to develop,

produce, and market new products. It also depends

on the availability of competing products and

patents and other factors that protect the market

position of the innovating company. Finally, because there is uncertainty surrounding each facet of

the development and commercialization of new

products, innovation in the private sector will take

place only if the prospective reward-risk ratio is

considered favorable.

Regulation can affect each of these factors. First,

the compliance costs of regulation increase the costs

of developing new products. Second, the regulatory

process adds to the time required to develop and

introduce new products. Third, use restrictions can

limit the market for a product, or in the extreme case

of a ban, eliminate the market altogether. Fourth,

reporting requirements may lead to the disclosure of

proprietary information that may compromise the

competitive position of the innovating company.

Finally, because regulation can add uncertainties

regarding costs, delays, protection of proprietary

data, and so on, it adds to the financial risk of

developing new products.

An important aspect of how a regulation affects

incentives for innovation concerns the manner in

which the regulatory process acts as a barrier to the

commercialization of new products. In this regard

there are important differences between the premarket screening requirements of TSCA versus

those of FIFRA and FFDCA. The key difference is

in the way the prescreening process assigns the

burden of proof to demonstrate that a new product

does or does not pose unreasonable risks (see table

8-2). Under the notification requirement of TSCA,

the burden falls on the regulatory agency to make a

finding that a product may pose an unreasonable

risk. Under the licensing mechanisms of FIFRA and

FFDCA, the burden falls on the innovating company. The regulatory agency can withhold approval

for marketing of a new product until it is satisfied

that the firm has conducted sufficient testing to

establish that the product poses no unreasonable

risks.

Numerous studies have sought to assess the

aggregate effects of Federal regulatory changes on

11A ~elat~ but ~n~@c~ly more complica[~ issue concerns whe~er he impact of health and safety re@ations on incentives tO hmovate prOdUCe

a net gainor loss to society. The temporal framework for analysis must be long enough to consider the positive and negative impacts of emerging chemical

and drug technologies under various levels of regulatory control. Regulatory analyses usually lack this perspective. Risk-benefit analysis of proposed

pesticide controls, for example, usually focuses on short-term economic impacts (3 to 5 years) and considers only currently registered chemical and

nonchemical controls as alternatives (31).
Chapter 8-Economic Considerations in Regulating Neurotoxic Substances . 219

innovation in the drug, pesticide, and chemical

industries. 12 These studies have measured changes

in an industry’s innovative efforts in terms of the

resource inputs and outputs of the innovative process. Measures of inputs into innovation have included: total research and development (R&D)

expenditures per year; R&D expenditures as a

percentage of annual sales or profits; time from

initial discovery to commercialization; and development cost per new chemical entity. Typical output

measures have included the number of new products

registered or licensed per year and effective patent

lifetimes. These measures have been examined

before and after implementation of a change in a

regulatory program or a change to ascertain whether

there are significant quantitative differences. Although it is beyond the scope of this chapter to

evaluate these studies critically, it is useful to

summarize their findings and discuss some of the

difficulties encountered in measuring the impact of

regulation on innovation in the chemical, pesticide,

and drug industries.

One difficulty in using total R&D expenditure

measures has been the difficulty of distinguishing

between R&D costs of truly new compounds (i.e.,

new chemical entities or new active ingredients for

pesticides) and costs of new applications and combinations of previously discovered compounds. A

second difficulty is that a substantial amount of the

R&D expenditures for testing new chemicals is

integral to their development. For pesticides, for

example, toxicity testing and metabolism and residue studies are essential in understanding the

properties and mechanisms of action on target

organisms. Similar test information is needed in

drug development. In other words, there is considerable overlap in the generation of test data needed to

develop an application for a new substance and data

needed to ensure its safety.

Drug R&D Studies

The most studied area of regulatory impact on

innovation to date has been the effects of the 1962

amendments to FFDCA on R&D in the pharmaceutical industry. For the most part, studies agree that the

overall rate of new drug introductions declined

substantially from the 1950s to the 1960s and even

more into the 1970s (see, e.g., 15,17,32,51). Studies

have shown that development time and cost to

manufacturers increased significantly after enactment of the 1962 amendments (see, e.g., 7,20,26,38).

Although these studies demonstrate consistent,

adverse effects on drug innovation after a change to

a more stringent regulatory regime, they do not agree

on the relative importance of regulation as a factor

in these impacts. Other influences not related to

regulation, for example, declining drug research

opportunities and exogenous increases in R&D

costs, have been hypothesized as being partially

responsible for the observed declines in drug innovation during this period. U.S. data showing that the

decline in new approvals was already under way

before 1962 and international data demonstrating

comparable trends in other countries tend to support

the conclusion that regulation has been only partially

responsible for these declines (15).

Pesticide R&D Studies

Although there have been no studies of how

regulatory efforts directed specifically toward neurotoxicity have affected pesticide innovation, there

have been studies of the aggregate effects of pesticide

regulation on R&D. A study by the Council on

Agricultural Science and Technology (8) found that

from 1968 to 1978—before and after enactment of

the 1972 amendments to FIFRA-direct costs of

bringing anew pesticide to market increased, delays

from discovery to registration grew, and the composition of R&D expenditures shifted from synthesis,

screening, and field testing to registration, environmental testing, and residue analysis.

Studies conducted by EPA (5) found little evidence of a reduction in pesticide innovation that

could be attributed to EPA regulatory requirements.

This conclusion was corroborated in an unpublished

OTA study (45). OTA reported that after 1972, total

pesticide industry R&D expenditures continued to

grow at the same rate as pesticide sales. In addition,

there was no apparent trend in pesticide registrations

over the period 1966 to 1980 that could be attributed

to regulation.

Chemical R&D Studies

In the late 1970s and early 1980s, prior to EPA’s

issuance of a final rule for premanufacturing notices

l~mrment ~view~of ~tudie~ of tie fipact of Feder~ re@ations on innovation in tie d~g, pesticide, and chemic~ industries, seerefs. 16,19,31.
220 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

(PMNs),13 many parties expressed concern that the

major economic effect of section 5 of TSCA would

be to reduce innovation by chemical companies

(46,37,36). Several studies were conducted to estimate the impacts of the PMN process on the

introduction of new chemicals (see, e.g., 3,37).

Impacts were assessed for several alternative PMN

filing formats proposed by EPA and were dependent

on the direct costs of preparing and submitting the

PMN as well as the indirect costs of delays and

uncertainty associated with the ultimate disposition

of the PMN.

One of the difficulties in assessing the impacts of

the PMN rule on innovation in the chemical industry

is that data on the number of new chemicals

introduced annually, prior to the implementation of

the PMN rule, are quite limited. It has not been

possible, therefore, to establish a good baseline

against which to measure the rate of chemical

innovation since implementation of the rule.

EPA’s estimates of direct filing costs for the final

PMN rule were rather nominal ($3,000 to $18,000 in

1983 dollars per new chemical introduction) (19).

However, some parties, notably the Chemical Specialties Manufacturing Association, argued that

even costs in this range would have a disproportionate distributional impact on introductions of smallvolume chemicals (19). Some of the smallervolume, lower-value chemicals are not able to

absorb even the relatively low compliance cost

burdens represented by these estimates.

Utility of Regulatory Analyses in Devising

Environmental Regulatory Policy

It is the need to document the economic impacts

and potentially high costs of Federal regulatory

decisions that continually motivates agencies to

evaluate the effectiveness of these decisions. The

goal in conducting these evaluations has been to

improve regulatory decisionmaking through systematic development of information, preferably

quantitative information, about the positive and

negative economic impacts of proposed regulations.

From an analytical point of view, the ability of any

evaluative technique to influence the selection of a

particular regulatory alternative depends on the

degree to which that technique can provide clear-cut

distinctions among alternatives. Because of large

gaps in underlying scientific information, estimates

of costs, risks, and benefits are more often than not

quite crude and highly uncertain. Consequently,

cost-benefit and other regulatory analysis techniques are approximate and capable usually of

distinguishing only between clearly superior and

clearly inferior alternatives.

Improving Regulations

Despite their limitations, cost-benefit and costeffectiveness analyses have influenced the development of regulations. In a recent assessment of impact

analyses for 15 major regulations, EPA concluded

that cost-benefit analysis had improved individual

environmental regulations by:

●

●

●

●

●

guiding the development of the regulation (i.e.,

showing that net benefits increase or decrease

if the proposed regulation is made more or less

stringent);

leading to the specification of additional alternatives for analysis and consideration;

eliminating alternatives that are clearly not

cost-effective;

adjusting alternatives to account for differences

between industries or segments of industry; and

supporting decisions (i.e., showing that there

are net benefits for a regulatory decision that

have been formulated under a different decision

framework).

EPA noted that in some cases it is precluded by

law from allowing the results of a cost-benefit

analysis to influence rule-making. 14 In some of these

instances, the Agency has prepared cost-benefit

analyses anyway, to conform with the requirements

of Executive Order 12291.

The General Accounting Office, in reviewing the

utility of cost-benefit analysis at EPA, noted this

difficulty and recommended that the Agency forward its analyses to Congress, since they could still

lsAlthou@~e ~atutow r~uirements for prernanufacturenotif ication and review ( 15 U.S.C. 2604(a)(l )(A)) do not stipulate that these processes must

be stated in a rule or that the information be provided in a particular form, EPA ( 19) determined that the issuance of a PMN rule was in the best interest

of all concerned parties. Toward this end, the Agency began operating the PMN program on an interim basis in July 1979. The final rule establishing

PMN requirements and review procedures was not issued until 1983 (48 FR 21742).

ldunder tie Clean Air ~t, for exap]e, Pnmq national ~bient ~ qll~ity s~nd~ds must ~ bad solely on he~ti effwts, without consideration

of benefits, costs, or economic impacts (42 U.S.C. 7409(b)(l).
Chapter 8-Economic Considerations in Regulating Neurotoxic Substances ● 221

provide useful information for congressional oversight (41). EPA supported this recommendation but

noted that care should be taken in interpreting the

findings because of the uncertainties and gaps in

data that are likely to exist (48).

Additional Contributions

EPA noted several other contributions that costbenefit analysis has made. As the Agency has gained

experience in quantifying benefits, it has been able

to transfer analytical expertise from one regulatory

area to another. For example, part of what EPA

learned from evaluating the health benefits of

removing lead from gasoline has been applicable in

estimating the benefits of reducing lead in drinking

water.

Application of the cost-benefit approach has

improved the consistency and comprehensiveness of

regulatory analyses of proposed rules. Evaluation of

regulations to control pollutants that have the same

health outcome (e.g., cancer) has encouraged more

uniformity in analyzing data on health effects. For

multimedia pollutants, the application of costbenefit analysis has increased awareness that regulatory action against pollution of one medium has

ramifications for human exposures to pollutants in

other media.

Economic Principles of Cost-Benefit and

Cost-Effectiveness Analyses

As indicated above, cost-benefit and costeffectiveness analyses seek to quantify and compare

the economic inputs and outputs of a regulatory

decision. If cost-benefit analysis confirms that the

net benefits (i.e., the benefits minus the costs) of a

regulatory proposal are positive, the regulation is

said to produce an economically efficient allocation

of resources. Thus, implementation of that regulation will result in a net economic gain to society.

Concepts and Definitions

In general, the concepts of cost-benefit and

cost-effectiveness rest on the basic economic concept of opportunity cost: that is, the true cost of any

activity consists of the value of alternative endeavors that might have been undertaken with the same

resources. For example, the opportunity cost of

premarket testing of a chemical is the value that

resources used for toxicity testing would have had if

used in production, sales, or other research activities.

The principal technical distinction between CBA

and CEA, as noted earlier, is that CBA benefits are

valued in monetary units, whereas CEA benefits are

valued in natural, or nonmonetary, units. Because all

costs and benefits are measured in the same units in

CBA, this technique can be used to compare similar

or widely divergent types of decisions. Thus CBA

might be used to compare different regulatory

options such as protective labeling, use limitations,

or a total product ban. In the health area, analysts

frequently prefer CEA to CBA because of the

difficulty or undesirability of placing a dollar value

on life. When using CEA to evaluate health programs that have both mortality- and morbidityreducing consequences, analysts must often compare noncommensurable outcomes. How are two

programs to be compared when one saves several

lives but has a limited impact on morbidity, while

the other saves a few lives and has a more extensive

impact on illness? To address this problem, analysts

have developed a measure called quality-of-lifeadjusted years.

Cost-effectiveness is useful in making relative

comparisons among regulatory options, and it is

more meaningful when two or more alternatives are

compared. For example, instead of considering the

cost-effectiveness of toxicity test A standing alone,

analysts examine the cost-effectiveness of test

protocol A compared to protocol B or protocol C.

Protocol A is cost-effective if it yields the required

test data at a lower cost than protocol B or C; or A

is cost-effective if it produces more useful data than

B or C when the same level of resources is utilized

in each test protocol. In both of these comparisons,

protocol A would be regarded as the most economically efficient alternative of the three (economic

efficiency is also a relative concept and refers to the

alternative that provides the greatest return for a

given level of resource expenditures).

THE COSTS OF

NEUROTOXICITY TESTING

Animal toxicity testing and the resources expended for this purpose are now considered essential

features in the development of new chemicals and

drugs. FFDCA and FIFRA require demonstration of

the ability of drugs and pesticides, that is, of the

designed toxic properties, to attack diseases or target

organisms. The relative safety of a drug (as measured in terms of unintended toxic effects) or a
222 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

pesticide (as measured in terms of morbidity or

mortality to nontarget organisms) must also be

demonstrated. TSCA emphasizes establishing a

minimal set of information about a chemical’s toxic

properties before it is introduced into commerce.

Under TSCA, manufacturers can also be requested

to provide additional test data if there is cause to

believe that a chemical may present an unreasonable

risk to human health or the environment (see ch. 7).

Over the years, Federal authorities responsible for

regulating chemicals have paid attention primarily

to the potential carcinogenic, mutagenic, and teratogenic effects of pesticides and toxic substances.

Although concerns regarding neurotoxic effects

were occasionally mentioned, in most cases they

were of secondary importance. With steady advances in the field of neurotoxicology and corresponding improvements in the ability to understand

and to test for the neurotoxic effects of chemicals,

the adverse effects that a substance may have on the

nervous system have become of increasing interest

and importance in regulatory decisionmaking.

In order to gauge the economic significance of

requirements for increased neurotoxicity testing,

this section discusses factors in the costs of animal

tests for neurotoxicity. Estimates obtained by the

Office of Technology Assessment (OTA) of the

costs of conducting certain neurotoxicity tests are

then presented. Finally, the incremental effects that

the costs of neurotoxicity testing will have on total

R&D costs for new chemical technologies are

discussed.

Determinants of the Costs of Toxicity Tests

The costs of animal toxicity tests vary greatly

from laboratory to laboratory. Many factors contribute to these variations, but they can be placed into

two categories: scientific, or differences in protocol

requirements, laboratory personnel, facilities, and so

on; and financial, or differences in laboratory costs,

rates, and fees.

Scientific Determinants

There are five major scientific considerations that

determine the costs of any toxicity testing: protocol

requirements, quality assurance, personnel, laboratory capabilities, and laboratory automation. Each of

these is discussed below.

Protocol Requirements—The requirements of

the test protocol are the single most important factor

in determining the costs of toxicity testing. Of these

requirements, duration of exposure has the greatest

impact on costs. Tests to identify the adverse effects

of acute exposures are usually completed within 1

month; tests for chronic exposures may require up to

2 years of animal dosing and observation. Because

of the time difference alone, direct labor costs may

differ by as much as a factor of 40.

Route of exposure is the next most important cost

factor in protocol design. Because of the relative

ease of dose administration, oral exposure via

gavage (force-feeding) is least costly, followed by

oral feeding, dermal exposure, and inhalation exposure. Dermal and inhalation exposures require special preparations and equipment. Inhalation also

requires special monitoring equipment to measure

the concentration of the test substance in the air

breathed by the animals.

Although EPA has promulgated toxicity testing

guidelines (50 FR 39397-39470), these protocols are

not rigid recipes. Chemical manufacturers may

exceed EPA requirements (e.g., an increased number

of dosage groups or animals per group) or suggest

additional testing based on previous experience and

test findings.

Quality Assurance-Quality assurance affects

the costs of toxicity testing in proportion to the

accuracy and precision of the measurements required by the protocol. To achieve greater accuracy,

more effort is needed in controlling contamination

or other factors that may bias measurements. To

achieve greater precision, more effort is needed in

making duplicate measurements and analyses.

Federal good laboratory practice guidelines and

regulations have, for the most part, required laboratories to establish in-house quality assurance units.

The number of persons in these units varies by

laboratory. Some laboratories do not have fill-time

quality assurance personnel and rely on outside

consultants or part-time personnel, whose costs may

be lower. Laboratories with large quality assurance

units perform functions well beyond the basic test

requirements, and their costs usually are much

higher.

Quality assurance personnel perform protocol

evaluations, general laboratory inspections, evaluation of technical procedures, verification of raw data,

interim and final report audits, and verification of the

final report. The time required for these procedures
Chapter 8-Economic Considerations in Regulating Neurotoxic Substances ● 223

varies with the degree of automation at the laboratory, the degree of report standardization and computerization, the amount of data audited (which may

range from 10 to 100 percent), and the experience

and efficiency of the personnel.

Personnel—The levels of professional and technical expertise required for a particular toxicity test

can significantly influence costs, particularly in

acute studies. The education and experience required may be specified by the protocol, Federal

regulatory requirements, or general consensus, any

of which will result in cost variations. Smaller

laboratories may have only limited personnel available for performing the tests (i.e., senior scientists

may be performing procedures that would normally

be done by technicians).

Laboratory Capabilities-Cost may also vary

with mix of capabilities within a laboratory. Many

laboratories do not perform the full complement of

required test functions (i.e., analytical chemistry or

electron microscopy) in house. Laboratories that use

consultants or subcontractors to perform these functions increase costs by adding general and administrative fees. Laboratories that have extensive inhouse capabilities but do not operate at full capacity

incur greater overhead.

Laboratory Automation-There are major cost

differences between manual and automated methods

of data collection. Highly sophisticated, on-line

computer systems can capture data electronically,

lowering facility and animal monitoring costs.

Examples include automatic control, monitoring,

and recording of environmental conditions within

the laboratory, as well as computerized data stations

for animal body weights, food consumption, and

clinical observations.

Financial Determinants

Four financial factors influence laboratory costs:

1) overhead rates, 2) general and administrative

rates, 3) fees, and 4) labor rates.

Overhead Rates-Overhead costs are the indirect

expenses, such as rent, heating, lighting, equipment,

computer services, telephone, insurance, and so on,

associated with the operation of a laboratory. Overhead costs are usually computed as a percentage—

called the overhead rate-of total direct labor costs.

Overhead rates vary significantly among laboratories, for numerous reasons. Geographical location

can affect overhead rates through variation in utility

costs; rent, land, or construction costs; property

taxes; State income taxes; and Federal corporate

income taxes. The number of years the commercial

laboratory has been in business may influence its

overhead rate. Newer firms typically have a smaller

work force, a large capital investment in new

equipment, and sizable expenses in order to generate

new business. Older, established firms often support

a significant portion of employees on overhead,

offer a better benefits package, and buy more

up-to-date instrumentation.

The overall capabilities offered by a laboratory

also affect the overhead rate. The more varied the

capabilities, the more equipment and personnel are

required. On the other hand, laboratories with more

limited capabilities must hire consultants and subcontractors to perform certain tests, which may be

quite expensive,

General and Administrative Rates-General and

administrative costs represent the salaries of administrative and support personnel who do not engage in

the study, but whose functions are essential to the

operation of the laboratory. Examples include management, personnel, accounting, contracts, marketing, and legal employees. Usually, commercial

laboratories have general and administrative rates of

5 to 25 percent of total direct labor costs. The more

established laboratories tend to have higher general

and administrative rates because of higher ratios of

support to nonsupport personnel.

Fees—Fees refers to the profit expected from a

study. Due to the confidential nature of such

information, it is difficult to obtain data on fees

received by commercial laboratories, but they range

from 5 to 40 percent.

The wide range in profits may reflect marketing

strategy and the volume of studies being performed.

If volume is low, lower fees may be charged to

attract new business. To encourage volume testing,

many laboratories will also offer discounted prices

for multiple testing packages. These package deals

may be significantly lower than the sum of the unit

costs for each of the individual tests in the package.

Furthermore, acute toxicity protocols are often bid at

or below actual cost in order to encourage future

business.

Labor Rates-Labor rates vary substantially from

one laboratory to another, depending on the mix of
224 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

individuals required to conduct a specific test.

Salaries for similar types of technical positions also

vary with regional economic conditions.

Cost Estimates for Neurotoxicity Testing

Because experience with neurotoxicity testing is

still relatively limited, there is considerable uncertainty regarding testing costs. Recently, in support of

the TSCA Test Guidelines Program, EPA (50)

prepared estimates for several toxicity testing protocols that include neurotoxicity testing. These estimates were constructed by a senior toxicologist who

is experienced in managing contract laboratory

operations for toxicity testing. Because of the

uncertainty regarding the representativeness of test

cost estimates that are essentially from one source,

it was decided as part of this study to obtain

independent estimates of the costs of neurotoxicity

testing.

To obtain these estimates, OTA surveyed researchers in several industrial, government, and

contract laboratories (35). Researchers were selected

on the basis of their experience in neurotoxicity

testing, not the type of laboratory in which they

work. Because the potential pool was small, it was

not possible to obtain enough individuals to represent in a statistically valid way each of the three

laboratory settings.

The chief purpose of the survey was to obtain a

better understanding of the range of costs for animal

tests to characterize the neurotoxicity of a specific

chemical. A questionnaire was prepared to obtain

cost estimates for acute, subchronic, and chronic

toxicity tests of a single chemical that include

various neurological evaluations. Cost estimates

were requested for acute, subchronic, and chronic

toxicity tests augmented with four neurotoxicity

tests: functional observational battery, motor activity, neuropathologica1 evaluations, and schedulecontrolled operant behavior. (See ch. 5 for a

description of these tests.) Duration and route of

exposure were specified for each protocol. The

protocols for which cost estimates were solicited are

indicated in table 8-3.

In addition to total costs for each test protocol,

respondents were asked to provide separate estimates of the incremental costs for each of the four

neurotoxicity tests. The purpose was to assess how

much each type of neurotoxicity test would contribute to total test costs and whether neurotoxicity test

requirements would lead to substantial increases in

costs. This information is not available in the EPA

estimates (50).

The ranges for the different test cost estimates that

were obtained from this survey are presented in table

8-4. These are the highest and lowest cost estimates

for the indicated toxicity tests and the highest and

lowest incremental cost estimates for each of the

added neurotoxicity tests. As expected, estimates of

acute toxicity test costs are lower than those for

repeated-dose studies, and estimates of costs for

tests using the oral route of exposure are lower than

those for tests using the inhalation route.

Median cost estimates for each of the base test

protocols and each of the added neurotoxicity tests

are presented in table 8-5. (Because this kind of

survey is likely to yield outliers at both the high and

low ends of distribution, the median is the preferable

estimate.) The median estimates indicate that a

complete set of core neurotoxicity tests, including a

functional observational battery, motor activity, and

neuropathology, may add from 40 to 240 percent to

the cost of conventional toxicity testing of a single

chemical. The major portion of the added cost is due

to the requirements of the neuropathological examinations. Based on its survey, OTA found that acute

neurotoxicity tests (including EPA’s functional

observational battery, motor activity test, and neuropathology evaluations) are likely to add a total of

about $50,000 to standard toxicity test costs of a

single chemical. Subchronic neurotoxicity tests may

add up to $80,000, and chronic tests may add well

over $100,000. The EPA subchronic schedulecontrolled operant behavior test (which is only likely

to be done after the other neurotoxicity tests) may

add about $64,000. However, the functional observational battery alone would add only $2,500 to the

cost of a conventional acute toxicity test. The added

cost impact is highest for the acute test protocols. A

conventional acute test involving oral exposure

costs about $21,000.

EPA median cost estimates (50) are considerably

lower than OTA survey estimates for identical

protocols—from one-half to nearly one-fourth. Although the EPA estimates were developed approximately 6 months before the OTA study, the 1988

inflation rate of 4 to 5 percent during this period does

not account for differences of this magnitude.
Chapter 8--Economic Considerations in Regulating Neurotoxic Substances ● 225

Table 8-3-Protocols for Which Cost Estimates Were Solicited

Neurotoxicity Test

ScheduleFunctional Controlled

Observational Motor Neuro- Operant

Protocol Battery Activity pathology Behavior

Acute inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x x

Acute oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x x

Subchronic inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x x

Subchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x

Subchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x x

Chronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x x x

SOURCE: Office of Technology Assessment, 1990.

Table8-4-Ranges in Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity Evaluations for 1988

(thousands of dollars)

Neurotoxicity Test (incremental costs)

ScheduleFunctional Controlled

ToxicityTest Observational Motor Neuro- Operant

Protocol Base Cost Battery Activity pathology Behavior

Acute inhalation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $8.8-47.2 $11-213 $1.2-12.3 $4.7-187.6 NA

Acute oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.9-39.7 1.1-21.3 1.2-11.3 4.7-179.6 NA

Subchronic inhalation . . . . . . . . . . . . . . . . . . . . . . . . 99.1-391.0 2.9-32.9 2.1-11,8 6.2-362.9 NA

Subchronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69.5-183.0 2.7-32.9 2.1-11.8 6.2-271.5 NA

Subchronic oral (NP & SCOB)* . . . . . . . . . . . . . . . . 69.5-183.0 NA NA 6.2-271.5 11.0-80.3

Chronic oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234.0-783.9 3.8-85.8 4.8-38.2 11.3-602.0 NA

“Neuropathology (NP);schedule-controlled operant behavior (SCOB)

SOURCE: Office of Technology Assessment 1990.

Table 8-5-Median Cost Estimates for Animal Toxicity Tests Combined With Neurotoxicity Evaluations for 1988

(thoussnds of dollars)

Neurotoxicity Test (incremental rests)

ScheduleFunctional Controlled Median Increment

Toxicity Observational Motor Neuro- Operant Total as a Percent

Protocol Base Costa Battery Activity pathology Behavior lncrementa of Base

Acute inhalation . . . . . . . . . . . . . . . . . . . . $ 26.6(7) a $ 2.5(5) $ 4.5(6) $42.0(5) NA $ 49.9(5)b

188

Acute oral . . . . . . . . . . . . . . . . . . . . . . . . . 21.2(7) 2.4(5) 4.4(6) 42.0(5) 49.9(5) 235

Subchronic inhalation . . . . . . . . . . . . . . . 190.6(7) 4.8(5) 4.7(6) 42.0(5) NA 79.1(5) 42

Subchronic oral . . . . . . . . . . . . . . . . . . . . 111.0(7) 4.8(5) 4.7(6) 29.7(5) 79.1(5) 42

Subchronic oral(NP & SCOB)* . . . . . . . 109.8(5) NA 41.7(4) 64.1(5) , 87.0(4) 79

Chronic oral . . . . . . . . . . . . . . . . . . . . . . . 308.0(6) 12.5(5) 19.8(6) 59.7(5) NA 113.2(4) 37

aNumbr ofobservations shown inparentheses.

b~cau=ofinmmplete responses, columnsdo notadd tototal.

*Neuropathology (NPhschedule-controlled operantbehavior (SCOB)

SOtJRCE: Office ofTechnology Assessmen~ 1990.

NEUROTOXICITY TEST COSTS

AND INNOVATION

In order to assess the impacts of testing for

neurotoxicity on innovation in the drug, pesticide,

and chemical industries, it is essential to describe the

patterns of innovation for drug, pesticide, and

chemical products. While there are certain similarities among the three, there are important economic

differences between the development process for

new chemicals and that for new drugs or pesticides.

Drug and Pesticide Development

There are many similarities in the process of

developing new drugs and pesticides. The key

factors governing the pattern of innovation in these

industries are the high costs and long development

times experienced from discovery of a new compound to commercialization of it. Hundreds of new
226 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

compounds may be screened for each new pesticide

and drug that is eventually marketed. Approximately

10 years may elapse from discovery to first registration (31,33). The pharmaceutical industry estimates that it currently costs well over $100

mil1ion to develop, test, and bring to market a

new drug product (52). The pesticide industry

estimates development costs for anew pesticide of

about $25 million, with another $25 to $50 million

required for building and equipping production

facilities (4).15

Agrichemical and pharmaceutical companies spend

from 9 to 15 percent of sales revenue on R&D

(31,33). Most R&D in pesticide and pharmaceutical

companies is internally financed and conducted in

order to protect the proprietary status of new

innovations. The disadvantage of this practice is that

uncertainties imposed by the regulatory process,

either as delays in the introduction of new products

or as unexpected limitations or bans on the sale of

these products, may reduce the return on industry’s

investments in research.

The high costs and long time from discovery to

commercialization force the development process

for new pesticides and drugs toward those applications that are likely to have very high returns. Only

a relatively small number of markets are large

enough to make it economically worthwhile for

firms to develop these products. Consequently,

pesticides are developed and initially registered for

major uses, for example, on crops such as corn or

soybeans. Subsequently, they are tested for use on

minor crops.

The actual discovery of a new drug entity-anew

chemical with therapeutic potential-is just the first

step in a lengthy process of R&D. The discovery

phase of the process consists of chemical synthesis

and animal testing to establish a compound’s

toxicology and pharmacology. The development

phase encompasses clinical testing to assess potential toxic effects in healthy humans and, subsequently, to establish in patients the therapeutic

efficacy of a new drug candidate.

The average effective period of patent protection

for anew chemical entity declined between 1966 and

1979 (16). The estimate of 9.5 years of protection is

about one-half the maximum period of patent

protection of 17 years. This decline in patent life,

which has been largely attributed to longer development and regulatory approval times, became a major

policy issue in the early 1980s. Congress addressed

the problem in 1984 with the Drug Price Competition and Patent Restoration Act (Public Law 98-

417) 0 This law allows restoration of part of the patent

protection time that elapses during development and

FDA approval.

The recent estimate of $125 million (1986 dollars)

as the total research and development cost for an

approved new drug is based on new drugs approved

between 1970 and 1985 (52). The increasing costs of

developing new drugs are due in part to an increasing

focus on therapies for chronic conditions. The

development of drugs of this kind requires more

extensive testing (33).

Neurotoxicity Tests and Innovation

in Dregs and Pesticides

The above discussion of the processes for developing drugs, pesticides, and chemicals provides a

framework within which the innovation impacts of

conducting animal tests for neurotoxicity may be

assessed. The impacts of testing on innovation

depend on overall test costs, duration of the tests,

and the timing (scheduling) of the tests within the

innovation period.

One possibility would be for the animal toxicity

tests with combined neurological evaluations to take

place during the preclinical and pre-field testing

phases for drug and pesticide development, respectively. In this scenario, the additional costs of testing

for neurotoxicity would occur during the second or

third years of a 10-year developmental period.

If neurotoxicity test protocols are totally incompatible with other concurrent animal toxicity testing,

then the additional costs of obtaining neurotoxicity

data would be the capitalized value of the full test

costs at the expected date of marketing approval.

The expected date of marketing approval is 7 to 8

years in the future. At the assumed 10 percent rate of

interest, the capitalized value of $190,000-the

median cost estimate for subchronic oral toxicity

testing with functional observation, motor activity,

and neuropathology evaluations-is from $370,000

to $430,000. The capitalized value of $420,000-the

median cost estimate for chronic oral toxicity testing

with the same neurotoxicity evaluations-is from

15~e= ~omt~ ~PPW t. ~ in ]~e wi~ ealier &~~l~ e5tirnate5 by Gofig ( 14) of tie coss of commercializing a new pesticide.
Chapter 8-Economic Considerations in Regulating Neurotoxic Substances ● 227

$820,000 to $900,000. These amounts are small,

compared to current estimates of total capitalized

costs of developing a new drug or pesticide.

A second possibility would be for neurotoxicity

test data to be requested at the very end of the drug

or pesticide development process. In this instance,

timing of the tests is of much greater importance

than their costs. Testing that, for example, extends

the innovation period by 1 year at the end of the

development period has an associated opportunity

cost equal to the interest on the total cumulative

R&D investment. For drugs and pesticides, the costs

of delaying marketing approval at this point clearly

overshadow any outlays required to conduct the

tests.

Neurotoxicity Tests and Innovation

in Chemicals

The pattern of new product innovation in chemicals is considerably different from that of drugs or

pesticides (45). For one thing, there is greater

diversity among chemical products, which include

plastics, solvents, fibers, detergents, catalysts, and

basic organic and inorganic chemical feedstocks.

More important from an economic perspective,

however, is the fact that new drugs and pesticides are

developed for quick penetration into large markets.

In contrast, the initial market for the vast majority of

new chemical products is very small, and failure

rates are high. Markets for large-volume chemicals

develop slowly over a number of years.

Data on the number of new chemicals introduced

annually into commerce before TSCA are uncertain.

Estimates of the rate of new chemical innovation

range from 700 to 1,400 compounds annually (3,12).

Of these, as many as 70 percent were estimated to

have annual production volumes of less than 1,000

pounds, which is regarded as a threshold level of

output for a viable commercial product (3). Furthermore, many low-volume products were, in all

likelihood, developed and marketed by very small

firms in the business of “custom-manufacturing”

chemicals. Since the implementation of the final

PMN rule in 1983, the annual receipt of PMNs by

Photo credit: U.S. Environmental Protection Agency

EPA has increased steadily, to nearly 1,700 compounds in 1986 (6).

Under section 5 of TSCA, EPA does not require

that chemical manufacturers conduct toxicity testing

prior to submission of a PMN; manufacturers are

only required to supply any health or environmental

test data that are available at the time of submission.

Although EPA can request additional toxicity testing of new chemicals, it has used this authority

sparingly.lb In a recent analysis of 8,000 PMNs

received by EPA from July 1979 through September

1986, fewer than one-half contained toxicity test

data (6).

Although data are not readily available on the

average costs of developing and introducing a PMN

chemical, as noted above, many of them are produced and marketed as specialty products. Expected

profits from the sale of small-volume chemicals

161f, ~ ~evie~ng tie pMN subnlisslon, EpA decides the chemical may pre~nt ~easonab]e risks to hea.1~ or tie environment, the a$pCY Call lh’ilit

production and utilization of the substance while more test data are developed ( 15 U.S.C. 2604(e)). If EPA decides the chemical will present unreasonable

risks, the agency can require the development of additional test data (15 U.S.C. 2604(0). Aw and Gould repoti hat EPA had order~ submission

of more test data for about 200 PMN chemicals from 1979 to 1986. An additional 150 PMNs had been subject to voluntary actions, some of which

involved testing. Finally, 164 chemicals were voluntarily withdrawn by the submitted when presented with the likely prospect of conducting more testing

(6).
228 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

cannot, in most cases, cover the costs of extensive

testing, especially if there are substitute products

already on the market. Thus, a request for neurotoxicity testing, which could add substantially to costs

of testing currently being done, could lead to a

reduction in the rate of innovation in certain classes

of low-volume products, particularly those that are

vulnerable to even modest regulatory compliance

costs.

ECONOMIC BENEFITS OF

REGULATING NEUROTOXIC

SUBSTANCES

It is important to distinguish between the adverse

effects of neurotoxic substances and the benefits of

reducing or “preventing these adverse effects. The

adverse effects of neurotoxic substances are expressed as impacts on human health and the environment and are measured in terms of mortality,

morbidity, disability, and environmental damage.

They should include effects on mental status, such as

memory loss and cognitive dysfunction, that may be

associated with exposures to neurotoxic substances.

Reducing or preventing the risks of exposure to

neurotoxic substances means reducing the magnitude of these adverse effects. The human and

monetary values placed on risk reductions are a

measure of the benefits of regulation. In the economics of health and safety, several approaches have

been used to assign monetary values to reduced risk

of mortality, morbidity, and disability. These approaches have been broadly categorized as valuation

through adjudication (jury awards), political processes, individual preferences, and resource or opportunity costs.17 Valuation through resource or opportunity costs will be discussed here.

Knowledge Requirements for

Estimating Benefits

To estimate the benefits of policies to reduce or

prevent neurotoxic risks requires knowledge and

quantification of the following:

. the relationship between economic activities

and the rates of use of neurotoxic substances;

. the relationship between the environmental fate

and transport mechanisms that determine ambi-

●

●

●

ent environmental concentrations and, hence,

human exposures to these substances;

the relationship between the activities of individuals (e.g., eating, working, exercise) and the

rates of human intake of these substances;

the biological mechanism by which these

substances cause disease in humans; and

the relationship between changes in health

status and the utilization of health care.

Only the first and the last of these relationships are

basically-although not exclusively—in the realm

of economics. The intervening ones represent the

interface of science and economics-in particular,

they are the substance of risk assessments of

exposures to neurotoxic substances (35).

The fact that exposures to neurotoxic substances

result in more effects and more varied effects on

health than, say, exposures to carcinogens is an

important distinction and one that poses analytical

difficulties in risk assessment and benefits analysis.

In contrast to carcinogenicity, which can usually be

characterized as a single outcome with discrete

measures of health status (i.e., the disease is present

or it is not), neurotoxicity may be manifested as

multiple effects, each of which may produce a

continuum of health states ranging from mild to

severe.

The Health Costs of Neurotoxicity

As noted above, the opportunity costs of morbidity and mortality that can be attributed to neurotoxic -

ity provide a measure of the potential economic

benefits of reducing neurotoxic risks to human

health. These opportunity costs, frequently called

the social costs of illness, include direct and indirect

costs of illness and death. The direct costs of illness

consist of the payments for health-care products and

services utilized in providing patient care. The

indirect costs of illness encompass the expected

earnings an individual loses as a result of not

working. Medical care costs and foregone earnings

are estimated for each year from the onset of illness

to expected year of death. This time stream of costs

is then discounted to present values.

Estimating benefits in this manner is known as the

productivity, or human capital, approach. Most

economists regard this approach as providing lower17v~UatiOn ~Wor&ng t. individU~ preferences, or Wi]]ingness to pay, is frequently c,it~ by ~onomists as the most appropriate measure Of the V~U(?

of redueing the risks of adverse health effects (13).
Chapter 8--Economic Considerations in Regulating Neurotoxic Substances .229

Table 8-6-Personal Health-Care Expenditures for the 10 Most Expensive Medical Conditions in the United States

in 1980 (millions of dollars)

Medical condition All ages Under 65 65 or over

Diseases of the circulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . $33,184 $13,078 $20,015

Diseases of the digestive system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31,755 26,084

Mental disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20,301 14,612 5,689

Injury and poisoning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19,248 15,042 4,206

Diseases of the nervous system and sense organs. . . . . . . . . . . . . . . . . . . . . . . . . . . 17,499 13,028 4,471

Diseases of the respiratory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17,305 13,164 4,141

Diseases of the musculoskeletal system and connective tissue . . . . . . . . . . . . . . . . . . 13,645 9,821 3,824

Neoplasms . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13,623 8,302 6,322

Diseases of the genitourinary system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13,162 10,721 2,441

Endocrine, nutrition metabolic system, and immunity disorders. . . . . . . . . . . . . . . . . 7,656 4,689 2,968

SOURCE: U.S. Department ofHealth and Human Services, PubiicHeaith Servie8, National CenterforHealth Statistics, /+ea/th UntiedStates, 1983, DDHS

Pub. No. (PHS)84-1232 (Washington, DC: U.S. Government PrintingOffiee, 1983)

bound estimates of the benefits of improving health

because it does not attempt to measure and include

the disutility experienced by persons having these

diseases or by their families and friends. This kind

of disutility is particularly relevant for dementia,

retardation, and other mental disorders in which

neurotoxicity may be a causative or contributing

factor.

The Costs of Mental Disorders and Diseases

of the Nervous System

Mental disorders and diseases of the nervous

system contribute substantially to health costs in the

United States. In 1980 (the most recent year for

which costs of illness were estimated for specific

disease categories) they ranked as the third and fifth

most expensive medical conditions, respectively, in

terms of personal health-care expenditures (table

8-6). The estimate of nearly $40 billion (1980

dollars) for these two categories of morbidity does

not include values for lost productivity, restricted

activity, and other social costs (e.g., rehabilitation

for drug and alcohol abuse) that may accompany

mental illness or other forms of cognitive and

behavioral impairment.

The Costs of Neurotoxicity

As an Element of Dementia

Dementia is defined as the loss of intellectual

function. It is manifested as a complex of symptoms

that can be caused by as many as 70 underlying

conditions. The causes of disorders that produce the

vast majority of dementia cases are still not understood (44); however, some dementias maybe caused

or exacerbated by neurotoxic substances in prescription drugs, metals, solvents, and other chemicals

(21). Other dementia diagnoses include necrosis of

brain tissue due to vascular obstruction, various

infectious diseases, tumors, and toxicity from alcohol (21).

Although the costs of dementia to the Nation can

be only crudely approximated, they are high and are

bound to increase as the population ages. Estimates

of the costs of dementia are presented here as a basis

for estimating the health costs of neurotoxicity. One

study has estimated that at least 2 to 3 percent of

dementia patients were diagnosed as having disorders involving drug toxicity (21). If this can be

regarded as a lower-bound estimate, then from 2 to

3 percent of the costs of dementia may be taken as

a lower-bound estimate of the social costs of

neurotoxicity. Applying 2 to 3 percent to each of the

above estimates for the overall costs of dementia

yields estimates of $0.5 billion to $1.5 billion

annually for neurotoxicity alone.

The Costs of Exposure to Lead

Epidemiologists have demonstrated associations

between excessive lead exposure, particularly during childhood, and several kinds of adverse neurological and behavioral effects.18 In the past, public

health agencies focused principally on severe lead

exposure and the resultant symptoms of overt lead

poisoning.

More recently, medical scientists have shown that

important neurochemical changes are induced by

lead in much smaller amounts than those generally

associated with clinical symptoms of lead poisoning. Finally, there is considerable epidemiological

evidence that low-level exposure can result in

altered behavior, including attentional disorders,

lwor a r~ent comprehensive review of the adverse health effecrs of lead, s= ref. 47.
230 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

learning disabilities, or emotional disorders that

impair classroom performance.

For these reasons, an analysis of the health costs

attributable to excessive lead exposure during childhood must recognize at least three categories of

costs:

●

●

●

direct medical care expenditures, including

hospitalization, doctors’ fees, drugs, and convalescent care for preschool children who have

been diagnosed as being at risk with respect to

lead absorption;

special education or institutionalization costs,

or both, for school-age children who suffer

permanent neuropsychological effects from

exposure to lead; and

costs to society in terms of reduced production

and tax contibutions from adult members of

the labor force who have permanent impairments stemming from excessive exposure to

lead during childhood.

Calculating health costs of lead exposure involves

multiplying estimates of the number of preschool,

school-age, and adult individuals with lead-induced

health and intelligence deficits by cost factors that

represent the opportunity costs to avoid or correct

those deficits (34). Two recent analyses of regulatory proposals to reduce human exposures to lead

used this approach.

In a cost-benefit analysis of options for removing

lead additives from gasoline, one study (39) estimated the reduction in the number of children who

would have elevated levels of lead in their blood

(defined in this study as more than 25 grams per

deciliter) as a consequence of removing lead from

gasoline.19 The study assumed that 20 percent of all

children with elevated levels would be affected

severely enough to warrant compensatory education

for up to 3 years. Other studies suggest that the

cognitive effects and lead-induced behavioral problems may persist for at least 3 years (9,10). In the

valuation step, the number of person-years in

compensatory education was multiplied by an estimate of the additional costs of providing part-time

special education to a child for 1 year. These

estimates are presented in table 8-7. The benefits of

reducing lead in gasoline continue to increase for a

number of years, as the use of leaded gasoline is

gradually phased out. As the table indicates, the total

health benefits of reducing the neurotoxic effects of

lead on U.S. children was estimated to total more

than $500 million annually between 1986 and 1988.

If adult exposure to lead, including workers’ exposure, were included, the benefits would be considerably greater.

Another study developed similar estimates of the

savings in medical care and compensatory education

costs that would occur in a single year as a

consequence of reducing the maximum contaminant

level for lead in drinking water from 50 to 20 grams

per liter (23). The health benefits estimate for this

one-time reduction were $81.2 and $27.6 million (in

1985 dollars) for compensatory education and medical care costs, respectively.

SUMMARY AND CONCLUSIONS

Regulating neurotoxic substances involves consideration of both the economic benefits of using

these substances and their actual or potential risks to

human health and the environment. The problem of

balancing benefits, risks, and the costs of regulation

is not unique to the control of neurotoxic substances;

it arises in all forms of health, safety, and environmental regulation. Regulations that are designed to

reduce or prevent neurotoxic risks can benefit

society through improvements in public health and

environmental amenities. In most cases, however,

society incurs costs to achieve these regulatory ends.

The costs of complying with health and safety

regulations may also result in increases in market

prices, reductions in industry profits, and declines in

new product innovation.

Many of the key Federal laws under which

neurotoxic substances are regulated require agencies

to ascertain the positive and negative economic

consequences of regulation. In implementing these

laws, Congress has generally intended that agencies

prepare regulatory analyses and document the balancing of benefits, costs, and risks of proposed

alternatives.

191n order tO ~~fiate fie he~~ ~nefi~ of controlling neurotoxic substances, it is important to have good data on tie extent to which human

populations are exposed, as well as epidemioiogical data that link exposures to adverse health effects. Estimates of the benefits of reducing human

exposures to lead were greatly facilitated by the availability of national estimates of the prevalence of lead exposure obtained through the National Health

and Nutrition Examination Survey (NHANES-11) (2).
Chapter 8--Economic Considerations in Regulating Neurotoxic Substances . 231

Table 8-7-Estimates of the Health Benefits of Reducing the Neurotoxic Effects of Lead in Children

(millions of 1983 dollars)

Savings

Service 1985 1986 1987 1988 1989 1990

Compensatory education. . . . . . . . . . . . . . . . . . . . . .,. $187 $447 $408 $374 $338 $309

Medical care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 155 141 130 117 107

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 602 549 504 455 416

SOURCE: J. Schwartz et al., Costs and Benefits of Reducing Lead in Gasoline: Final Regulatory Impact Analysis, EPA-230-05-85-O06 [Washington, DC: U.S.

Environmental Protection Agency, 1985). -

In addition to these legislative provisions, the

executive branch,. through the Office of Management and Budget, has also mandated that agencies

conduct regulatory impact analyses for regulations

that may have major effects on the economy. The

current OMB requirement, which has evolved

through a series of executive orders, specifies that

agencies must conduct benefit-cost evaluations for

any regulatory proposal that is likely to have an

annual effect on the economy of $100 million or

more.

To date, only a small number of regulatory

actions, and hence a small number of regulatory

analyses, have been directed at reducing the risks of

neurotoxicity. Most of these actions have been taken

to control environmental and occupational exposures to lead. Regulatory impact analyses of regulations to reduce the amounts of lead in gasoline and

in drinking water provide some of the best examples

to date of assessments of the economic consequence

of controlling neurotoxic risks.

Analyzing the economic consequences of controlling neurotoxic risks is a two-step process. The first

step, risk assessment, involves using data from

epidemiological, toxicological, and other studies to

estimate the health and environmental risks associated with various levels of exposure to the substance

in question. The second step involves making

estimates of the costs, benefits, and other economic

impacts associated with achieving a specific level of

risk reduction.

One economic issue that has emerged in regulating neurotoxic substances concerns the costs of

screening and testing these substances for their

neurotoxic hazard potential. Experience with neurotoxicity testing is still relatively limited, creating

uncertainty regarding the available cost estimates

for this type of testing. Because of the uncertainty

regarding these costs, OTA obtained estimates of the

costs of several types of neurotoxicity tests from a

. . . , “ ,

number of individuals in government, industry, and

academia.

Cost estimates were obtained for standard acute,

subchronic, and chronic toxicity test protocols

augmented with four neurological evaluations: functional observational battery, motor activity, neuropathology, and schedule-controlled operant behavior. The

median estimates derived from OTA’s survey indicate that a complete set of core neurotoxicity tests,

including a functional observational battery, motor

activity, and neuropathology, may add from 40 to

240 percent to the costs of conventional toxicity tests

currently required by EPA. By far the largest portion

of the added cost comes from the addition of

neuropathology evaluations, which are needed to

determine whether structural change in the nervous

system has occurred and the nature and significance

of the change. Based on its survey, OTA found that

acute neurotoxicity tests (including EPA’s functional observational battery, motor activity test, and

neuropathology evaluations) may add about $50,000

to the cost of standard acute toxicity tests. Subchronic neurotoxicity tests may add $80,000, and

chronic tests may add about $113,000. The EPA

subchronic schedule-controlled operant behavior

test may add about $64,000. However, the functional

observational battery alone would add only $2,500

to the cost of conventional acute toxicity test. A

conventional acute test involving oral exposure

costs about $21,000.

Testing costs should be viewed in the context of

the total cost to industry of marketing anew product,

potential profits resulting from the sale of the

product, the impact of initially high test costs on the

innovation process, and the health benefits of

minimizing public exposure to neurotoxic substances.

For the development of new drugs and pesticides,

which have development times of 8 to 10 years and

development costs of $50 million to $100 million or
232 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

more, the costs of additional neurotoxicity testing

are very small. For industrial chemicals with specialty uses, on the other hand, additional neurotoxic -

ity testing could add substantially to costs of tests

that are currently done and could lead to a reduction

in the innovation of certain classes of low-volume

products.

The benefits of regulating neurotoxic substances

can be measured in terms of the human and monetary

values placed on reduction of risk. A number of

approaches have been used to assign monetary

values to reducing the risks of mortality, morbidity,

and disability. Lead has been the subject of an

in-depth economic analysis. A 1985 study estimated

that the total health benefits of reducing the neurotoxic effects of lead on U.S. children would be more

than $500 million annually between 1986 and 1988.

If adult exposure to lead, including workers’ exposure, were included, the benefits would be considerably larger.

Although the health and economic benefits of

limiting public exposure to neurotoxic substances

are more difficult to estimate than the costs of

regulation, the example of lead illustrates the

importance of considering the potentially large

monetary benefits of regulatory actions. Like other

toxicity testing, neurotoxicity testing is conducted to

prevent adverse health effects; hence, the benefits of

such testing may not be readily apparent and may

accrue well into the future. Often, the immediate

costs of testing receive considerable attention, but

the sizable potential benefits of preventing public

exposure to a hazardous substance receive comparatively little attention.

As indicated earlier, neurotoxic substances, in

particular abused drugs, play a significant, causal

role in the development of neurological and psychiatric disorders; however, the precise extent of the

contribution remains unclear. Mental disorders and

diseases of the nervous system contribute substantially to health costs in the United States. In 1980,

they ranked as the third and fifth most expensive

medical conditions in terms of personal health-care

expenditures (see table 1-3 in ch. 1). The estimate of

nearly $40 billion (1980 dollars) does not include

values for the lost productivity, restricted activity,

and other social costs that frequently accompany

mental illness or other forms of mental impairment.

1.

2.

3.

4.

5.

6.

‘7.

8.

9.

10.

11.

12.

13.

14.

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234 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

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Chapter 9

International Regulatory

and Research Activities

‘‘The need for generally accepted scientific principles and requirements in all areas of toxicology particularly

applies to the newly developed field of neurotoxicology. Methods continue to be developed in isolation, and

the comparability of results is often in doubt. Furthermore, until scientific principles have been agreed on,

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Sandra Marquardt

Exporting Banned Pesticides: Fueling the Circle of Poison

Greenpeace USA, 1989
CONTENTS

Page

INTERNATIONAL REGULATORY ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + + .

U.S. Regulation of Neurotoxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

International Effects of U.S. Export Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulatory Policies in Other Industrialized Nations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulatory Issues in Developing Nations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

INTERNATIONAL NEUROTOXICOLOGICAL RESEARCH . . . . . . . . . . . . . . . . . . . . .

Major Directions of Academic, Industrial and Government Research . . . . . . . . . . . . . .

Neuroepidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .* .. .. .. .. ..+. . . . . . . . . . . . . .

International Cooperation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Comparison of U.S. and Foreign Research Programs . . . . . . . . . . .. .. . ... ... ...+....

Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Foreign Governments Likely To Take Leadership Roles . . . . . . . . . . . . . . . . . . . . . . . . . .

SUMMARY AND CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CHAPTER PREFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. $.. ... .......+

Box

9-A.

9-B.

Problems With Neurotoxic Pesticides

Boxes

237

239

242

245

248

256

256

259

259

259

259

259

260

260

261

Page

in Developing Countries . . . . . . . . . . . . . . . . . 251

Incident at Lake Volta. Ghana .. .. .. .. .. ... ... ~..._... . . . . . . . . . . . . . . . . . . . . . . . . . 252

Figures

Figure Page

9-1. Total U.S. Pesticide Exports, 1983-88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ● . . . . . . 237

9-2. U.S, and World Pesticide Sales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237

9-3. Total U.S. Food Imports, 1983-88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

9-4.

9-5.

Domestic Production v. Imports of Selected Major Crops . . . . . . . . . . . . . . . . . . . . . . . 239

Pictograms for Agrochemical Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Table

9-1. Neurotoxic Substances Investigated in Papers Published

Journals, by Country, 1979-87 . . . . . . . . . . . . . . . . . . . . . .

9-2. Subjects of Neurotoxicological Research Presented at a Major

International Conference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Page

in Two International

. . . . . . . . . . . . . . . . . . . . . . . . . 258
Chapter 9

International Regulatory and Research Activities

This chapter examines the international regulatory and research programs devoted to neurotoxic

substances in general and neurotoxic pesticides in

particular. The first part of the chapter addresses the

export of neurotoxic pesticides that have been

banned or severely restricted (a limited ban) in the

United States. Regulatory programs in foreign

countries, both industrialized nations and developing nations, are discussed. The second part of the

chapter focuses on international research activities.

This chapter does not address the export of food

additives, drugs, and other chemicals.

INTERNATIONAL REGULATORY

ACTIVITIES

According to the U.S. General Accounting Office

(GAO), from 1977 to 1987, the worldwide agricultural chemical market doubled in size, to more

than $17 billion. U.S. pesticide export sales

currently represent approximately one-quarter

of the world pesticide market. Although U.S.

export statistics vary, the best estimates conclude

that about 400 to 600 million pounds of U.S.-

manufactured pesticides are exported each year

to foreign countries. According to GAO, unregistered pesticides, including banned or restricted

pesticides as well as pesticides that may never

have sought U.S. registration, now account for

about 25 percent of all U.S. pesticide exports (61).

7.5

7.0

6.5

6.0

5.5

5.0

4.5

Figure 9-l—Total U.S. Pesticide Exports, 1983-88

Billions of dollars

4.8

m

1983

6.3

7

1984 1985 1986 1987 1988

SOURCE: Office of Technology Assessment, 1990, based on U.S. Department of Commerce, Bureau of the Census, Statistical Abstract

of the United States 1989, 109th ed. (Washington, DC: 1989).

According to other estimates, the United States

supplies approximately one-half of the pesticides

imported in most Latin American countries,

where a substantial amount of the fresh fruits and

vegetables eaten in the United States in the winter

months are grown (42). Figure 9-1 illustrates U.S.

pesticide exports for 1983 to 1988. In recent years,

approximately 50,000 different pesticide products

have been registered for use by the Environmental

Protection Agency (EPA) (61). This figure does not

include pesticides that have never been registered

but are manufactured and exported for use outside

the United States. Figure 9-2 compares U.S. pesticide sales with world pesticide sales for 1987.

Some developing nations have few or no regulations to protect workers and consumers from the

harmful effects of neurotoxic substances. Developing nations that do have regulations often do not

have adequate resources to implement and enforce

them. This lack of effective regulation and enforceFigure 9-2—U.S. and World Pesticide Sales

(Basic Producer Level, 1987)

20 Billions of dollars

1

18

+

16

14

12

i

1 0

8

6

4

[

JzL

Herbicides Insecticides Fungicides Other Total

Iz2 Us. = World

SOURCE: Pesticide Industry Sales and Usage: 1987 Market Estimates,

Economic Analysis Branch, Biological and Economic Analysis

Division, Office of Pesticide Programs, Environmental Protection Agency, Washington, DC, September 1988.
238 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

ment in developing nations has a negative impact not

only on the public health and environment in user

countries, but also in industrialized nations, including the United States, where people process and

consume imported crops that may contain pesticide

residues.

Despite many regulations promulgated in this

country for the protection of consumers and workers,

U.S. citizens are exposed to banned and severely

restricted pesticides through what has come to be

referred to by critics as the ‘‘boomerang effect’ or

the “circle of poison” (41,70). At times, food in

U.S. supermarkets has been imported from developing countries where farmers use pesticides manufac-

.’-”. ‘<

. . \ ‘ . .

.“- . \“ ---

Illustrated by: Ray Driver

tured in the U.S. that have been banned, severely

restricted, or never registered for use here. Figure 9-3

indicates the dollar value of total U.S. food imports

from 1983 to 1988. One organization has estimated

that 70 percent of the pesticides exported to developing countries are used on crops grown for export to

industrialized countries (70). This effectively circumvents the protection that the regulatory action

was intended to provide.

Federal law currently permits U.S. companies to

manufacture and distribute banned, severely restricted, and never registered pesticides for use in

developing nations, despite the possibility that food

products containing residues of these pesticides may

be imported to the United States and made available

to U.S. consumers. Little definitive information

exists on the identity and quantity of residues of

banned, severely restricted, and never registered

pesticides that return to the United States on

imported crops and meats. This is due in part to the

relatively small number of Food and Drug Administration (FDA) and U.S. Department of Agriculture

(USDA) personnel available to screen sufficient

quantities of imported crops and to limitations in the

technology for detecting residues (62). However,

data are available on the dollar value of crops that are

produced domestically versus the value of crops that

are imported. Figure 9-4 compares domestic production with imports of selected major crops. Some

crops, such as coffee, are not produced domestically,

so the United States must depend entirely on imports

to supply consumer demand.

One example of the effect of current policies is the

export of the insecticide chlordane. This product was

taken off the U.S. agrichemical market in 1978 due

to concerns about its carcinogenicity (it is also

neurotoxic) and its persistence in animal fatty tissue

and in the environment. Yet Federal law allows it to

be manufactured and exported, without prior notification, to developing countries which do not have to

adhere to U.S. use controls. Chlordane and heptachlor export formulations were both registered

under section 3 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and as such are

exempt from the export notification requirements

imposed by language in section 17 of FIFRA. At

least twice in 1988, adulterated beef from Honduras,

contaminated with chlordane, was imported into the

United States and consumed by people in Florida,

Kentucky, and Minnesota before the contamination

was discovered (33,54). In one such instance, the
Chapter 9-International Regulatory and Research Activities ● 239

Figure 9-3-Total U.S. Food Imports, 1983-88

Millions of pounds

aoo~

400 -

200 -

414

1983

527

1984

598

492

1986

507

.

550

1987 1988

SOURCE: Office of Technology Assessment, 1990, based on U.S. Department of Commerial-

, Bureau of the Census, Statistical Abstract

of the United States 1989, 109th ed. (Washington, DC: 1989).

Figure 9-4-Domestic Production v. Imports

of Selected Major Crops

Billions of dollars

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

1,8s

Tobacco Olives Bananas Pine- Straw- Coffee Tomatoes

apples berries

_ Domestic production [“’”~ Imports

SOURCE: Office of Technology Assessment, 1990, based on U.S. Department of Commerce, Bureau of the Census, Statistic/Abstract

of the United States 1989, 109th ed. (Washington, DC: 1989).

chlordane residue was reported to be eight times the

approved tolerance (33). Chlordane has been banned

for all agricultural use in the United States yet is

widely used in agricultural settings in countries such

as Argentina, Australia, Colombia, and the Dominican Republic (33). In some cases, residues are not

the result of direct application to crops or livestock.

The Honduran problem was attributed to the use of

chlordane on nearby sugarcane.

The misuse of registered chemicals, many of them

neurotoxic, is an equally important issue (38).

Registered chemicals used by untrained farmworkers without proper protective clothing and equipment, in inappropriate amounts on inappropriate

crops, and without attention to other safety regulations, have been known to cause significant public

health and environmental problems. Moreover, a

substantial proportion of all pesticides are used to

destroy pests that primarily affect the appearance of

agricultural crops. Consumers often demand that

their fruits and vegetables look “picture perfect”;

however, cosmetic imperfections usually do not

affect either the taste or the nutritional value of most

foods (22). Although limited use of less hazardous

pesticides is generally considered to be economically beneficial and to pose a minimal health risk,

overuse of the more hazardous pesticides is an

increasing concern among public health officials

worldwide.

U.S. Regulation of Neurotoxic Substances

Export Laws

The United States has several laws governing

export of toxic substances. The Toxic Substances

Control Act (TSCA) was enacted in 1976 to address

the risks presented by hazardous chemicals and is

the primary statute regulating the export of industrial

chemicals. Section 12 of TSCA addresses exportation of hazardous chemicals. Section 3017 of the

Resource Conservation and Recovery Act (RCRA)

discusses the export of hazardous waste, and section

17 of FIFRA governs importation and exportation of

pesticides and devices.

Under TSCA, chemicals for domestic use that

present an unreasonable risk of injury to humans and

are imminent hazards to the environment can be

regulated. The Act requires that regulation be done

in such a way as not to impede unduly or create

unnecessary economic barriers to technological

innovation. Section 12 provides that, in most

instances, the requirements of TSCA do not

apply to substances manufactured, processed, or

distributed for export. The requirements will

apply, however, if it is determined that the

substance, mixture, or article will present an

unreasonable risk of injury to the health of

persons within the United States or to the

environment of the United States. The Act also

provides that any person who exports or intends to

export a substance for which submission of data is

required under this Act must notify the Administra-
240 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

tor of the Environmental Protection Agency of the

exportation or intent to export. Moreover, the

Administrator shall then furnish to the government

of the importing country notice of the availability of

the data submitted for each substance.

RCRA provides for the management and disposal

of solid wastes to avoid contamination of the

environment. Section 3017 prohibits any exporting

of hazardous waste unless the importing country has

been given notice of and has consented to the

shipment of the waste. However, exporters are not

required to describe the contents or toxicity of the

waste they are shipping. In addition, incinerator ash

and municipal waste, both of which contain neurotoxic metals and chemicals, are not covered by the

consent scheme.

Section 17 of FIFRA states that pesticides and

devices intended solely for export are exempt from

the testing and review requirements of the Act.

Accordingly, pesticide manufacturers and distributors can legally export pesticides that have

been banned or never registered for use in this

country. Little is known about pesticides that have

never been registered because they are exempt from

public health and environmental testing requirements if domestic use is not intended (32).

U.S. pesticide manufacturers are required to

notify the importing purchaser, and EPA notifies the

country, if the pesticide to be exported has been

banned or never registered for use in the United

States. EPA requires these statements annually for

the first shipment of each banned or unregistered

product to a particular purchaser for each importing

country. Although EPA has streamlined the transmittal process for export notices to U.S. embassies,

no formal procedures govern the processing and

transmittal of FIFRA notices once they arrive at an

embassy (61). Most embassies destroy files as recent

as 1985, and staff at every embassy surveyed by

GAO indicated that they sometimes do not retain

copies when transmitting files to the foreign governments (61 ). According to GAO, as recently as 1988,

EPA had no program to determine whether

pesticide manufacturers were complying with the

export notification requirements and had no

assurance that importing countries were adequately notified of unregistered U.S. pesticides

entering their borders (61 ). Moreover, shipment of

the unregistered pesticide may proceed before the

foreign government has received the notice, since its

purpose is only informational.

Although the language in section 17(a) of FIFRA

governing notification requirements for unregistered

pesticides provides for no exceptions, EPA, in 1980,

established a policy that effectively waives notification requirements for unregistered pesticides that are

“minor variations” on formulations and active

ingredients registered in the United States and that

are ‘‘similar in composition and use” to registered

pesticides. These exempted pesticides are commonly referred to as “me-toos.” Thus, neverregistered pesticides must bear the statement “Not

Registered for Use in the United States of America’

when they are exported to foreign markets, but

me-toos are exempt from the labeling requirement,

despite the fact that the active ingredient and inert

ingredient formulation may be different from that

registered in the United States and thus pose a

different risk (32). Accordingly, it would be difficult

for an importing foreign purchaser or nation to know

the degree of hazard of such a product. Moreover,

GAO determined that EPA did not send required

notices for three of four pesticides, despite the fact

that they were voluntarily canceled because of

concern about toxic effects (42). Although EPA

finalized cancellations of these four pesticides

between 1975 and 1987, a notice was issued on only

one of them (42). Consequently, foreign governments may not be alerted to unreasonable hazards

associated with using particular pesticides.

Section 17(b) of FIFRA requires that EPA notify

foreign governments and appropriate international

agencies “[whenever a registration, or a cancellation or suspension of the registration of a pesticide

becomes effective, or ceases to be effective. . . .“

EPA has no regulation or formal policy statement on

when to issue such a notice. Instead, the Agency

issues notices for cancellations and suspensions it

deems to be of “national or international significance” (42). EPA periodically publishes a booklet

summarizing and clarifying its actions on canceled,

suspended, and restricted pesticides (67); however,

this booklet was last published in 1985. If updated

annually, this booklet could be used by foreign

governments and others as a reference guide to U.S.

regulatory actions on pesticides (42).

On January 15, 1981, several days before the end

of his term, President Jimmy Carter issued Executive Order No. 12264, “On Federal Policy Regard-
Chapter 9-international Regulatory and Research Activities ● 241

ing the Export of Banned or Significantly Restricted

Substances,’ including pesticides. This order put

controls on exports of substances that were banned

or severely restricted in the United States. Several

days after becoming President, Ronald Reagan

revoked the order.

Regulation of Pesticide Residues in

Domestic and Imported Food

Federal jurisdiction over pesticide residues in

food is divided among three agencies—EPA, FDA,

and USDA. Their authority derives primarily from

five laws: FIFRA; Federal Food, Drug, and Cosmetic Act (FFDCA); Federal Meat Inspection Act

(FMIA); Poultry Products Inspection Act (PPIA);

and Egg Products Inspection Act (EPIA) (62).

Under FIFRA, a pesticide must be registered

(even conditionally) or have its registration pending

before it can be used in the United States. In

registering a pesticide, EPA considers the results of

numerous public health and environmental fate

studies (submitted by the manufacturer) to determine the risks and benefits associated with the use

of that pesticide. Registration includes identification

of the specific commodities on which the pesticide

can be used. During the registration process, EPA

attempts to determine if the pesticide’s use will

cause an unreasonable risk to humans or the

environment (see ch. 7). The registration requirements for pesticides are set forth in section 3 of

FIFRA and are defined more fully in EPA regulations (40 CFR 1987 ed. 158, 162).

If use of a pesticide will leave a residue on food

or feed commodities, EPA, under FFDCA, establishes a legal maximum level, or “tolerance,” for

the pesticide residue. A tolerance, or an exemption

from a tolerance, must be granted before a pesticide

is registered. Tolerances cannot be legally exceeded,

and residues of pesticides for which no tolerance has

been established or exempted are prohibited on

foods. Commodities that violate these prohibitions

are subject to seizure by FDA, USDA, or a State

enforcement agency (62).

If a pesticide has never been registered for use in

the United States and the manufacturer does not

expect residues to occur on imported foods, a

tolerance will not necessarily have been set. Also,

tolerances may not have been established if a

Photo credit: Michael Hansen

registration application is pending. Any imported

food contaminated with a pesticide that does not

have a tolerance is considered adulterated and is

subject to seizure at the U.S. border. However, if

USDA and FDA border inspectors are not told that

these pesticides have been used or they are unable to

test for them, illegal residues in imported food will

not necessarily be detected.

One pesticide industry spokesman has indicated

that increased monitoring for pesticide residues

would strengthen and bolster U.S. consumer confidence in the quality of the food supply (35).

Additional testing of agricultural chemicals, called

‘‘reregistration, ‘‘ is under way, and over the next 9

years, the agricultural chemical industry expects to

pay $170 million in fees to help EPA finance the

effort (35).

FDA, under FFDCA, is responsible for enforcing

tolerances established by EPA for food and animal

feed in interstate commerce. It is also responsible for

enforcing the prohibition in food or animal feed of

residues of pesticides for which no tolerance has

been set or exemption given. In the past, when FDA

considered low levels of a residue to pose little risk

to human health, it would set informal residue levels,

called action levels. At these levels, FDA would

take regulatory action; below them the food was

considered safe. A recent court opinion struck down
242 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

this practice, and EPA and FDA are currently

determining how to address this issue.1

The USDA is responsible for enforcing tolerances

in meat and poultry under authority of the Federal

Meat Inspection Act and the Poultry Products

Inspection Act. It is also responsible for monitoring

pesticide residues in raw egg products (dried, frozen,

or liquid eggs) and for enforcing tolerances at

establishments having official USDA egg products

inspection services, under authority of the Egg

Products Inspection Act (62). While most of the

focus has been on food crops, more insecticide is

used on cotton on a worldwide basis than any other

crop (23).

International Effects of U.S.

Export Practices

Regulations governing the export and import of

neurotoxic substances are far from uniform. Many

nations, including the United States, have policies

and procedures in place, but too often they work only

on paper. In practice, they may allow neurotoxic

substances to slip through the regulatory cracks.

Regulatory requirements designed to protect workers and consumers from the harmful effects of toxic

substances may be ineffective in some countries.

The United Nations Food and Agriculture Organization (FAO) has implemented an International Code

of Conduct on the Distribution and Use of Pesticides

to outline responsible behavior on the part of persons

who deal with pesticides. Pesticides are known as

the group of chemical products that includes insecticides, acaricides, molluscicides, rodenticides, nematicides, anthelmintics, fungicides, and herbicides

(26). Although many consider the code a step in the

right direction in terms of providing notification,

use, and transport protections (among others), it is

only a voluntary code, and FAO has no enforcement

authority. The objectives of the code are to set forth

standards of conduct for all entities engaged in

distributing and using pesticides. Pesticides are

biologically active, and their uncontrolled release

will always present a potential threat to the environment (27). The code describes the shared responsibility of many segments of society, government,

industry, trade, and international institutions to use

pesticides when necessary without adversely affecting people or the environment (40).

The Pesticide Development and Safe Use Unit of

the International Program on Chemical Safety has

toxicologically evaluated 83 pesticides widely used

in agriculture and public health and established

average daily intake and maximum residue limits for

23 of them (43). The Codex Alimentarius Commission (Codex) has established maximum residue

tolerances for numerous chemical residues, contaminants, and food additives (43). Sampling and

analysis principles to determine pesticide residues in

food and animal feed have also been developed (43).

Despite numerous regulations governing the export and import of pesticides and other neurotoxic

products in the United States and abroad, some

countries do not have the regulatory framework and

resources to adequately protect human health and

the environment from these substances. Nearly all

major U.S. corporations producing pesticides

that have been banned, severely restricted, or

never registered for use in the United States are

multinational and have subsidiaries or other

distributors in developing countries. In some

cases it is through these subsidiaries and distributors that such pesticides are imported and distributed in developing countries. This also allows

corporations with stocks of toxic substances that

can no longer be sold in the United States to sell

existing products.

In addition to concern about food products that are

imported into the United States with residues of

banned, severely restricted, or unregistered pesticides, critics are concerned that exported pesticides

may not be properly packaged or labeled. At times,

the package labeling and instructions may be written

in English instead of the native language of the

importing country. In some cases, farmworkers

using the pesticides are illiterate and thus could not

read the labels even if they were written in their

native language.

Improper labeling may prevent implementation of

appropriate safety measures or precautions by farmworkers and consumers. In July 1986, phosdrin, a

potent neurotoxic insecticide classified by the World

Health Organization (WHO) as “extremely hazardous, ” was purchased in Benguet Province, Philippines. The product label had seven labeling infringements, all of them in direct violation of the FAO

code (20). Similar violations of the FAO code have

ISCX 21 cm WCS. 109 and 509, 1987; FDA Compliance Policy Guides, 1986. The informal process by which these action levels wem set wu vac~~

by the Federal Appeals Court in the District of Columbia Consumer Nutrition institute v. Young, 818 F.2d 943 (D.C. Cir. 1987).
Chapter 9-International Regulatory and Research Activities ● 243

been discovered recently in Ecuador, Papua New

Guinea, Thailand, Senegal, Colombia, South Korea,

Sudan, and Mexico (18). In Iraq in 1973, an

epidemic of methyl mercury poisoning resulted from

improper labeling. Farmers and their families ate

bread made from seed treated with mercury. The

bags in which the grain was imported were clearly

labeled in English and Spanish (neither of which is

a native language of Iraq). More than 1,000 people

died from mercury poisoning, and 10 times more

were hospitalized (see box 2-A, in ch. 2) (2).

In some instances, even if the pesticide is properly

packaged and labeled when it leaves the exporting

country, it is repackaged in the importing country

without the necessary labeling. Accordingly, the

pesticide product that actually reaches the user may

lack very important health and safety information.

Repackaging is frequent, because pesticides are

often shipped in 35- to 100-gallon drums and are

then transferred into smaller, more manageable sizes

for the consumer. On an international scale, pesticides are widely available to the general public, and

few warnings are given (18). In some countries,

pesticides are sold in markets alongside vegetables

and grains. People can scoop up pesticides in

cartons, bottles, cans, plastic or paper bags—

whatever they bring to the market. Often they do not

know the name of the chemical they are purchasing

because the container is not labeled. In some

countries, pesticides are marketed as ‘‘plant medicines, " and farmers are encouraged to use them to

keep their crops healthy in much the same way that

medicines are used to keep people healthy (24).

The pesticide industry is aware of the illiteracy

problem and is taking steps to circumvent it. One

approach is to use illustrations, or ‘‘pictograms, ’

that convey to an illiterate worker the appropriate

way to mix, use, store, or clean up pesticides. These

pictograms were designed by the International

Group of National Associations of Manufacturers of

Agrochemical Products, an international consortium

of pesticide manufacturers, formulators, and distributors, in cooperation with the FAO. Figure 9-5

shows examples of pictograms currently used by

some pesticide companies in developing countries.

It is not yet known how extensively the pictograms

are used or with what degree of success.

It is not only in export and use that pesticides pose

problems, however. Pesticides are frequently manufactured in developing countries, where there are

less stringent regulations. U.S. manufacturers claim

that it is safer to produce pesticides in the United

States, with its many regulations, than in developing

countries. The combination of lethal ingredients and

deficient safety precautions was dramatically demonstrated by the 1984 leak at the Union Carbide

pesticide plant in Bhopal, India, which killed more

than 2,000 people and injured tens of thousands (69).

Pesticide manufacturers justify U.S. export practices and advocate increased use of pesticides by

maintaining that developing nations need pesticides

to combat famine. The world population is growing

rapidly: in 1975 it was 4.1 billion; in 1987 it had

grown to 5,1 billion; and the projected figure for

2005 is 6.7 billion (64). Feeding this ever-increasing

population is a problem because land available for

farming is not increasing significantly. Moreover,

the population increase is greatest in developing

nations.

Critics of U.S. export practices argue that pesticides in the developing world are more often applied

to luxury export crops than to staples eaten by local

inhabitants and that, in any case, nonchemical

methods of pest control could and should be

implemented (70). According to the World Bank, the

world produces enough grain alone to provide every

human being on the planet with 3,600 calories a day

(72). In a major 1986 study of world hunger, it found

that a rapid increase in food production does not

necessarily result in less hunger. Hunger can only be

alleviated by redistributing purchasing power and

resources to those who are undernourished (72). In

India, for example, despite a 24-million-ton grain

surplus (25), per-capita consumption of grain has not

increased in 20 years and nearly half the population

lacks the income necessary to buy a nutritious diet

(63). Availability of grain in India has actually

declined in recent years, despite a rise in pesticide

use (57). Furthermore, numerous plantations and

other agricultural areas have been forced to turn

away from pesticide use due to resistance problems

developed by insects, weeds, and fungi overdosed

with pesticides (23).

The USDA has addressed the issue of world

hunger, particularly in developing nations, as follows:

First, the food problem of the developing countries is not a global lack of food. More than enough

food is produced and stored in the world to provide
244 ● Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

Figure 9-5-Pictograms for Agrochemical Pesticides

Storage

pictogram

Activity

pictograms

Keep locked

away and

out of reach

of children

Handling

liquid

concentrate

\

\ n

Handling

b

Application

dry

Concentrate

:..

.

. ....

. . .

w %

,,:.,

,., ,..,

,,, ,.

,, ,. , $ .

, , . .

Wear

gloves

Advice

pictograms

Wear

boots

Warning

pictograms

Dangerous/

harmful to

animals

Wear

protection

over nose

and mouth

Dangerous/

harmful to

fish–do not

contaminate

lakes, rivers,

ponds,or

streams

Wear

respirator

SOURCE: International Group of National Associations of Manufacturers of Agricultural Products, 1988 Pictograms for Agrochemical Labels: An Aid to the

Safe Handling of Pesticides.
Chapter 9-International Regulatory and Research Activities ● 245

people everywhere with adequate diets. In times of

crises, countries have the capacity to respond quickly

with food and other needed supplies to alleviate

hunger and suffering. Unfortunately, political differences within and between countries and logistics

sometimes impede the efforts to save lives, as in the

current food crisis in sub-Saharan Africa (59).

Regulatory Policies in Other

Industrialized Nations

For the most part, regulations in industrialized

countries are enforced, and public health and environmental problems from pesticide importation,

distribution, and use are not as severe as in developing nations. However, this does not mean that

pesticide problems are nonexistent in industrialized

nations. The following discussion summarizes the

activities of some industrialized nations with major

regulatory programs.

Canada

Within Canada primary responsibility for environmental issues with international and interprovincial components lies with the federal government,

while the provinces are generally responsible for

enforcing regulations governing industries within

their borders (12). Environment Canada, established

in 1971, is the federal department that administers

legislation relating to environmental protection. A

major reorganization of Environment Canada in

1986 and 1987 consolidated the department’s activities into three main branches: Conservation and

Protection, Atmospheric Environment (responsible

for meteorology), and Parks (responsible for maintenance of national parks). Conservation and Protection includes the Canadian Wildlife Service, Environmental Protection, and the Inland Waters and Lands

Directorate.

The primary federal legislation controlling the

availability, sale, and use of pesticides is the Pest

Control Products Act, administered by Agriculture

Canada (12). The Act requires annual registration of

pesticides and prohibits import or sale of unregistered pesticides. It is intended to ensure that no

person shall use a pesticide under conditions that are

unsafe to human or animal health or that will

adversely affect the environment. The Act also

requires that such products be effective for their

intended purposes (46). There are currently plans to

upgrade the legislation to require more stringent

testing of pesticide products.

Agriculture Canada calls on various federal departments to provide expert advice on hazards that

may be associated with the use of a product. Health

and Welfare Canada requires and reviews a range of

toxicological studies to assess potential health

hazards that may be associated with exposure to a

chemical, including acute, subacute, chronic, reproduction, teratology, and metabolism studies. In

addition, studies to estimate anticipated human

exposure during typical field use of the chemical are

required.

The federal departments primarily involved in the

pesticide review process are Agriculture Canada,

Fisheries and Oceans Canada, Environment Canada,

and Health and Welfare Canada (12). The Pesticides

Directorate of Agriculture Canada receives the

manufacturer’s application for registration of the

pesticide and is responsible for the evaluation

process and the coordination of reviews from the

other agencies (46).

Federal Republic of Germany

The Federal Republic of Germany, one of the

world’s largest exporters of pesticides, divides and

sometimes shares lawmaking and enforcement powers between the federal government (Bund) and the

11 states (Lander). The Federal Ministry for Environment, Nature Protection, and Nuclear Safety was

created in 1986, in the aftermath of the accident at

the nuclear power plant in Chernobyl in the Soviet

Union. It was created out of the Environment and

Nuclear Safety divisions of the Ministry of Interior

and the Nature Protection Division of the Ministry

of Nutrition, Agriculture, and Forest (MNAF) (14).

Pesticides are regulated under the Pfalnzenschutgesetz (Plant Protection Law), which outlines

the terms of licensing, prohibition, or restriction of

use, application, and export (43). Licensing, which

is issued only if the pesticide is safe, efficacious, and

in compliance with requirements for human and

animal health and safety, provides for classification,

testing, labeling, and packaging (43).

The Federal Environmental Agency (FEA), under

the authority of the MNAF, is responsible for

general environmental policy-related research, including maintenance of an environmental information planning system, collection of information

necessary to develop and implement federal laws,

and preparation of legislation and administrative

regulations. The FEA has done considerable work
246 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

on the development of environmental impact assessment procedures (14). A separate organization, the

Conference of State Ministers for the Environment,

which includes the Federal Environment Ministry, is

the major forum for coordination of state and federal

environmental policy. Federal-state working committees have been established to coordinate programs in all major areas of environmental protection

(14).

The Federal Ministry for Foreign Affairs is

responsible for international relations and environmental policy. The Federal Ministry of Food,

Agriculture, and Forestry houses the Agricultural

Research Center, which monitors soil biology,

agrichemicals, agricultural waste recycling, plant

ecophysiology, and water pollution, and the Federal

Center for Biological Research in Agriculture and

Forestry, which is responsible for pesticide measurement and control, biological pest control, and

inspection of commercial chemical preparations for

plant protection and pest control (14).

A number of environmental laws are in effect. The

Act on Protection Against Dangerous Substances,

which was adopted in 1980 and amended in 1986,

establishes a testing and notification system for new

chemical substances placed on the market after

September 1981. The Act seeks to protect public

health and the environment from harmful effects of

dangerous substances by: 1) compulsory testing of

and notification regarding substances; 2) compulsory classification, labeling, and packaging of dangerous substances and preparations; 3) prohibitions

and restrictions on use; and 4) specific legal

provisions concerning toxicity and occupational

safety. The Act covers foodstuffs, tobacco products,

cosmetic agents, animal feedstuffs and additives,

pharmaceuticals, wastes, radioactive wastes, waste

water, and waste oils (14).

The Act requires notification at least 45 days prior

to placing a substance into initial circulation in a

country that is a member of the European Community (EC), whether on a commercial basis or within

the framework of any other business undertaking.

There is no requirement for notification if the

substance was manufactured and notified by an

equivalent procedure in any other EC member

country (14). Six administrative regulations have

been adopted concerning information required in

notifications, designation of the Federal Office for

occupational and Safety Policy to receive notifications, inventory of existing chemical substances,

labeling of hazardous substances, and general administrative procedures.

Criminal violations of environmental legislation

are generally codified in division 28 of the criminal

code, adopted in 1975 and last amended in 1987.

Penalties range from fines to jail sentences and are

usually defined in the particular environmental law

(14).

Belgium

Environmental programs in Belgium are less well

developed than those in other European countries.

Because implementing legislation must, in most

instances, be enacted by the regional administrations, norms and enforcement vary throughout the

country (11).

A 1969 act regulates the manufacture, composition, storage, transport, and marketing of pesticides.

Such activities may be carried out only by licensed

persons. The maximum concentrations of residue

after decomposition may also be controlled under

the act, as well as the conditions of use of pesticides.

Pesticides themselves are subject to an approval

procedure, and the license usually lasts for 10 years.

The approval is made subject to conditions, and it is

an offense to use pesticides other than in accordance

with these conditions (1 1).

A royal order of 1975 regulates the storage, trade,

and use of pesticides and plant protection products.

Pesticides are subject to premarket registration, and

certain labeling and packaging requirements are set

out (11). A royal decree of 1977 implements EC

Directive 76/1 16, which prohibits the marketing of

manure and fertilize, as well as all products with a

specific action to stimulate crop production. This

decree also regulates the information and indications

to be put on the package, the documents required for

transport, the packaging requirements, and the

method of taking and analyzing samples (11).

A royal decree of 1982 requires that before

placing a dangerous substance on the market, any

manufacturer or importer must submit to the Minister of Public Health a dossier that includes a

declaration of the unfavorable effects of the substance for the various uses envisaged. The decree

establishes a Committee on Dangerous Substances,

composed of officials of different ministerial departments and attached to the Ministry of Public Health.

The committee is responsible for examining the
Chapter 9-International Regulatory and Research Activities ● 247

notification procedure and advises on the completeness of the application. A dangerous substance

cannot be placed on the market during the 45 days it

takes to complete the notification procedure (1 1).

France

Pesticides for agricultural use are governed by a

1972 law that controls manufacture, sale, and use as

well as packaging and labeling (43). Prior to

approval for production, toxicity and efficacy must

be assessed, and the pesticide must be classified in

terms of toxicity (43). Tolerance limits in foods are

prescribed by presidential decree (43).

The Chemicals Control Law, adopted in 1977,

governs hazardous substances. It is intended to

protect public health and the environment against

risks that may arise from natural or industrially

produced chemicals, but it does not apply to

chemicals used in research or to food additives,

cosmetics, or drugs (13). The law provides for

premanufacture notification for all chemicals that

have not yet been marketed. Producers or importers

must declare any new risk that may result from a

change of manufacturing process or from emission

of the said chemical into the environment (37).

Producers or importers of new chemicals must

also submit a technical dossier providing the information needed for assessment of potential hazards.

The competent authority may classify a substance as

a “dangerous product’ request from the manufacturer or importer any relevant information with

respect to potential health or environmental effects;

and prohibit or restrict the production, composition,

storage, transportation, conditioning, labeling, marketing, use, or disposal of any chemical where

deemed necessary to protect the public (37).

Producers of already marketed substances maybe

required to provide public authorities with appropriate technical or toxicological data to evaluate

potential health or environmental risks. Violation of

the law may result in imprisonment or fines or both.

Japan

Agricultural chemicals are regulated by a 1948

law that has been amended several times, most

recently in 1983 (43). It requires that pesticides be

registered with appropriate government agencies,

which classify pesticides according to persistence in

crops and soil and water pollution potential (43).

Limits are placed on the amount of active ingredients and the maximum allowable harmful ingredients for each pesticide (43). The applicant must

provide test results on pesticide effectiveness, toxicity, phytotoxicity, and persistence (43). Labeling

and packaging must represent truthfully all statements and facts on which the pesticide was registered and must include, among other things, the

dangers posed and precautions to be taken for

storage and use (43).

Other toxic substances are regulated by the

Chemical Substances Control Law of 1973. The

need for comprehensive measures to prevent environmental pollution has been recognized following

environmental crises such as the mercury poisoning

incident at Minamata Bay in the 1950s (see ch. 2).

The law requires notification and testing of all

new chemical substances produced in quantities

exceeding 100 kilograms. The law does not apply to

chemicals in use before the law came into effect, but

an agreement reached in the Diet makes some 800

existing chemicals subject to the same review

standards as the new substances. The law also

provides that, prior to production or importation, all

new chemicals must be submitted to official examination regarding persistence, accumulative tendency, and toxicity to human beings.

A substance may be classified as a “specified

chemical substance” if it accumulates easily in

biological organisms, if it resists chemical changes

caused by natural effects, and if it may harm human

health when ingested over a period of time. The law

was passed in response to polychlorinated biphenyl

(PCB) poisoning (9). Chemicals tested and designated ‘‘specific substances’ are subject to prohibition or restriction. Although only PCBs have been

formally listed as specific substances under the law,

government officials say that two or three chemicals

are withdrawn from testing every month when

manufacturers learn that the chemicals probably

would be specified and the manufacturer’s name

revealed. Another two or three applications for

approval are suspended each month for lack of data

(9).

The Pollution-Related Health Damage Compensation Law of 1974 was further modified, in the case

of Minamata victims, by the Minamata Relief Law

in 1978. The beneficiaries of this law are the victims

of certain pollution-related diseases who have ‘lived,

worked, or otherwise been present” in designated

areas. Testing for functional developmental disor-
248 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

ders, including behavior disorders, has become one

of the most important aspects of the evaluation of

developmental toxicity of chemicals, especially

pharmaceutical drugs. There are two guidelines for

developmental toxicity testing of chemicals-one a

three-segment study for drugs, the other a multigeneration study plus embryotoxicity for environmental

chemicals (56). In the case of specific diseases,

where the source of pollution is known, the company

responsible must pay compensation. In nonspecific

cases, there is a levy on polluting industries to cover

claims. Certified victims, that is, persons who have

been examined by government medical panels, are

entitled to medical care expenses and a monthly

physical handicap payment, the amount being determined by the victim’s age, sex, and ability to work.

There are also child compensation allowances and

survivors’ benefits. Payment is made by local

governments through the Pollution-Related Health

Damage Compensation Association. The government covers the association’s overhead costs, but

payments to victims are financed by polluters.

United Kingdom

Pesticides are regulated under the Dangerous

Substances Regulations and the Food and Environment Protection Act (43). The regulations specify

which toxicity tests are necessary to categorize each

pesticide, based on EC Directive 78/631 of 1978

(43). Packaging and labeling requirements are also

set out in the regulations (43). Pesticide manufacturers must notify the government prior to marketing a

new pesticide or suggesting new uses of an old one

(43). Manufacturers must also provide sufficient

data to enable government assessment of pesticide

dangers, and warnings, precautions, and names of

active ingredients must be included on all labels

(43). The government has authority to request

withdrawal of unsafe products and to specify maximum pesticide residues on crops, foods, and livestock feed (43).

Responsibility for protection of the environment

lies primarily with the Department of the Environment. It has responsibility for introducing and

implementing acts of Parliament and statutory

instruments. Other ministries also have some responsibility for environmental protection. These

include the Ministry of Agriculture, Fisheries, and

Food, which controls the ocean disposal of wastes

and has joint responsibility with the Department of

the Environment and the Welsh Office for control of

radioactive discharges from nuclear sites; the Department of Employment, which is responsible for

health and safety; the Department of Health and

Social Security; and the Department of Transport.

Within the Department of the Environment is the

Central Directorate on Environmental Pollution,

staffed by a pool of scientists and administrators

coordinating national regulatory policy in the environmental protection field, including participation

in international activities (10).

Numerous divisions within the department are

concerned with land use, conservation of wildlife

and habitats, control of toxic substances, air and

water pollution, and wastes. The Toxic Substances

Division, for example, is responsible for developing

policy aimed at protecting human health and the

environment. Its responsibilities also extend to

participation in international initiatives. However,

the International Division has prime responsibility

for coordinating United Kingdom policies on environmental affairs and presenting those policies

before the United Nations, the Organization for

Economic Cooperation and Development, the EC,

and other bodies (10).

In 1987, a new, centralized agency was formed to

enforce environmental laws and regulations in

England and Wales. Her Majesty’s Inspectorate of

Pollution brought together several existing pollution

control agencies: HM Industrial Air Pollution Inspectorate, for controlling major emissions to the

atmosphere; HM Radiochemical Inspectorate, for

controlling all radioactive discharges and disposals;

the Hazardous Wastes Inspectorate, for monitoring

the activities of local Waste Disposal Authorities;

and the divisions of the Department of the Environment and the Welsh Office responsible for issuing

consents for discharges by the Water Authorities.

Regulatory Issues in Developing Nations

Developing nations, especially those with a large

agricultural economy, depend on pesticides to produce maximum yields. In many of these nations,

agriculture is the primary industry and provides the

country’s primary income. In Ghana, for example,

cocoa exports provide a majority of foreign exchange earnings (8). Misuse and excessive use of

pesticides and chemicals are a significant and

widespread problem in developing countries (15).

The WHO has estimated that someone in a

developing country is poisoned by pesticides
Chapter 9-International Regulatory and Research Activities ● 249

every minute (65). This is due in part to lack of a

pesticide policy in many developing nations. The

FAO estimated in 1988 that some 50 countries

still did not have pesticide regulations (20). Those

nations with a policy often do not have the infrastructure or economic resources to implement the

policy. Moreover, in some developing nations,

government officials charged with enforcing pesticide policies have a vested financial interest in

maintaining a strong pesticide economy (20). In fact,

the governments of many countries are pesticide

importers, manufacturers, and exporters, as well as

regulators of pesticides (20). Consequently, regulations designed to protect public health and the

environment may receive little attention. In other

cases, pesticides are heavily subsidized, making it

cheaper to use pesticides than not (45).

Because of the lack of governmental controls,

many developing nations must depend on the

pesticide industry to regulate the importation, distribution, and use of pesticides, as well as to safeguard

public health and the environment. In light of this,

discussions of regulatory policy often focus on how

much responsibility pesticide manufacturers and the

governments of pesticide exporting countries should

assume. Nations around the world agree that responsibility for safety and efficiency in distribution and

use of pesticides must be shared by foreign manufacturers, exporters, and importers, as well as local

formulators, distributors, repackers, advisers, and

users (58). To facilitate the implementation of this

duty, FAO adopted in 1985, and amended in 1987,

a code covering such issues as proper pesticide

transport, marketing and advertising, recalls, and

notification on the part of regulators and manufacturers.

The code calls on industry to adhere voluntarily to

its provisions and places an even higher responsibility on industry in countries that lack appropriate

pesticide legislation and advisory services (58). The

code maintains that manufacturers have a duty to

retain an active interest in following their products to the ultimate consumer. Some assert that the

ultimate consumer is the local farmer who buys a

small amount of repackaged pesticide product for

use. Following this line of reasoning, the manufacturer’s duty would end with this purchase. On the

other hand, there is the argument that a farmer who

produces cash crops, as distinguished from a subsistence farmer, is not a consumer but a producer (6).

These producer-farmers use factors of production—

land, seed, labor, water, fertilizer, pesticides-to

produce a cash crop. The consumerism the person who

buys the produce with the intent of eating it.

Accordingly, the pesticide manufacturers have a

duty to retain an active interest in following their

products—pesticides-to the dinner tables of the

families and individuals of the world community(6).

One could further argue that U.S. manufacturers

have a special duty to protect and ensure the safety

of food treated with U.S.-manufactured pesticides

and eaten by U.S. consumers, regardless of where

that food is grown.

One controversial provision of the code intended

to address the issues of regulation and education is

that of prior informed consent (PIC). Under PIC, a

pesticide that has been banned or severely restricted

in one country cannot be exported to another country

unless the importing country’s government has been

fully informed of the reasons for the regulatory

action and has consented to the importation of the

pesticide (58). Pesticide exporting countries generally do not favor PIC and assert that it is too

time-consuming, expensive, and burdensome for

industry (20). Representatives of importing countries, on the other hand, claim that, in the absence of

regulatory controls, PIC is the only avenue for

allowing governments to determine if pesticides

banned in other countries should be permitted within

their borders. Although PIC is still a voluntary

practice, the Netherlands became the first country to incorporate it into legislation and seek to

make it legally binding (20).

The WHO has classified pesticides on the basis of

the hazards they pose. Hazard is defined as the

likelihood that a pesticide will cause immediate or

short-term adverse effects or injury under circumstances of ordinary use. These classifications are

based on the oral and dermal toxicity of the

pesticide’s active ingredient. Countries adopting the

FAO code are also supposed to adhere to the

following WHO toxicity classification in labeling

their pesticides:

. IA Extremely Hazardous,

. IB Highly Hazardous,

. 11 Moderately Hazardous, and

. III Slightly Hazardous.

In addition, the Pesticide Action Network (PAN)

has initiated a Dirty Dozen Campaign on an

international scale to publicize the 12 most hazardous pesticides used worldwide, most of which are
250 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

neurotoxic. Since the campaign began, some countries have banned certain pesticides on the Dirty

Dozen list, and others have restricted the availability

of them (20). The pesticides are:

●

●

●

●

●

●

●

●

●

●

●

●

camphechlor (toxaphene),

chlordane/heptachlor,

chlordimeform (Galecron),

dibromochloropropane (DBCP),

DDT,

aldrin/dieldrin/endrin,

ethlene dibromide (EDB),

lindane/hexachlorocyclohexane (HCH),

paraquat,

ethyl parathion,

pentachlorophenol (PCP), and

2,4,5-T.

Pesticide workers in developing countries are

frequently not provided with appropriate protective

clothing and equipment to guard against oral and

dermal exposure when applying pesticide products

(30). In tropical or semitropical climates, the temperature is often too hot to permit workers to comfortably wear protective clothing designed for use in

more temperate climates (protective clothing is

often made of plastic, rubber, or other nonporous

material). Despite workers’ lack of protective clothing, pesticides are sometimes sprayed from aircraft

while workers are in the fields. Pesticides may also

be sprayed from canisters strapped to the backs of

unprotected workers.

Besides allowing the export of pesticides that

have been banned or severely restricted for use in

this country, present EPA regulations allow the

export of pesticides that have never been reviewed

by the Agency. Some critics argue that if a pesticide

is not safe enough for use in the United States, it

should not be exported. The FAO code holds that the

fact that a product is not used or registered in the

exporting country is not necessarily a valid reason

for prohibiting export of that pesticide (58). Most

developing countries are located in tropical and

semitropical regions. Their climatic, ecological,

agronomic, and environmental conditions, as well as

their social and economic needs, may be different

from those of industrialized nations. Accordingly,

their pest problems may be quite different. The

government of the exporting country, therefore, may

not be in the best position to judge the suitability,

efficacy, safety, or fate of the pesticide under

conditions in the country where it may ultimately be

used.

Critics of this export policy argue, however, that

foreign relations problems could arise if products

considered too unsafe and hazardous for use by

people in the United States are deemed safe for use

by people abroad. Although people in developing

countries use only 10 to 25 percent of the world%

pesticides (7,21), it is estimated that they account

for as much as 50 percent of the acute poisonings

of pesticide applicators and between 73 and 99

percent of their deaths (15). Furthermore, residents

of the exporting nation are exposed to potentially

dangerous chemicals during domestic production

and eventual consumption of imported foods treated

with the pesticides.

Following is a summary of regulatory activities in

certain developing countries where pesticides are

used. Boxes 9-A and 9-B illustrate problems that

have occurred in developing nations. Although each

of the profiled countries has some regulatory structure in place, each also has many problems with the

import, distribution, and use of pesticides, resulting

in health problems of varying degrees for farmworkers and consumers. In selecting the countries for this

section, an attempt was made to obtain a geographic

spread.

Malaysia

The Pesticides Board under the Malaysian Department of Agriculture has regulatory authority for

pesticides in Malaysia. The Pesticides Act, the

Pesticide Registration Rules of 1976, the Pesticide

Rules on Importation for Educational or Research

Purposes of 1981, and the Food Act of 1983 set out

the language governing pesticide use (39).

Malaysia follows FAO guidelines with respect to

data requirements for pesticide registration. However, all data, including efficacy data, may be from

foreign sources. Data are evaluated and a recommendation is submitted to the Pesticides Board, which

has authority to grant registration (39). Accordingly,

a pesticide may be reviewed and approved for use in

Malaysia with the approving authority depending

entirely on data from the country of export.

The Department of Customs controls the import

of all pesticides except those imported for research

purposes, which are controlled by the Malaysian

Department of Agriculture. The Department of

Agriculture also controls the production, sale, and
Chapter %-international Regulatory and Research Activities . 251

Box 9-A—Problems With Neurotoxic Pesticides in Developing Countries

Irregularities concerning labeling, packaging, storage,

sale, import, and advertising of pesticides have caused

illness, injury, and death in many developing countries, as

the following examples illustrate:

 Pesticides are commonly repackaged without labels

in Senegal, but labels are of little use anyway,

because most pesticide users are illiterate. Instructions such as “in case of intoxication, call a doctor”

are meaningless in rural areas where there are no

doctors for miles, no telephones, and only sporadic

transport.

. In Indonesia, an outbreak of mosquito-spread dengue

fever caused several deaths. The Ministry of Health

sent an officer to spray the area with malathion, a

class HI, slightly hazardous pesticide. The officer was

photographed spraying malathion while children

Photo credit: Widjanarka

were running behind him to play in the pesticide mist (see photograph above).

● In Papua, New Guinea, very few companies provide labels in Tok-Pisin, the widely spoken local language.

Some pesticide products had labels in French. One pesticide, selecron, was found in stores with no label at

all.

● Many of the pesticides in Thailand, Indonesia, and the Philippines do not have child-proof packaging. Some

liquid pesticides have easily opened screw caps, and powdered pesticides can be bought in plastic bags that

an older child can open.

. In Indonesia, some pesticides were repackaged into clear plastic bags without labels. Workers wore no masks

or gloves. Unlabeled bags of temik, which is 10 percent aldicarb, a class IA, extremely hazardous neurotoxic

pesticide, were available in stores. Aldicarb is more acutely toxic to mammals than any other pesticide

presently in use.

. In the Sudan, a family of eight died in 1985 from eating pesticide-poisoned bread made from pretreated

wheat meant for seed. The pretreated wheat had been in badly labeled sacks stacked next to consumable

wheat in an agricultural store.

 In Brazil, a 1987 advertisement described deltamethrin as “the safest insecticide in the world.”

Deltamethrin is classified as class II—moderately hazardous by the International Code of Conduct on the

Distribution and Use of Pesticides of the Food and Agriculture Organization of the United Nations.

● In Senegal, used pesticide containers are often recycle-d to carry food, milk, or cooking oil. In one village,

19 people from two families died as a result. The cook used oil sold in a bottle that had previously contained

ethyl parathion, a class Ia, extremely hazardous pesticide.

. In Brazil, when a number of states passed laws banning imports of pesticides banned in their countries of

origin, translational pesticide corporations and importers filed legal action and succeeded in getting the laws

declared unconstitutional.

SOURCE: G. Goldenman and S. Rengam, Problem Pesticides, Pesticide Problems (Penang, Malaysia: International Organization of Consumers

Unions and Pesticide Action Network, 1988).

use of pesticides and checks for compliance with killed by exposure to just that one pesticide (48).

regulatory policies. The Pesticides Board regulates

advertisements of pesticides (39).

Residues on vegetables are monitored under the

Food Act of 1983. To date, there is no system for

monitoring pesticide poisoning except for occasional reports from hospitals. Following the deaths

of two teenage girls from field exposure to paraquat

in 1985, it was revealed that 1,200 workers had been

Both government and the private sector have implemented training programs on the safe handling of

pesticides. These programs are geared toward farmers, applicators, dealers, distributors, manufacturers,

and medical personnel (39).

Residues on vegetables are monitored under the

Food Act of 1983, which prescribes maximum

residue limits (5). In reality, monitoring and testing
252 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 9-B—Incident at Lake Volta, Ghana

In Achedemade Bator, a fishing village on Lake Volta, a serious poisoning incident resulted from improper

use of Gammalin 20, the trade name for lindane, a potent neurotoxic substance. The villagers, almost all of them

illiterate, derived their income through fishing on the lake. The village fishermen discovered that by pouring lindane

into the lake, fish would float to the surface and could be easily caught. This proved to be a very quick and efficient

way of hauling in a catch. Any fish not consumed were salted, smoked, or sold.

Exposure to lindane may cause dizziness, headaches, convulsions, muscle spasms, brain disturbances, and

unconsciousness. Some villagers experienced symptoms of lindane poisoning from consuming poisoned fish and

using the lake as a source of drinking water but never associated their health problems with use of the chemical.

Fishermen knew something was wrong when the fish population in the lake rapidly declined, and housewives could

easily identify Lake Volta fish by their smell, but villagers continued to eat the deadly fish. When a connection was

made between the illnesses and fish consumption, villagers cut off the heads of the fish and continued to eat the

bodies, believing that decapitation would rid the fish of all poison.

Other plants and animals in the lake were killed as well. It was not until the intervention of the Association

of People for Practical Life Education, a Ghanian organization, and the blessing of the village witch doctor that the

villagers stopped using lindane for fishing and returned to nets and traps. In villages throughout Africa, fishing with

pesticides continues where people have not been educated about the safe and effective use of these toxic substances.

SOURCE: R. Norris (cd.), Pills, Pesticides & Profits (Croton-on-Hudson, NY: North River Press, 1982).

are minimal (5). Concern about pesticide residues in Philippine Institute for Pure and Applied Chemistry,

food has resulted in the formation of the Consumers

Association of Penang (CAP), the largest and most

vocal citizens’ organization in the developing world

focusing specifically on consumer rights (70). CAP

has discovered organochlorine pesticides (DDT,

aldrin, BHC, dieldrin, chlordane), many of which are

banned in the United States, in Malaysia’s rainwater,

soil, drinking water, and food crops. CAP monitors

pesticide poisoning of workers and residues in food

and has pressured the Malaysian government to

tighten its regulations on pesticides (70). In a recent

study conducted by the Malaysian Department of

Agriculture, it was discovered that 54 percent of

the 1,214 agricultural workers studied had experienced some form of pesticide poisoning (22,44).

Philippines

In the Philippines the private sector controls the

pesticide industry, which is dominated by local

organizations representing the major multinational

companies (5). Virtually all of the pesticide business

is transacted by some 20 companies in the trade

association-the Agricultural Pesticide Institute of

the Philippines (5).

There are several laws affecting the pesticide

industry. A presidential decree enacted in 1977

regulates pesticides. Quality control of pesticides is

done by the Fertilizer and Pesticide Authority (FPA)

through the Bureau of Plant Industry (BPI) and the

on the basis of complaints from users (39). Quality

control during production and for imports is done by

private companies. Pesticide dealers and ports of

entry in the 72 provinces and 12 regions are

inspected, but critics argue that this system needs

improvement and strengthening (39). An FPA permit is required for all imports of pesticides, regardless of quantity. The FPA controls production, sale,

and use of pesticides through a licensing scheme,

and in collaboration with the Philippine Board of

Advertisers controls advertisements of pesticides

(39).

There is no system in operation to monitor

pesticide poisoning cases in humans except for

occasional reports from hospitals and doctors

trained under the FPA Agro-Medical Program.

Pesticide dealers must be trained in the safe handling

of pesticides before they can obtain a retail license.

Commercial pest control companies must obtain

certification for all of their operators (39). Marketbasket samples of vegetables are routinely analyzed

for residues, particularly for organochlorines and

organophosphates, by the BPI (5). Other agencies

monitor residues in lakes, rivers, and streams, while

exporters of agricultural products analyze shipments

prior to export (5).

The Philippines is the home of the International

Rice Research Institute, which helped create the

green revolution of the 1970s. This revolution saw
Chapter 9-International Regulatory and Research Activities ● 253

the production of new hybrid seeds, developed to

produce higher yields with the correct amount of

fertilizer and water (70). These laboratory-bred

seeds were more susceptible to pests and required

increased use of pesticides. Although the new seeds

have increased production, the Philippines remains

one of the hungriest nations in Asia, according to the

Asian Development Bank and WHO (70).

Some. years ago, the Farmer’s Assistance Board

was formed by peasants and students to study

pesticides. The board blames the large volume of

pesticide use in the Philippines on the big exporters,

as well as on the International Rice Research

Institute. The board points to the demand for highest

yield and blemish-free products as the reasons for

the country’s continued dependence on large quantities of pesticides.

India

The Insecticides Act (1968) and the Insecticides

Rules (1971) govern pesticides in India. The Act

regulates manufacture, formulation, distribution,

and sale of pesticides through a licensing system.

Five agencies have been created to implement these

laws. Locally generated toxicity and residue data for

formulations are required in most instances; however, complete efficacy data are required only for

registration of a new pesticide. The Pesticide Registration Committee and the Central Insecticides

Board review data for registration, referring to

publications and decisions by FAO, WHO, and

EPA, among other organizations. India does not

adhere to FAO guidelines with respect to labeling. It

does follow the FAO color coding of labels based on

toxicity, but the warning symbols differ from those

suggested by FAO. Pesticides are classified into

various categories of toxicity, but the limits set differ

from those recommended by WHO (39). To date,

119 active ingredients and their formulations have

been registered.

The improper use of pesticides is a major problem

in India (5). Few farmers are aware of the potential

hazards associated with the use of pesticides (5).

Crops are often sprayed with insecticide immediately before and after harvest because of a belief that

pre- and postharvest spraying will increase freshness

and preservation (5).

India “phase registers” new pesticides. First

there is a trials clearance, then a provisional registration, which is valid for 2 years and subject to certain

conditions, and finally a full registration. There is

also “me-too” registration, which allows a second

registrant to obtain registration for a pesticide

subject to proof that the product is identical to the

one already registered. There is usually a letter of

agreement between parties on use of data (39).

The Insecticides Act mandates that pesticide

quality be checked by the Central Insecticide Laboratory. Rigid controls are set for preregistration

purposes, but once a product is on the market,

quality control is not pursued (39). Quality control

of products during production is monitored not by

the government, but by private companies. Compliance with regulatory policies is enforced by state

governments, and imports are allowed only through

certain ports of entry (39). No pesticide may be

imported without a registration certificate. It is

interesting to note that many pesticides which have

been banned or severely restricted in the United

States are produced in India (70). Several foreign

manufacturers have plants in India (70).

Increased agricultural output does not necessarily

mean increased food consumption for local residents

if the residents are too poor to afford food. Despite

the fact that there were vast increases in wheat yields

in the Punjab district in the 1960s, the portion of the

rural population living below the poverty line

increased from 18 to 23 percent (28). While true that

pesticide use may increase crop yield and bolster the

economy of a developing country, in this particular

instance the economic prosperity of the local inhabitants declined.

The Central Food Laboratories monitor pesticide

residues and adulterants in food, but this system

needs strengthening. State governments are required

to obtain reports from their officers on pesticide

poisonings, but this is not a thorough monitoring

system. Both state and central governments and the

pesticide industry have implemented training programs for safe use and application of pesticides (39).

Costa Rica

The Law for the Control of Pesticides (1979) and

the Law Governing Occupational Health (1981)

regulate pesticides in Costa Rica. Along with other

Central American countries, Costa Rica has adopted

the provisions of the Basic Document on Regulation

of Registration, Marketing and Control of Agricultural Chemicals for Countries of Central America,

prepared under the auspices of the Inter-American
254 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Institute for Cooperation on Agriculture in 1985. A

Pesticide Commission has also been formed to carry

out the pesticide registration program (39).

Registration requirements are generally in accordance with FAO guidelines. Local efficacy data for

new products are to be generated either directly by

government research organizations or by private

companies under government supervision. Efficacy

data from other Latin American countries are

acceptable for products already registered. EPA

tolerances must also be submitted, along with a

certificate of registration and a certificate of analysis

from the country of origin and evidence of registration from other countries. Labeling is evaluated

according to guidelines agreed on under the Basic

Document. Full registration is valid for 3 to 5 years,

experimental permits are issued, and me-too registration is allowed. As with Mexico and Ecuador, all

chlorinated compounds that accumulate in the food

chain are banned, but the government reserves the

right to use them in cases of emergency when

economical substitutes are not available (39).

Costa Rica has one of the strongest enforcement

systems in Central America. Import permits are

necessary, and there is a licensing scheme for

formulation, distribution, and sale of pesticides. The

Ministry of Health has done some monitoring of

food residues and keeps a record of poisoning cases.

The government and private sector carry out training

programs for pesticide workers, and the government

has published a training manual for physicians.

Mexico

In Mexico, the principal pesticide legislation is

the Law on Plant and Animal Protection, which was

adopted in 1940. The law was amended in 1974, and

rules were added in 1980 to implement it. FAO

guidelines are generally followed, with local efficacy data generated either directly by government

research organizations or by private companies

under government supervision (39). All test protocols must be approved by the government. Emphasis

is on evaluation of efficacy data, while toxicological

and residue data are reviewed by experts. Label

evaluation follows the Basic Document guidelines

agreed on by Latin American countries, and the

WHO classification system for pesticides has been

adopted, with certain modifications (39). Full registration is valid for 3 to 5 years, with permits issued

Photo credit: Kay Treakle, Greenpeace

Unprotected workers spray paraquat on coffee plants, Chiapas, Mexico
Chapter International Regulatory and Research Activities . 255

for experimental purposes. Me-too registration is

allowed with the same data and information requirements as for all registered products.

All chlorinated compounds that accumulate in the

food chain are banned, but the government reserves

the right to use them in cases of emergency when

economical substitutes are not available (39). As

recently as 1987, some 28 pesticides that were

banned or severely restricted in the United States

were being used in Mexico (18). Endrin, which was

severely restricted in the United States in 1979, was

given a renewal registration for 2 years in 1984 (18).

Mexico imports a large percentage of pesticides, but

there are also some 300 formulation plants in the

country (18). In 1987, domestic production of

pesticides was estimated at 32,000 tons per year

(18).

The government and private industry share responsibility for quality control, but compliance with

regulatory policies is usually enforced only after

complaints from the field. Training programs for

farmers, distributors, and physicians are sponsored

by government and private industry, but monitoring

of pesticide poisonings is sporadic. Imports are

controlled through the issuance of import permits,

and formulation, distribution, and sale of pesticides

is controlled through a licensing scheme (39).

Residues in export crops are monitored regularly,

following regulations imposed by the importing

country (39).

Ecuador

In addition to enacting its own legislation in 1984,

Ecuador has consented to implement guidelines

dealing with registration data and labeling agreed on

by Latin American countries in the Andean region.

FAO guidelines form the basis for data requirements. Either government research organizations or

private companies under government supervision

must generate local efficacy data. Further, proof of

registration in the country of origin and registration

in other countries is required (39).

There is little evaluation of data except for

efficacy. Labeling is strictly evaluated, based on the

guidelines agreed on by the Latin American countries. Other organizations are looked to for guidance,

among them FAO, WHO, EPA, the National Agricultural Chemicals Association, and the International Group of National Associations of Manufacturers of Agrochemical Products.

Photo credit: Amerkan Cyanamid

Worker spraying banana plants in Ecuador

All chlorinated compounds that accumulate in the

food chain are officially banned, but the government

reserves the right to use them in cases of emergency

when economical substitutes are not available (39).

Parathion and toxaphene are two pesticides banned

in Ecuador, while DDT and methyl bromide are

among those restricted to specified uses. U.S. EPA

regulations regarding banning and restrictions are

supposed to be closely followed (39), yet DDT,

which has been banned by EPA for use in the United

States, can be used in certain circumstances in

Ecuador.

Both government and private industry have quality control programs. The Fundacion Natura (Nature

Foundation), an environmental group, monitors

compliance with regulatory policies and reports

violations to the government. Government inspectors are also assigned to monitor compliance. The

Department of Commerce and the Ministry of

Agriculture issue import permits, and there is a

licensing scheme for formulation, distribution, and

sale of pesticides.

Prior government approval is needed for any

pesticide advertising, but there has been minimal
256 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

monitoring of residue on food and crops. A record of

any poisoning cases reported by hospitals is maintained by the Ministry of Health. Government and

the private sector, as well as industry, have training

programs for extension workers, farmers, distributors, doctors, and technical and sales representatives.

Kenya

In Kenya, the Pesticide Control Board Act was

implemented in 1982, with regulatory authority

vested in the Pesticide Control Product Board. The

Specialist Approval Committee for Agricultural

Pesticides evaluates data generally, in accordance

with FAO guidelines. At present, there is no

information available concerning labeling requirements, no national residue tolerances, and no system

of pesticide classification, although WHO classification is being reviewed for possible adoption. Only

registered products can be imported and used, but

there are no restrictions regarding the availability of

these products (39).

For the most part, quality control is left to

industry. Residue monitoring is not usually done,

and there is no system in operation for monitoring

pesticide poisoning cases (39).

INTERNATIONAL

NEUROTOXICOLOGICAL

RESEARCH

Active interest in neurotoxicity began in the

United Kingdom during and after World War II.

Since that time, research efforts in the United States

have gradually increased. The United States is now

the world leader in environmental legislation and in

government funding of neurotoxicology research.

Research in other countries has been narrower and

more specific. The Scandinavian countries have

been active in research on the neurotoxicity of

organic solvents (73), and other European countries

have supported research on compounds of particular

concern in occupational settings, such as pesticides

and heavy metals (16,36). In most cases, however,

no systematic national effort has been undertaken

similar to that in the United States (2).

Several international conferences have taken place

during the past 10 years on the subject of neurotoxicology, some of which were sponsored by EPA and

the National Institutes of Health. Two international

journals published in the United States, Neurotoxicology and Teratology and Neurotoxicology, were

Photo credit: Monsanto Agricultural Co.

Surveying the harvest, Kenya

established in 1979, and the Society of Toxicology

in the United States has a sizable subsection devoted

to neurotoxicology. Outside the United States,

sufficient interest has been generated in neurotoxicological issues that a new society, the International

Neurotoxicology Association, has been formed.

This society held its first meeting in 1987, with

attendance by approximately 200 scientists from

Europe and the United States. The first comprehensive text on neurotoxicology was published in 1980

(52).

Major Directions of Academic, Industrial, and

Government Research

In the past, research efforts were often initiated

following industrial exposures that caused severe

human intoxications. For example, with the advent

of the vulcanization of rubber, carbon disulfide

poisoning in workers in the rubber industry became

common in many European countries (71). With the

introduction of rayon, the manufacture of which also

required the use of carbon disulfide, poisonings due

to use of this solvent became a worldwide problem

(68). Improvements in occupational hygiene have

largely eliminated cases of severe poisoning; nevertheless, what has emerged instead is the problem of

chronic low-level exposures to this and other compounds. The development of human testing procedures to measure more subtle symptoms has been

largely accomplished in Finland (49).

The toxicity of lead has been known since

antiquity (51 ). Nonetheless, large-scale lead poisoning continues to be an international public health

problem because of lead water pipes, the use of
Chapter 9-International Regulatory and Research Activities . 257

Illustrated by: Ray Driver

lead-based paints, and the addition of lead to

gasoline. Much of the basic research involving

animal models of lead toxicity was done in the

United States (67). Using the diagnostic procedures

developed for the detection of exposure to organic

solvents, Finnish researchers have demonstrated

nervous system damage in low-level occupational

exposures of adults to lead (49). Research into lead

toxicity is still supported enthusiastically in many

countries because of accumulating evidence that

even exposure levels previously considered harmless (particularly in children) have been shown to

have adverse effects on health (ch. 9). This has led

the WHO European Office to sponsor a multinational study of the effects of childhood lead intoxication. As of 1989, lead additives have been restricted

in the United States and in some parts of Europe.

Thus, worldwide interest in lead toxicity continues,

although outside the United States research is not

supported in a programmatic way by individual

governments. It appears that this role has been taken

over by international bodies such as WHO.

Another major environmental contaminant is

mercury. Exposures to mercury in industrial settings

have been well described since the 19th century (34).

Mercury became a public health problem because of

the widespread use of organic mercury compounds

in agriculture as fungicides. The first major outbreak

of methyl mercury poisoning occurred in Japan in

1953 and was followed by outbreaks in many other

parts of the world, notably Iraq (see ch. 2). Japanese

scientists have actively pursued research on the

mechanism of neurotoxicity of organic mercury

compounds (55). This was followed by a large

Scandinavian (mostly Swedish) research effort because of contamination of lakes by mercury runoff

(19). U.S. investigators have been involved in

mercury research since the Iraq episode, in 1971 to

1972, and have examined such problems as the

teratogenic effects of methyl mercury on the behavior of animals (17). Other metals that have been

studied internationally include manganese, cadmium, and the organotins.

Interest in the neurotoxicity of organic solvents

has increased in recent years. Pioneering work in

Scandinavia was followed by mechanistic studies in

the United States (47) that revealed the relationship

between human symptoms and underlying biological alterations. Scandinavian workers have been the

focus of a number of occupational hazard studies. A

recent monograph entitled Organic Solvents and the

Central Nervous System was published jointly by

WHO and the Nordic Council of Ministers (73). This

document addresses the problems of occupational

exposures, the illness caused by these exposures,

and the diagnostic procedures for identifying the

illness. In 1988, the WHO-Nordic Council of

Ministers met to design the “definitive” study of

chronic effects of exposure to solvents on the

nervous system of workers (75).

The widespread use of highly toxic pesticides has

led to intense worldwide research on the neurotoxicity of these compounds. In fact, the beginning of the

environmental movement has been attributed to the

publication of Rachel Carson’s book Silent Spring,
258 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

which dealt with the ecological effects of indiscriminate pesticide application. The continuing development of new pesticides has caused the research effort

to be sustained, not only to protect human populations, but also to safeguard nontarget populations

from inadvertent exposure to these compounds.

One way to document international research

trends is to summarize the distribution of research

papers published by non-U.S. authors in the two

international journals devoted to neurotoxicology.

Table 9-1 indicates the various neurotoxic substances investigated in papers published in two

journals between 1979 and 1987.

Heavy metals as a group clearly represent the

major area of interest. They are followed by organic

solvents, pharmaceutical agents, and pesticides.

Since the two neurotoxicology journals are relatively new, one can assume that a large proportion of

neurotoxicological research has also been published

in other journals. In addition, each of the non-Englishspeaking countries listed has journals in its own

language, and researchers also publish in those

journals. This is particularly true of scientists in the

Soviet Union, who publish only infrequently in

English-language journals. Thus, while this survey

of published research outside the United States may

not be truly representative of international neurotoxicological research, it is probably a reasonable

indicator of general trends in international research.

To gain another view of current research trends, it

is useful to examine projects presented at the first

meeting of the International Neurotoxicology Association in the Netherlands, May 10-16, 1987. The

meeting was attended by 135 scientists from 21

countries. The largest contingent came from the

United States (23), followed by the Netherlands

(20), West Germany (15), England (1 1), Italy (1 1),

and all other countries (fewer than 10 each). An

examination of their places of employment indicates

that 37 percent of the attendees were from government laboratories, 37 percent from academia, 23

percent from industry, and the remainder from a

variety of institutions. Of the U.S. participants, 22

percent were from government laboratories, 65

percent from academia, and 9 percent from industry.

An examination of the topics presented indicates

that the trends outlined above have not changed

markedly (table 9-2). Following tradition, 50 percent

of the papers dealing with solvent toxicities came

from Scandinavian countries.

Table 9-1-Neurotoxic Substances Investigated in

Papers Published in Two International Journals,

by Country, 1979-87

Country Substances investigated (No. of papers)

Canada

England

Italy

India

Japan

France

Mexico

Finland

Ethanol (3); manganese (2); cadmium (2); lead (2);

pharmaceutical agents (2); acrylamide (1 ); zinc (1 );

aluminum (1); herbicides (1); hydrogen peroxide (1);

chlorinated hydrocarbons (1)

Pyrethrins (7); pharmaceutical agents (7); organophosphates (2); solvents (l); acrylamide (l);

mercury (1); herbicides (1)

Pharmaceutical agents (8); organophosphates (2);

mercury (1); solvents (1); bismuth (1); caffeine (1)

Manganese (4); organophosphates (l); lead (l);

cadmium (1); solvents (l); sulfur dioxide (1); zinc

(1); styrene (l); herbicides(1)

Mercury (5); solvents (3); cadmium (l); pyrethron

(1); pharmaceutical agents (1)

Mercury (3); solvents (1); tellurium (l); lead (1)

Solvents (6)

Lead (4): solvents (4): ethanol (1)

SOURCE: Office of Technology Assessment, 1990.

Table 9-2-Subjects of Neurotoxicological Research

Presented at a Major International Conference

Chemical Papers (No.)

Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

PCBs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Acrylamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Methyl mercury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Styrene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Carbon monoxide . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Nitrous oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Pharmaceutical agents . . . . . . . . . . . . . . . . . . . . . . 4

Experimental compounds . . . . . . . . . . . . . . . . . . . . 6

SOURCE: Office of Technology Assessment, 1990.

One meeting may not represent a typical sample

of international research in neurotoxicology, but it

provides a useful example of current neurotoxicological research in the Western industrialized world.

No researchers from the Soviet Union attended this

meeting; however, two individuals from Eastern

Europe, one each from Hungary and Czechoslovakia, attended. The number of neurotoxicologists in

both of these countries is very small, as determined

by publications in the literature. For much of the rest

of the world, neurotoxicology as a discipline does

not exist. There are some exceptions, however. For

example, there are active researchers in Japan, India,

China, and Argentina, with well-identified centers

for such research. Indian researchers have traditionally published in English, and this practice is

becoming increasingly common among Chinese

researchers as well. In addition, experimental re-
Chapter 94-International Regulatory and Research Activities ● 259

search on the neurotoxicity of the grass pea is now

under way in Ethiopia.

Neuroepidemiology

International activities in neuroepidemiology have

taken place on all six inhabited continents. Neuroepidemiologists in England are currently studying risk

factors for stroke and are investigating the epidemiology of multiple sclerosis. In Japan, epidemiological inquires into the etiology of neurodegenerative

disorders (including amyotrophic lateral sclerosis,

Parkinson’s disease, Alzheimer’s disease) have been

undertaken. One country with a major effort in

neuroepidemiology is Italy. Italian efforts in this

area may be traced back to a series of courses on

neuroepidemiology taught in 1979 by a group of

U.S. and Italian epidemiologists. The fruits of these

efforts have included major work in the epidemiology of dementia. More recently, WHO has begun an

international initiative in the epidemiology of dementia. It is not clear, however, whether this work

will be extended to other neurodegenerative conditions. It is possible that some of these efforts will be

focused on geographic isolates of neurological

conditions, for example, the Faroe Islands and

multiple sclerosis, Guam and dementia, and Guam

and amyotrophic lateral sclerosis. An international

collaboration to investigate the latter two phenomena is now forming and will likely begin its activities

within the next year (31 ).

International Cooperation

Neurotoxicological research has been primarily

an intranational effort. In recent years, some international cooperation has been initiated by WHO and

the U.S. National Toxicology Program, but thus far

this has occurred only in specific areas, such as lead

toxicity, solvent toxicity, and the development of

testing methodologies (74). The limited scope of

international cooperation is large] y due to the lack of

funds available for such efforts.

Comparison of U.S. and Foreign

Research Programs

The neurotoxicity research effort in the United

States is larger in depth and scope than that in other

nations. Both leading books in this area were written

by American authors and editors (4,52). Both

international journals in the field are published in the

United States, and a review of the published

literature in neurotoxicology reveals that about 90

percent originates in the United States. The quality

of the work is generally considered to be excellent.

As mentioned previously, other countries have

excelled in some areas of research; this is particularly true with respect to the solvents research

conducted in Scandinavia. American research on the

mechanisms of toxicity of solvents is generally

considered to be outstanding.

Resources

The United States has a limited number of

doctoral-level training programs in neurotoxicology. Because of its unique educational system, more

scientific manpower is available in the United States

than in other countries. In most European countries,

the standard educational program in the life sciences

is the medical degree, or the equivalent of the M.D.

Consequently, almost all researchers in Italy, Scandinavia, and Germany are trained first as physicians

and then as researchers. These individuals may

eventually obtain a doctorate if they choose a

research career. In countries such as Italy, where

research positions are very difficult to obtain, most

physicians choose nonresearch careers rather than

risk being unemployed. Although employment opportunities are somewhat better in Scandinavia than

in Italy, it is still difficult to establish a research

career because of the scarcity of positions.

The success of the American research enterprise

is due not only to the relative availability of funding,

but also to the manner in which the funds are

administered. Despite some inherent flaws, the peer

review system in the United States generally ensures

that the best scientists in a given field obtain

funding. In many other parts of the world, research

is often supported by a system in which funding

decisions are made solely by the director of an

institute or the chairman of a department, without

peer review of the proposed research.

Future Directions

A recent review (1) listed 850 chemicals in the

workplace that may be neurotoxic. Apart from the

substances listed in tables 9-1 and 9-2, most of these

chemicals have not been studied. The international

chemical industry produces several thousand new

chemicals every year, most of which are not tested

for neurotoxicity. Japan and France now require

neurotoxicity testing for new chemicals (53), but

these tests are elementary in nature and are likely to

miss more subtle and insidious toxic effects.
260 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Photo credit: Jerry Deli

At present, the major classes of neurotoxic

substances-heavy metals, solvents, and pesticides—

have been identified. However, despite major research efforts, there is still no clear understanding of

the mechanisms of toxicity of most of these chemicals. In order to protect human populations from

chronic low-level intoxication, it is essential to

understand the properties and potential health effects of new and existing chemicals. Because of the

enormity of the testing task, a coordinated international approach would be highly beneficial.

Foreign Governments Likely To Take

Leadership Roles

In some European countries, notably West Germany and Sweden, environmental movements are

becoming increasingly influential. It is likely that

these nations will play leading roles in supporting

research and in developing regulations to control

toxic substances. The Federal Republic of Germany

has already acted to remove lead from gasoline and

to fund studies of lead toxicity in children. As

outlined above, all of the Scandinavian countries

(Sweden, Denmark, Norway, and Finland) have

traditionally supported research on solvents. These

patterns are likely to continue and may broaden to

the investigation of other agents as environmental

movements grow. Political events in the Soviet

Union have led to the emergence of an environmental movement, and it appears that the Soviet

government will also take a more active role in these

issues. In the Far East, both the People’s Republic of

China and Japan are faced with major pollution

problems and are becoming increasingly involved in

toxicological issues.

SUMMARY AND CONCLUSIONS

Like most environmental concerns, neurotoxicity

is a problem not limited by national boundaries.

Pollutants can readily cross national borders, hazardous chemicals are frequently imported and exported among both industrialized and developing

nations, and adulterated food and commercial products enter the United States despite current regulatory efforts. Strategies to limit human exposure to

neurotoxic substances should be devised in the

context of both national and international regulatory

and research initiatives.

Despite numerous regulations governing the export and import of neurotoxic chemicals and products containing them, most countries do not adequately protect human health and the environment

from these substances. Most industrialized nations

have policies and procedures in place to regulate the

import, distribution, and use of toxic chemicals,

implicitly including neurotoxic substances. Some

developing nations have limited regulations to

protect workers and consumers from the adverse

effects of neurotoxic substances. Developing nations that do have regulations often do not have the

resources to enforce them. Developing countries use

only 10 to 25 percent of the world’s pesticides, but

they account for as much as 50 percent of the acute

poisonings of pesticide applicators and between 73

and 99 percent of their deaths. This lack of effective

regulation and enforcement in developing nations

has a negative impact not only on public health and

environment in the user country, but also in industrialized nations, including the United States, where

people process and consume pesticide-treated crops

imported from developing nations.
Chapter 9-Internatioral Regulatory and Research Activities ● 261

Both TSCA and FIFRA contain provisions exempting certain products produced for export from

the requirements that apply to products sold for use

in the United States. In most instances, TSCA

requirements do not apply to substances manufactured, processed, or distributed for export. The

requirements do, however, apply if it is determined

that the substance will present an unreasonable risk

of injury to public health or the environment within

the United States. In addition, because pesticides

intended solely for export are exempt from the

public health protection provisions of FIFRA, pesticide manufacturers can legally export banned, severely restricted, or never registered substances that

have been deemed too hazardous for use in this

country. Companies that do so are required to notify

the importing country that the exported pesticides

have been banned, severely restricted, or never

registered for use in the United States. Some such

pesticides are used on food crops that are imported

back into the United States for consumption. Critics

of this practice have termed it the ‘circle of poison.

On January 15, 1981, several days before the end

of his term, President Jimmy Carter issued an

Executive Order which put controls on exports of

substances that were banned or severely restricted in

the United States. Several days after Ronald Reagan

became President, he revoked the order.

While pesticides may be needed to obtain sufficient food to feed the ever-increasing world population, many observers argue that ample food supplies

are currently available and that better distribution of

existing food stores is necessary. Responsible conduct on the part of persons who manufacture,

distribute, and use pesticides is mandatory if irreversible harm to world public health and the world

environment is to be minimized. Education and

literacy levels of persons handling pesticides must

be considered and appropriate information tailored

to their needs. Regulations currently in place must be

adhered to and new legislation enacted when the

need arises. Alternative methods of pest control

should be investigated and developed. Cooperative

efforts on the part of governments in industrialized

and developing countries, industry, environmental

groups, and other international organizations are

necessary to ensure the safety of the world community.

Active interest in neurotoxicity began in England

during and following World War H. Since that time,

efforts in the United States have gradually increased.

Today, the United States is the world leader in

environmental legislation and government funding

of neurotoxicological research. The Scandinavian

countries have been active in research on the

neurotoxicity of organic solvents. Other European

countries have supported research on compounds of

particular concern in occupational settings, such as

pesticides and heavy metals.

International research activities tend to focus on

the heavy metals (lead and mercury), organic

solvents, and pharmaceutical agents. Foreign neurotoxicology-related scientific papers published in

international journals most often originate from

authors in Canada, England, Italy, Australia, and

Japan. A number of papers originate from authors in

France, India, Sweden, Finland, and Mexico, as

well.

International cooperation in the neurotoxicology

field is very limited. Neurotoxicological research

has been primarily an intranational effort. In recent

years, some international cooperation has been

initiated by WHO and the U.S. National Toxicology

Program, but thus far this has only occurred in

specific areas, such as lead toxicity, solvent toxicity,

and the development of testing methodologies. The

limited scope of international cooperation is largely

due to the lack of funds available for such efforts.

In some European countries, notably the Federal

Republic of Germany and Sweden, environmental

movements are becoming increasingly influential. It

is likely that in the future these governments will

play leading roles in supporting research and in

developing regulations to control toxic substances.

The Federal Republic of Germany has already acted

to remove lead from gasoline and to fund studies of

lead toxicity in children. All of the Scandinavian

countries have traditionally supported solvent research. This will likely continue and may broaden to

include the investigation of other agents as environmental movements grow.

1.

2.

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Moore, M.R., “Lead in Humans,” Lead Toxicity, R.

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264 . Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

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Chapter 10

Case Studies: Exposure to Lead,

Pesticides in Agriculture, and

Organic Solvents in the Workplace

“If we were to judge the interest excited by any medical subject by the number of writings to which it has

given birth, we could not but regard the poisoning by lead as the most important to be known of all those that

have been treated up to the present time. ”

M.P. Orfila

A General System of Toxicology

1817

“mere is . . . no systematic monitoring of the health or exposure to pesticides of the more than 2 million

farmworkers, applicators, harvesters, irrigators, and field hands who work around pesticides. Industrial

workers who produce these pesticides receive the benefits of such monitoring. ”

National Academy of Sciences

Alternative Agriculture

1989

“When I was in the Navy, I remember my commanding officer called me in and he was very upset because

an air control operator had abandoned the tower, his position of duty, with seven aircraft stacked up calling

for landing instructions. I was supposed to examine him. As I look back, I completely missed what was

happening until years later. He was working in his off hours loading pesticides into spray planes, which caused

a tremendous change in his personality and his behavior and his ability to cope. ”

Gordon Baker, M.D.

Testimony before the Committee on Environment and Public Works

U.S. Senate

March 6, 1989

t< ..+ doctors tell me my nervous system has been heavily damaged, my brain has been damaged, and I suffer

chemically induced asthma. I also have kidney, liver, and vision difficulties. I had a tumor removed from my

eyes less than 1 year ago, and have been told that I have more, not to mention the chronic muscle pains

throughout my body . . . . Throughout my entire 8 years at this truck manufacturing company, I was never

informed of the hazards of the solvents I used, None of these products were adequately, clearly, or should I

say, truthfully labeled. Yet the hazards for most of the products had been known for years by the chemical

manufacturers and other people.

Frank Carsner

Testimony before the Committee on Science and Technology

U.S. House of Representatives

October 8, 1985
CONTENTS

Page

INTRODUCTION .. .. .. .. .. .. .. .. .. ... .+. ......+ .. .. .. .. .. .. ”” .0 +. ”O”. sD”o+QIo. 267

ExPOSURE TO LEAD . . . . . . . .. .. .. .. .. .. .. .. .. ..+. ... +....”+ ..+~’”0+”””+’~~o+T” 267

Sources of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . ......”””””””..”””~”””o”Qo ““+0”+0”~ 268

Routes of Exposure . . . . . . . . . . . . . . .. .. .. .. .. .+ .. ... ... ..+..... ..”+++~n....o+o.+. 269

Levels of Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ .. ~.. .. ””.””.”. “++” ~~~

Effects of Lead on the Human Body . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Regulatory Activity Regarding Exposures to Lead. .. .. .. ... ... .....+. ,.......~.. 273

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .+ .. ”~. ”+. ~.. .o.’~. + 281

EXPOSURE TO NEUROTOXIC PESTICIDES IN AGRICULTURE . . . . . . . . . . . . . . . . 281

Extent of Exposure of Agricultural Workers .. .....................++. ... .......+ 283

Documented Adverse Effects on the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283

Federal Regulation .. . .. .. .. .. ...+.... . . . . . . . . . . . . . . . . . ......”...”.””... ‘.””.”.. 285

State Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . .. ................+.. “..+...o.”s.”s. 289

Examples of Neurotoxic Pesticides .. .. .. +. . . . . . . . . . . . . . . .. .............++.. .“+.+ 290

Summary and Conclusions . . . . . . . . . . . . . . . . . . . .. .. .. .. .. . .. .. ... ..”..++ ...”.++... 295

EXPOSURE TO ORGANIC SOLVENTS IN THE WORK PLACE . . . . . . . . . . . . . . . . . . 296

Uptake, Distribution, and Elimination of Solvents .. .. .. .. *. .. .. C. ... .+. .+...+. . . . 298

Neurological and Behavioral Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .?. ... ..+....” 298

The Solvent Syndrome: A Current Controversy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Health Protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..............+”...~”.+..+ ● +.. 300

OSHA Regulations . . . . . . . . . . . . . . . . . . . .. ........,....”..+.. .....+.”.+.”~~..00.. 301

Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........,.~””.”...””.. 304

CHAPTER 10 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...* 304

Boxes

Box Page

10-A. Lead: A Historical Perspective .. .. .. .. .. .. ... .. .+....... ..........+..”””~+”~ 268

IO-B. Lead Poisoning and IQ . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. .+ .. .. .. ... ... ,.. .,*.o 273

10-C. State Wad Poisoning Prevention Programs . . . . . . . . . . . . . . . . . . . .. ..........9+.. 278

10-D. Lead in Water Coolers . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ ... ... ......+” ~...~.~.. 280

10-E. Pesticides in Food .. .. .. .. .. .. .+ . . . . . . . . . . . . . .. .. .. .. . .. .+ .. ... .. ”..+”.”. f++ 2$2

10-F. Organic Farming and Alternatives to Chemical Pesticides .. ................,.+ 291

10-G. Engineering Controls v. Personal Protective Devices . . . . . . . . . . . . . . . . . . . . . . . . . 301

Figures

. . . . . . . Figure Page

10-1.

10-2.

10-3.

10-4.

10-5.

10-6.

Table

1o-1.

10-2,

10-3.

10-4.

10-5.

10-6.

eChildren’s Blood Lead Levels Considered Acceptable by Various Agencies . . . . .

Adverse Health Effects of Lead . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .+ +. ... ... .~~.”..

Lead Used in Gasoline Production and Average Blood Lead Levels . . . . . . . . . . . .

Dietary Lead Intake .. .. . .. . .. .. ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .~a”+~~”+

Food Can Shipments .. .. .. ... ..+. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Classes of Organic Solvents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .cO. .9+. .40t.

Tables

Significant Sources of Exposure to Lead . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Estimated Number of Children Exposed to Sources of Lead . . . . . . . . . . . . . . . . . . .

Organophosphorous and Carbamate Insecticides . . .. .. .. .. . .. .+. . . . . . . . . . . .+..

Neurotoxic Effects of Acute Exposure to High Levels of Oganophosphorous or

Carbamate Insecticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... +......

Organochlorine Insecticides . . . . . . . . . . . . . . . . . . . .. .. .. .. .. .. ~. .+ ... +. ”......+.

Representative Exposure Limits to Solvents . . . . . . .. .. .. .. .. .. ... ~.. ....+... .-.

271

272

275

275

275

297

Page

269

269

292

294

294

303
Chapter 10

Case Studies: Exposure to Lead, Pesticides in Agriculture,

and Organic Solvents in the Workplace

INTRODUCTION

The best way of illustrating the adverse effects of

toxic substances on the nervous system is by looking

at substances or classes of substances that are known

to be neurotoxic. These case studies discuss attempts

to control human exposure to lead, pesticides, and

organic solvents. They illustrate the prevalence of

neurotoxic substances, the susceptibilities of certain

subpopulations, special hazards in occupational

settings, and how Federal agencies address these

concerns.

As it exists in the earth, lead is bound in chemical

compounds and presents little risk to humans. As it

is mined and utilized, however, it is distributed

throughout the environment, presenting a risk to the

entire population, but especially children, who are

most vulnerable to its effects. Research shows that

children are directly exposed to multiple sources of

lead, are more sensitive to exposure, and suffer

worse effects than adults. A great deal of progress

has been made by Federal agencies in reducing

public exposure by regulating the lead contents of

paint, gasoline, plumbing systems, and food containers, but lead poisoning continues to be a major

national health problem.

Chemical pesticides also present a significant risk

to the population as a whole, but especially to

agricultural workers and others who apply them or

work close to them. Several Federal agencies have

regulations that are intended to protect these workers

from pesticide poisoning, but critics argue that more

could be done. Many States have their own regulations, some of which are more stringent than Federal

regulations, especially in protecting farmworkers.

This chapter reviews the different types of pesticides

in use and summarizes what is known about their

neurotoxic effects.

Many solvents are neurotoxic and threaten the

health of the industrial workers who come in contact

with them. Solvents may cause a variety of functional changes, ranging from temporary memory

loss to unconsciousness, depending on the duration

and extent of exposure; major structural changes in

the nervous system may also result. Engineering

controls to avoid contamination, isolation of workers, and issuance of protective equipment to workers

are some of the preventive measures currently in use.

This chapter gives examples of how various solvents

have been regulated under the Occupational Health

and Safety Act, including the new standards for

worker protection proposed by the Occupational

Health and Safety Administration in 1988. It discusses criticisms of the existing regulations and

offers suggestions as to how they might be improved.

EXPOSURE TO LEAD

As discussed in previous chapters, regulation of

neurotoxic substances is a two-part process, one

being identification of new hazardous chemicals and

prevention of human exposure to them, the other

being reduction of exposure to existing toxic substances. Lead is a prominent example of a substance

long known to be toxic to the human nervous system

(see box 1O-A). Unlike some elements, such as

sodium or zinc, lead serves no useful biological

purpose; since the body can neither use nor metabolize it, lead accumulates in body tissues, especially

bones and teeth. Debate continues as to what

maximum level is tolerable, although the only way

to prevent any toxic accumulation is to limit

exposure to zero. This chapter highlights some of the

difficulties of removing or preventing exposure to a

neurotoxic substance that has been extensively used

in industry and therefore is especially prevalent in

the environment.

Efforts to reduce public exposure to lead by

removing current sources and preventing new ones

have been undertaken by several Federal agencies.

The Environmental Protection Agency (EPA) and

the Food and Drug Administration (FDA) have

taken steps to reduce the amount of lead in gasoline

and food, and EPA is currently considering more

stringent methods for controlling exposure to lead

from drinking water. Other sources of lead, however,

are more difficult to control. Lead has been used

consistently in industrial and commercial activities

and, despite awareness of its inherent dangers,

continues to be used in product manufacturing. The

use of lead in manufacturing ultimately results in its

distribution in the environment in the form of waste.

–267-
268 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 10-A—Lead: A Historical Perspective

Lead is the oldest, most extensively studied, and probably most ubiquitous neurotoxic substance. It is

mentioned in ancient Egyptian manuscripts and was used by the Egyptians as a cosmetic; both the Egyptians and

the Remans used lead in cooking tools and vessels. The Remans used it as a sweetener and preservative in wines

and eiders; lead acetate is often called “sugar of lead” because of its sweet taste. The Remans also used lead in

building houses and transporting water. In fact, the words plumber and plumbing originate from the Latin word for

lead, plumbum. Lead was mined in Great Britain as far back as the reign of Julius Caesar. Remnants of these mines

contaminate local farms and gardens today.

At least some of the toxic effects of lead were known early on. The Greek thinker Dioscorides stated in the

2nd century B.C. that “Lead makes the mind give way.’ Pliny the Elder cautioned that inhaling the fumes of molten

lead was dangerous (although he continued to recommend that it be used in making wine). Indeed, the continued

use of lead, despite recognition of its dangers, has caused many outbreaks of lead poisoning over time. Benjamin

Franklin may have been the first person to recognize lead as an occupational hazard: in a letter about lead poisoning

he wrote, “How long a useful truth may be known and exist, before it is generally receiv'd and practis’d on.”

SOURCES: A. Fischbein, “Environmental and Occupational Lead Exposure, ” Environmental and Occupational Medicine, W.N. Rom (cd.)

(Boston, MA: Little, Brown, 1983); J.S. Lin-Fu, “Lead Poisoning and Undue Lead Exposure in Children: History and current

Status,’ Low Level Lead Exposure: The Clinical lrnplications of C“urrent Research, H.L. Needleman (cd.) (New York, NY: Raven

Press, 1980); R.H. Major, ‘‘Some Landmarks in the History of bad Poisoning, “ Annals of Medical History 3:218-227, 1931; H.L.

Needleman and D. Bellinger, “The Developmental Consequences of Childhood Exposure to Lead: Recent Studies and

Methodological Issues,’ Advances in Clinica/ Child Psychology, vol. 7, B,B. Lahey and A,E. Kazdin (eds.) (New York, NY: Plenum

Press, 1984); H. Waldron, “kad Poisoning in the Ancient World,” Medicaf History 17:391-398, 1973.

For example, lead is found in commodities such as sources of exposure to inorganic lead include water,

solders, batteries, and paint, but it is also present in

dust and soil as waste material. There is no

agreement as to who bears responsibility for removing the various forms of lead from the environment.

Although the Consumer Product Safety Commission has reduced the amount of lead permitted in

paint to prevent future exposure, the danger of lead

poisoning from leaded paint in old housing remains.

In addition to the remedial measures being taken,

preventive measures must be considered for some

currently minor sources that may become larger

problems in the future, Incinerators, for example,

may significantly increase exposure to lead in the

environment as we attempt to reduce our reliance on

landfills.

Sources of Exposure

Lead exists in both organic and inorganic forms.

Although organic lead is more toxic than inorganic

lead because it degrades quickly in the atmosphere

and the body, it constitutes only a small proportion

of the total lead to which the population is exposed

(16). Organic lead is most commonly found as a fuel

additive and can reach significant levels in heavy

traffic areas and underground garages (16), but it is

rapidly converted to the inorganic form. This chapter

will therefore focus on inorganic lead. Significant

food, soil, lead-based paint, leaded gasoline, and

industrial emissions (see table 10-1).

Levels and sources of exposure vary according to

surroundings. In remote areas, proximity to stationary sources of lead such as smelters maybe the main

source of exposure, whereas in older cities leaded

paint may be the most common source (165).

Individuals living near industrial sources of lead,

people who drink contaminated water, adults with

occupational exposure, and children who ingest

lead-contaminated paint, soil, or dust have the

greatest exposure to lead (109,172).

When discussing exposure to lead, a distinction is

often made between children and adults, since

children both ingest and inhale more lead per

unit of body weight than adults and are more

vulnerable to its effects (165). Children, given their

normal tendency to put things in their mouths, are

likely to ingest paint, soil, or dust, all of which are

potential sources of lead. Lead gives paint a sweet

taste, increasing its appeal for children. Children

also have a higher absorption rate of ingested lead

than adults: whereas adults absorb between 5 and 15

percent of ingested lead and usually retain less than

5 percent of what is absorbed, one study found that

infants on regular diets absorb an average of over 40

percent of ingested lead and retain over 30 percent
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 269

Table 10-l Significant Sources of Exposure to Lead

Leaded paint

. lead released into the air through destruction and weathering of

structures painted with leaded paint

● lead ingested by children from household dust, less commonly

by eating leaded paint chips

Leaded gasoline

. lead released into the air in exhaust fumes

. lead released into the air during fueling

Stationary sources

. lead released into the air by industrial activity, e.g., smelting,

refining, and battery recycling

. occupational exposure of factory workers, exposure of children

to lead on the clothing of parents

Dust, soil

. paint

. industrial activity

. gasoline

Water, plumbing

. lead in water source

. leaching from lead pipes

. leaching from lead solder

. leaching from brass or bronze

Food

. lead contained in food items from contaminated water or soil

. lead-soldered food cans

● lead deposited on crops from automobile exhaust

. lead deposited on crops from industrial activity

● lead contamination during food processing

. lead glazes in dishes and pottery

SOURCE: Office of Technology Assessment, 1990.

of that amount (57). Children also retain more of the

lead they absorb than do adults, since lead in blood

is stored in growing bones (165). The effects of lead

on children are more severe than the effects of lead

on adults: children have less bone tissue in which

lead can be stored, and thus lead remains in the

bloodstream, free to exert toxic effects on various

organs of the body. Nutritional deficiencies, more

likely to occur in the growing child, can also

contribute to higher absorption levels of lead (165,169).

Children’s nervous systems, especially their bloodbrain barriers, are not yet fully developed, and the

same cellular lead exposure may produce disproportionate results in children compared to adults (84,145).

Also, cognitive effects occur at lower levels in

children. For similar reasons, fetuses may be even

more vulnerable to lead’s toxicity than children (84).

There is some evidence that lead stored in women’s

bones from previous exposure may be mobilized

during pregnancy and lactation, and thus expose the

fetus and infant through the placenta and breast milk

(148).

Estimates of the number of children exposed to

lead, listed by source, are found in table 10-2. The

Table 10-2-Estimated Number of Children

Exposed to Sources of Lead

Number of childrena

Source (millions)

Leaded paint . . . . . . . . . . . . . . . . . . . . . . . . . . 12.00

Leaded gasoline . . . . . . . . . . . . . . . . . . . . . . . . 5.60

Stationary sources. . . . . . . . . . . . . . . . . . . . . . 0.23

Dust, soil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.90-11.00

Water, plumbing . . . . . . . . . . . . . . . . . . . . . . . . 10.40

Food . . . . . 0 . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.00

~umbers in the table are not additive since children are usually exposed

to multiple sources of lead in the environment.

SOURCE: U.S. Department of Health and Human Services, Public Health

Service, Agency for Toxic Substances and Disease Registry

and Center for Environmental Health and Injury Control, “Childhood Lead Poisoning—United States: Report to the Congress

by the Agency for Toxic Substances and Disease Registry,”

Morbidity and Mortality VMsek/y Report 37:4S1-4S5, 19S8.

type and availability of data for each of these sources

vary considerably, therefore the estimates are not

comparable and cannot be used to rank the severity

of the problem by source of exposure (165).

For adults, the workplace is a major source of

exposure. The National Institute for Occupational

Safety and Health has listed 113 occupations that

potentially increase workers’ exposure to inorganic

lead (74). In adults not exposed to occupational

sources of lead and in children older than 6 to 8

years, food and water are most likely to be the major

sources (74). For most adults, lead in the air is no

longer as significant a source of exposure as lead in

the diet, but as one study found, levels of lead in the

blood of adults remain correlated with levels of lead

in air (74), as do levels of lead in children’s blood

(15). Before the phase-out of lead from gasoline,

however, airborne lead was the predominant source

of exposure to lead for adults and children (6,173,

175).

Routes of Exposure

Lead can enter the human body through three

routes: inhalation, ingestion, or absorption through

the skin, although the latter is significant only for

organic compounds of lead (51). Intake through

inhalation depends on particle size and volubility in

body fluids (51). Gastrointestinal absorption is

influenced by a number of factors, primarily age and

nutritional status (72). The proportion of lead

absorbed through ingestion and inhalation differs by

age and principal source of exposure, as discussed

earlier.
270 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Levels of Exposure

Lead is stored in the circulating blood, soft tissue,

and bone. Because it has a long biological half-life

and is only slowly excreted from bone, lead can

accumulate in the body. Thus, the concentration of

lead in the blood (the blood lead level) is not an

accurate indicator of total exposure to lead, only of

recent exposure. The amount of lead found in teeth

and bones is a more useful indicator of cumulative

exposure, but it yields no information about the time

or duration of exposure, nor of current exposure.

Furthermore, teeth are easily obtained only from

young children, who lose their baby teeth. A

technique using X-ray fluoroscope was developed in

1984 to measure lead in bone (28,77); its feasibility

as a testing method is being evaluated (186).

For the most part, neurological deficits in adults

have not been noted below a blood lead level of 40

micrograms of lead per deciliter of blood (ug/dl)

(192), although elevations in blood pressure have

been noted at 5 ug/dl (125, 126, 144). In children,

however, adverse neurological effects are seen at

much lower levels (33,87,165), and since 1943 the

blood lead level found to be associated with

neurobehavioral dysfunction has steadily decreased. Before that year, the cumulative effects of

Photo credit: U.S. Environmental Protection Agency

EPA has estimated that exposure to lead in drinking water is keeping more than 240,000 children from realizing their

full intellectual potential.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 271

lead poisoning went unrecognized, and physicians

generally believed that if a child did not die of lead

poisoning there would be no lasting effects (1 18). In

1943, however, researchers found that a group of

children with mild lead poisoning in infancy did not

progress satisfactorily in school, and they suggested

that lead poisoning early in life might be widespread

(22). Since then, the aggregate effects of lead

poisoning have been recognized and its long-term

effects have been studied. Researchers have correlated blood lead levels with neurobehavioral dysfunction.

Before the 1960s a blood lead level below 60

ug/dl was not considered dangerous (169). In 1975,

the Centers for Disease Control (CDC) lowered the

acceptable level for children to 30 ug/dl, and in 1985

it lowered the level again, to 25 ug/dl (169). The

World Health Organization (WHO), in a 1986

report, stated that 20 ug/dl was the upper acceptable

level (193). EPA% Clean Air Scientific Advisory

Committee associated lead levels of 10 to 15 ug/dl

and possibly lower with adverse effects (see figure

10-1) (172) and recommended 10 to 15 ug/dl as

the maximum acceptable level. Recently, subtle

deficits in neurobehavioral performance have been

reported in fetuses and newborn babies exposed to

low levels of lead (12,33,87,121,165).

In 1986, Congress requested that the Agency for

Toxic Substances and Disease Registry (ATSDR)

prepare a report on lead poisoning in children. One

of the report’s mandates was to estimate the total

number of children exposed to potentially hazardous

concentrations of lead. Approximately 2.4 million

U.S. children age 6 months to 5 years living in

Standard Metropolitan Statistical Areas (SMSAs)

(or 17.2 percent) have blood lead levels greater than

15 ug/dl; 200,000 (1.5 percent) have blood lead

levels greater than 25 ug/dl. No economic stratum

of children was found to be free from the

potential health risk of lead poisoning. However,

since the data covered only black and white children,

no reliable prevalence rates could be calculated for

Hispanic children and children of all other races;

further, since SMSAs include only about 80 percent

of the children in the United States, the actual

number of children with blood lead levels above

15 ug/dl may be higher than the ATSDR report

indicates: more likely estimates are between 3

and 4 million affected children (21.4 to 28.6

percent) (165). The CDC is considering lowering

its target level for medical intervention again.

Figure 10-l- Children’s Blood Lead Levels

Considered Acceptable by Various Agencies

Blood lead level (ug/dl)

35

CDC

3 0 -

2 5 -

2 0 -

1 5 -

1 0 -

5 -

WHO

EPA

1975 1985 1986 1986

Year level set or recommended

= 10 to 15 ug\dl IS the recommended maximum acceptable level.

SOURCE: Office of Technology Assessment, 1990.

It is significant that some of the studies on

children have not detected a threshold for adverse

effects of lead (87,117,123), indicating that as tests

for various impairments become more sensitive, the

level at which adverse effects are observed may

decrease further. Accurate, current information as

to the lowest blood lead levels associated with

neurotoxic effects is crucial for policymaking,

since the regulations that set safety levels at 25

ug/dl do not adequately protect the many children whose blood lead levels fall below that; these

children may be endangered at levels of 10 to 15

ug/dl, or possibly lower.

Effects of Lead on the Human Body

Lead causes numerous adverse health effects. A

summary of some observable effects and the blood

lead levels with which they have been correlated is

given in figure 10-2. In children, brain damage

resulting from exposure to lead can range in severity

from inhibited muscular coordination to stupor,

coma, and convulsions at high levels (72). Acute

brain damage is rare in adults; when it appears it is

usually a result of high exposures to lead and is often

accompanied by other factors, such as alcoholism.

High exposures to lead can also damage the peripheral nervous system.

Since the discovery of chelation treatment, which

removes lead from the blood, mortality from acute

lead poisoning has declined. Yet as our ability to
272 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Figure 10-2-Adverse Health Effects of Lead

Lowest

observed Brain, Pregnant

effects of lead nervous woman or Red blood

(ug/dl) Cardiovascular

system fetus Kidney cells system

100

90

80

70

60

50

40

30

20

10

r

Clinical signs

of brain injury

Nerve

dysfunction

Decreased

I.Q.

Altered

performance on

neurobehavioral

tests

i

?

T

Pregnancy

complications

1

Chronic

neuropathy

I

I

Heart

injury

1

1-

Anemia

1

1-

Reduced

heme synthesis

T

I

Byproducts

of heme in

Premature Impaired blood and urine

birth vitamin D I

t

Decreased

growth

i

?

synthesis

7

Enzvme

L

inhibition

1

?

T

Elevated

blood pressure

I?

o

SOURCE: U.S. Environmental Protection Agency, “Drinking Water Regulations; Maximum Contaminant Level Goals and National Primary Drinking Water

Regulations for Lead and Copper; Proposed Rules” (53 FR 31565), 1966.

detect subtle neurological deficits has improved, Chronic low-level exposure may ultimately be more

estimates of morbidity have increased. Effects of damaging than acute exposure that is treated immepermanent damage to the central nervous system— diately (21).

for example, mental retardation, hyperactivity, seiFactors such as genetic variation in susceptibility, zures, optic atrophy, sensory-motor deficits, and

behavioral dysfunctions-have been observed (see nutritional status, behavior, and age may alter an

box 10-B). There is also some recent evidence that

individual’s vulnerability to lead poisoning (1 18).

Most of these factors affect toxicity by altering the

lead may cause minor hearing impairments (146). absorption of lead.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace .273

Box IO-B—Lead Poisoning and IQ

A study in 1979 found that children exposed to Cumulative frequency distribution (%)

lead had intellectual, attentional, and behavioral deficits, It

also found a difference of about 5 points in the mean IQ 100

(intelligence quotient) of children with elevated lead levels

and those with low lead levels. While this number is 90-

statistically significant, some question was raised as to

whether it was biologically significant. 80-

As the figure shows, the significance of this difference in 7O

IQs shows up most clearly at the ends of the IQ spectrum. I

High lead

Children with elevated lead levels were three times more 60 \

likely to have a verbal IQ below 80; furthermore, none of 50

them had superior IQ scores (greater than 125), while 5 — Low lead

percent of the children with low lead levels had scores in that 40

range.

30

A follow-up study published in January of 1990 concluded

that the effects of lead exposure upon cognitive development 20

in early years persist into early adulthood. In this study,

children who were originally examined in the first grade 10-

were reexamined as high school students. The subjects o

underwent extensive neurobehavioral analysis using a vari- 50 60 70 80 90 100 110 120 130 140

ety of tests for hand-eye coordination, grammatical reason- Verbal IQ

ing, and reaction times. Deficits in central nervous system functioning resulted in poorer classroom performance,

reduced vocabulary and reasoning scores, and higher absentee rates in school.

SOURCES: H,L. Needleman, C. Gunnoe, A, Leviton, et al., “Deficits in Psychologic and Classroom Performance of Children With Elevated

Dentine bad hvels,” New England Journaf of Medicine 300:689-695, 1979; H.L, Needleman, A. hviton, and D. Bellinger,

“Lead-Associated Intellectual Deficit,” New EnglandJournal of Medicine 306:367, 1982; B. Weiss and ‘EW, ClarkSon, “’Ibxic

Chemical Disasters and the Implications of Bhopal for Technology Transfer,” The Milbank Quarterly 64:216, 1986. H.L.

Needleman, A. Schell, D. Bellinger, et al., ‘‘The Imng Term Effwts of Exposure to Low Doses of Lead in Childhood,’ New England

Journal of Medicine 322(2):83-88, 1990.

Regulatory Activity Regarding Exposures gasoline and stationary sources, such as lead smeltto Lead ers.

Action by Congress and various executive agen- In 1978, EPA promulgated regulations stating that

cies has led to a reduction in exposure to lead in the the level of lead in the air must not exceed 1.5

United States. Their response marks the first time micrograms per cubic meter (ug/m3

). Under the

that specific neurobehavioral effects of a toxic Clean Air Act, the States had to take steps to meet

substance were considered in determining regula- that standard by 1982. The standard includes contritory policy. Although progress has been made, butions from both automobiles and industrial sources

there is evidence that lead poisoning in the United and was designed to prevent children from being

States still occurs in epidemic proportions. exposed to concentrations of lead in the air that

could lead to blood lead levels of more than 30 ug/dl

Lead in the Air (96).1

Removing lead from the air is the responsibility of In 1973, EPA promulgated regulations requiring

EPA, whose statutory authority comes from the that major gasoline dealers sell at least one grade of

Clean Air Act, passed in 1970 and amended in 1977. “unleaded” gasoline (defined as containing no

The two major sources of lead in the air are leaded more than 0.05 gram of lead per gallon of gasoline).

lme r~ornrncndcd rn~imurn for children’s blood lead levels has been repeatedly revised: EPA Science Advisory Bowd establlslm.1 10 to 15 W@

and possibly lower as the blood lead level of concern in 1986 (173).
274 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Lead in Food

Regulation of lead in food is the responsibility of

FDA. Although the agency has set acceptable levels

of lead for pesticides and food utensils in domestically produced food, much of its activity has focused

on eliciting voluntary cooperation from domestic

food manufacturers and processors (165). The success of this effort is illustrated in figure 10-4.

Regulation of lead by FDA began in the 1930s,

when the agency established guidelines for limits on

the use of lead in pesticides.2 The next item of

concern was lead in canned evaporated milk. In

1974, the agency proposed a tolerance level of 0.30

part of lead per million parts of milk (ppm) (39 FR

-H—-.— .—- I!iil.

.

------- HB.-~..+

.4

iiiiii/ iijiiij

.

“. ~,,”

..”.

. - .-. ‘?. -:

Photo credit: National Archives

zCurrent permissible levels of lead in pesticides are 1 microgram per gram (u~g) on citrus fruits and 7 qzJg on otierfi~andveget~les.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 275

Figure 10-3-Lead Used in Gasoline Production and

Average Blood Lead Levels

Total lead used per Average blood lead

6-month period (thousands of tons) W levels (ug/dl) (=)

““~1”

110 -

Lead used

100- In gasollne

+

/

9 0 - Average

blood

lead levels

8 0 -

0

7 0 -

+

1

16

15

50 J

*

~ 10

~ ~

40 ‘–--1—9-7–6---T

—1 977 ‘T 1978 1

1 9

1979 198 0

Yeal

SOURCE: J. Schwartz, H. Pitcher, R. Levin, et al., Costs and 8er?efits of

Reducing Lead in Gasoline: Final Regulatory Impact Analysis,

EPA-230-05-85-O06 (Washington, DC: U.S. Government Printing Office, 1985).

Figure 10-4-Dietary Lead Intake

Average lead intake (ugtday)

100 I I

9 0 - -

8 0 --

70

60

50

{

Toddler (2 Yeara)

40

\~

\

30

20 + /

Infant (6-11 montha)

10-

o

1975 76

~Y

77 78 79 80

~+

81182 82184 84186 86188

Year

SOURCE: U.S. Department of Health and Human Services, Public Health

Service, Food and Drug Administration, Center for Food Safety

and Applied Nutrition, FDA Total Diet Study (Washington, DC:

1989).

42745). As a result of its own studies and FDA’s

recommendations, the milk industry reduced the

levels of lead in evaporated milk from 0.52 ppm in

1972 to 0.08 ppm in 1982 (30,109). Manufacturers

of infant juices also took steps to lower lead levels

in their products, eventually switching voluntarily

from tin cans to glass jars (109), as did manufacturers of canned infant formula, who switched from

lead-soldered cans to other types of cans (96).

There has been a significant decrease in the use of

lead solder for food cans manufactured in the United

States. In 1979, more than 90 percent of such cans

contained lead solder; by 1989, less than 4 percent

did. Figure 10-5 demonstrates the trend in reducing

lead solder in cans and reflects the can manufacturing industry’s plans to eliminate lead solder in all

domestically produced food cans in the next 2 to 3

years (24). The number of imported cans containing

lead solder is not known but maybe large (165).

Materials used for packing food have also been a

source of concern. These materials are considered

indirect food additives, because contaminants may

migrate from packaging materials into the food. As

of 1980, three indirect food additives were subject to

limitations on the amount of lead they can contain

(109)0

Regulations concerning lead used in food utensils, specifically ceramic and hollowware products,

have been promulgated by FDA (54 FR 23485).

Large containers (in which food is likely to be

stored) and cups used by children have lower limits

on permissible lead content than do small utensils

(100,109). FDA is currently considering lowering

the acceptable limit for large containers. Although

these limits apply to both imported and domestic

utensils, few imported utensils are tested for lead

content. In response to public concern, some retailers are testing imported dishes on their own (100,

182).

Figure 10-5-Food Can Shipments

Billions of cans

3 0

20

10

I

[

Total food can.

/

cans

I

1 1 I I 1 1 1 , 1

I i

1979 1980 1981 1982 1983 1984 1985 1986 1987 1988

Year

SOURCE: Can Manufacturers Institute, Washington, DC, personal communication, 1989.
276 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Occupational Exposure to Lead

In contrast to the reduction of lead in food, where

strict regulations have not had to be imposed by

government, the reduction of occupational exposure

to lead has required more intervention. In response

to the Occupational Safety and Health Act of 1970,

the Occupational Safety and Health Administration

(OSHA) promulgated regulations in 1978 (29 CFR

1910.1025) that set a maximum permissible level for

lead in the air inhaled by workers.3

The lead industries immediately sued OSHA,

challenging the validity of the standard. In 1980, the

U.S. Court of Appeals for the District of Columbia

Circuit upheld the limit and most other provisions of

the regulation but ordered that the feasibility of

engineering controls be reconsidered for many

affected industries (180). OSHA states explicitly

that industries must use engineering controls to

reduce the overall level of lead in the air at the

workplace, as opposed to simply giving workers

respirators to remove lead from the air they inhale.

The court instructed OSHA to reassess the feasibility of such engineering and work controls for

approximately 40 industries. Only one of these

studies has not been completed; however, because

the courts will reexamine all the studies at once,

these 40 industries are currently exempt from the

requirement to achieve 50 ug/cm3 through engineering and work practice controls.

The regulatory framework for ensuring minimal

occupational exposure to lead is in place. Occupational exposure has been reduced considerably in

most large industries, as indicated by decreases in

cases of high-dose lead poisoning, mean blood lead

levels in workers, and mean air lead levels in most

workplaces (75). It remains a problem in small

shops, however, which are covered by OSHA

regulations but may not be routinely inspected.

Some critics assert that enforcement of OSHA

regulations is inadequate. Others state that, as

revealed by several State screening programs, many

employers are unaware of their responsibilities, and

others ignore them. Many employees are not aware

of their rights or are reluctant to report employers for

fear of losing their jobs.

Lead in Paint

Although lead-based paint is now only rarely

used, the paint that remains on the walls of older

housing is the most significant source of lead

poisoning today. Many children are exposed to

lead-based paint, and efforts to remove paint from

the walls as a preventive measure vary greatly from

State to State. The U.S. Department of Health and

Human Services reported in 1988 that 52 percent

of all residential buildings have paint containing

lead in concentrations greater than or equal to

that considered dangerous by the CDC (165, 169).

In 1971, Congress attempted to address the issue

of lead poisoning from lead-based paint. The LeadBased Paint Poisoning Prevention Act and its 1973

and 1976 amendments directed the Consumer Product Safety Commission (CPSC) to establish a level

of safety for lead in paint.4 Most paints are regulated

under this standard, but lead is still used in some

paints (most often as a weather-resistant coating for

metals) (51), and the yellow paint used for lining

highways and roads contains lead as well (42). The

CPSC has no control over lead-based paints already

in houses and other dwellings or lead-based paint

manufactured before 1977, when the regulation went

into effect (165).

A second aspect of the lead-based paint legislation involves removing lead paint from housing

under Federal jurisdiction, an activity that falls to the

Department of Housing and Urban Development

(HUD). HUD can only regulate paint in public

housing or federally assisted dwellings (165). The

Department’s regulations currently ensure notification of residents in and purchasers of HUDassociated housing constructed before 1950 of the

hazards of lead poisoning from lead-based paint.

The regulations also prohibit the use of lead-based

paint in HUD housing and federally owned and

assisted construction or rehabilitation of residential

structures, and ensure removal of lead-based paint in

HUD-associated housing and federally owned prop3Bef~ 1978, tie permissible ~xw~me ]fiit ~m 200 @mq (over an average time period of 8 hours). me regulations lowed tie limit to 50 ug/t’t13

(43 FR 52952 and 43 FR 54354) and set an action level of 30 u@q (an action level is based on the same criteria as a tolerance). At this action level,

the industry must initiate environmental monitoring, recordkeeping, education, training, and medical surveillance. Medical removal protection

(removing the employee to an area with exposure below the action level) is directed by the medical surveillance findings (109).

4c~c*s au~onty ~ ~s ~ea ~omes from the con~wer ~~Wt Stiety ~t, which gives the Commission the power to ban ~ hz~dous my

consumer product that presents an unreasomble risk of injury (15 U.S.C. 2057). The current regulations state that paint may contain no more than 0.06

percent lead.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 277

Photo credit: U.S. Environmental Protection Agency

The paint that remains on the walls of older housing is a

significant source of lead poisoning.

erties (109). Removal of lead-based paint from walls

is dangerous in itself. Workers can be exposed to

lead dust if not adequately protected, and dust and

paint chips can be released into the nearby environment if not properly disposed of, resulting in

markedly increased exposure of inhabitants. HUD is

currently conducting a study to determine the extent

of the lead-based paint problem in public housing

and to study the efficacy of alternative abatement

procedures.

The Lead-Based Paint Poisoning Prevention Act

also created a Federal program to fund lead poisoning prevention programs for children. Initially funded

through the Bureau of Community Environmental

Management, the program was transferred to the

CDC in 1973, and until 1981 the CDC administered

grants to the States for prevention programs. In

1981, the Omnibus Budget Reconciliation Act

rolled a number of categorical health programs,

including the lead poisoning prevention program,

into the Maternal and Child Health Services Block

Grant. Thus, the allocation of money among the

various health programs, previously dictated by the

Federal Government, became the decision of each

individual State. Accordingly, States now choose

how much money, if any, to apply to lead poisoning

prevention programs (see box 10-C). Because many

of these programs have been reorganized at the State

level and because reporting of lead poisoning

prevention expenditures is now voluntary, it is

difficult to determine how expenditures on lead

poisoning prevention programs have changed. According to a 1984 General Accounting Office study

on the Maternal and Child Health Block Grant, lead

screening projects have received “the greatest

reduction in emphasis’ (179), and a 1987 survey by

the National Center for Education in Maternal and

Child Health indicated 10 States have no lead

poisoning prevention activities at all (1 11). In 1988,

the Lead Poisoning Prevention Act authorized $66

million for community screening between 1989 and

1991 in order to compensate for deficits in lead

poisoning prevention programs at the State level.

Lead-based paint remains a significant source of

lead poisoning, despite the laws and regulations

that specifically address this problem.

Lead in Drinking Water

Both EPA and Congress are currently addressing

the problem of lead in drinking water. In 1986, EPA

estimated that 42 million Americans drank tap

water containing more than 20 parts of lead per

billion parts of water, the proposed drinking

water standard (which has since been lowered).

The Agency further estimated that exposure to

lead in drinking water is keeping more than

240,000 children from realizing their full intellectual potential (171).

Lead rarely originates from source water but

leaches out of plumbing containing lead pipes and

fixtures or lead solder. EPA estimates that there are

approximately 4.4 million lead service lines in use in

the United States and that approximately 25 percent

of water suppliers have some lead service lines

within their distribution system (53 FR 31521).

Since more acidic water leaches more lead out of

plumbing systems, lead in drinking water may be

regulated by controlling its pH (a measure of
278 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 10-C-State Lead Poisoning Prevention Programs

Some States do nothing about lead poisoning, largely because it is not considered a significant problem. Others

identify children with high blood lead levels through mandatory reports from laboratories that conduct blood tests,

then follow up by treating the children and removing the environmental source of lead, if possible. Other States have

an outreach program, whereby children in high-risk areas are screened and appropriate follow-up action is taken.

Some communities have lead poisoning prevention programs.

A number of States have either passed legislation or are considering legislation addressing the issue of

childhood lead poisoning. Massachusetts, for example, has extensive legislation that requires statewide screening

of children under age 6, reporting of cases of childhood lead poisoning by physicians, and art education campaign

about the dangers and sources of lead poisoning. The law also outlines lead-based paint abatement standards and

a program for removing or covering lead in soil, among other provisions. Generally, areas of the country with

industrial pollution, older housing, and large cities appear to have the most active lead poisoning prevention efforts.

Given the variability of these prevention efforts, it is difficult to characterize the extent of screening at the State

and local levels. However, a survey conducted by the Public Health Foundation in 1983 yields some relevant data.

Of the 48 State and territorial health agencies surveyed, 33 operated lead poisoning prevention services. Thirty of

these programs reported screening 676,600 children ages 1 to 5. Of the children screened, 9,317, or 1.6 percent, had

confined lead toxicity (defined as blood lead levels greater than 30 ug/dl and erythrocyte protein levels greater than

50 ug/dl, the CDC standard at that time). Of these children, 92 percent received medical care,l and environmental

investigations were conducted for 96 percent. The source of lead was determined in 80 percent of the cases of

confirmed lead toxicity, and 98 percent of those sources were lead-based paint. Of the children with identified

hazards, the hazards were abated for 91 percent.

In one sense, these data are encouraging, since the majority of children with elevated blood lead levels

evidently obtained medical treatment and hazard abatement. On the other hand, the number of children identified

and treated is only a small percentage of the 200,000 children estimated to have elevated blood lead levels. Thus,

a large number of children with potentially dangerous exposure to lead are not being helped.

IFr~m ~~ ~~t on, ~rcentages we b- on data reported by those State and territorial health agencies hat co~d provide ~~ the

numerator and the denominator for their percentages. As not all agencies reported all the relevant data, not all are represented in these numbers.

SOURCES: Public Health Foundation, Special Report: State Health Agency Lead Poisoning Prevention Activities, 1983 (Washington, DC:

1986); U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry,

The Nature and Extent of Lead Poisoning in Chila?en in the United States: A Report to Congress (Washington, DC: 1988).

acidity), and EPA argues that the least expensive Water Act listed 83 contaminants, including lead,

method for reducing lead in drinking water is central

corrosion control treatment (84,171).

Under the Safe Drinking Water Act (1974), EPA

must establish maximum contaminant level goals

(MCLGs) and national primary drinking water

regulations (NPDWRs) for contaminants that may

have an adverse effect on the health of the population

drinking the water. While MCLGs are nonenforceable health goals, NPDWRs are enforceable standards. NPDWRs include maximum contaminant levels (MCLs) or treatment technique requirements, or

both. In 1986, amendments to the Safe Drinking

for which EPA had to develop MCLGs and

NPDWRS.

5

In 1988, EPA proposed an MCLG of zero for lead.

The proposed NPDWRs establish an MCL of 0.005

milligram of lead per liter of water (mg/l) for water

entering the distribution system (to replace the

current MCL of 0.05 mg/l); require corrosion control

treatment techniques if specified levels of lead,

copper, and water acidity are not met (the Agency

issued regulations for copper and lead simultaneously); and require public education if other meas5The 1986 ~en~ents to the Stie Dritiing Water Act also banned the use of lead solder or flux and lead-bearing pipes and fittings. This ban was

effective in 1986, and States were required to implement and enforce it as of June 1988. EPA is currently developing a program to withhold Federal

grants for programs to improve the quality of drinking water from States that fail to enforce the ban (53 FR 31516).
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 279

l——

Illustrated by: Ray Driver

ures fail.6 Some argue that the proposed regulations

are not strict enough and claim that EPA has both the

authority and the responsibility to set MCLs at the

tap. 7 Water suppliers, on the other hand, find the

corrosion control program to be unwarranted and

expensive.

The debate over regulation of lead in drinking

water focuses on whether the public water supplier

.

or the consumer is ultimately responsible for preventing high levels. Public water systems control the

quality of the water they distribute, including the

parameters that determine how much lead will leach

from plumbing into the water. On the other hand, the

water passes through a distribution system that is

owned partially by the water supplier and partially

by the consumer. If the regulation is enforced at the

tap, the water supplier must assume responsibility

for some lead contributions from the consumer’s

plumbing. If lead levels are enforced at the beginning of the distribution system, the consumer must

assume responsibility for some of the water supplier’s plumbing or the corrosivity of the water

supplied by the water system, or both. Undercurrent

EPA regulations, the supplier is responsible both for

lead levels in the water in the distribution system and

for the water quality at the tap.

Lead in drinking water remains a serious

problem in some water supplies, especially in

schools. The efficacy of the regulations promulgated by EPA will be crucial in determining how

serious a problem it remains. (Another widely

discussed issue concerns lead in water coolerssee box 10-D.)

Lead in Incinerator Ash

The United States produces approximately 160

million tons of solid waste every year. Currently,

approximately 83 percent of this waste is put in

landfills, 11 percent is recycled, and 6 percent is

incinerated (86). As landfills are rapidly being filled,

there is much discussion concerning other methods

of disposing of this waste. EPA estimates there will

be a sixfold increase in the capacity for waste

incineration in the United States over the next 15

years (76).

Incineration has both advantages and disadvantages. Its major advantage is that it reduces the

volume of waste by 75 to 80 percent. Furthermore,

it can be used to generate electricity and can be

linked with recycling methods to remove such solids

as iron, steel, glass, and paper from the waste stream

GUnder hew pmPd relations, all water leaving the treatment plant would have to meet the O.(N5 m#l st~dtid. TO ref@ate how much led

the water can pick up as it travels from the distribution point to the consumer, EPA proposed that targeted samples be taken from consumers’ taps. If

the average lead level is less than orqual to 0.01 mg/1, the average copper level less than or equal to 1.3 mg/1, and the pH greater than or equal to 8.0

in at least 95 percent of the samples, then the supplier is not required to take any further action. If any of these three standards is not met, the water supplier

would be required to implement or improve its corrosion control. If the lead levels are above 0.02 m~, the supplier would have to launch a public

education program to encourage consumers to reduce their exposures to lead in drinking water (53 F’R 31516).

T~ere is ~me concern that EP”S measures do not adequately treat the problem, since: 1) the NPDWR of 0.005 mg/1 does not reflect the MCLG

of O mg/l; 2) the tap standard is not enforceable; and 3) limited sampling at the tap will necessarily overlook some households with high lead levels (1 16).
280 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Box 10-D-Lead in Water Coolers

Another source of lead in drinking water, water coolers, has received considerable attention in the press and

is the subject of legislation passed in the 100th” Congress. Some water coolers may contain lead-lined tanks or lead

solder that comes into contact with the water. Data solicited by Congress from manufacturers reveal that close to

1 million water coolers currently in use contain lead (U.S. Congress, Committee on Energy and Commerce, 1988).

These water coolers are of special concern because they are frequently used in schools.

The Lead Poisoning Prevention Act of 1988 addresses this situation through the following provisions: 1)

recalling all water coolers with lead-lined tanks; 2) banning the manufacture or sale of water coolers that contain

lead; 3) setting up a Federal program to assist schools in evaluating and responding to lead contamination problems;

and 4) making funds available for the initiation and expansion of lead poisoning prevention programs (for all sources

of lead poisoning). This last provision is designed to expand on Federal funds for lead screening from the Maternal

and Child Health Services Block Grants. The legislation also requires that the Environmental Protection Agency

publish a list of water coolers that are not lead-free within 100 days of enactment (U.S. Congress, Committee on

Energy and Commerce, 1988). The Agency released a proposed list in April 1989. The original draft of the

legislation contained a section that set a Safe Drinking Water Act maximum contaminant level at the tap, but this

section was eventually deleted because of political pressure (’‘House Staffers, ’ 1988).

SOURCES: “House Staffers Scrap Lead Standard to Speed Drinking Water Bill’s Passage,” inside EPA 9:6, 1988; U.S. Congress, Committee

on Energy and Commerce, Subcommittee on Health and the Environment, Lead Contamination (Washington, DC: U.S. Government

Printing Office, 1988).

(76). However, byproducts of incineration may have Although the amount of human exposure to

adverse effects on the environment and on human

health. Residue remaining from incineration (bottom ash), particles removed from the air after

combustion (fly ash), and airborne emissions (stack

emissions and fugitive emissions) may contain high

concentrations of toxic substances, including lead

and other toxic heavy metals (76). Compared to

landfills, stack and fugitive emissions may greatly

increase exposure. On the other hand, when ash is

placed in landfills, the lead may leach out of the ash

into the groundwater, eventually ending up in lakes,

ponds, and rivers that may be used for recreation or

drinking water.

EPA has the authority to regulate incinerator ash

under the Resource Conservation and Recovery Act,

but there is some debate as to whether incinerator

ash should be considered a hazardous substance

because the municipal solid waste which is burned

to create it is not designated hazardous waste. Some

environmentalists call for testing all incinerator ash

and treating it as hazardous waste if the tests indicate

it has hazardous properties.

Congress has been interested in this issue as well.

Legislation has been introduced in the 10lst Congress to amend the Clean Air Act, directing EPA to

promulgate regulations that would control emissions

of specified air pollutants, including lead, from

municipal waste incineration sites and ensure safe

management of municipal incinerator ash.

lead from municipal waste incinerators is not

large now, the projected increase in the number

of such incinerators indicates that it could become a problem in the future.

Lead in Soil

EPA is conducting a project under the Comprehensive Environmental Response, Compensation,

and Liability Act (CERCLA, or Superfund) to

determine whether abatement of soil lead (by

removal or some form of isolation) will reduce

Photo credit: National Archives

Lead may be released into the air through the

weathering of structures painted with

lead-based paint.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 281

childhood exposure to lead (as determined by the

amount of lead measured on the hands and in the

blood of children). Studies are being conducted in

Boston, Cincinnati, and Baltimore. The studies will

not focus on high-lead areas, such as areas near lead

smelters, or on children who need clinical attention.

Instead, the focus is on intermediate lead levels,

which are more typical urban exposures (42).

Summary and Conclusions

Public health measures have achieved a substantial decrease in human exposure to lead in recent

years; lead poisoning, however, remains a significant problem, especially in children. As tests become more sensitive, studies indicate that neurobehavioral dysfunction is associated with lower blood

lead levels than previously believed. The precise

level of exposure which causes impairment is

controversial: there may be no threshold level for

adverse effects, in which case the more sophisticated

our ability to detect impairments from lead poisoning becomes, the lower the levels at which impairments may be found. Since 10 to 15 ug/dl is the limit

most recently proposed as a maximum blood lead

level and the medical treatment techniques now

available are not able to reduce blood lead levels

below approximately 20 ug/dl, prevention is crucial.

Since lead poisoning was clearly identified as a

public health problem, it has received a great deal of

attention from Congress and a number of Federal

agencies. EPA’s reduction of lead in gasoline has

greatly reduced the amount of lead in the air; FDA

and the food industry have together reduced the

amount of lead in food; and EPA has recently

implemented a regulatory program to control the

amount of lead in water. OSHA regulations have

reduced lead exposure in most large lead-using

industries. Federal and State programs have begun to

remove lead paint from older housing. The regulatory framework that now exists, if properly enforced,

could continue to reduce many sources of exposure

to lead.

Despite these areas of success, progress remains

to be made. Not everyone is satisfied with the steps

that have been taken. Some argue that the existing

regulations fail to treat the problem of lead in

drinking water adequately. Some feel the OSHA

regulations for lead exposure in the workplace are

not properly enforced and have too many exceptions. Also, there are no Federal programs to remove

lead-based paint in old houses or to establish

mandatory, centralized reporting of lead poisoning.

Many argue for stronger measures to prevent lead

toxicity. Prevention might be improved by a general

screening program for all children and by adopting

alternatives to incineration of waste, thus avoiding

increased exposure to lead in the air. Federal

programs to improve conditions in the workplace

and remove lead-based paint from all houses could

be implemented. Lead content in water could be

monitored strictly, and if need be, regulations could

be revised. Public education programs could be

introduced in high-risk areas near industrial or

waste-disposal sites. Federal money could be designated for specific lead poisoning prevention programs rather than including lead poisoning programs under the block grant umbrella.

Designing programs to remove lead from the

environment is most problematic when responsibility for removing contamination is not clear. A baby

poisoned by lead from canned milk is clearly the

food industry’s responsibility, therefore that industry was prompt and thorough in its response to the

lead poisoning problem. In many cases, however,

such as controlling lead in drinking water, responsibility for lead poisoning cannot be so clearly

ascertained: some public water suppliers question

whether they or consumers are responsible for

plumbing with lead pipes or lead solder. The Nation

must address difficult questions such as this if

continued progress is to be made in reducing public

exposure to lead.

EXPOSURE TO NEUROTOXIC

PESTICIDES IN AGRICULTURE

The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) of 1947 defines a pesticide as:

. . . any substance or mixture of substances intended

for preventing, destroying, repelling or mitigating

any insects, rodents, nematodes, fungi, or weeds or

any other form of life declared to be pests. . . and any

substance or mixture of substances intended for use

as a plant regulator,8 defoliant or dessicant.

8AlW (daminozide), for example, is called a pesticide for regulatory purposes, even though it dws not kill Psts. It is u~ as a gro~ ~@at~ b

promote a uniform red color in apples and to prolong shelf-life.
282 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Human exposure to pesticides can occur in a number

of ways—through contaminated drinking water,

through eating foods containing pesticide residues

(see box 10-E), through pesticides used in the yard,

home, and office, and through exposure in various

occupational and agricultural settings. Besides field

workers and pesticide applicators, those at risk in

agricultural settings include nursery, greenhouse,

forestry, and lawn care workers. Although pesticides

are a major health concern in the home and for

exterminators, highway workers, grain elevator

operators, and pesticide manufacturing and formulating employees, this section focuses on pesticide

exposure in the agricultural setting.

Approximately 1 billion pounds of pesticides are

used annually in agriculture in the United States, and

approximately 4 billion pounds are used annually

worldwide (102,174). Approximately $7 billion is

spent annually on pesticides in the United States.

Agriculture accounts for more than two-thirds of the

expenditures and approximately three-fourths of the

quantity used (174).

Agricultural workers who may be exposed to

pesticides include pesticide handlers (handling is

defined as mixing, loading, applying, flagging,9 and

equipment cleaning, repairing, and disposal), who

work with concentrated forms of pesticides; workers

performing hand labor in fields treated with pestiBox 10-E—Pesticides in Food

A report released in February 1989 by the Natural Resources Defense Council (NRDC), Intolerable Risk:

Pesticides in Our Children’s Food, has spurred considerable debate about the risks to humans, particularly children,

of pesticide residues in food. The report analyzed the extent of children’s exposure and attempted to determine the

potential hazards, focusing on increased risk of cancer and neurobehavioral damage. Data analyzed in the study were

obtained from the Environmental Protection Agency (EPA), the Food and Drug Administration, and the Department

of Agriculture.

After examining 23 pesticides known to have adverse health effects, the report concluded that preschoolers are

being exposed to hazardous levels of pesticides in fruits and vegetables. Twenty of these pesticides were found to

be neurotoxic. NRDC estimated that, from raw fruits and vegetables alone, at least 17 percent of the preschool

population, or 3 million children, are exposed to neurotoxic organophosphorous pesticides above levels the Federal

Government has described as safe.

NRDC criticized EPA for setting legal limits for pesticides in foods based on data collected 20 years ago and

on adult consumption of fruit and vegetables (children generally eat more produce than adults). A few of NRDC’s

primary recommendations follow:

 Congress must clarify EPA’s authority to change tolerance levels quickly.

. EPA must consider risks from ‘‘inert’ ingredients when regulating pesticides.

. Neurotoxicity testing should be required for all pesticides used on food.

. Congress should establish national definitions of “integrated pest management” and ‘‘organic” farming

technologies and develop a national certification process for goods grown using these technologies.

The report also includes recommendations to the public to reduce their exposure to pesticides.

EPA believes that the NRDC study overstates the risks from pesticides. The Agency stated that the benefits of

pesticide use outweigh the minimal risks and that EPA routinely takes into account the potentially higher exposure

of children. However, EPA officials do concede that the report raises valid questions. In a news release distributed

the same day as the NRDC study, the National Food Processors Association (NFPA) stated that pesticides are

virtually nonexistent in packaged foods and that, when detected, they are far below allowable levels. The NFPA

attributes this absence of residues mainly to the NFPA Pesticide Protective Screen Program, which spells out proper

pesticide control and monitoring practices for growers producing crops for the food industry.

SOURCES: (Mice of Technology Assessment, 1990; D. Duston, ‘‘Hotline Helps Growers Find Alternatives to Pesticides,’ Associated Press,

Mar. 22, 1989; D. Duston, “Eight in 10 Americans Prefer Chemical Free Food; Half Would Pay More,” Associated Press, Mar.

19, 1989; A.K. Naj, “Panel Assails Pesticide Study, Calls Food Safe,” Waff Street Journal, Apr. 6, 1989, sec. B, p. 3; Natural

Resources IXfense Council, intolerable Risk: Pesticides in Our Children’s Food (Washington, DC: 1989).

g~aggers are worke~ who direct crop dusters as they spray pesticides on fields.
Chapter 10-Case Studies: Exposure to Lad, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 283

cides (called farmworkers in this report); and workers in forests, nurseries, and greenhouses where

pesticides are used.

Extent of Exposure of Agricultural Workers

Agriculture is the primary source of income for an

estimated 4 to 5 million Americans, a significant

proportion of whom are children under the age of 16

(102). Many of these persons are exposed to higher

levels of pesticides than the general public. Approximately 2.7 million agricultural workers in the

United States are migrant and seasonal farmworkers

(164), and most seasonal work involves contact with

pesticide residues on crops such as cotton, vegetables, fruits, and nuts. Another group with significant

exposure to pesticides is pesticide handlers: EPA

estimates there are approximately 1.3 million certified pesticide applicators in the United States (176).

The number of agricultural workers performing

other pesticide-handling jobs is unknown.

The seventy of illnesses caused by pesticides

depends mostly on the dose absorbed and the

inherent toxicity of the product. Farmworkers are

exposed to pesticides primarily through residues on

foliage and crop surfaces, during aerial and hand

spraying, picking, packing, and sorting, but also

during hoeing and other field work. Forest, greenhouse, and nursery workers are exposed by similar

means. Mixers, loaders, and applicators may be

exposed to concentrated doses of pesticides in the

course of their daily work. Exposure usually occurs

by absorption through the skin, except in the case of

fumigants, which are inhaled. The amount of pesticide absorbed depends on the nature of the work

being performed, the clothing the worker is wearing,

the part of the body exposed, and the condition of the

worker’s skin (absorption increases with dermatitis,

cuts, and abrasions). Another relevant factor in

exposure is the rate at which pesticides degrade,

which varies with conditions such as heat and

moisture.

Estimates of the incidence of pesticide-related

health problems among workers vary. The annual

worldwide incidence of pesticide poisonings is

estimated to be between 500,000 (192) and 2.9

million (69), with a fatality rate of approximately

1 percent (102). In the United States, the prevalence of pesticide-related illness among farmworkers may be as high as 300,000 cases,l0 only

1 to 2 percent of which are thought to be reported

(31). The majority of reported cases of pesticiderelated illness involve exposure to neurotoxic pesticides (102,185), but the lack of reporting of most

cases complicates the assessment of any persisting

neurological and psychiatric problems. Some observers have estimated that in developed countries 4

to 9 percent of acutely poisoned individuals suffer

long-term neurological and psychiatric effects (46).

Special Risks to Children

Pesticides are thought to pose a considerably

higher risk to children than to adults (106,114).

Children can be exposed in a number of ways:

through prenatal maternal exposure, from being in

the fields where their parents work, contact with

pesticide residues on parents’ clothing, living in

migrant camps next to fields being treated, and

working in the fields themselves. Since they absorb

more pesticide per pound of body weight, children

may receive substantially higher doses of pesticides

than adults, and their immature development may

make them more susceptible to neurotoxic effects.

EPA and OSHA standards for worker safety are

based on adult exposure only.11 Many organ systems, including the nervous and reproductive systems, are still developing in infants and young

children. The effects of pesticides on these developing systems are largely unknown. There are important lessons to be drawn from the case of lead, which

has severe effects on the developing nervous system

and other organs of children.

Documented Adverse Effects on the

Nervous System

Although many pesticide-induced illnesses among

agricultural workers are thought to be severe and

acute, some evidence suggests that they are in fact

moderate and chronic (31). The full effects on

learning and perception and the emotional changes

associated with pesticide exposure are not known

because of the difficulty of testing these functions

and establishing a normal range (5). Failure to report

illness and the lack of comprehensive studies of the

agricultural worker population may result in underl~isfi~ is based on extrapolation of data collected in California. Tracking the prevalence of farmworkers’ pesticide-related il~ews is difflc~t

because of the lack of reporting requirements in most States and the limitations of those that do exist. These limitations are discussed later in this chapter,

llThe N~on~ Actiemy of Sciences recently initiated a 2-year study to assess the risk of exposure of children to p=ticides.

20-812 - 90 - 7 : CL 3
284 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Photo credit: U.S. Environmental Protection Agency

Current EPA regulations establish basic protective clothing

requirements for agricultural workers who enter treated

fields. However, recent studies document significant

pesticide exposures despite the use of typical

protective clothing.

estimation of the true extent of both short- and

long-term neurological effects. Organophosphorous

insecticides, which make up approximately 40

percent of all pesticides used in the United States, are

currently the most commonly reported source of

worker illness. The more persistent organochlorine

pesticides, used extensively in the 1940s through

1970s, are now either banned or restricted in the

United States and thus do not contribute as much to

worker illness. What is known about the effects on

worker health of a few commonly used classes of

pesticides is examined later in this chapter.

Short-Term Effects on the

Central Nervous System

Some cases of worker illness are mild and persist

for a few hours. In more severe cases, symptoms may

not peak until 4 to 8 hours after onset and may persist

from 1 to 6 days. Some recovery periods are longer

(90):

●

●

In a moderately severe poisoning of 24 field

workers, including children, exposed to residues of two pesticides, mevinphos (Phosdrin)

and phosphamidon (Dimecron), in California,

anxiety and other symptoms were reported after

70 days (98,184). In this case, farmworkers

were working in cauliflower fields prior to the

legal reentry interval.

There have been several documented poisonings of entire crews who entered fields after the

permissible reentry interval. In 1987,78 farmworkers in three different crews developed

moderate to severe pesticide poisoning from

contact with phosalone (Zolone), used in California vineyards, long after it was thought safe

to reenter. Because of its persistence and risk to

farmworkers, phosalone is no longer used on

grapes in California (23).

● In 1988, two crews were poisoned by a highly

toxic insecticide, methomyl, in California. In

the first case, 34 orange harvesters went into a

methomyl-treated orchard 1 day after application, and 17 developed symptoms of pesticide

poisoning that required hospital treatment. In

the second case, grape workers were hospitalized after exposure to methomyl. As a result of

these poisonings, the reentry interval for methomyl in California was increased from 2 to 14

days (23).

Long-Term Effects on the

Central Nervous System

The nature of long-term neurobehavioral effects

of exposure to organophosphorous insecticides is

unresolved and deserves further investigation. The

evidence supporting the existence of delayed, persistent, or latent effects in humans includes case

reports, epidemiological studies of agricultural workers with and without histories of acute poisoning,

and deaths resulting from neurobehavioral disease

among agricultural workers.

Case Studies—The pesticides parathion, mevinphos (Phosdrin), and malathion are frequently

reported as causing health problems. Case reports

and studies of acute poisonings of agricultural and

other workers indicate that 4 to 9 percent of the

acutely poisoned individuals experienced delayed or

persistent neurological and psychiatric effects (46).

These effects include agitation, insomnia, weakness,

nervousness, irritability, forgetfulness and confusion, and depression (56,64,65,1 55); persistent mental disturbances—reported as delirium, combativeness, hallucinations, or psychoses—are noted in

some cases of pesticide poisonings (62). Occupations most frequently mentioned in case reports

include mixers, loaders, applicators, pilots, flaggers,

nursery and greenhouse workers, pesticide manufacturing workers, agricultural and pest control operators, and inspectors. Farmworkers tend not to appear

in the reports, for reasons that are discussed later in

this chapter.
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace .285

Epidemiological Studies-Although few epidemiological studies of agricultural workers have been

done, approximately 500 subjects from various

cohorts have been subjected to standardized neurobehavioral assessments examining memory, reaction time, behavior, visual ability, and mood. Subjects tend to be young, mostly male, and employed

in agricultural occupations for unspecified periods.

In field studies, quantitative data on exposure are

lacking.

In general, this research demonstrates that pesticide poisoning can lead to poor performance on tests

involving intellectual functioning, academic skills,

abstraction, flexibility of thought, and motor skills;

memory disturbances and inability to focus attention; deficits in intelligence, reaction time, and

manual dexterity; and reduced perceptual speed.

Increased anxiety and emotional problems have also

been reported. Exposed groups included farmers

without symptoms (73), industrial workers with

accidental exposures (97), pest control workers (90),

and a wide variety of agricultural workers tested an

average of 9 years after an acute poisoning was

diagnosed by a physician (140).

Neurobehavioral Disorders, Mortality, and Accidents—Analysis of occupation and causes of death

reported on death certificates suggests that agricultural workers are at risk of dying from neurobehavioral disorders and accidents. Approximately twice

the expected mortality from behavioral disorders

(i.e., those resulting from altered perception or

judgment) has been reported among white male

farmworkers and orchard laborers from Washington

(99) and among California farmworkers (154).

Both of these studies and one of British Columbia

farmworkers (55) found disproportionate mortality

due to external causes, particularly motor vehicle

accidents. The precise role of pesticides, if any, in

the mortality patterns is unknown. Based on worker

reports of feeling “fuzzy” at the end of the work

day, researchers have speculated that farmworker

exposure to pesticides impairs judgment and coordination and may contribute to motor vehicle accidents (155). There are numerous case reports of near

misses and fatal workplace accidents involving farm

machinery and crop-dusting aircraft in which behavioral effects of pesticides are implicated (38,62,

135,136,149,191).

Suspected Adverse Effects and

Limitations of Existing Data

The occurrence of neurobehavioral disorders after

chronic low-level exposure in the absence of acute

poisoning has not been adequately studied. Neuropsychological assessments of occupational groups

have yielded inconsistent results, perhaps reflecting

differences among pesticides and differences in the

type and scope of tests used. Subtle neurobehavioral

effects have been observed most consistently in

young, asymptomatic male workers who have been

employed for a long time (19,194), who have been

previously diagnosed as having acute pesticide

poisoning, or who are recovering from an acute

exposure (38,73,140). Few studies have assessed the

duration of impairment. Field studies have not

provided sufficient data on exposure levels or

duration to understand dose-response relationships,

nor have most studies controlled for age, education,

or other potential confounding factors. Few studies

have examined exposed workers prospectively,

subgroups of women or aging workers, interactions between pesticides, or interactions between

pesticides and pharmacological agents (including

ethanol or common medications).

Federal Regulation

Most workers in the United States are protected

by the Occupational Safety and Health Act, which

affords them certain rights, including permissible

exposure limits, personal protective equipment and

clothing, access to medical and exposure records,

training about the risks of exposure, and protection

against employer retaliation. Pesticide handlers and

workers in forests, nurseries, and greenhouses are

covered under these regulations. OSHA requires that

field workers be provided with toilets, drinking

water, and water for hand washing; however, handling of pesticides is covered under FIFRA, which

is administered by EPA. Since 1983, manufacturing

workers have had the right to information on the

hazards of the chemicals with which they work

under OSHA’s Hazard Communication Right-toKnow Standard. Since 1988, other industrial workers have also had this right.

FIFRA was enacted in 1947 to protect farmers

from ineffective and dangerous pesticides by requiring that a pesticide be registered before it is

marketed. The legislation was amended extensively

in 1972 (Public Law 92-516), with new provisions
286 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

allowing for direct controls over the use of pesticides, classification of selected pesticides into a

restricted category, registration of manufacturing

plants, a national monitoring program for pesticide

residues, the inclusion of environmental effects in

the cost-benefit analysis of the pesticide regulation

process, and the required reregistration of older

pesticides to ensure that they meet new data

requirements (2).

Since FIFRA was amended in 1972, controversies

about its implementation and its ability to protect

farmers and farmworkers have received repeated

congressional attention. In 1988, after considerable

political debate, a compromise bill (dubbed “FIFRA

lite” because of its restricted scope) was passed by

Congress and signed by the President.

The new law requires EPA to review within the

next decade the 600 active pesticide ingredients and

to charge manufacturers for some of EPA’s costs

(under previous law, the government was responsible for virtually all of the cost). The bill also partially

repeals the indemnification provision that required

the government to pay manufacturers or users of

pesticides for existing stock whose registration was

canceled by the Agency. This provision was a major

obstacle to EPA’s cancellation or suspension of

some of the most toxic pesticides.12 Many issues,

however, were lost in the final bill, including

farmworker protection standards and specific requirements for EPA review and testing of pesticides.

Two efforts to strengthen Federal authority were

defeated: 1) synchronization of data requirements,

which would have prevented States from requiring

additional data before registering pesticides, and 2)

preemption of States from setting more stringent

tolerances for pesticide residues in food.

EPA promulgated regulations under FIFRA in

1974. Of particular interest here are those regulations dealing with the occupational safety and health

of agricultural workers (40 CFR 170 and 156). The

1974 regulations apply only to workers performing

hand labor in fields during or after pesticide application. Their main provisions are a prohibition against

spraying workers; specific reentry intervals (i.e., the

time that must elapse between application of a

pesticide and the return of workers to the treated

Photo credit: Douglas Watts/Christophar Brady

area) for 12 pesticides and a general reentry interval

for all other agricultural pesticides; a requirement

that protective clothing be worn by any worker who

has to reenter a treated area before the reentry

interval has expired; and a requirement for “appropriate and timely” warnings to workers when they

are expected to work in fields that have been or will

be treated with pesticides.

FIFRA has been criticized as inadequate to

protect workers and the public from pesticides

known to cause or suspected of causing serious

chronic effects, including cancer, reproductive problems, and neurological damage (178). EPA has set

reentry intervals for only 68 of more than 400 active

ingredients currently used to manufacture thousands

of agricultural pesticide products.

In addition, FIFRA requires a balancing of risks

and benefits to determine whether a hazardous

pesticide should be canceled or suspended. This

provision can delay or prevent EPA from regulating

pesticides that are potentially neurotoxic, depending

on whether the perceived benefits of its use outweigh the perceived risks. Risk-benefit analysis,

however, rarely includes the costs of ill health to

those exposed, including lost work time, hospital

care, and other medical care.

In 1983, EPA reviewed the regulations under

FIFRA and determined that they were inadequate to

protect workers occupationally exposed to pestil~~ordane was on~nally prop~ for cancellation in 1974 because of its adverse health effects. There is some fwlkg that the considerable Cmt

to EPA of indemnifying chlordane’s manufacturers and users may have influenced its decision not to cancel the registration. While agricultural uses of

chlordane were canceled in 1984, it was still used widely to kill termites until 1988. On Feb. 3, 1989, the U.S. Court of Appeals overturned an earlier

decision and permitted the sale of existing chlordane stocks (112).
Chapter 10--Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 287

cides. The Agency proposed new regulations in

1988. These regulations would cover workers in

forests, nurseries, and greenhouses; pesticide handlers; and workers performing hand labor in treated

fields. Some of the key items of the proposed

regulations follow:

●

●

●

●

●

●

General pesticide safety information must be

placed in a prominent location at each farm,

forest, nursery, and greenhouse during the

growing season. Workers who do not speak

English must be given a written warning in

their own language to obtain a translation of

this information. Training must be provided for

all persons who handle agricultural pesticides

and for all persons who enter treated areas

before the reentry interval has expired. Any

person who handles a pesticide must be provided, on request, all information from the

labeling of that pesticide.

All workers must be clearly and adequately

notified about pesticide application and relevant reentry intervals. The methods of notification will vary according to the site, but will

include a requirement that warning signs be

posted outside pesticide-treated areas with a

reentry interval of more than 48 hours.

All pesticide handlers and early reentry workers

must wear minimum personal protective equipment, as specified by pesticide labels. Determination of the appropriate equipment must take

into account the toxicity of the pesticide, the

handling technique, and the route and type of

exposure.

The minimum reentry interval will be “until

sprays have dried, dusts have settled, or vapors

have dispersed. ” Reentry intervals will be set

at 48 hours for organophosphorous and nmethyl carbamate insecticides in toxicity category I (most acutely toxic) and 24 hours for the

same pesticides in toxicity category II and all

other pesticides in toxicity category I.

Workers must be provided with water, soap,

and disposable towels after exposure to pesticides or pesticide residues. Information about

and transportation to nearby medical facilities

must be provided to workers in emergency

cases of pesticide poisoning or injury.

Commercial handlers who are exposed to

toxicity category I or II organophosphorous

insecticides for 3 consecutive days or any 6

days in a 21-day period must be monitored for

cholinesterase inhibition (177).

The proposed regulations have been criticized by

farmworkers’ and farmers’ groups, growers, and

pesticide users and producers. Critics argue that the

standards fail to address many needs, including

those for mandatory education of all farmworkers

concerning the neurotoxic and other health effects of

pesticides and safety training in the use of pesticides;

telling workers what pesticides they have been

exposed to; more protective reentry intervals; and

consideration of the additive and synergistic effects

of exposure to multiple pesticides. Critics also argue

that the proposed standard could increase farmworkers’ risks by permitting early reentry into treated

fields as long as workers are given protective

equipment.

Pesticide regulation and policy have historically

been made at the Federal level, yet the Office of

Pesticide Programs has consistently had one of the

smallest budgets of any EPA program. Resources for

the review of toxicological data, monitoring programs, and worker protection standards have been

limited. EPA currently provides no funds to State

agencies to conduct worker and public health

evaluations. Indeed, EPA officials have stated that

farmworker protection standards are not part of

current State enforcement grants under FIFRA

(105).

Areas of Particular Concern

Pesticide Registration-An important obstacle to

protecting farmworkers from neurotoxic pesticides

is the major gaps in data in many pesticide registration files. In 1984, the National Academy of

Sciences found that 67 percent of pesticides

studied had undergone no neurotoxicity testing

at all, and all of the neurotoxicity tests performed

were judged inadequate (108). The 1988 FIFRA

amendments gave EPA 9 years to complete its

pesticide registration review, but the battery of tests

currently required by EPA for pesticide registration

is geared toward detecting only the most obvious

neurotoxic effects. Only one type of test specifically

intended to detect nervous system impairments is

currently included in EPA’s pesticide assessment

guidelines, although new test guidelines are being

devised (see ch. 5). EPA was petitioned by a group

of consumer advocates and professional organizations to develop more extensive neurotoxicity test

guidelines (26).
288 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Another gap in protection is the lack of data on

effects of exposure to the so-called inert ingredients

in pesticides. These ingredients are used as carriers

of the active ingredient and do not appear on

pesticide labels because of their trade secret status. 13

They are inactive only to the extent that they are

thought to have no effect on the targeted pest. Hence,

they may be defined as inert yet be toxic to humans.

Of the 1,200 substances designated as inert, EPA

concludes that 55 are “toxicologically significant,” with another 65 structurally related to

substances known to be toxic. As of 1987, EPA did

not know the toxicity of some 800 inert ingredients

contained in pesticide products and regarded some

200 as generally safe (2); the Agency has since

incorporated inert ingredients into its ongoing review of the toxicity of pesticide ingredients.

FIFRA permits States to register for 5 to 8 years

pesticides needed to fill “special local needs” and

“crisis” situations. This may, under certain conditions, provide a substantial loophole in farmworker

protection, because it allows States to register

pesticides that have not met Federal testing requirements. There has been considerable criticism of this

practice.

Public attention was drawn to the issue of the

quality of data submitted for the registration of new

products by the discovery that one of the major

laboratories providing data to EPA had falsified

findings (31,143). In 1984, EPA’s internal review

process for evaluation of toxicological data was

criticized because of cases in which EPA reviewers

had incorporated information provided by manufacturers, apparently without any independent analysis.

In 1989, the Senate Environment and Public Works

committee initiated an oversight review of EPA’s

registration standards when it was learned that seven

of the eight members of EPA’s Science Advisory

Panel had apparently served as consultants to the

chemical industry (93,163). Thus, although EPA is

working to fill the data gaps in pesticide registration,

there remain questions about the impartiality of the

Agency’s regulation process.

Reentry 1ntervals-Unlike industrial workers,

farmworkers are not protected by specific maximum

levels of exposure to chemicals. Rather, they are

protected by reentry intervals, which restrict entry to

a field after pesticide application (40 CFR 1988 ed.

170). When they were first instituted in 1974,

specific reentry intervals were set only for the 12

chemicals with the highest observed toxicity; access

to all other active ingredients was restricted only

“until sprays have dried or dusts have settled. ”

Currently, specific reentry intervals have been set

for 68 active ingredients for which animal studies

demonstrated need. These 68 active ingredients are

used in about 90 percent (by volume) of pesticides

used in agriculture.

EPA claims that these reentry intervals protect

workers from the most toxic active ingredients used

in pesticides, but many observers are concerned that

the existing regulations do not adequately protect

farmworkers from neurotoxic pesticides. Farmworker protection advocates argue that the blanket

reentry interval which covers other pesticides improves farmworker safety somewhat, but more

adjustments need to be made for specific chemicals.

There have been episodes of worker poisoning and

even fatalities, particularly involving parathion, due

to inadequate reentry intervals (102,151). Toxic

residues can persist on foliage for weeks after

application and are known to persist longer in dry

climates (102). In California, most farmworker

poisonings from neurotoxic pesticides have occurred because of inadequate reentry intervals (185).

Several States have gone beyond EPA’s standard

and imposed longer reentry intervals based on local

conditions. California, for example, has set many

longer reentry intervals based on local conditions.

Texas has set a minimum 24-hour reentry for all

labor-intensive activities and has set longer reentry

intervals for a number of pesticides. New Jersey and

North Carolina require a 24-hour reentry interval for

all toxicity category I pesticides. Other States, too,

are revising their standards for reentry intervals.

The 1988 FIFRA amendments address some of

the shortcomings of piecemeal regulation. EPA is

currently drawing up proposals for stricter regulations, including longer reentry intervals for more

chemicals.

Protective Clothing-current EPA regulations

establish a basic protective clothing requirement for

workers who must enter treated fields before the

reentry interval has elapsed. Proposed EPA regulalspeaiciks ~not ~ncr~ly appli~ ~ a Pwe f-.me ~sticik (~so ~o~ ss tie active in@ient) is USU@ diluted by a solv~t or ~ inactive

solid (known as the inert ingredient).
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 289

tions would specify particular items to be worn,

depending on the task being performed, the circumstances of potential exposure, and the toxicity class

of the pesticide. However, some persons argue that

protective clothing and equipment are not adequate

to protect workers from harmful exposures. All too

frequently, employers do not provide protective

clothing and equipment or employees do not wear

them because of the excessive heat or their constraints on movement. Furthermore, recent studies

document the significant exposures workers may

receive even while using an approved respirator or

wearing typical protective clothing (48).

Lack of Pesticide Illness Reporting—Because

there are inadequate reporting mechanisms for acute

pesticide poisoning episodes and none for adverse

chronic effects among farmworkers in the United

States, the true rate of pesticide-related illness

among farmworkers may be underestimated. Even if

there were more centralized reporting, physicians

often have little training in occupational medicine

and thus may not recognize instances of pesticide

poisoning, and patients rarely have access to information about the pesticides to which they are

exposed. The lack of occupational histories and

accurate exposure data make proper diagnosis

and treatment difficult, if not impossible (103).

Furthermore, many ill workers never actually see a

doctor.

Farmworkers, especially migratory farmworkers,

whose immigration status and language barriers

make them especially vulnerable, are often not

represented by unions that influence standards of

health and safety in the workplace. On a State level,

most migrant farmworkers are excluded from workers’ compensation and unemployment insurance

(103). These exclusions from governmental protections prevent accurate estimates of pesticide illness,

lost work time, and medical costs. Persons who

advocate greater protection for farmworkers argue

that reporting requirements for national pesticide

illness and pesticide use would enable regulators to

target pesticides for regulatory action and better

assess their effects on health (134).

Monitoring Methods and Needs

There is no regular or required biological monitoring of agricultural workers exposed to pesticides in

the United States, except for periodic cholinesterase

tests for a small group of certified applicators

exposed to organophosphorous and carbamate insecticides on a regular basis in California. Proposed

EPA regulations would require monitoring of commercial pesticide handlers under certain circumstances. One direct means of assessing workers’

exposure to chemicals is by measuring the parent

substance or its metabolizes in the blood or urine;

however, this methodology is available for only a

limited number of pesticides (101). A promising

new field cholinesterase test has been developed and

used in Central America to identify workers suffering adverse effects (88); such a test might improve

worker awareness and enhance preventive medical

care (157) if workers can be induced to participate.

Monitoring programs are most effective when

they are based on an understanding of the nature of

farmworker exposure and the patterns of pesticide

use. More extensive monitoring would allow better

assessment of the extent of neurobehavioral problems caused by pesticide exposure among farmworkers; but conducting assessments of non-Englishspeaking, migratory populations may be difficult,

there may not be qualified medical personnel and

adequate equipment in rural areas, and the availability of monitoring devices may be a disincentive for

employers to prevent exposures in the first place.

State Regulation

Under current law, States may set more stringent

requirements for pesticide use than those provided in

Federal statutes. Several States, notably Texas,

California, and Washington, have initiated their own

worker and public programs to fill the gaps in

Federal regulations. Other States, for example, Iowa,

Minnesota New Jersey, New York, North Carolina,

and Wisconsin, have also taken steps to address

critical needs at the State level. Nine States have

laws requiring reporting systems for pesticide illness

or pesticide use, although most of them are unenforced; 16 other States have limited forms of data

collection; and 16 States have mandatory worker

compensation programs for agricultural workers (53

FR 25973).

California has an extensive and well-funded

pesticide registration and worker safety program that

exceeds EPA standards in addressing local conditions and patterns of pesticide use. As mentioned

earlier, California and Washington require reporting

of pesticide illness. California enacted the Birth

Defects Prevention Act of 1984 to require adequate

data on the 200 most widely used pesticides
290 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

suspected to be hazardous to humans. This law

prohibits the conditional registration of any new

pesticide without complete and valid data on health

effects. It also requires cancellation of any pesticide

containing an active ingredient that causes significant adverse effects on health.

Texas has adopted several farmworker protection

measures, including a 24-hour minimum reentry

interval for all pesticides used on labor-intensive

crops and certain prior notification and posting

provisions for workers and other persons adjacent to

treated fields. The most far-reaching development is

Texas’ Agricultural Hazard Communication (right-toknow) Law, the first such law in the Nation. It

requires agricultural employers to provide their

workers with information about the health risks of

pesticides and ways to minimize these risks. Employers are required to maintain a list of all

pesticides used and to make it accessible to workers,

their physicians, and other designated representatives. Farmworker training (in a form and language

understood by workers) is also guaranteed by this

law, through crop sheets and other written and

audiovisual materials (185,187).

New Approaches to Pest Control

The simplest way to protect farmworkers is to

reduce the overall use of pesticides, particularly the

most toxic ones. Movements to build sustainable

agricultural systems based on limited use of pesticides and fertilizers and on integrated pest management (IPM) systems have been initiated in several

States (see box 10-F). IPM relies on the coordination

of a number of control tactics. It attempts to

minimize the use of pesticides by making maximum

use of biological controls (e.g., natural predators and

parasites, disease-causing microorganisms, pheromones, and pest-resistant plants) and cultural controls (e.g., crop rotation and removal of crop residues

that shelter pests after harvest). Chemical controls

are used prudently, in conjunction with these other

methods (176). IPM practices can potentially

reduce pesticide use by as much as 50 percent

(161).

Research on IPM techniques is slowly spreading

to the more labor-intensive crops, but limited

Federal funding has delayed implementation of this

promising technology (187). The U.S. Department

of Agriculture is researching and developing sustainable agriculture strategies which include IPM

[14 U.S.C. 1463(C)]. In 1988, an estimated 8 percent

of crop land (27 million acres) was enrolled in some

30 State IPM programs (104).

Examples of Neurotoxic Pesticides

The following discussion introduces several of

the most common classes of pesticides known to

have neurotoxic effects.

Cholinesterase-Inhibiting Insecticides

Organophosphorous and carbamate insecticides,

the cholinesterase-inhibiting pesticides, represent a

large and important class of neurotoxic substances

(see table 10-3). Because of their widespread use and

high toxicity at acute exposures, they are the most

common cause of agricultural poisonings. Both

affect target insects and humans by inhibiting

acetylcholinesterase, an enzyme that breaks down

the neurotransmitter acetylcholine. Inhibiting this

enzyme creates a build-up of the transmitter, which

causes nervous system dysfunction.

Some cholinesterase-inhibiting pesticides cause

hyperactivity, neuromuscular paralysis, visual problems, breathing difficulty, abdominal pain, vomiting, diarrhea, restlessness, weakness, dizziness, and

possibly convulsions, coma or death (see table

10-4) (102,141,195). The extensive literature on

neurobehavioral toxicology in laboratory animals

exposed to pesticides has been reviewed by others

(14,29,34,41,71,189). The onset and duration of

symptoms in acute poisoning of workers depends on

the inherent toxicity of the insecticide, the dose, the

route of exposure, and preexisting health conditions.

Deaths have occurred in the past when workers were

not treated properly for their exposure. The inhibition of acetylcholinesterase by both organophosphorous insecticides and n-methyl carbamates is reversible; however, inhibition caused by n-methyl carbamates is generally considered more readily and

rapidly reversible than that caused by organophosphorous insecticides. For several of the organophosphorous insecticides, inhibition of acetylcholinesterase is so slowly reversible that an accumulation

of the effect can occur. Once exposure ceases,

however, full recovery usually results (102,106).

Some researchers have found delayed effects after

an episode of acute organophosphorous insecticide

poisoning: these include irritability, depression,

mood swings, anxiety, fatigue, lethargy, difficulty

concentrating, and short-term memory loss. These

symptoms may persist for weeks and months after
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 291

Box 10-F-Organic Farming and Alternatives to Chemical Pesticides

In response to growing consumer demand, the cost of chemical fertilizers and pesticides, and evidence of risk

to human health and the environment more farmers are turning to organic production. There is no single definition

of organic farming, but it generally requires some degree of abstinence from use of chemical fertilizers and

pesticides. In Texas, a farm is only certifiably organic if no pesticides have been used for 3 years and no chemical

fertilizers have been used for 2 years, but standards may vary from State to State. Where there is no State regulation

of organic farming, responsibility for setting standards usually falls to trade organizations, and there is frequent

controversy over how strictly to limit pesticide use.

Organic farming is gaining the attention of consumers, growers, and legislators. A California trade organization

reported that sales of organic produce in the United States doubled between 1983 and 1988, to $1 billion. A 1989

Harris poll reported that 84,2 percent of Americans would buy organic food if it were available, with 49 percent

of those willing to pay more for it (organic produce currently costs between 5 and 15 percent more than crops on

which pesticides are used). This public concern is reflected by distributors such as Sunkist Growers, Inc., and Dole

Foods Co., who are beginning to grow organic produce, and by supermarkets, which are beginning to issue written

policies requiring chemical-free produce from suppliers. State legislatures have been slower to address the pesticide

problem. To date, only a small percentage of States has any regulations for organic farming, and only a few of these

have certification programs.

Historically, organic farming has been more expensive because it is more labor-intensive, it is done on smaller

farms, and it results in smaller yields. The resulting products, however, tend to have a higher profit margin than the

more abundant crops grown on large farms where pesticides are used, As biological alternatives to pesticides are

researched and developed, costs of alternative farming might be reduced further.

Despite the promises organic farming offers for human health and the environment there is awareness of its

drawbacks even within the organic farming community. Complete rejection of chemical pesticides may reduce crop

yields. Even some environmentally aware and health-conscious farmers agree that chemical pesticides are

occasionally required.

Insufficient regulation of organic foods and farming methods is another drawback to organic farming. Apart

from the lack of precise definition of what organic farming is, public safety maybe threatened by lack of enforced

regulation of so-called organic produce, as well as a lack of testing at the supplier level to confirm that foods are

free of toxic substances. According to the Consumers Union, most grocery stores rely on their suppliers’ word that

produce is pesticide-free, yet when that organization tested apples bought in stores which claimed not to sell apples

treated with Alar, 55 percent of the apples contained it.

Rather than attempting to end all use of chemicals in agriculture, a solution may be found in integrated pest

management or other alternative agriculture systems, which use chemicals discriminately, if at all, in conjunction

with biological controls designed to fit local conditions. A National Research Council report released in September

1989 concludes that Federal farm subsidy programs encourage the use of chemical pesticides when nonchemical

alternatives may be as or more effective. The report recommends that at least $40 million be allocated annually for

research on alternative farming.

SOURCES: “Apple Grower Says Chemicals Sometimes Needed When All Else Fails,” Associated Press, Apr. 3, 1989; D. Duston, “Eight in

10 Americans Prefer Chemical Free Food; Half Would Pay More,” Associated Press, Mar. 19, 1989; “Entomologists Defend

Chemicals as Necessary in Food Production,” Associated Press, Mar. 25, 1989; “Farmers Hope to Replace Chemicals with

Biological Fertilizers,’ Associated Press, Apr. 3, 1989; P. Fikac, “Consumers Union: Ask Grocers About Reduce,” Associated

Press, Mar. 30, 1989; National Academy of Sciences, National Research Council, Alternative Agriculture (Washington, DC:

National Academy Press, 1989); S.L. Nazario, “Big Firms Get High on Organic Farming: Pesticide Scare Reinforces Shift in

Techniques,’ Wall Street Journal, Mar. 21, 1989; ‘‘Pesticide Scares Fuel Already Growing Organic Food Popularity,” Associated

Press, Apr. 10, 1989.

the initial exposure (17,82,83,137,147). Whether persistent alteration of brain function (36,56,59,97,

there are significant chronic effects of exposure to 141), while others have noted no long-term effects

low-level organophosphorous and n-methyl car- (10,13,29,153,155).

bamate insecticides (and, indeed, of exposure to Some organophosphorous insecticides can propesticides in general) is a matter currently under duce delayed and persistent neuropathy by damagdebate. A number of researchers have observed ing certain neurons in the spinal cord and peripheral
292 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table 10-3-Organophosphorous and Carbamate Insecticides

Highly toxica Moderately toxica

tetraethyl pyrophosphate (TEPP) - - -

dimefox (Hanane, Pestox XIV),

phorate (Thimet, Rampart, AASTAR)

disulfotonb (Disyston)

fensulfothion (Dasanit)

demetonb (Systox)

terbufos (Counter, Contraven)

mevinphos (Phosdrin, Duraphos)

ethyl parathion (E605, Parathion, Thiophos)

azinphos-methyl (Guthion, Gusathion)

fosthietan (Nem-A-Tak)

chlormephos (Dotan)

sulfotep (Thiotepp, Bladafum, Dithione)

carbophenothion (Trithion)

chlorthiophos (Celathion)

fonofos (Dyfonate, N-2790)

prothoate b (Fac)

fenamiphos (Nemacur)

phosfolanb (Cyolane, Cylan)

methyl parathion (E 601, Penncap-M)

schradan (OMPA)

mephosfolanb (Cytrolane)

chlorfenvinphos (Apachlor, Birlane)

coumaphos (Co-Ral, Asuntol)

phosphamidon (Dimecron)

methamidophos (Monitor)

dicrotophos (Bidrin)

monocrotophos (Azodrin)

methidathion (Supracide, Ultracide)

EPN

isofenphos (Amaze, Oftanol)

endothion

bomyl (Swat)

famphur (Famfos, Bo-Ana, Bash)

fenophosphon (trichloronate, Agritox)

nervous system. The resulting muscle weakness may

progress to paralysis. Onset is usually 2 to 4 weeks

after the acute exposure (27,70,150). The initial

symptoms of peripheral neuropathy are usually

cramps in the calves and numbness and tingling in

the feet. Increased weakness and flaccidity of the

legs follows, accompanied by varying amounts of

sensory disturbance. The arms may also be affected

(106). There is no specific treatment, and the rate and

extent of recovery vary considerably.

Organochlorine Insecticides

The organochlorine insecticides are chlorinated

hydrocarbon compounds that act as central nervous

system stimulants (see table 10-5). Organochlorines

accumulate in both the environment and the body. In

general, they are considered less acutely toxic than

organophosphorous and n-methyl carbamate insecticides, but they have a greater potential for chronic

toxicity. The prototype organochlorine, DDT, was

discovered in 1939 and was used extensively in

bromophos-ethyl (Nexagan)

Ieptophos (Phosvel)

dichlorvos (DDVP, Vapona)

ethoprop (Mocap)

demeton-S-methyl b (Duratox, Metasystox (i))

triazophos (Hostathion)

oxydemeton-methyl b (Metasystox-R)

quinalphos (Bayrusil)

ethion (Ethanox)

chlorpyrifos (Dursban, Lorsban, Brodan)

edifenphos

oxydeprofos b (Metasystox-S)

sulprofos (Bolstar, Helothion)

isoxathion (E-48, Karphos)

propetamphos (Safrotin)

phosalone (Zolone)

thiometon (Ekatin)

heptenophos (Hostaquick)

crotoxyphos (Ciodrin, Cypona)

phosmet (Imidan, Prolate)

trichlorfon (Dylox, Dipterex, Proxol, Neguvon)

cythioate (Proban, Cyflee)

phencapton (G 28029)

pirimiphos-ethyl (Primicid)

DEF (De-Green, E-Z-Off D)

methyl trithion

dimethoate (Cygon, DeFend)

fenthion (mercaptophos, Entex, Baytex, Tiguvon)

dichlofenthion (VC-13 Nemacide)

bensulide (Betasan, Prefar)

EPBP (S-Seven)

diazinon (Spectracide)

profenofos (Curacron)

formothion (Anthio)

pyrazophos (Afugan, Curamil)

agriculture and against mosquitoes and other insects

that transmit human disease before it was banned

from most uses in the United States in 1972.

From 1940 through the 1970s, a number of other

organochlorine compounds, such as aldrin, dieldrin,

toxaphene, mirex, endrin, lindane, heptachlor, and

chlordane, were widely used as insecticides. Following recognition of their accumulation in the environment and in human and animal tissues, and observation of some adverse effects on wildlife, most have

been banned or severely restricted in use. For

example, chlordane, introduced in 1947 and since

then one of the most widely used of this family, was

originally targeted by EPA for restricted use in 1974.

It was banned for most uses except termite control in

1978 (102). A decade later, EPA banned almost all

uses of chlordane.

The organochlorines are easily absorbed by inhalation or ingestion and may also be absorbed through

the skin. They are generally distributed to fatty
Chapter 10-ase Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 293

Table 10-3-Organophosphorous and Carbamate Insecticides-Continued

Highly toxica Moderately toxica

dialifor (Torak) naled (Dibrom)

cyanofenphos (Surecide) phenthoate (dimephenthoate, Phenthoate)

dioxathion (Delnav) IBP (Kitazin)

mipafox (Isopestox, Pestox XV) cyanophos (Cyanox)

crufomate (Ruelene)

fenitrothion (Accothion, Agrothion, Sumithion)

pyridaphenthion (Ofunack)

acephate (Orthene)

malathion (Cythion)

ronnel (fenchlorphos, Korlan)

etrimfos (Ekamet)

phoxim (Baythion)

merphos (Fo!ex, Easy off-D)

pirimiphos-methyl (Actellic)

iodofenphos (Nuvanol-N)

chlorphoxim (Baythion-C)

propyl thiopyrophosphate (Aspen)

bromophos(Nexion)

tetrachlorvinphos (Gardona, Appex, Stirofos)

temephos (Abate, Abathion)

Carbamate Insecticide

aldicarbb (Temik)

oxamyl (Vydate L, DPX 1410)

methiocarb (Mesurol, Draza)

carbofuran (Furadan, Curaterr, Crisfuran)

isolan (Primin)

methomyl (Lannate, Nudrin, Lanox)

formetanate (Carzol)

aminocarb (Matacil)

cloethocarb (Lance)

bendiocarb (Ficam, Dycarb, Multamat, Niomil,

Tattoo, Turcam)

dioxacarb (Elocron, Famid)

promecarb (Carbamult)

bufencarb (metalkamate, Bux)

propoxur (aprocarb, Baygon)

trimethacarb (Landrin, Broot)

pirimicarb (Pirimor, Abel, Aficida, Aphox, Fernos,

Rapid)

dimetan (Dimethan)

carbaryl (Sevin, Dicarbam)

isoprocarb (Etrofolan, Ml PC)

Wompounds are listed in order of descending toxioity. “Highly toxic” organophosphates have listed oral LDW (median

lethal dose) values (rat) less than 50 mgkg; “moderately toxic” agents have LDW values in excess of 50 mgkg.

bThe~ in~ticides are systemic; they are taken up by the plant and translocated into foliage and sometimes intO the

fruit.

SOURCE: D.P. Morgan, Recognition and Management of Pesticide Poisoning, EPA pub. No. 540/9-S8-001

(Washington, DC: U.S. Government Printing Office, 19S9).

tissue, the liver, and the nervous system. Most are

metabolized by the liver and excreted in urine. For

some pesticides, accumulation in fat tissue occurs

during chronic exposure, so elimination is slow.

DDT, for example, is metabolized and excreted

slowly and can still be found in the fat of most people

exposed to it years after its use was terminated (62).

Acute intoxication from organochlorines can

produce nervous system excitability, apprehension,

dizziness, headache, disorientation, confusion, loss

of balance, weakness, muscle twitching, tremors,

convulsions, and coma. Uncontrolled seizures, respiratory problems, or both, may lead to brain or other

organ damage. Children may be particularly sensitive to brain and nerve damage from organochlorine

pesticides and may suffer from long-term behavioral

and learning disabilities as a result of exposure (41).

One of the most serious cases of severe poisoning

occurred in manufacturing workers handling chlordecone, commonly known as Kepone (see ch. 2).

These workers suffered tremors, disturbances in

vision, and difficulty in walking (156). As a result,

this pesticide’s registration was canceled by EPA in

1977 (42 FR 18855).

Fumigants

Fumigants-used to kill insects, insect eggs, and

microorganisms-are the most acutely toxic pesticides used in agriculture. Because they are gases,

fumigants are usually taken directly into the lungs,

where they readily enter the blood and are distributed throughout the body. Although inhalation is the

most serious source of exposure and can lead rapidly

to death, absorption of fumigants through the skin

can also be a significant hazard (103).
294 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table 10-4-Neurotoxic Effects of Acute Exposure

to High Levels of Organophosphorous or

Carbamate Insecticides

Function of nervous system

when stimulated by Effect of excessive stimulation

acetylcholine of the nervous system

Activate salivary, sweat,

and tear glands

Constrict bronchi

Contract pupil of eye

Control heart function

Increase spasms in

digestive tract

Increase spasms in

urinary tract

Activate skeletal

muscles

Alter brain function

Increased salivation, sweating,

watering of eyes

Tightness in chest, coughing

and wheezing, difficulty

breathing

Pinpoint pupils, blurring of

vision

Abnormal heart beat, change

in blood pressure

Stomach cramps, nausea, vomiting, diarrhea

Urinary frequency and incontinence

Twitching, restlessness, tremuIousness, impaired coordination, generalized muscle

weakness, paralysis, and

death or brain injury caused

by asphyxiation after muscle paralysis

Headache, giddiness, anxiety,

emotional instability, lethargy, confusion; eventually

severe central nervous system depression and coma

SOURCE: B.B. Young, Neurotoxicity of Pesticides,” Journal of Pesticide

Reform 6:8-11, 1986.

Table 10-5-Organochlorine Insecticides

Insecticide

endrin (Hexadrin)

aldrin (Aldrite, Drinox)

endosulfan (Thiodan)

dieldrin (Dieldrite)

toxaphene (Toxakil, Strobane-T)

Iindane (gamma BHC or HCH, Isotox)

hexachlorocydohexane (BHC)

DDT (chlorophenothane)

heptachlor (Heptagran)

chlordecone (Kepone)

terpene polychlorinates (Strobane)

chlordane (Chlordan)

dicofol (Kelthane)

mirex (Dechlorane)

methoxychlor (Marlate)

dienochlor (Pentac)

TDE (DDD, Rhothane)

ethylan (Perthane)

SOURCE: D.P. Morgan, Recognition and Management of Pesticide Poisoning, EPA pub. No. 540/9-88-001 (Washington, DC: U.S.

Government Printing Office, 1989).

Fumigants have caused severe illness and death in

human beings (11,63,81,132). Poisoning initially

causes headache, nausea, vomiting, and dizziness,

followed by drowsiness, fatigue, slurred speech, loss

of balance, and disorientation. In severe poisonings,

seizures, loss of consciousness, respiratory depression, and death may occur. Tremors and generalized

seizures may also occur, particularly from methyl

bromide poisoning.

Methyl bromide, one of the most widely used

pesticides in the United States, is a colorless gas at

room temperature. It has a faint, somewhat agreeable

odor, making it difficult to detect, even at toxic

levels (127). This pesticide has caused death and

severe neurotoxic effects in fumigators, applicators,

and structural pest control workers. Acute exposure

to methyl bromide can result in visual and speech

disturbances, delirium, and convulsions. Both acute

and chronic poisoning from methyl bromide may be

followed by prolonged, and in some cases permanent, brain damage marked by personality changes

and perception problems. Chronic exposure can result

in progressive peripheral neuropathy, with loss of

motor control, numbness, and weakness (4,63).

Chlorophenoxy Herbicides

Chlorophenoxy herbicides include 2,4-dichlorophenoxyacetic acid(2,4-D),2,4~-trichlomphenoxyacetic

acid (2,4,5-T), 2-methyl-4 -chlorophenoxyacetic acid

(MCPA), and 2,4,5 -trichlorophenoxypropionic acid

(Silvex). These herbicides were among the most

widely used until EPA suspended many of their uses

because of potential adverse effects on human health

(43 FR 17116). The chlorophenoxy herbicides

continue to be used widely in forestry and weed

control in agricultural and urban settings. Farmworkers can be exposed to these pesticides during

mixing and loading or by drift from nearby applications. Although these compounds are readily metabolized and excreted and are of relatively low

toxicity to mammals, they are often contaminated

with dioxins, which may be toxic themselves (102).

There are more than 75 different dioxin isomers, but

TCDD, a contaminant of 2,4,5-T, is believed to be

the most toxic (68).

Most current knowledge of the effects of TCDD

on humans comes from overexposures of workers

manufacturing 2,4,5-T or the compound from which

it is derived (61,66,68). Acute exposure to high

doses has led to peripheral neuropathy, sometimes

accompanied by difficulty in walking and coordinating the legs. Irritability, insomnia and hypersomnia,

lethargy, impotence, and psychiatric disturbances

have also been reported in cases of acute exposure

(102). Peripheral neuropathy resulting from dermal
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 295

absorption and death resulting from ingestion have

been reported for 2,4-D (102).

The most notorious chlorophenoxy herbicide is

the defoliant Agent Orange. Agent Orange consists

of a 1:1 mixture of 2,4,5-T and 2,4-D and was widely

used in Vietnam from 1962 to 1970. A number of

adverse effects on Vietnamese and on American

soldiers in Vietnam have been alleged. A recent

report indicates that the probability of exposure of

U.S. veterans was small (162), and whether Agent

Orange was the cause of the alleged health effects is

still unresolved (102).

Pyrethroids

Pyrethroids, a group of insecticides, are highly

toxic to insects but less toxic to mammals, which

metabolize and excrete them quickly. Pyrethroids

act by altering the flow of sodium ions through the

nerve cell membrane, resulting in repeated firing of

the nerve cell (106).

Because pyrethroids appear to be less acutely

toxic than other insecticide groups, their use is likely

to increase. In response to the observation of axonal

swelling in rats subsequent to pyrethroid ingestion,

EPA requires a special new pathological evaluation

as part of the 90-day rodent feeding study from all

companies attempting to register a pyrethroid (37).

Summary and Conclusions

Approximately 1 billion pounds of pesticides products, made up of 600 active pesticide ingredients, are

used annually in agriculture in the United States

(102). Many of these active pesticide ingredients

have never been tested for potential neurotoxic or

neurobehavioral effects, damage to the reproductive

system, or other effects on human health. Historically,

few pesticides have been banned or restricted by EPA.

Although everyone is exposed to low levels of

pesticides in food and water, an estimated 2.7

million migrant and seasonal farmworkers face

greater risk because they are regularly exposed to

higher levels of pesticides and because existing

protections do not always cover them adequately.

Pesticide applicators, loaders, and mixers, as well as

nursery, greenhouse, forestry, and lawn care workers, may be exposed to particularly high levels of

pesticides as well. Children, who constitute a

significant proportion of the agricultural work force,

are especially vulnerable because their nervous

systems are not fully developed. The majority of

pesticides used are organophosphorous and nmethyl carbamate insecticides, both of which are

neurotoxic. They can produce acute effects (ranging

from moderate symptoms to death) and perhaps

chronic effects as well, although the data are

inconclusive. Some organophosphorous insecticides

can also cause delayed damage to the peripheral

nervous system.

It is not possible to estimate accurately the extent

of illness among farmworkers because there is no

national pesticide illness reporting system or worker

monitoring program. Extrapolations by others from

available data suggest a prevalence of more than

300,000 pesticide-related illnesses among farmworkers, although only a small percentage of these

cases are reported (31). The total number of worker

deaths and the extent of chronic health problems

caused by exposure to pesticides are also unknown.

Limiting the use of neurotoxic pesticides would

be a straightforward way to control exposure.

Integrated pest management systems offer alternative approaches to pest control and minimize the use

of pesticides.

More research is needed to understand the neurotoxic effects of new and existing chemicals and to

protect agricultural workers from them. EPA’s

pesticide registration review should require information on pesticide neurotoxicity based on the most

current knowledge of dose-response relationships,

mechanisms of action, and structure-activity relationships. Premarket testing could include effects on

learning, memory, conditioned behavior, and emotional disorders, rather than being limited to motor

function. More information is needed on the longterm effects of pesticides on the fetus, on children,

and on the aged.

The need for epidemiological studies of the

effects of pesticides on agricultural workers is

critical. Reporting and monitoring procedures could

be established and enforced to provide more accurate information on the prevalence and incidence of

pesticide illness; furthermore, to facilitate reporting,

both physicians and workers could be better educated in the signs and symptoms of pesticide illness.

In the near term, several actions could be taken to

provide greater protection to agricultural workers.

Establishing more specific reentry intervals, which

take into account the chemical and neurotoxic

properties of certain chemicals, would be a positive
296 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

step forward. EPA might also adjust its risk-benefit

assessment criteria for pesticide registration to

include the costs of pesticide poisoning of workers.

Workers could be regularly monitored for exposure

to pesticides, provided with appropriate protective

clothing, trained in safe application for specific

circumstances, educated about the health effects of

exposure, and better informed about the chemicals

they use under right-to-know laws. Mandatory

recordkeeping on pesticide application could be

included in the latter to ensure that workers can

obtain information about previous exposures. EPA

has proposed decontamination facilities and emergency provisions for all workers, but more could be

done to prevent pesticide poisoning. Since the

chronic effects of pesticide poisoning remain unknown, efforts may be best directed toward prevention.

EXPOSURE TO ORGANIC

SOLVENTS IN THE WORKPLACE

According to the National Institute for Occupational Safety and Health (NIOSH), approximately

9.8 million workers are exposed to solvents every

day through inhalation or skin contact (166).

Acute exposure to organic solvents can affect an

individual’s manual dexterity, speed of response,

coordination, and balance; it can also produce

feelings of inebriation. Chronic exposure to some

organic solvents can result in fatigue, irritability,

loss of memory, sustained changes in personality or

mood, and decreased learning and concentration

abilities; in some cases, structural changes in the

nervous system are apparent.

Organic solvents are a group of simple organic

liquids that are volatile; that is, in the presence of air

they change from liquids to gases and therefore are

easily inhaled. Figure 10-6 illustrates the general

classes of organic solvents. Solvents usually serve

one of two general functions. They may be used in

separation processes to selectively dissolve one

material from a mixture, or they may act as a

processing aid, facilitating fabrication of a material

(usually a polymer) by reducing its viscosity (188).

They are components of a variety of products,

including paints, paint removers and varnishes;

adhesives, glues, coatings; decreasing and cleaning

agents; dyes and print ink; floor and shoe creams,

polishes, and waxes; agricultural products; pharmaceuticals; and fuels. In 1984, approximately 49

million tons of industrial organic solvents were

produced in the United States (167).

There are many occupations in which workers are

exposed to solvents. For example, painters may

come in contact with methyl alcohol, acetone,

methylene chloride, toluene, and complex mixtures

of petroleum products. Depending on the exposure

levels in air, house painters may experience a variety

of adverse effects, including fatigue, impaired memory, difficulty in breathing, slurred speech, nausea,

dizziness, difficulty in concentrating, and dermatitis.

Some researchers believe that painters may develop

a “psycho organic syndrome” from exposure to

chronic low levels of solvents (49,58). The syndrome is characterized by fatigue, difficulty concentrating, learning, and remembering, and personality

changes (32).

In order to protect workers, NIOSH recommends

that employers educate them about the materials to

which they are exposed, the potential health risks

involved, and work practices that will minimize

exposure to these substances (166). NIOSH also

recommends that employers assess the conditions

under which workers may be exposed to solvents,

develop monitoring programs to evaluate the extent

of exposure, establish medical surveillance for any

adverse health effects resulting from exposure, and

routinely examine the effectiveness of the control

methods being employed in order to reduce exposures to the permissible exposure limits (PELs)

mandated by OSHA. There are three basic methods

for minimizing worker exposure to organic solvents:

using effective engineering controls, isolating workers from the source of exposure, and using personal

protective equipment (8).

Organic solvents are of particular concern because most are toxic in different ways and to varying

degrees and many are also flammable. The increase

in the number of available organic solvents and the

development of new processes utilizing them present major occupational health challenges (8,166).

Some organic solvents are also subject to abuse by

inhalation. The extent of this abuse is much greater

than is generally recognized. The National Institute

on Drug Abuse reports that the lifetime incidence of

solvent abuse among seniors in high school (thus

excluding dropouts) is exceeded only by alcohol,

tobacco, marijuana, and stimulants (113). The abuse

of solvents by Hispanic and Native Americans is

widespread in some regions, exceeded only by
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 297

Figure 10-6-Classes of Organic Solvents

Allphatic hydrocarbons

(Acyclic)

Straight or branched chains of

carbon and hydrocarbons

Alcohols

Contain a single OH group

Halogenated hydrocarbons

A halogen atom has replaced

one or more hydrogen

atoms on the hydrocarbon

If

HHHHH H

111111

H—C—C—C—C—C—C— H

~~~~1~

c l

cl—c—c l

H—C–OH

J

cl

n- Hexane Carbon tetrachloride

Methyl alcohol

Cyclic hydrocarbons

(cycloparaffins, naphthenes)

Ring structure saturated and

unsaturated with hydrogen

Esters

Formed by interaction of an

organic acid with an alcohol

Ethers

Contain the C–O–C linkage

i’!’

7/0

‘–~–c\o–$–~–H

II

H H

Ethyl acetate Cyclohexane

Ethyl ether

Ketones

Contain the double bonded

carbonyl group, C = O, with 2

hydrocarbon groups on

the carbon

Nitrohydrocarbons

Contains an NO, group Glycols

Contain double OH groups

Ethyl nitrate

Aromatic hydrocarbons Ethylene glycol

Contain a 6-carbon ring

structure with one

hydrogen per carbon bound

by energy from several

resonant forms

Acetone

Aldehydes

Contain the double bonded carbonyl

group, C = O, with only

one hydrocarbon group on the carbon ‘PI

H–c/c”-ckc–H \

c= c

/

~~

Acetaldehyde

Benzene

SOURCE: Alliance of American Insurers, Handbook of Organic Industrial Solvents, 6th edition, 1987, pp. 1-20.
298 ● Neurotoxicity: Identfying and Controlling Poisons of the Nervous System

alcohol abuse (l). Such exposures greatly exceed

those encountered in the workplace and can be

associated with severe and irreversible toxicities.

Uptake, Distribution, and Elimination

of Solvents

Solvents may enter the body by inhalation, dermal

contact, or ingestion. The hazards associated with

dermal exposure and ingestion can be severe; in fact,

numerous fatalities have resulted from exposure to

methanol by these routes. However, because of the

volatility of these chemicals, a major route of

exposure is inhalation. Exposure to the skin is

another important route. For example, immersion of

hands in methylene chloride causes neurological

damage (159), and carbon disulfide produces shaking of the hands and loss of feeling (89).

The amount of the solvent entering the body

depends on such factors as route of exposure, the

concentration of the solvent in the air, the volubility

of the solvent in blood, and the amount of physical

work being performed at the time of exposure. A

sedentary worker on a factory floor will absorb less

solvent than a worker engaged in a vigorous physical

task because the latter will be inhaling more rapidly

and deeply (thereby moving more solvent to the site

of uptake in the lungs) and more blood will be

traveling through the lungs (carrying the solvent

throughout the body).

Some solvents tend to be distributed unequally

among the organs of the body. This is both because

the volubility of a particular solvent varies with

different tissues and because the blood supply to

tissues varies greatly. Thus, an organ like the brain,

with its high fat content and very rich blood supply,

achieves high levels of solvents quickly. Given a

constant concentration of solvent in the air, the

amount of solvent present in body tissues eventually

reaches a plateau in each tissue, but the time required

to achieve that plateau varies among tissues and

among individuals.

At the same time that the body is absorbing

solvents, it is working to eliminate them. If exposure

ceases or is reduced, the solvent begins to be

exhaled, or “blown off. ” Enzymes may change the

structure of the solvent, making it more water

soluble and enabling the kidneys to eliminate it. The

metabolism of solvents can be a two-edged sword,

however, since the metabolize may be more toxic

than the parent solvent. Mixtures of solvents or

Photo credit: United Automobile, Aerospace, and Agricultural Improvmnt

Winkers of America-UA’VPublic Relations Department

Respirators may be useful in minimizing exposure to

solvent vapors when engineering or work practice controls

are inadequate.

industrial grade solvents may be more toxic than

pure solvents, either because of toxic contaminants

or because of chemical interactions.

Neurological and Behavioral Effects

All solvents are soluble in fat and will at some

level of exposure produce effects on the central

nervous system (35). For a wide variety of drugs and

chemicals, the more soluble the chemical is in brain

membranes, the more potent it is and the longer it

acts.

Interest in the effects of solvents on the central

nervous system dates back to the early search for

anesthetics, when many agents were examined.

Short-term exposures at low toxicity may produce

mucous membrane irritation, tearing, nasal irrita-
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace .299

tion, headache, and nausea (35). With repeated

inhalation of high levels of solvents, a state of severe

narcosis may be produced; at lower levels, the

effects resemble those of alcohol. There may be

initial euphoria, loquaciousness, and excitement,

followed by confusion, dizziness, headache, motor

incoordination, ataxia, unconsciousness, and death.

These so-called nonspecific narcotic effects of

solvents are the major reason they are regulated in

the workplace; they can impair work performance

and the ability to avoid hazards (35).

Toxicity studies and health problems in the

workplace have revealed other effects that are

specific to individual solvents or classes of solvents.

For example, neuropathies may result from chronic

exposure to hexane, methyl-n-butyl ketone, and

related solvents. This disorder (sometimes referred

to as hexacarbon neuropathy) is characterized by

numbness in the hands and feet and may progress to

muscle weakness and lack of coordination (152).

Some solvents produce seizures and convulsions on

acute exposure, for example, such alkylcycloparaffins

as methylcyclopentane and methylcyclohexane (79,

80,129). Indeed, epileptic seizures in the workplace

may be mistakenly attributed to an undiagnosed

neurological defect of the worker rather than to a

chemical exposure.

Adverse effects on the inner ear may also be

caused by exposure to solvents. For example,

exposure to high levels of alkylbenzenes such as

toluene and xylene can damage the inner ear, leading

to high-frequency hearing loss (128,130,133). Dizziness and vertigo have been reported following acute

exposure to a variety of solvents. Exposure may also

adversely affect various visual functions and the

sense of smell (43,94,95).

Some solvents may cause emotional disorders.

Carbon disulfide can produce a raging mania and has

been associated with increased risk of suicide (92).

In 1902, Thomas Oliver described his visits to

India-rubber factories in London and Manchester,

noting “the extremely violent maniacal condition

into which some of the workers, both female and

male, are known to have been thrown. Some of them

have become the victims of acute insanity, and in

their frenzy have precipitated themselves from the

top rooms of the factory to the ground” (122).

Other disorders associated with exposure to

solvents include sleep disturbances, nightmares, and

insomnia (18,190). Trichloroethylene or its contaminants may damage facial nerves and produce facial

numbness (20). Severe brain injuries (chronic encephalopathies) have been documented following prolonged exposures to high levels of solvents, such as

during deliberate self-administration of solvents.

This has produced concern about the likelihood of

such effects occurring in the workplace. Prolonged

exposure to styrene may produce impairments in

perceptual speed and accuracy, memory, and cognitive performance (60).

The Solvent Syndrome: A Current Controversy

There is considerable evidence that toxic encephalopathy may be caused by high-level, prolonged,

and repeated exposure to some organic solvents

(158). Encephalopathy consists of a wasting of brain

matter, which leads to expansion of the fluid-filled

cavities in the brain. The syndrome is associated

with motor disorders and impaired mental function.

Several Scandinavian countries have identified a

new disease entity, a toxic encephalopathy following chronic solvent exposure, and compensate workers who develop it at the workplace (52). However,

the studies used to document the syndrome’s existence are the subject of controversy (45,58). A

multinational study of workers exposed to solvents

is being funded by a consortium of industrial groups

(158). In studies of this type, many variables may

obscure the detection of an effect or erroneously

suggest its existence. These include age, concurrent

exposure to other chemicals, excessive alcohol

intake, drug abuse, and socioeconomic status. In

fact, a recent reanalysis of test data failed to confirm

an earlier report of a ‘‘chronic painters’ syndrome”

with dementia (54). Many studies suffer from not

having extensive documentation of workplace exposure levels. It was having such information on

exposure that enabled investigators to do landmark

studies of carbon disulfide neurotoxicity. These

studies revealed differences in suicide rates among

workers in a rayon factory as a function of work

assignment and associated carbon disulfide exposure within the plant (92).

Although painters are exposed for long periods of

time to solvents, their exposure is moderate in

comparison to that of solvent abusers, who routinely

expose themselves to very high concentrations. The

injuries to the nervous system suffered by solvent

abusers are unequivocal and severe (53,78,1 38,142).

A scientific conference recommended directions

that human and animal research should take (9). The
300 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

lack of an animal model inhibits the normal regulatory process of hazard identification, risk assessment, and risk management. Just as prudent regulatory actions are undertaken to minimize the risk of

cancer in humans when tumors are observed in

laboratory animals, a nervous system injury or

behavioral disorder identified in laboratory animals

could be the basis for regulation to reduce the

likelihood of injury to the human nervous system. To

date, little effort has been devoted to developing an

animal model of the solvent syndrome.

Health Protection

There are several methods for controlling worker

exposure to organic solvents, including worker

isolation, use of engineering controls, and personal

protective equipment. Proper maintenance procedures and education programs are important ingredients of protection programs. OSHA regulations

require that workers be informed about the hazards

associated with the chemicals present in the

workplace (29 CFR 1987 ed. 1910.1200). NIOSH

recommends that employers establish a medical

surveillance program to evaluate both the acute and

chronic effects of exposure to organic solvents and

that workers undergo periodic medical examinations

(166). Both physicians and workers should be given

information regarding the adverse effects of exposure to organic solvents and an estimate of the

worker’s potential for exposure to the solvents. This

information should include the results of workplace

sampling and a description of protective devices that

the worker may be required to use (166).

Contaminant Controls, Worker Isolation, and

Personal Protective Equipment

The primary means of preventing contamination

is by applying appropriate engineering controls.

These may be necessary to eliminate the potential

for exposure and to prevent fires and explosions.

Achieving an adequate reduction of exposure to a

solvent depends on the construction and maintenance of the engineering control applied to the

system, the exposed liquid surface, and the temperature and vapor pressure of the solvent. Closed

system operations are the most effective method of

minimizing worker exposure. Closed system equipment can be used for manufacturing, storing, and

processing organic solvents. As an alternative,

workers can be isolated from the process by being

enclosed in a control booth.

Photo credit: United Automobile, Aerospace, and Agricultural Implement

Workers of America-UAWPublic Relations Department

Millions of workers come into contact with toxic substances

every day through inhalation or skin contact, Many of the

substances are known to be or are potentially neurotoxic.

When a closed system cannot be implemented,

exhaust fans can be used to direct vapors away from

workers and to prevent the contaminated air from

recirculating in the workplace (166). In addition,

personal protective equipment may be necessary

(see box 10-G).

Respirators may be needed to minimize exposure

when engineering or work practice controls are

inadequate for this purpose. Respirator may be

required for protection in certain situations such as

implementation of engineering controls, some shortduration maintenance procedures, and emergencies.

The use of respiratory protection requires that the

plant or company institute a respiratory protection

program (166). Direct contact of organic solvents

with the skin can be prevented by wearing solventresistant gloves, aprons, boots, or entire work suits.

Depending on the workplace and on the hazardous
Chapter 10-Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 301

Box 10-G-Engineering Controls v. Personal Protective Devices

The scientific and technical community has generally preferred engineering controls, that is, changes in

the design of the physical environment and equipment used in the workplace, to personal protective devices,

such as respirators, because:

● workers are erratic in their use of personal protective devices;

 such devices are cumbersome and, in the case of respirators, even the most conscientious worker may

have difficulty ensuring an effective seal between face and mask;

. personal protective devices themselves require maintenance, such as periodic replacement of air

filters; and

● it can be difficult to know when a personal protective device has failed.

The Occupational Safety and Health Act (OSH Act) was designed to decrease worker exposure to toxic

substances and to provide information to employees about remaining occupational health risks. Maintaining

low levels of toxic substances in the workplace through engineered controls has historically been given

priority over the use of personal protective devices, except in those cases where it is not feasible to use

engineering controls to reach the OSH Act exposure limit. Engineering controls are generally more expensive

than personal protective equipment, and small plants and businesses often cannot afford to make expensive

changes.

The mandate of the Act, however, has been to maintain a safe workplace, regardless of the size of the

business. If it is not feasible to institute engineering controls or to engineer down to what the Act determines

to be a safe level of exposure, then personal protective equipment is an acceptable choice. Recent changes

in the existing rule on methods of compliance (54 FR 23991) allow respiratory protection to be used in lieu

of administrative or engineering controls under the following circumstances (54 FR 23991):

1. during the time necessary to install or implement feasible engineering controls;

2. where feasible engineering controls result in only a negligible reduction in exposures;

3. during emergencies, recovery operations, unscheduled repairs, shutdowns, and field situations where

there are no utilities for implementing engineering controls;

4. operations requiring added protection where there is a failure of normal controls; and

5. entries into unknown atmospheres (e.g., entering vessels, tanks, or other confined spaces for

cleaning).

In addition to regulatory requirements, there are important ethical arguments about engineering controls

versus personal protective devices. What are the important values at stake? The health, well-being, and

autonomy of the worker are obviously important. (Autonomy refers to behaviors that reflect the capacity of

competent adult individuals to formulate life plans and make decisions freely, without coercive influences.)

The Act is designed to ensure a safe and healthful workplace by setting exposure levels and establishing

standards on behalf of the worker. One can argue that the option of using personal protective devices gives

the worker a choice in determining the extent of exposure to hazardous substances. Yet it is difficult to imagine

why a worker would prefer to use a cumbersome device like a respirator rather than have the workplace and

equipment engineered to be safer. In situations in which it is not feasible to engineer safe levels of exposure,

the use of personal protective devices may be the only option for working safely. On occasion, employees

may decide to work in an area that requires the use of personal protective equipment in order to gain a

particular type of work experience or to make more money. From an ethical standpoint however,

circumstances in which there exists some coercive element are objectionable.

On balance, the interests of the worker seem to be best served by the use of engineering controls that

lower levels of exposure to toxic substances for most workers most of the time. Some employers, however,

can and do continue to argue that the greatest good for the greatest number requires at least some reliance on

the use of personal protective devices.

SOURCE: Office of Technology Assessment, 1990.
302 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

properties of the substance, face shields and safety

goggles may be required.

OSHA Regulations

The principal reason for the enactment of the

Occupational Safety and Health Act of 1970 was to

protect workers from occupational safety and health

hazards. To accomplish this goal, OSHA sets

minimum standards for working conditions. Hazards not mentioned in the standards are covered by

the “general duty clause,” which requires each

employer to maintain a workplace ‘‘free from

recognized hazards. ” All work environments must

meet the regulations and standards set by the law (29

CFR 1987 ed. 1900-1910). OSHA has the authority

to conduct inspections, determine compliance with

the standards, and initiate enforcement actions

against employers who are not in compliance.

If an inspector documents a violation, it is

reported to the OSHA area director, who then

informs the employer of the citation or proposed

penalty. If the employer disagrees with the action, he

or she may contest it by informing the Department

of Labor within 15 working days of the citation.

When notification is received that an action is being

contested, the Occupational Safety and Health

Review Commission is notified, and this review

commission assigns the hearing to an administrative

law judge. Following the hearing, the judge may

issue an order to affirm, modify, or vacate the

citation or proposed penalty. The order is final after

30 days unless the commission reviews the decision.

If the employer decides not to contest the citation, he

or she must correct the situation that is in violation

of the standards. If the employer cannot do so within

the proposed abatement period, an extension maybe

requested. The law provides for fines of up to $1,000

for each violation and up to $10,000 if the violation

is willful or repeated (29 CFR 1987 ed. 1903).

The PEL Controversy

OSHA recently published a revised standard that

increased the protection of workers by implementing

new or revised PELs for 428 toxic substances,

including a number of organic solvents (53 FR

20960-20991). The final standard was published in

January 1989. According to the Department of

Labor, the new limits will reduce considerably the

risk of illness, including cancer, by using the force

of law to ensure that workers are not exposed at

levels above the new PELs. The final rule was

effective in March 1989, and the start-up date for

compliance with any combination of controls (e.g.,

personal protective equipment) was September 1989,

whereas compliance with engineering controls is

delayed until December 31, 1992, or in some cases

a year later.

The PELs are listed in the so-called Z tables in the

OSHA regulations (29 CFR 1910.1000). The recent

changes include revising the PELs, adding shortterm exposure limits (STELs) to complement the

8-hour time-weighted average (TWA) limits, and

where necessary designating skin or ceiling limits

for the substances (54 FR 2332-2403). According to

the Department of Labor:

OSHA has reviewed health, risk and feasibility

evidence for all 428 substances for which changes to

the PEL were considered. In each instance where a

revised or new PEL is adopted, OSHA has determined that the new limits substantially reduce a

significant risk of material impairment of health or

functional capacity among American workers, and

that the new limits are technologically and economically feasible. This determination has been based on

further review of the material discussed in the

Proposal, public comments and a detailed review of

the entire record for this rulemaking (54 FR 2334).

The new rule established lower exposure limits

for approximately 212 substances already regulated

by OSHA. PELs would be established for the first

time for another 164 substances. A large number of

these are established to prevent adverse effects on

the nervous system. According to the Department of

Labor:

. . . Benefits will accrue to approximately 4.5

million workers who are currently exposed in excess

of the PEL and are expected to include over 55,000

occupational illness cases, including almost 24,000

lost workdays annually. If not prevented, these

illnesses would eventually result in approximately

700 fatalities per year. . . . The annual cost is

approximately $150 per worker protected, and is

never more than a fraction of 1 percent of sales and

less than 2 percent of profits (usually substantially

less) except for a very few segments . . . (54 FR

2335).

The approach used to develop the regulations of

the new PELs has been controversial (54 FR

3272-2377). In evaluating the PELs, OSHA used the

threshold limit values (TLVs) published by the

American Conference of Governmental Industrial

Hygienists (ACGIH) published in 1988 and the
Chapter 10--Case Studies: Exposure to Lead, Pesticides in Agriculture, and Organic Solvents in the Workplace ● 303

recommended exposure limits (RELs) developed by

NIOSH as its starting point. The agency compared

the PELs to the Z tables and to the TLVs. If the two

differed, the PEL was evaluated for revision. The

agency first determined if the TLVs and RELs were

similar. If they were, or if there was no REL, then

OSHA studied the TLVs. If the TLV and REL

differed significantly, OSHA examined the scientific basis of each recommendation and determined

which was more appropriate. According to OSHA:

In its review, OSHA determined frost whether the

studies and analysis were valid and of reasonable

scientific quality. Second, it determined, based on

the studies, if the published documentation of the

REL or TLV would meet OSHA’s legal requirements for setting a PEL. Thus, OSHA reviewed the

studies to see if there was substantial evidence of

significant risk at the existing PEL or, if there was no

PEL, at exposures which might exist in the

workplace in the absence of any limit. Third, OSHA

reviewed the studies to determine if the new PEL

would lead to substantial reduction in significant

risk. If this was so, and if the new PEL was feasible,

OSHA proposed the new PEL (54 FR 2372).

The TLVs, RELs, and old and new PELs of some

selected solvents are listed in table 10-6.

The final standard has been controversial because

it represents a substantially different approach to

OSHA rule-making. Until this action, OSHA addressed toxic substances individually, a process that

produced standards for only 24 substances in 17

years. In this single rule-making, however, OSHA

established new exposure limits for 376 toxic

substances by adopting the TLVs published by

ACGIH. Industry and several unions expressed

concern that OSHA was delegating its regulatory

authority to a nongovernment organization and that

in some cases TLVs are not based on recent studies

(25,139). The extent of corporate influence on TLVs

has also been the subject of debate (25). Some

unions contended that ACGIH is dominated by

industry and that OSHA’s action subverts the

activities of NIOSH (139).

NIOSH offers RELs for chemicals following

careful review of available data and bases its

recommendations solely on the chemical’s effects

on health. However, OSHA, by law, cannot enforce

a standard with a recommended exposure limit

(REL) that is not technologically or economically

feasible. These constraints often prevent OSHA

from lowering a limit on the basis of health

Table 10-6-Representative Exposure Limits

to Solvents

Measure (ppm)

Solvent R EL

a T LVb Old PELC New PEL

Toluene ., . . . . . . . . . . 100 100 200

Xylene . . . . . . . . . . . . . . 100 100 100

Cresol . . . . . . . . . . . . . . 2.3 5d 5d

Acetone . . . . . . . . . . . . 250 750 1,000

Styrene . . . . . . . . . . . . . 50 50 100

Tetrachloroethylene . . . — 50 100

Methyl chloroform . . . . 200 350 350

Allyl chloride . . . . . . . . . 1 1 1

Furfuryl alcohol . . . . . . 50 10d

50

Ethylene dichloride , . . 1 10 50

Benzene . . . . . . . . . . . . 0.1 10

Carbon disulfide . . . . . . 1 10 d Z.

Trichloroethylene . . . . . 25 50 100

Chloroform . . . . . . . . . . — 10 50

100

100

4

750

50

25

350

1

10

1

10

4

50

2

aREI-s (recommended exposure hmits) are set by the National hIstltute for

Occupational Safety and Health.

%LVS (threshold limit values) are set by the American Conference of

Governmental Industrial Hygiemsts.

CPELS (permissible exposure limits) are set by the Occupational safety and

Health Administration.

dThe ACGIH designation “skin’’(s) refers to the potential contribution Of

exposure by the cutaneous route, including mucous membranes

and eyes.

SOURCES: 54 FR 2332-2983; 29 CFR 1987 ad. 1910.1000; R.B. Dick,

“Short Duration Exposures to Organic Solvents: The Relatlonshlp Between Neurobehavioral Test Results and Other indicators,” Neurotoxicology and Teratology 10:39-50, 1988; U.S.

Department of Health and Human Services, National Institute

for(lccupational Safety and HeaJth, ‘Organic Solvent NeurotoxicIty,” Current Intelligence Bulbtin 48:1-39, 1987.

considerations alone, that is, on NIOSH’s recommendation.

Public comments submitted to OSHA on the PEL

proposal were in broad agreement that the PELs

needed updating; however, many thought the project

was being undertaken hastily and that the public

interest would not be well served by such a major

procedural change. Some commentors recommended

that periodic updates be conducted on a more

frequent and less harried basis.

By using the ACGIH list of TLVs as the basis for

its selection, OSHA was able to save a great deal of

the time it would have taken to address these

chemicals through the usual regulatory procedures.

OSHA is constrained to conduct a number of

analyses by statute or executive order, including

extensive economic analyses. By its own admission,

OSHA states that it follows more extensive and

elaborate administrative procedures than other

health regulatory agencies:

. . . Clearly an improved approach to regulation is

needed to solve this problem in a reasonable time

period. OSHA’s traditional approach, which has
304 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

permitted on the average less than two major health

regulations per year, is not adequate to address the

backlog of at least 400 chemicals generally recognized as needing new or lower exposure limits.

OSHA has reviewed the law, Congressional intent,

its history, and the recommendations of experts . . .

[and has] concluded that this approach has a greater

health benefit and will prevent more deaths and

various deleterious health effects, than could be

achieved by allocating the same resources to comprehensive rulemaking for a small group of substances. . . (54 FR 2370).

The advisability of using the recommended exposure standards of a private organization instead of

NIOSH is likely to be a subject of continuing

controversy in the occupational health arena.

Summary and Conclusions

Organic solvents and mixtures of solvents with or

without other toxic substances are widely used in the

workplace. It is estimated that 9.8 million workers

come into contact with solvents every day through

inhalation or skin contact. Some solvents may

profoundly affect the nervous system. Acute exposure to solvents can affect an individual’s manual

dexterity, response speed, coordination, or balance.

Chronic exposure may lead to reduced function of

the peripheral nerves and such adverse neurobehavioral effects as fatigue, irritability, loss of memory,

sustained changes in personality or mood, and

decreased learning and concentration abilities.

In order to protect workers, OSHA requires that

employers inform and educate workers about the

potential health risks of the materials to which they

are exposed and adopt work practices that minimize

exposure to hazardous substances. NIOSH recommends that employers assess the conditions under

which workers may be exposed to solvents, develop

monitoring programs to evaluate the extent of

exposure, establish medical surveillance for any

adverse health effects, and routinely examine the

effectiveness of the control methods.

OSHA recently updated the permissible exposure

limits for 428 substances, many of them solvents.

The new ruling established lower PELs for 212

substances already regulated by the agency. PELs

were also established for the first time for another

168 substances, while existing limits for 25 substances were reaffirmed. This marks the first time in

17 years that a new set of exposure standards has

been established. The mechanism by which the new

PELs were set, however, is the subject of controversy.

For many companies, meeting the new standards

may require stricter engineering controls or more

frequent use of respirators and other personal

protective devices, or both. OSHA requires companies to educate workers about the hazards of the

substances to which they are exposed, to institute

control methods to prevent exposure, and to formulate plans or procedures to maintain compliance with

the new rulings.

There is insufficient information available to

regulatory agencies to distinguish dangerous solvents from ones that are not dangerous. Creative

approaches are needed to protect workers while

avoiding unnecessary and overly burdensome regulations. To fill this need, research programs in

academia, industry, and government will have to be

expanded significantly. If NIOSH is to play an

important future role in the development and analysis of information on safe exposure levels for

solvents, then additional resources will be required

and the Institute will have to make a commitment to

focus more attention on the neurological and behavioral effects of solvents. Improvement in the development of toxicity standards will require a substantially closer working relationship between OSHA

and NIOSH.

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Appendixes
Appendix A

The Food Additive Approval Process: A Case Study

The primary responsibility of the Food and Drug

Administration (FDA) is to ensure that the food and drugs

Americans consume and the medical devices and cosmetics they use are safe. In so doing, it ties not to deny or

delay unnecessarily Americans’ access to new or more

affordable foods, food additives, and therapeutics. To

illustrate how FDA’s review procedures work, this case

study discusses the approval process for aspartame, a food

additive for which questions about possible neurotoxic

effects were raised.

Aspartame, more commonly known as Nutrasweet, is

an artificial sweetener that is used by more than 100

million people (3). Users include persons with a medical

need to reduce sugar intake, such as diabetics and obese

individuals, as well as the general population. The

sweetener is composed of phenylalanine and aspartic

acid, two naturally occurring amino acids. Aspartame’s

extreme sweetness, 180 to 200 times that of sugar, was

discovered serendipitously in 1965 by two G.D. Searle

Corp. scientists, 8 years before submission of the first

food additive petition for the compound, After aspartame’s approval as an additive, the amount added to foods

increased substantially each year until 1985, when it

appeared to reach a plateau. Approximately 75 percent of

all the aspartame used in the United States is used in

carbonated diet beverages. An ongoing dietary survey of

aspartame ingestion undertaken by FDA indicates that 35

percent of the population (40 percent of adults) are regular

users of aspartame.

The Application Process

preapplication

The first step in the food additive approval process, an

informal meeting with FDA staff, is optional. The staff of

the Center for Food Safety and Applied Nutrition

(CFSAN) encourage applicants to discuss with them the

nature of the compound, available animal toxicity data

and uses for which approval is sought before formally

submitting a petition. In these meetings, potential problems can be identified, enabling applicants to begin any

necessary research quickly. Although both CFSAN and

the Center for Drugs and Biologics encourage these

meetings, they occur much more frequently with druglicensing applications, where problems are often more

evident. G.D. Searle did meet informally with CFSAN

staff before submitting its petition in February 1973.

Application

Searle petitioned FDA for permission to market

aspartame as an additive for certain foods (38 FR 5921).

Section 409 of the Federal Food, Drug, and Cosmetic Act

requires FDA to evaluate and act on petitions for approval

of food additives. Petitions are evaluated for toxicology,

chemistry, probable consumption levels, and potential

environmental and health impact. The applicable safety

standard is the “reasonable certainty of no harm, ” and the

burden of proof is on the petitioner. This standard is less

stringent than that for new drugs, which must be proven

‘‘safe and effective” in human studies.

The Act does not require specific tests to measure the

neurotoxic potential of any compound, and FDA generally assumes that adverse neurobehavioral effects will

become apparent during routine toxicological studies in

animals. However, if neurotoxic potential is suspected

because a substance is structurally similar to a known

neurotoxic substance or for any other reason, FDA may

specifically require a neurotoxicological evaluation. Normally, only animal toxicity (preclinical) studies are

required for foods and food additives. In contrast, new

drug approval requires that the results from three phases

of human studies be submitted for review.

Review

Following receipt of a petition, FDA personnel identify

the types of reviews appropriate for the particular

application. Reviews are frequently solicited from FDA

staff in other divisions with relevant expertise.

Every application is reviewed for potential toxicity.

The ancient Roman credo “moderation in all things” is

the first principle of toxicology. Virtually every food and

chemical in existence can be toxic in excessive quantities;

therefore, the first step is to assess the chemical to which

humans will be exposed and estimate the degree of

exposure. This is done by testing what happens when the

food additive is administered to laboratory-grown mammalian cell lines and animals and by analyzing the

chemistry of the compound, including identifying the

additive and products of its metabolic breakdown and

estimating the likely level of human exposure. These

studies identify the types of toxicity caused by the

compound and determine the amounts required to produce the toxic effects.

Initially, concerns were raised that aspartame might

lead to significantly higher concentrations of phenylalanine in the blood, which could lead to mental retardation in

children with the genetic disease phenylketonuria (PKU).

One in every 50 to 70 Americans carries the gene for

PKU, and every year 200 children are born with this

disease (1 of every 14,000 to 15,000 live births). PKU

results only if a child has two copies of the gene, one from

each parent. Fortunately, if PKU is identified at birth,

mental retardation can be prevented by a diet that is

restricted in phenylalanine. By law, all newborn babies in

the United States must be tested for PKU.

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316 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Approval

Toxicological studies on animal models were determined to be sufficient, and Searle’s petition to add

aspartame to some foods was approved on July 26, 1974

(39 FR 27317-27319). It was approved for consumer use

as a dry sugar substitute in granular and tablet form and

for industry use as an addition to cold breakfast cereals,

chewing gum, and dry bases for beverages, instant coffee

and tea, gelatins, puddings, fillings, and nondairy toppings.

The toxicity research on which approval was based

included 2-year feeding studies in rats and dogs as well as

a lifetime feeding study in rats first exposed to aspartame

as fetuses. Based on these studies, a no observed effect

level (NOEL), or the largest amount of the additive that

could be administered without evidence of toxicity in

animals, was established-namely, 2 grams of aspartame

per kilogram of body weight. The acceptable daily intake

for humans is somewhat arbitrarily set at 100 times less

than the NOEL for animals, thus the acceptable daily

intake was set at 50 milligrams of aspartame per kilogram

of body weight per day. For a 140-pound man, this is the

equivalent of approximately 17 (12-ounce) diet sodas or

100 packets of coffee sweetener per day (4). Estimates of

the probable maximum daily intake (1.3 to 1.7 grams)

were sufficiently close to the acceptable daily intake to

permit product approval. The petitioner submitted data

from clinical (human) studies which showed that the

approved levels of aspartame would not elevate concentrations of phenylalanine in the blood.

Appeal

Two parties objected to the approval of aspartame on

grounds of questionable safety and, as is their right,

requested a hearing before a judge. However, because of

the scientific controversy surrounding the approval process, FDA decided instead to convene a Public Board of

Inquiry (15). The board, consisting of three experts

appointed by the FDA Commissioner, would hear evidence and make a recommendation to the Commissioner,

who would then make the final decision. The board was

asked to consider whether aspartame, alone or in combination with glutamate, an amino acid found in monosodium

glutamate (MSG), could contribute to brain damage or

mental retardation. In addition, if marketing approval

were recommended, the board was to suggest appropriate

labeling and use restrictions. In response to an additional

objection, the board also evaluated evidence that aspartame ingestion resulted in cancer in rats. (The Delaney

clause prohibits approval of any food or additive that is

shown to be carcinogenic in animals following appropriate testing. If carcinogenic potential is demonstrated, the

clause mandates that no level of usage for humans can be

considered reasonably safe.)

Before the Public Board of Inquiry was convened,

Searle voluntarily suspended plans to market aspartame,

pending the resolution of an additional objection, a

question about the role of diketopiperazine (DKP, a

product of the metabolic breakdown of aspartame) in the

development of benign growths in the uterus of female

rats (5). (The eventual conclusion was that DKP did not

promote the development of these benign growths.) An

additional complication resulted from questions raised

about the reliability of the animal testing data submitted

by the petitioner. As a result, FDA stayed the approval,

pending additional review and audit of the animal studies

(40 FR 56907). The audit was performed both by the FDA

and an independent organization, Universities Associated

for Research and Education in Pathology. The process

took more than a year and resulted in the conclusion that

there were no discrepancies sufficiently significant to

compromise the results of the studies.

This conclusion cleared the way for convening the

Public Board of Inquiry in January 1980. The board was

composed of three distinguished scientists with expertise

in neurology, pathology, and nutrition. The role of this

board, like other FDA advisory committees, was merely

advisory; its conclusions were not binding on FDA, which

has statutory responsibility for approval decisions. Solicitation of outside expert opinion, a regular procedure in the

evaluation of drugs and biologics, occurs less often in

CFSAN. This is presumably because most of their

decisions are not controversial. In fact, this board was the

first external advisory panel convened by CFSAN.

The panel heard 3 days of testimony, including new

clinical data, from FDA staff, G.D. Searle staff, and

interested scientists. To the consternation of both FDA

and Searle staff, the board’s report was not delivered until

the fall of 1980. The new clinical data that were presented

allowed the board to establish an estimate of the

maximum daily intake of aspartame (34 milligrams) by an

average-sized man. This step was essential for an

evaluation of the toxic potential of aspartame use. The

data also demonstrated that the ingestion of very large

quantities of aspartame, equivalent to 12 liters of aspartamesweetened beverage in a single sitting, raised phenylalanine concentrations in the blood to only slightly above

normal [from the normal 6 to 12 micromole per deciliter

of blood (uM/dl) to 20 uM/dl]. Studies of people with

PKU have shown that only sustained, extremely elevated

concentrations (above 100 uM/dl, or 50 uM/dl for

pregnant women) are associated with developmental

brain damage. This damage can be prevented by restricting dietary phenylalanine. Therefore the board

concluded, and FDA concurred, that aspartame use

would not contribute to the type of brain damage

associated with sustained high levels of phenylalanine

in the blood. However, the board did recommend that

all aspartame-containing products carry informational
Appendix A-The Food Additive Approval Process: A Case Study .317

statements to alert people on phenylalanine-restricted

diets.

Additional animal and clinical studies demonstrated

that the products resulting from the metabolic breakdown

of aspartame, alone or in combination with other dietary

compounds, including glutamate, had no neurotoxic

potential. Clinical studies of possible toxicity are

almost never required for the approval of foods or

food additives. The aspartame application was unusual in that the sponsor voluntarily conducted clinical

studies and submitted the results to FDA during the

review process. Indeed, ‘‘extensive clinical safety studies

were conducted under the (original) food additive petition

with the awareness and encouragement of the FDA” in

various populations with metabolic disorders (17). The

resolution of questions of clinical toxicity requires that

clinical studies be carried out, so these would presumably

have been required by FDA even if they had not been

provided by the sponsor.

The board also found, however, some questions about

whether aspartame caused tumors in rats. This finding

was based on an incidence of brain tumors, equivalent in

the aspartame-treated and control rats, that was higher

than the expected incidence of spontaneous tumors. This

conclusion would result in automatic disapproval of the

food additive petition, as required by the Delaney clause.

FDA disputed the validity of the data and cited wide

variations in the literature regarding spontaneous incidence of brain tumors in rats, as well as the lack of a

statistically significant difference between the treated and

control groups.

Final Approval

A decision on the merits of the aspartame application

was further delayed to allow all interested parties to

prepare exceptions to the findings of the board. In early

March 1981, a number of FDA staff members were

selected to serve as advisors to the Commissioner for this

petition. This group’s deliberations were perhaps hurried

by Searle’s intention to file suit in Federal court against

the FDA for unreasonable delay (18). Searle’s major

concern was that its period of patent exclusivity was being

significantly diminished. In 1982, the Senate passed an

amendment to the Orphan Drug Act which extended the

patent life of products that had experienced unusual

regulatory delays in approval.

Following evaluation of additional studies on the

question of whether aspartame induces tumors in rats,

FDA issued its final ruling in July 1981, a year after the

meeting of the board and 8,5 years after the original filing

of the petition (see table A-1). The FDA report concluded

l!!

Illustrated by: Ray Driver

that there was no evidence that either aspartame or its

breakdown product, DKP, contributed to the development

of brain tumors in rats. This avoided the obligatory

invocation of the Delaney clause,l FDA concluded that

proper handling of foods containing aspartame would

prevent this breakdown and that the consumption of a

mishandled product, although possibly unsavory, would

be safe.

An additional concern addressed by FDA was that

methanol, a metabolize of aspartame, might cause adverse

effects. A review of the data revealed that aspartame

consumption resulted in the production of smaller amounts

1~ 1977, ~A, on tie bml~ of ~onv~c~g ~viknm of tie ~Uc~ogeNc po~nti~ of ~~~hfi in rats, ~d attempt~ to ret’n~e sa~~from the “getlerdly r~gIli~

as safe’ list. The resultant public outay caused Congress to .spedlcally exempt saccharin from the requirements of the Delaney clause, but at the same time required that

foods containing saccharin carry a prominent w arning label (8).
318 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Table A-l-Chronology of the Aspartame

Petition Process

Date Action

February 1973

July 1974

April 1975

December 1975

September 1976

December 1978

June 1979

January 1980

October 1980

January 1981

March 1981

JUIY 1981

Petition filed

Petition approved

Searle voluntarily suspends plans to market a

response to objections

FDA stay of approval to review and authenticate data

Data audit initiated

Data found acceptable

Notice of public hearing

Public Board of Inquiry covered

Board report represented to FDA

Deadline for comments on Board report

FDA advisors to Commissioner selected

Petition approved

SOURCE: Office of Technology Assessment, 1990.

of methanol than resulted from eating many fruits and

vegetables and that this toxic potential was therefore

negligible. A final concern was that aspartame, eaten

alone or in combination with carbohydrates, might alter

the activity of neurotransmitters. A study of infant

monkeys fed large quantities of aspartame or phenylalanine continually for 9 months showed that their development and behavior were normal and that there was no

evidence of seizures or irregularities in brain waves (1 1).

Therefore, aspartame was finally approved as a food

additive in July 1981 (46 FR 38285-38308; 40 FR 46394)

and for use in carbonated beverages in July 1983 (48 FR

31376-31382).

In the case of aspartame, approval was based on a

massive amount of data derived from animal and

human studies. However, the vast majority of food

additive petitions are approved on the basis of animal

studies alone. It has been repeatedly demonstrated

that the effects of active chemicals in animals are not

always predictive of their effects in humans.

FDA has supported limited research on the development of neurobehavioral testing methods to assess

potential neurotoxic effects of food additives. Indeed, a

1983 article written by FDA staff concludes with the

statement:

Within the general field of toxicological testing, the

FDA Bureau of Foods views the development of behavioral teratological or neurotoxicological testing as one of

the most important and urgent areas for future improvement. We await with keen interest the creation of testing

paradigms that can be recommended for routine measurement of the neurotoxic potential of food additive

substances (5).

Postmarketing Surveillance

Until recently, there was no formal postmarketing, or

Phase IV, procedure for evaluating any adverse reactions

to a newly approved food additive; however, aspartame’s

approval agreement of 1981 included the establishment of

a postmarketing survey. The survey had two components:

1) a poundage survey, in which sales of aspartame to food

and pharmaceutical industries were reported; and 2) a

dietary survey, in which actual ingestion of aspartame by

a sample population was reported. Partially in response to

the publicity surrounding the approval of aspartame, FDA

also established a passive system of review of consumer

complaints. In 1985, FDA asked the Centers for Disease

Control (CDC) to evaluate the complaints received. The

CDC concluded, on the basis of interviews conducted

with 517 complainants, that “although it may be that

certain individuals have an unusual sensitivity to the

product, these data do not provide evidence for the

existence of serious, widespread, adverse health consequences attendant to the use of aspartame” (2).

A more extensive postmarketing reporting system, the

Adverse Reaction Monitoring System, was implemented

in July 1985 for all food additives as part of FDA’s Plan

for Action, Phase I. This monitoring system was strengthened in December 1985 with the publication of a

“Request for Reports of Adverse Food Reactions” in the

FDA Drug Bulletin. This announcement requested that

physicians and other health professionals inform CFSAN

of any severe, well-documented reactions associated with

foods, food additives, or dietary practices. In the FDA

Plan for Action, Phase II, announced in 1987, this system

was expanded to incorporate data from other government

agencies, industry, and professional organizations.

Besides monitoring adverse reactions, FDA conducted

research in the postmarketing period on the safety of

aspartame. A contract was awarded to Battelle Memorial

Institute to evaluate the effects of altered amino acid

balances on rodent brain function, with an emphasis on

neurotransmitters. Also, FDA transferred funds to the

National Institute of Environmental Health Sciences in

February 1987 for study of the impact of amino acid

imbalances on seizure thresholds and neurobehavioral

function in rodents. This study is still under way, but

preliminary results demonstrate that large doses of

aspartame do not affect the sensory or motor functions,

learning and memory, or seizure induction in rats (19).

Another interagency agreement transferred funds to the

Federal Aviation Administration to study the effects of

aspartame on the performance of airplane pilots on a

number of complex laboratory-based tests of physical and

mental function.

Claims of Adverse Effects

Despite the preclinical evidence of safety, there have

been numerous consumer complaints alleging that aspartame use resulted insignificant medical problems, including seizures, severe headaches, tremors, insomnia, dizziness, panic attacks, and moodiness. Many of the patients’
Appendix A-The Food Additive Approval Process: A Case Study ● 319

symptoms were reportedly reversed when use of aspartame was discontinued. In many of the anecdotal

reports there may have been contributing factors, such as

excessive dieting, fluid intake, and caffeine consumption.

One study (partially supported by the Nutrasweet Co.) of

people who claimed to get headaches following ingestion

of aspartame demonstrated no difference in their headaches when they ingested aspartame or a placebo (12).

However, another placebo-controlled study (in a very

small number of patients) found that there was an

association between aspartame ingestion and migraines

for some patients (7). To date, these are the only

controlled studies of the effects of aspartame on people

who claim to be sensitive to it, A recent review of research

on aspartame was conducted by the Nutrasweet Co.,

which concluded that ‘‘available evidence confirms that,

other than in individuals with homozygous phenylketonuria, who must consider aspartame as an additional source

of phenykdanine, aspartame is a remarkably safe food

additive” (l).

It is plausible that there may be a small portion of the

population that is vulnerable to neurological side-effects

following consumption of aspartame. Other “restaurant

syndromes” afflicting subpopulations with unusual sensitivity include susceptibility to caffeine, MSG, red wine,

and chocolate (13).

The Council on Scientific Affairs of the American

Medical Association, in a report based on members’

expertise and the scientific literature, concluded in 1985

that “Available evidence suggests that consumption of

aspartame is safe except by individuals with homozygous

phenylketonuria or other individuals needing to control

their aspartame intake” (2). Similarly, in his November

3, 1987, statement to the Senate Committee on Labor and

Human Resources, the FDA Commissioner expressed his

confidence that no serious, reproducible adverse reactions

can be associated with aspartame use. He added that

widespread use of aspartame and the publicity regarding

possible adverse effects would have guaranteed their

identification had they existed (16). Nonetheless, he

committed the FDA to continue the postmarketing

monitoring of aspartame and to maintain close communication with aspartame’s critics. He agreed that some

people may be exquisitely sensitive to aspartame and that

some people are allergic to the compound. FDA has the

authority to remove substances from approved lists on the

basis of new information (5). This occurred in 1970, when

cyclamate was removed from the “generally recognized

as safe” list.

Summary and Conclusions

Because of the continuing dispute about aspartame’s

safety (9), FDA’s approval procedures have been the

subject of careful scrutiny. The General Accounting

Office and others have concluded that FDA acted entirely

properly and according to established policy during the

aspartame approval process, but it is not clear whether the

established procedures are optimal, striking the best

balance between consumer dietary wishes and public

health. Critics argue that the procedures are only minimally sufficient and that products which have not been

adequately tested are entering the marketplace.

Some of the safety questions emerged as a result of

postmarketing passive surveillance, an activity that is

optional for food additives but mandatory for drugs. In

fact, this distinction between food additives and drugs is

itself arbitrary. The acting director of the Bureau of Drugs

recommended in an FDA memorandum (which was not

issued) that ‘‘safety evaluations of proposed new sugar

substitutes be conducted as Phase I studies under the

Investigational New Drug (IND) Regulations” (15),

Postmarketing monitoring is nearly impossible unless the

presence of additives is clearly noted on the food package.

Some critics argue that, even when there are unsubstantiated anecdotal reports of toxicity due to ingestion of a

food additive, people who feel they are vulnerable to these

toxic effects have a right to know the identity and quantity

of the suspect additive, This would allow concerned

individuals to monitor their intake and would facilitate the

reporting of adverse effects. Clearly, consumers cannot

report an adverse effect if they are not aware of what they

have ingested. This view is supported by some investigators who contend that ingestion of quantities exceeding

the acceptable daily intake is possible in some individuals

(such as children) and that increasing rates of consumption could lead to more frequent ingestions exceeding the acceptable daily intake (6,10). On the other hand,

the Nutrasweet Co., although not opposing the labeling of

all food ingredients, would not agree that sufficient

scientific evidence of possible toxicity exists to warrant

singling out aspartame for obligatory labeling (14).

The value of postmarketing surveillance for identification of neurotoxic effects has been demonstrated several

times with new drugs; therefore, many persons argue that

establishment of postmarketing surveillance-at least a

passive system—should be required for all new products.

Because of the difficulty of identifying and quantifying

subtle neurological damage and because of the differences

between the nervous systems of humans and other

animals, an optimal approval process would require

clinical studies.

Appendix A References

1.

2.

Butchko, H. H., and Kotsonis, F. N., “Aspartame:

Review of Recent Research,” Comments in Toxicology, 1988.

Council on Scientific Affairs, American Medical

Association, “Aspartame, Review of Safety Issues,”

Journal of the American Medical Association 254:40@

401, 1985.
320 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Dews, P. B., “Summary Report of an International

Aspartame Workshop,” Food and Chemical Toxicology 25:549-552, 1987.

Franz, M., “Is It Safe To Consume Aspartame

During Pregnancy? A Review,” The Diabetes Educator 12:145-147, 1986.

Hattan, D. G., Henry, S.H., Montgomery, S.B., et al.,

“Role of the Food and Drug Administration in

Regulation of Neuroeffective Food Additives,” Nutrition and the Brain, R.J. Wurtman and J.J. Wurtman

(eds.) (New York, NY: Raven Press, 1983).

Janssen, P.J.C.M., and van der Heijden, C. A., “AsPartame: Review of Recent Environmental and

Observational Data,” Toxicology 50:1-26, 1988.

Koehler, S. M., and Glares, A., “The Effect of

Aspartame on Migraine Headache,” Headache 28:10-

13, 1988.

Lecos, C., ‘ ‘The Sweet and Sour History of Saccharin

Cyclamate , . . Aspartame,” FDA Consumer

15(4):8, 1981.

Maher, T. J,, and Wurtman, R. J., “Possible Neurologic Effects of Aspartame, a Widely Used Food

Additive,” Environmental Health Perspectives 75:53-

57, 1987.

Partridge, W. M., “Potential Effects of the Dipeptide

Sweetener Aspartame on the Brain,” Nutrition and

the Brain, R.J, Wurtman and J,J. Wurtman (eds.)

(New York, NY: Raven Press, 1983), pp. 199-241.

Reynolds, W.A., Bauman, A. F., Stegink, L. D., et al.,

“Developmental Assessment of Infant Macaques

Receiving Dietary Aspartame or Phenylalanine,”

Aspartame, L.D. Stegink and L.J. Filer, Jr. (eds.)

(New York, NY: Marcel Dekker Press, 1984), pp.

405-423.

Schiffinan, S. S., Buckley, C. E., III, Sampson, H. A.,

et al., ‘‘Aspartame and Susceptibility to Headache, ’

New England Journal of Medicine 317:1181-1185,

1987.

13.

14.

15.

16.

17.

8.

9.

Settipane, G. A., “The Restaurant Syndrome,” New

England and Regional Allergy Proceedings 8;39-46,

1987.

Shapiro, R. B., “Statement of Robert B. Shapiro,

Chairman of the Board and Chief Executive Office

of the Nutrasweet Company, Before the Committee

on Labor and Human Resources, ’ Nutrasweet

Health and Safety Concerns, U.S. Senate hearing

100-567 (Washington, DC: U.S. Government Printing Office, 1988), pp. 412-423.

U.S. Congress, General Accounting Office, Food and

Drug Administration: Food Additive Approval Process Followed for Aspartame, report to the Honorable

Howard M. Metzenbaum, GAO/HRD-87-46 (Washington, DC: 1987), p. 38.

U.S. Congress, Senate, Nutrasweet Health and

Safety Concerns, hearings before the Committee on

Labor and Human Resources, hearing 100-567 (Washington, DC: U.S. Government Printing Office, 1988),

p. 227.

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, FDA Medical Review of Clinical Safety Studies,

FAP No. 3A2885, Aug. 20, 1973,

U.S. Department of Health and Human Services,

Public Health Service, Food and Drug Administration, internal memorandum from the Acting Associate Commissioner for Health Affairs to the Commissioner, Apr. 24, 1981.

Young, F. E., “Statement of Frank E. Young, Commissioner, Food and Drug Administration, Before

the Committee on Labor and Human Resources,”

Nutrasweet-Health and Safety Concerns, U.S. Senate hearing 100-567 (Washington, DC: U.S. Government Printing Office, 1988), pp. 74-77.
Appendix B

Workshop on Federal Interagency Coordination of

Neurotoxicity Research and Regulatory Programs

Federally sponsored activities in neurotoxicology are

diverse and highly decentralized. They involve more than

15 different institutes, centers, and independent agencies,

such as the Environmental Protection Agency (EPA) and

the Consumer Product Safety Commission (CPSC), as

well as agencies in several departments, including the

Department of Health and Human Services (DHHS), the

Department of Energy (DOE), the Department of Labor,

and the Department of Defense (DoD). Coordination of

neurotoxicity research and regulatory activities tends to

be informal within agencies and more formal but less

extensively developed between agencies. Notable exceptions at the interagency level have included the coordinating efforts of at least two Federal organizations-the

Interagency Regulatory Liaison Group and, within DHHS,

the Committee to Coordinate Environmental Health and

Related Programs.

Results of research into the mechanisms of neurotoxicity must be made available rapidly to risk assessors and

other officials at regulatory agencies. This need is

magnified by current budgetary constraints, which provide a considerable impetus for improving coordination

of Federal research and regulatory activities. Improved

coordination of Federal neurotoxicological research could

well benefit not only the regulatory sector, but also

industry and consumers.

With such considerations in mind, representatives from

more than a dozen Federal organizations were convened

on May 23-24, 1989, at a workshop, ‘Federal Interagency

Coordination of Neurotoxicity Research and Regulatory

Programs,” sponsored jointly by the congressional Office

of Technology Assessment (OTA) and EPA (l).

Overview of Federal Neurotoxicology

Research Programs

Federal research in neurotoxicology spans the spectrum from basic to targeted. Coordination of Federal

research and regulatory programs in neurotoxicology

varies widely—with informal communication being the

dominant means, particularly among basic researchers.

Much of the data developed in Federal programs-but

certainly not all of it—is being made accessible by

publication, through on-line computer networks, or both.

However, some information, including a great deal of data

developed in the private sector and furnished to Federal

regulatory agencies to support drug, pesticide, and other

product marketing applications, is often unavailable

except through cumbersome means, such as requests via

the Freedom of Information Act. Still other data submitted to Federal agencies by companies in the private sector

are considered proprietary and therefore confidential. The

following section provides a brief overview of Federal

research and regulatory activities in this area.

Department of Health and Human Services

The responsibility for overseeing neurotoxicologyrelated activities within DHHS falls to the Office of the

Assistant Secretary for Health. The Committee to Coordinate Environmental Health and Related Programs operates within that office.

National Institutes of Health

Several Institutes within the National Institutes of

Health (NIH) sponsor a great deal, perhaps the majority,

of the U.S. basic research effort in neurotoxicology. Most

NIH research is investigator-initiated, and the data

produced are published in the scientific literature. The

principal Institutes with such programs are the National

Institute on Neurological Disorders and Stroke (NINDS),

the National Institute of Environmental Health Sciences

(NIEHS), the National Institute on Aging (NIA), and the

recently created National Institute on Deafness and other

Communication Disorders (NIDCD). These Institutes

support a broad range of basic studies of the nervous

system, including development of model systems for the

etiology of neurological diseases, particularly chronic

degenerative conditions.

Neurotoxicological research within NINDS is divided

into two areas of interest: exogenously applied and

endogenously occurring neurotoxic agents, The action of

synthetic neurotoxicants may cause damage that mimics

neurodegenerative diseases. For instance, the synthetic

compound MPTP, sometimes formed during the illicit

synthesis of a meperidine-like drug, destroys dopamineproducing cells of the central nervous system, making the

drug a powerful tool for studying Parkinson’s disease.

Among endogenous toxins, the reactive forms of oxygen

that can damage membranes through lipid peroxidation

are now being studied as possible mediators of damage

when cell protective mechanisms go awry.

NIEHS, which supports the most targeted of the several

NIH-sponsored neurotoxicity research programs, is now

taking a “broader look” at toxicology than it did when

carcinogen testing dominated its activities. The Institute

conducts and supports research to identify environmental

agents that may cause adverse reproductive, neurological,

and other effects on human health in addition to cancer.

NIEHS oversees a substantial extramural grants program

in the neurotoxicology field.

The National Toxicology Program within NIEHS

conducts tests of selected chemicals, including suspected

neurotoxic agents, and develops databases on them.

-321-
322 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Although the selection of chemicals for testing receives a

great deal of attention, the program ‘ ‘shouldn’t be driven

purely by the [chemical] nomination-based process,’ said

one NIEHS official. Compounds are selected on the bases

of extent of human exposure, quantity produced, adequacy of existing toxicological data, and regulatory and

research agency concerns regarding potential adverse

effects.

Although NIEHS, EPA, and the National Institute for

Occupational Safety and Health (NIOSH) have overlapping research interests and can use similar research and

testing technologies, there is little direct formal interaction between the agencies, according to an official from

NIEHS. The executive committee that oversees the

program is composed of directors or administrators from

NIEHS, the National Cancer Institute, NIOSH, the

Agency for Toxic Substances and Disease Registry

(ATSDR), the Food and Drug Administration (FDA),

CPSC, EPA, and the Occupational Safety and Health

Administration; the program is reviewed by nongovernment scientists.

Because of its mandate, NIA supports researchers

investigating the “special vulnerability of the aging

nervous system to toxins, ‘‘ noted an official from NIA. As

with programs in NINDS, the emphasis is on “the basic

neurobiology of the problem. ” The Institute also sponsors epidemiological studies to identify populations with

chronic exposures to toxic substances, such as aging

residents of rural areas, who maybe exposed to pesticides.

Alcohol, Drug Abuse, and Mental Health

Administration

The National Institute on Drug Abuse (NIDA), which

is part of the Alcohol, Drug Abuse, and Mental Health

Administration (ADAMHA), sponsors research to study

the neurotoxicological effects of addictive drugs as well

as drugs being developed to treat or prevent drug abuse.

Researchers at NIDA are trying to determine what areas

of the brain are affected by such drugs and whether their

effects are reversible. FDA and NIDA have an interagency agreement to develop and validate methods of

assessing the neurotoxic actions of drugs that are currently being prescribed or considered for treatment of

neuropsychiatric disorders. NIDA researchers are also

seeking avenues for coordinating some of their efforts

with officials of the Drug Enforcement Agency, but that

“gap is difficult to bridge,’ according to an official from

NIDA. Cooperative agreements with other Federal agencies to develop and validate neurotoxicity screening tests

and a neurotoxicity database should become priority

activities, noted another NIDA official.

The National Institute of Mental Health (NIMH),

another agency within ADAMHA, also sponsors research

on therapeutic agents that can exert neurotoxic effects on

brain function. NIMH researchers are helping to develop

a neurophysiological battery of tests for evaluating central

nervous system impairment, particularly among patients

with AIDS. Because NIMH and NIDA interact closely

with the pharmaceutical industry, some neurotoxicology

data they obtain may be kept confidential because it is

considered proprietary information.

Centers for Disease Control

The Centers for Disease Control (CDC) act as a sentinel

protecting the public health. Currently, CDC is updating

its regulations for setting lead safety standards and thus is

reexamining the concentrations in the blood at which this

potent neurotoxic agent exerts adverse effects.

NIOSH studies a broad range of products through both

intramural and extramural programs. Specifically, NIOSH

considers substances to which individuals may be exposed in the workplace, including field studies of

farmworkers and others exposed to pesticides. In addition, Institute researchers conduct studies using various

animal models. The primary concern of the NIOSH

intramural program is methods assessment.

NIOSH is participating in the National Health and

Nutrition Survey, which is organized under the auspices

of the National Center for Health Statistics. During the

course of this study, about 6,000 people will be given

three tests from the neurobehavioral evaluation system in

order to develop baseline data to assess future exposures

to neurotoxic agents. NIOSH is also participating with the

International Program on Chemical Safety and the World

Health Organization (WHO) invalidation of a neurobehavioral screening battery for rodents.

Agency for Toxic Substances and

Disease Registry

Under Superfund auspices, ATSDR carries out applied

research on health effects of exposures to hazardous

substances, including neurotoxic agents. ATSDR is

“looking at data gaps,” according to an official of the

Agency. By law, the Agency must make a list of the 200

most toxic substances found at Superfund sites and help

determine which of them maybe toxic in general as well

as neurotoxic. Officials also expect to develop a standard

battery of tests that could be used not only for broad

testing of the population, but also for workers and other

individuals at Superfund sites who might be exposed to

mixtures of neurotoxic agents. In December 1988, the

ATSDR cosponsored the Third International Symposium

on Neurobehavioral Methods in Occupational and Environmental Health with WHO and the Pan American

Health Organization. Discussions at the symposium have

helped ATSDR officials develop a list of scientific

priorities.
Appendix B-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatory Programs .323

Food and Drug Administration

FDA evaluates the adverse effects of drugs on the

nervous system through its general toxicological evaluations. Such testing is designed not only to detect drugs

with adverse effects on the central nervous system, but

also to evaluate psychoactive drugs, which generally act

directly on the nervous system. Before a drug is approved

for marketing, general toxicity is evaluated by a battery of

studies, ranging from short-term acute tests in several

species by different routes of administration to chronic

dosing studies in two species exposed at three dose levels

for up to 2 years. Behavior in test animals is monitored

periodically, and abnormalities are recorded. Mating,

fertility, developmental abnormalities, maternal behavior,

and survival are among the endpoints that are evaluated.

However, officials of some agencies voiced concern that

FDA’s general toxicological testing approach may miss

some neurotoxicological effects. Many neurotoxicologists believe that specific neurotoxicological testing is

necessary to detect some adverse effects.

Elsewhere in FDA, officials are concerned about

pesticides, contaminants, and additives in the food supply

and how they may affect individuals of different ages, on

various diets, or with other risk factors. In addition, the

National Center for Toxicological Research is developing

models and trying to enhance current risk assessment

methods in general, as it begins to examine neurotoxic

agents specifically.

Department of Energy

DOE sponsors a relatively small program to study toxic

chemicals. The Department is also interested in central

nervous system disorders such as Alzheimer’s disease.

DOE researchers typically are interested in the underlying

mechanisms of such diseases. Historically, their efforts

have led to the development of complex instruments for

examining central nervous system functions. DOE has

also conducted evaluations of Federal agency carcinogen

risk assessment procedures—an exercise that could prove

helpful as many agencies try to develop consistent risk

assessment procedures for analyzing neurotoxic substances.

Environmental Protection Agency

EPA faces a broad mandate under several statutes in

regulating neurotoxic agents. Throughout the Agency,

officials are refining risk assessment methods. Other

efforts focus more directly on neurotoxic substances. For

instance, the Agency maintains files on hundreds of

pesticides, many of which are neurotoxic. EPA sponsors

a sizable research program within the Office of Research

and Development, which focuses on development of

methods and applied research questions, including hazard

identification and characterization.

EPA is currently revising and adapting guidelines for

animal tests to screen organophosphorous pesticides for

neurotoxic activity. The Agency has found evidence that

pesticide residues in foods cause neurotoxic effects in

children, and the identification and characterization of

neurotoxic pesticides is a high priority for EPA officials.

An EPA Scientific Advisory Panel recommended that

routine testing of pesticides include observation for signs

of neurobehavioral abnormality and neuropathology.

Under Superfund legislation, EPA officials are cooperating with their counterparts at ATSDR to study chemical

mixtures at toxic waste sites, where individuals may be

exposed to complex mixtures of chemicals that might act

synergistically on the nervous system.

In 1986, EPA established an intra-agency work group

to look at substances that act as reproductive and

developmental toxicants. Testing guidelines for develop

mental neurotoxicity are now being drafted. According to

EPA scientists, animal models have consistently proved

useful for predicting human response to neurotoxic

agents.

Consumer Product Safety Commission

CPSC is beginning to develop neurotoxicity guidelines

for manufacturers. The Commission program is directed

at developing new regulations for products such as paint

thinners and art materials that may have neurotoxicological effects under certain conditions of use. Appropriate

labeling to warn of hazards, advise against hazardous uses

or exposures, and provide first-aid instruction is required

under statutes administered by CPSC.

Although the Commission develops guidelines and

regulations rather than conducting research, staff members are identifying areas where scientific research would

help them better fulfill their mandate. Development of test

methods for identifying toxicants that cause neurological

damage after chronic low-level exposures, identification

of key species differences to aid in extrapolating animal

test results to appropriate endpoints in humans, and

development of a better understanding of the relationship

between high- and low-dose neurotoxic effects are

research areas of particular interest to CPSC officials.

Department of Labor

Although charged with setting neurotoxicity health and

safety standards, the Occupational Safety and Health

Administration (OSHA) conducts no research of its own.

Instead, scientists at NIOSH and elsewhere supply OSHA

with information needed to promulgate health standards.

For example, to help in regulating neurotoxic agents,

OSHA officials would like to see research conducted on

subclinical effects of neurotoxic substances and at what

exposure levels such effects remain reversible. OSHA

would also like Federal agencies to standardize means for
324 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

conducting risk assessments, develop quantitative methods for expressing subtle behavioral changes, devise

simple tests to measure toxic effects on individual

workers, and publish a standardized list of neurotoxic

substances.

OSHA health standards become legal documents

intended to ensure that employees not suffer “material

impairment of health or functional capacity, ’ which the

courts interpret to include subclinical effects. Thus, in

setting standards, OSHA can act to prevent relatively mild

and reversible forms of potentially serious diseases, such

as those caused by a particular neurotoxic substance.

“Material impairment” can also mean workplace exposures to chemicals that cause temporary narcosis, which

can lead to accidents and injuries. The courts give OSHA

considerable latitude in determining “significant risk”

and the consequences of resetting exposure limits to

particular chemicals.

Department of Defense

DoD has carried out extensive testing of protective

drugs designed to counteract neurotoxic chemical agents.

Its current program involves 26 laboratories, including

support of research at laboratories within NIDA. To

evaluate such drugs, DoD has developed a four-part

procedure for extrapolating their effects to human performance in real-world situations, noted an official from

DoD. DoD has developed sophisticated performance

evaluation test batteries, risk identification procedures, a

computer-based task-analysis procedure, and a real-world

contingency analysis package, which provides information about the use and potential neurotoxic effects of

antidotes for chemical warfare agents.

Workshop Discussion Groups

Identifying Testing Needs

Although there are processes prescribed by the National Testing Program (within ATSDR) and by the

Interagency Testing Committee for nominating chemicals

for neurotoxicity testing and evaluation, the discussion

group concluded that the processes need revising. A major

difficulty in conducting evaluations that lead to a

chemical’s nomination is the inadequate number of

people with expertise in neurotoxicology. Having more

appropriately trained experts would also help in educating

regulators who select chemicals for such testing. The

notion that neurotoxicity is a valid endpoint for evaluating

chemicals needs general reinforcement.

Moreover, the scientific criteria for defining neurotoxicity, setting priorities, and selecting chemicals, including

structure-activity relationships and comparisons of chemicals and chemical classes, also should be reevaluated and

strengthened. For example, the volume of production and

likely extent of human exposure to a particular chemical

could be taken into account when deciding whether it

should be nominated for testing, an official from NIEHS

noted.

Thus, establishment of an independent advisory group

of experienced individuals to better define neurotoxicity,

to evaluate the nomination process, to review chemicals

going through it, and to act as an information “resource”

seems warranted, the discussion group concluded. If

established, such an advisory group would not “sup

plant’ the regulatory agency, but would help ‘sanction”

the decisions the agency makes, an EPA official said.

A battery of standardized human neurotoxicity tests is

needed, particularly for use in evaluating the effects of

environmental exposures to potentially hazardous agents.

Because several test batteries, such as the field performance battery used by DoD as well as another test battery

developed by NIOSH, have been developed for testing

humans exposed to suspected neurotoxic substances, it

may be possible to adapt existing procedures into a more

broadly applicable test battery.

‘‘If you’re going to do a particular test, at what level do

you consider that some adverse health effect has occurred?” asked an official from ATSDR. “What you’d

like is not only some tests, but indications for when to use

them. . . .The whole idea. . . is to get the biggest bang for

the Federal buck. ” In that context the lack of resources

for funding research and testing of suspected neurotoxic

substances is a critical “rate-limiting” step.

Development and Use of Standardized

Neurotoxicity Tests

Many neurotoxicity tests are now in use. The discussion group agreed that representatives from various

agencies could form a coordinating group to compare the

specific tests each agency is using and to evaluate

strategies for developing new tests.

Some effort to coordinate research involving animal

and human neurotoxicity testing is also needed. Improved

efforts to obtain relevant information, such as pharmacokinetic data about a chemical’s behavior in a particular

species, are part of this overall task, an FDA official said.

Despite differences in statutory authority, other agencies besides EPA need to acknowledge critical arenas,

such as developmental neurotoxicity, for evaluating

chemicals and drugs, noted an official from EPA.

However, any effort to move toward uniformity in testing

becomes challenging because so much depends on the

regulatory context in which a particular test will be used.

EPA, for example, is expected to set and observe

standards for tests that are mandated under several

legislative acts—particularly the Toxic Substances Control Act-that are unique to the Agency. Working under

quite different legislative mandates, NIDA and FDA have
Appendix B-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatory Programs ● 325

developed specific, highly sophisticated tests for particular categories of neuropharmacological agents. Whatever

the tests being performed, noted another EPA official, the

interpretation of results is “very dependent on the

expertise of your reviewers, ” For example, without

adequate training in neuropathology, agency reviewers

might overlook telltale signs of neurotoxicity in a

particular animal model test.

A practical consideration arising from mission and

statutory differences among regulatory agencies is that

the costs of testing commodity chemicals, for instance,

rather than drugs ‘‘can very often not be supported by the

anticipated market, ’ an EPA official pointed out. Nonetheless, sharing of adequately reviewed information

among agencies could help individual agencies in making

decisions about neurotoxic substances to fulfill their

particular legislative mandates. Whether test methods

should be standardized or merely codified remains an

unresolved issue.

Coordination of Federal Research Programs

Neurotoxicity research is defined broadly because the

definition is driven by individual investigators as well as

legislatively mandated regulatory agencies. Existing mechanisms for coordinating such research, particularly its

more basic components, are largely informal and often

fragmented. The discussion group did not reach a

consensus on whether a central coordinating mechanism

would be useful or desirable.

In particular, several representatives of the basic

research community thought that such a committee might

be viewed as an advocacy body trying to obtain a larger

share of resources for conducting neurotoxicity research

instead of studies in other areas. Thus, their misgivings

about a formal neurotoxicity research coordinating body

are based on an underlying fear that a central committee

might interfere with research freedom “through budget

leverage. ’

In addition, noted an official from NIH, although other

Federal activities involving neurotoxicity may well benefit from coordination, research “would be the least

important to coordinate. . . .We’re trying to solve a

nonproblem. ” Informal exchanges of information now

ensure that research interests and opportunities are shared

fairly freely between various Institutes within NIH, he

said. Moreover, that exchange of information occurs

outside the formal budget process. Sometimes it involves

efforts to minimize overlap, but it also permits a degree of

research ‘redundancy’—i.e., overlapping or even repetitive research by different investigators. (Such redundancy, when it occurs, is usually justified as a vital part of

the self-correcting, confirmatory aspect of basic research.)

There are plenty of “knowledge gaps” in the neuroscience, he said. “Instead of feeling redundant, we’re

working to fill the knowledge gaps. ”

Representatives from agencies that are purely regulatory or that also conduct research to support their

regulatory responsibilities see a need for more deliberate

efforts to coordinate research. “We need to identify gaps

in the research database available to the regulatory

agencies, ” said an official from EPA. “We need. . .to

transfer information [when] trying to develop research

strategies, added another EPA representative, “We

want to test their validity with other agencies. ”

Historically, basic research findings have had an

enormous impact on setting neurotoxicity-related regulations, The current effort within CDC, for instance, to

reevaluate safe blood levels for lead “arose from basic

research findings about lead’s neurotoxicity, ’ an EPA

official pointed out. “How can we [convey] basic

information about how the nervous system responds to

various insults . . . to [officials] to protect public health?”

He and many other participants at the workshop agreed

that such information could be evaluated and disseminated more effectively than current mechanisms allow.

They also agreed that, by making basic researchers more

aware of the scientific challenges facing regulatory

agencies, the nature of some research undertakings may

change in valuable ways. “We want NIH aware of

problems facing regulatory agencies ., , to see if it can

give a different emphasis to basic research,” an EPA

official noted.

Coordination of Testing and

Monitoring Programs

Several Federal agencies, including, EPA, OSHA,

NIOSH, FDA, and CPSC, have both passive and active

neurotoxicity monitoring capabilities and interests. Data

developed during the conduct of such activities typically

are stored by the agencies, Members of the discussion

group concluded that sharing such information among

agencies would be useful-as would identifying key

contact people at each agency and making agencyspecific databases compatible with one another.

The handling of data is seen as a challenge. Agencies

now have different criteria for evaluating such data. EPA,

for example, stringently reviews data before entering

them into the Integrated Risk Information System, an

Agency official noted. “These data have status. [As] an

agency policy. . . .1 would have to ask what status other

kinds of shared data would have. ’ The expected uses for

a “centralized database. , . to a large extent might dictate

what kind of data you would put in it” another EPA

official said.

Officials face serious questions in evaluating neurotoxicity test schemes. The development and validation of

new tests and test batteries are a central challenge.
326 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Moreover, there is no agreed-on basis for moving from a

tier-one to a tier-two battery of tests. A concise definition

of “significant biological effect” is needed, as are

consistent strategies for using test data when conducting

risk assessments, The exchange of information, sometimes at the early stage of description in grant applications, might expedite development of useful procedures.

In the same vein, it would be useful to track what

compounds are being tested by which agencies so that

interested parties could be kept informed about the status

of particular suspect neurotoxic agents, even during the

earliest stages of examination. Similarly, it would be

useful to reexamine past neurotoxicology data, in part to

gain a greater understanding of what test endpoints have

proved particularly reliable.

Coordination of Risk Assessment

and Regulatory Programs

Of the regulatory agencies represented at the workshop,

EPA apparently has the most stringent guidelines for risk

assessment. This stringency is dictated in part by EPA’s

need for consistency throughout its diverse programs and

across its regional offices. For example, engineers at

Superfund sites may be called on to make $20-million

decisions, pointed out an EPA representative, In such

circumstances, guidance and consistency are essential—

to support the on-site decision if it is subsequently

challenged in court.

Although other regulatory agencies may not have such

formal guidelines, they often have special offices for

addressing risk assessment, scientific, and policy issues.

OSHA, for instance, has promulgated guidelines for

carcinogens, according to an agency official. However,

developing those guidelines “was time-consuming and

not an effective process, ’ this same official noted, adding

that having consistent practices across agencies seems

more important than publishing specific guidelines.

Informally, many agencies follow a process outlined in

the National Research Council document Risk Assessment in the Federal Government: Managing the Process

(2). It distinguishes between risk assessment, which is

considered principally a scientific evaluation process, and

risk management, which involves political, economic,

and other considerations, Efforts to coordinate neurotoxicity risk assessment ought to emphasize “science and. . .

risk assessment and not . . . risk management” an EPA

official recommended.

“I don’t think you can make that kind of clean

distinction,’ another discussion group participant responded. “I don’t think you can live with that kind of

artificial situation. . . it’s the sort of thing that gets us into

trouble. And, noted another participant, “There is a

basic political premise that is involved in that separation

decision. If it works well for an agency under a set of

circumstances, great. But I don’t think it’s universally

clear that is the way to proceed. ”

The discussion group considered whether universal

guidelines for conducting risk assessments might exert

untoward effects, such as restricting scientific judgments

and, ultimately, impeding regulatory actions. “Standardized guidelines tend to stagnate the discipline,” said an

official from DOE. “Formalizing them too soon is not

good. The important part of risk assessment is [holding]

a social dialogue, focusing on a problem, and stimulating

research.” However, an official from EPA responded,

“What you say is very nice if the agency doesn’t have a

lawsuit accusing [it] of not making a regulatory decision .

There was general agreement that careful thought must

be exercised lest risk assessment concepts be introduced

too early. Nonetheless, some principles of risk assessment

may be applicable to neurotoxicity data from all regulatory agencies. Moreover, research issues common to

most, if not all, regulatory agencies can be addressed in a

coordinated fashion. “Looking at common research

issues could certainly be a marked advantage,’ the

discussion group agreed. However, concern was voiced

that other agencies feel “their input into what EPA is

doing in risk assessment is. . . retrospective.” Thus, there

is a need for them to have input earlier in the process so

as to have greater impact.

“Rather than adopt [guidelines] uniformly, we may

want to see how a particular agency’s guidelines work out

. . . and then learn from each other’s mistakes and

successes, ” suggested an official from FDA. “EPA and

FDA may start at the same point trying to detect

neurotoxic drugs or environmental agents, Later on, the

FDA decision on setting a neurotoxic threshold for a drug

will be different from [the standard] EPA sets for an

environmental agent. ”

The group was divided over how risk assessment

procedures for evaluating suspected carcinogens stand up

against procedures for evaluating putative neurotoxic

substances. “In some ways, we know more in the area of

neurotoxicity, ’ an EPA official argued. “We know about

variety, reversibility, as much or more about mechanisms. . . . [In neurotoxicity] somehow we are able to

accept a certain level of risk. . . .It’s not that cancer risk

assessment is more developed, [but] we put an arbitrary

structure on [it] largely in response to a political need. ”

Added an official from FDA, “The key is that we are

better able to set a safe limit for a neurotoxicant than. . .

for carcinogens.’

Sometimes the “politics of the situation require us to

say, ‘We don’t know enough about what we’re doing

here’,’ said another EPA official. However, both EPA

and FDA “have a long empirical track record of dealing
Appendix B Workshop on Federal Interagency Coordination of Neurotoxicity Research and RegulatoryProgr~ ● 327

with neurotoxic agents, of establishing safe levels. . . .So

we shouldn’t confuse ourselves.

Such considerations also have an impact on “risk

communication’ ‘—that is, notifying individuals of the

risk posed by particular substances. “That whole area is

under great scrutiny within the cognitive psychology

community, ” noted a participant. Research “to explain a

complex concept” and efforts to “develop a special

language” could help in getting the public to understand

risks more clearly.

Models for Coordinating Federal

Neurotoxicity Efforts

There are several models for coordinating interagency

neurotoxicity activities. The Interagency Regulatory Liaison Group was established more than a decade ago and

seemed to work well until it became too difficult to

manage, according to a DOE official. Moreover, with a

change in administrations came a change in activities

among regulatory agencies and a decreased emphasis on

coordination among them.

Within DHHS, the Committee to Coordinate Environmental Health and Related Programs (CCEHRP) could

coordinate neurotoxicity activities. The committee “is

authorized to establish subcommittees and could readily

accommodate interests in neurotoxicity among DHHS

agencies with liaisons to agencies outside the Department.

CCEHRP has a policy board and counsel that are

research- and program-directed, according to a representative from DHHS. CCEHRP is also integrated vertically,

meaning its membership includes researchers who work

at the bench as well as high-level managers.

Historically, the Office of Science and Technology

Policy (OSTP) within the Office of the President has

functioned as an organizing body for cooperative activities to establish risk assessment principles for carcinogens. The OSTP Chemical Carcinogens Document

published in the Federal Register on March 14, 1985, is

widely accepted as a model achievement. Moreover, with

OSTP leadership, representatives from academia, industry, and the Federal Government can work together in

developing acceptable policies. A risk in calling on OSTP

to undertake Federal coordination of neurotoxicity activities is that the issue could become too political. Thus,

some workshop participants argued that the coordination

of neurotoxicity activities to fulfill research and data

needs might prove more workable if organized from “the

bottom up. ” Once successful, agency officials then are

better positioned to convince management of particular

policy options to implement.

Proposal

Toward the close of the workshop, participants agreed

that an “Interagency Working Group on Neurotoxicology ” should be formed.1 The proposed working group,

which would be dedicated to improving the Federal

response to human health issues related to neurotoxicology, would include members from all Federal agencies

and organizations having research, regulatory, or other

pertinent interests in neurotoxicology. Such a forum for

exchanging information could help minimize duplication

of efforts. The working group could also help ensure that

negative as well as positive findings are shared by

individuals interested in neurotoxicology.

Although workshop participants limited their proposal

to a sketch of what such an interagency working group

should undertake, they did outline key areas where such

a body could fill gaps and help to coordinate otherwise

isolated efforts in research, testing, monitoring, risk

assessment, regulation, and other areas. The working

group also might develop a “conceptual framework. . .to

identify long-range needs related to neurotoxicology, ”

suggested an official from EPA. It might also “encourage

the Library of Medicine to participate in the establishment

of a neurotoxicology database.”

1.

2.

Appendix B References

This summary of the OTA/EPA workshop was prepared by Jeffrey Fox under contract No. L3-2630.O.

National Research Council, Risk Assessment in the

Federal Government: Managing the Process (Washington, DC: National Academy Press, 1983).

l~&t. 26,1989, knmew~ch~g~ to the Interagency committee on Neurotoxicology (l~N). ~ committee is adrninisteredthrough the Neurotoxicology Division

of EPA’s Health Effects Research Laboratmy in Research Triangle Park, NC.
328 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Federal Interagency Coordination of Neurotoxicity

Research and Regulatory Programs

Sponsored by the Office of Technology Assessment

and the U.S. Environmental Protection Agency

Lawrence W. Reiter, Workshop Chair

U.S. Environmental Protection Agency, Washington, D.C.

John S. Andrews, Jr.

Agency for Toxic Substances and Disease Registry

Atlanta, GA

Timothy M. Barry*

U.S. Environmental Protection Agency

Washington, DC

James R. Bean

U.S. Department of Energy

Washington, DC

Robert Biersner

National Institute for Occupational Safety and Health

Cincinnati, OH

Suzanne Binder

Centers for Disease Control

Atlanta, GA

William K. Boyes

U.S. Environmental Protection Agency

Research Triangle Park, NC

Margarita Collantes

Consumer Product Safety Commission

Bethesda, MD

Joseph F. Contrera

U.S. Food and Drug Administration

Rockville, MD

Miriam Davis

U.S. Department of Health and Human Services

Washington, DC

Errol B. de Souza

National Institute on Drug Abuse

Baltimore, MD

Sandra Eberly

Consumer Product Safety Commission

Washington, DC

Lynda Erinoff

National Institute on Drug Abuse

Rockville, MD

David G. Hattan

U.S. Food and Drug Administration

Washington, DC

Frederick Hegge

Walter Reed Institute of Research

Silver Spring, MD

Stephen Kennedy

National Institute of Mental Health

Rockville, MD

Zaven S. Khachaturian

National Institute on Aging

Bethesda, MD

Carole A. Kimmel

U.S. Environmental Protection Agency

Washington, DC

Annette Kirshner

National Institute of Environmental Health Sciences

Research Triangle Park, NC

Stephen H. Koslow

National Institute of Mental Health

Rockville, MD

Carl M. Leventhal

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Tina Levine

U.S. Environmental Protection Agency

Washington, DC

Robert C. MacPhail

U.S. Environmental Protection Agency

Research Triangle Park, NC

Craig McCormack*

U.S. Environmental Protection Agency

Washington, DC

Suzanne McMaster

U.S. Environmental Protection Agency

Washington, DC

*Organizing Committee
AppendixB-Workshop on Federal Interagency Coordination of Neurotoxicity Research and Regulatoryprograrns ● 329

Lakshmi C. Mishra

Consumer Product Safety Commission

Bethesda, MD

Lawrence S. Rosenstein

U.S. Environmental Protection Agency

Washington, DC

Bernard A. Schwetz

National Institute of Environmental Health Sciences

Research Triangle Park, NC

William Sette

U.S. Environmental Protection Agency

Washington, DC

Imogene Sevin-Rodgers

U.S. Department of Labor

Washington, DC

William Slikker

National Center for Toxicological Research

Jefferson, AR

Thomas J. Sobotka

U.S. Food and Drug Administration

Washington, DC

Letitia Tahan

U.S. Environmental Protection Agency

Washington, DC

Hugh A. Tilson

U.S. Environmental Protection Agency

Research Triangle Park, NC

Judith Weissinger

U.S. Food and Drug Administration

Rockville, MD

Harold Zenick

U.S. Environmental Protection Agency

Washington, DC

OTA Staff

Roger Herdman

Gretchen Kolsrud

Mark Schaefer

Timothy Condon

Peter Andrews

Joyce Ann Brentley

Blair Wardenburg

Gladys White
Appendix C

Decade of the Brain

Public Law 101-58, 101st Congress,

Joint Resolution

Whereas it is estimated that 50 million Americans are

affected each year by disorders and disabilities that

involve the brain, including the major mental illnesses;

inherited and degenerative diseases; stroke; epilepsy;

addictive disorders; injury resulting from prenatal events,

environmental neurotoxins, and trauma; and speech,

language, hearing, and other cognitive disorders;

Whereas it is estimated that treatment, rehabilitation

and related costs of disorders and disabilities that affect

the brain represents a total economic burden of $305

billion annually;

Whereas the people of the Nation should be aware of

the exciting research advances on the brain and of the

availability of effective treatment of disorders and disabilities that affect the brain;

Whereas a technological revolution occurring in the

brain sciences, resulting in such procedures as positron

emission tomography and magnetic resonance imaging,

permits clinical researches to observe the living brain

noninvasively and in exquisite detail, to define brain

systems that are implicated in specific disorders and

disabilities, to study complex neuropeptides and behavior

as well as to begin to learn about the complex structures

underlying memory;

Whereas scientific information on the brain is amassing

at an enormous rate, and the field of computer and

information sciences has reached a level of sophistication

sufficient to handle neuroscience data in a manner that

would be maximally useful to both basic researches and

clinicians dealing with brain function and dysfunction;

Whereas advances in mathematics, physics, computational science, and brain imaging technologies have made

possible the initiation of significant work in imaging brain

function and pathology, modeling neural networks and

simulating their dynamic interactions;

Whereas comprehending the reality of the nervous

system is still on the frontier of technological innovation

requiring a comprehensive effort to decipher how individual neurons, by their collective action, give rise to human

intelligence;

Whereas fundamental discoveries at the molecular and

cellular levels of the organization of the brain are

clarifying the role of the brain in translating neurophysiologic events into behavior, thought, and emotion;

Whereas molecular biology and molecular genetics

have yielded strategies effective in preventing several

forms of severe mental retardation and are contributing to

promising breakthroughs in the study of inheritable

neurological disorders, such as Huntington’s disease, and

mental disorders, such as affective illnesses;

Whereas the capacity to map the biochemical circuitry

of neurotransmitters and neuromodulators will permit the

rational design of potent medications possessing minimal

adverse effects that will act on the discrete neurochemical

deficits associated with such disorders as Parkinson’s

disease, schizophrenia and Alzheimer’s disease;

Whereas the incidence of necrologic, psychiatric,

psychological, and cognitive disorders and disabilities

experienced by older persons will increase in the future as

the number of older persons increases;

Whereas studies of the brain and central nervous

system will contribute not only to the relief of necrologic,

psychiatric, psychological, and cognitive, disorders, but

also to the management of fertility and infertility,

cardiovascular disease, infectious and parasitic diseases,

developmental disabilities and immunologic disorders, as

well as to an understanding of behavioral factors that

underlie the leading preventable causes of death in this

Nation;

Whereas the central nervous and immune systems are

both signaling systems which serve the entire organism,

are direct connections between the nervous and immune

system, and whereas studies of the modulatory effects of

each system on the other will enhance our understanding

of diseases as diverse as the major psychiatric disorders,

acquired immune deficiency syndrome, and autoimmune

disorders;

Whereas recent discoveries have led to fundamental

insights as to why people abuse drugs, how abused drugs

affect brain function leading to addiction, and how some

of these drugs cause permanent brain damage;

Whereas studies of the brain will contribute to the

development of new treatments that will curtail the

craving for drugs, break the addictive effects of drugs,

prevent the brain-mediated “high” caused by certain

abused drugs, and lessen the damage done to the

developing minds of babies, who are the innocent victims

of drug abuse;

Whereas treatment for persons with head injury,

developmental disabilities, speech, hearing, and other

cognitive functions is increasing in availability and

effectiveness;

Whereas the study of the brain involves the multidisciplinary efforts of scientist, from such diverse areas as

physiology, biochemistry, psychology, psychiatry, molecular biology, anatomy, medicine, genetics, and many

others working together toward the common goals of

-330-
Appendix C--Decade of the Brain ● 331

better understanding the structure of the brain and how it

affects our development health, and behavior;

Whereas the Nobel Prize for Medicine of Physiology

has been awarded to 15 neuroscientist within the past 25

years, an achievement that underscores the excitement

and productivity of the study of the brain and central

nervous system and its potential for contributing to the

health of humanity;

Whereas the people of the Nation should be concerned

with research into disorders and disabilities that affect the

brain, and should recognize prevention and treatment of

such disorders and disabilities as a health priority;

Whereas the declaration of the Decade of the Brain will

focus needed government attention on research, treatment and rehabilitation in this area: Now, therefore, be it

Resolved by the Senate and House of Representatives of

the United States of America in Congress Assembled,

That the decade beginning January 1, 1990, hereby is

designated the “Decade of the Brain,” and the President

of the United States is authorized and requested to issue

a proclamation calling upon all public officials and the

people of the United States to observe such decade with

appropriate programs and activities.

Approved July 25, 1989.

LEGISLATIVE HISTORY-H.J. Res. 174 (S. J. Res. 173):

CONGRESSIONAL RECORD, vol. 135 (1989):

June 29, considered and passed House.

July 13, considered and passed Senate.
Appendix D

Acknowledgments

OTA would like to thank the members of the advisory panel who commented on drafts of this report the contractors

who provided material for this assessment, and the many individuals and organizations that supplied information for the

study. In addition, OTA acknowledges the following individuals for their review of drafts of this report.

Jacqueline Agnew

The Johns Hopkins University

W. Kent Anger

Oregon Health Sciences University

Thomas E. Anderson

General Motors Research Laboratories

Zoltan Annau

The Johns Hopkins University

Arnold Aspelin

U.S. Environmental Protection Agency

Isaiah Baker

American University

James R. Bean

Jefferson, MD

John F. Beary, III

Pharmaceutical Manufacturers Association

Charles E. Becker

University of California

Robert J. Biersner

National Institute for Occupational Safety and Health

Michael Bolger

U.S. Food and Drug Administration

William K. Boyes

U.S. Environmental Protection Agency

Peter Breysse

University of Washington

Brian Broxup

Bio-Research Laboratory, Ltd.

Harriett H. Butchko

The NutraSweet Co.

Daniel M. Byrd

Distilled Spirits Council of the United States, Inc.

James W. Caldwell

U.S. Environmental Protection Agency

Margarita Collantes

U.S. Consumer Product Safety Commission

Joseph Contrera

U.S. Food and Drug Administration

Jacqueline Courteau

Hampshire Research Associates, Inc.

Wayne Daughtrey

Exxon Biomedical Sciences, Inc.

J. Michael Davis

U.S. Environmental Protection Agency

Miriam Davis

U.S. Department of Health and Human Services

John A. Dellinger

San Antonio, TX

Robert T. Drew

American Petroleum Institute

Cynthia Driscoll

E.I. du Pent de Nemours & Co.

Alan Ducatman

Massachusetts Institute of Technology

Robert S. Dyer

U.S. Environmental Protection Agency

David Eckerman

University of North Carolina

Rob Elias

U.S. Environmental Protection Agency

Lynda Erinoff

National Institute on Drug Abuse

Hugh L. Evans

New York University Medical Center

Henry Falk

Centers for Disease Control

Robert G. Feldman

Boston University School of Medicine

W. Scott Ferguson

National Agricultural Chemical Association

Shayne C. Gad

Searle Research& Development

Paul Garvin

Amoco Corp.

Carl Giannetta

U.S. Food and Drug Administration

Frank P. Grad

Columbia University Law School

Sidney Green

U.S. Food and Drug Administration

-332-
Appendix D-Acknowledgments ● 333

Richard A. Griesemer

National Institute of Environmental Health Sciences

Michael Hansen

Institute for Consumer Policy Research

David G. Hattan

U.S. Food and Drug Administration

Carol J. Henry

ILSI Risk Science Institute

Karen Hoffman

National Institute of Environmental Health Sciences

Anne K. Hollander

The Conservation Foundation

Pony Hoppin

The Conservation Foundation

Ken Hudnell

U.S. Environmental Protection Agency

Karl Jensen

U.S. Environmental Protection Agency

Barry L. Johnson

Agency for Toxic Substances and Disease Registry

E. Marshall Johnson

Jefferson Medical College

David L. Karmol

Can Manufacturers Institute

Carole A. Kimmel

U.S. Environmental Protection Agency

Philip J. Landrigan

The Mount Sinai Medical Center

Robert F. Lee, H

U.S. Environmental Protection Agency

Richard LetZ

Mount Sinai School of Medicine

Carl Leventhal

National Institutes of Health

Ronnie Levin

U.S. Environmental Protection Agency

Tina E. Levine

U.S. Environmental Protection Agency

David E. Lilienfeld

Mount Sinai School of Medicine

David C. Logan

Mobil Corp.

Robert C. MacPhail

U.S. Environmental Research Laboratory

Richard B. Mailman

University of North Carolina School of Medicine

Sandra Marquardt

Greenpeace USA

John F. McCarthy

National Agricultural Chemicals Association

Barbara McElgunn

Association for Children and Adults with Learning

Disabilities

John A. McLachlan

National Institute of Environmental Health Sciences

Donald E. McMillan

University of Arkansas

Rita B. Messing

University of Minnesota

Lakshmi Mishra

U.S. Consumer Product Safety Commission

Charles P. Mitchell

Center for Science in the Public Interest

Ira H. Monosson

American College of Occupational Medicine

Virginia C. Moser

NSI Technology Services

Warren R. Muir

Hampshire Research Associates, Inc.

Douglas L. Murray

Texas Center for Policy Studies

Robert A. Neal

Vanderbilt University School of Medicine

Herbert L. Needleman

University of Pittsburgh

Dorothy Nelkin

New York University

David A. Otto

U.S. Environmental Protection Agency

Howard G. Paster

Timmons & Co., Inc.

George H. Pauli

U.S. Food and Drug Administration

Nancy N. Ragsdale

U.S. Department of Agriculture

Imogene Sevin-Rodgers

U.S. Environmental Protection Agency

Allen Ruby

Office of Technology Assessment
334 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

Roger W. Russell

University of California, Los Angeles

Eldon P. Savage

Colorado State University

Robert A. Scala

Exxon Biomedical Sciences, Inc.

James L. Schardein

International Research & Development Corp.

Herbert H. Schaumburg

Albert Einstein College of Medicine

Brenda Seidman

Karch & Associates, Inc.

William Sette

U.S. Environmental Protection Agency

Ellen Silbergeld

Environmental Defense Fund

William Slikker

U.S. Food and Drug Administration

Thomas J. Sobotka

U.S. Food and Drug Administration

Judith P. Swazey

Acadia Institute

Letitia Tahan

U.S. Environmental Protection Agency

Hugh A. Tilson

National Institute of Environmental Health Sciences

Daniel C. VanderMeer

National Institute of Environmental Health Sciences

Charles V. Vorhees

Children’s Hospital Research Foundation

Andrea A. Wargo

Agency for Toxic Substances and Disease Registry

David E. Weill

U.S. Environmental Protection Agency

Judith Weissinger

U.S. Food and Drug Administration

Ellen Widess

Texas Department of Agriculture

Valerie A. Wilk

Farmworker Justice Fund

Ronald Wood

New York University Medical Center

Michael J. Wright

United Steelworkers of America

Richard J. Wurtman

Massachusetts Institute of Technology

Charles Xintaras

Agency for Toxic Substances and Disease Registry

Ralph Yodaiken

Occupational Safety and Health Administration

John S. Young

Hampshire Research Associates, Inc.
Appendix E

List of Contractor Documents

For this report, OTA commissioned six papers on various topics in neurotoxicology. The manuscripts

of all but one of these contract documents(*) are available from the National Technical Information Service,

5285 Port Royal Road, Springfield, VA 22161, telephone (703) 487-4650.

“Neurotoxic Pesticides and the Farmworker,” E. Widess, 1988.

“The Federal Regulatory Response to the Problem of Neurotoxicity,” J.B. Corteau, J.S, Young, and

W. Muir, Hampshire Research Associates, Inc., 1988.

“International Neurotoxicity Research: Current Activities and Future Directions,” Z. Annau, 1988.

“Assessing Human Risks Posed by Neurotoxic Substances,” Environ Corp., 1988.

“Economic Considerations in Regulating Neurotoxic Substances,” G. Provenzano, 1989.

*“ Neurotoxicity Research-Current Activities and Future Directions,” R. Wood, 1988.

-335-
Appendix F

Glossary of Terms and List of Acronyms

Glossary of Terms

Acceptable daily intake (ADI): See reference dose.

Acetylcholine: See neurotransmitter.

Acetylcholinesterase: An enzyme that catalyzes the

breakdown of the neurotransmitter acetylcholine. See

neurotransmitter.

Action level: The point at which steps must be taken to

reduce the concentration of a toxic substance in or on

food, air, or water. An action level is based on the same

criteria as a tolerance, but the action level is temporary,

until a tolerance level can be set and is not legally

binding. Compare tolerance level.

Active ingredient (of a pesticide): The component of a

chemical compound that produces the desired biochemical effect; specifically, the pesticide itself. Compare

inert ingredient.

Acute exposure: See duration of exposure, frequency of

exposure.

Administrative controls: Methods of reducing worker

exposures to occupational hazards through administrative arrangements. For example, rotating a worker

from areas of high exposures to areas of low exposures

reduces that worker’s average exposure level.

Axon: The long extension, or process, of the neuron along

which nerve impulses travel.

Axonopathy: Degeneration of axons. In centralperipheral distal axonopathy, degeneration usually

begins at the end of the axon and proceeds toward the

cell body (the cell body itself is not affected). In

central-distal axonopathy, a less common form, degeneration of the spinal cord, but not the peripheral

nervous system, occurs, Compare neuronopathy, neuropathy.

Biotransformation: The biochemical processes by which

a foreign substance is altered or metabolized by the

body (e.g., by the action of enzymes). Although

biotransformation usually results in less toxic compounds, it can result in more toxic compounds.

Blood-brain barrier: A layer of tightly juxtaposed cells

in blood vessel walls that protects much of the central

nervous system by selectively filtering out some

substances while allowing others to pass from the

blood into the brain,

Carbamate: A synthetic organic insecticide. As pesticides, carbamates are reversible inhibitors of cholinesterase.

Carcinogen: A substance that causes cancer.

Cell body: The relatively compact portion of the neuron

that contains the nucleus. Compare process.

Cell culture: Growth in the laboratory of cells isolated

from multicellular organisms. Although the cells

proliferate, they do not organize into tissue. See pure

cell culture, mixed cell culture, cell line, and cloned

cells.

Cell line: A group of malignant cells derived from a

primary culture at the time of first subculture; an

established cell line has the potential for indefinite

subculture in vitro.

Central nervous system: One of the two major divisions

of the nervous system, made up of the brain and spinal

cord. Compare peripheral nervous system.

Cerebellum: The part of the brain involved in coordination of muscles and the maintenance of equilibrium.

Cerebrum: The portion of the brain responsible for

conscious mental processes.

Cholinesterase inhibition: See acetylcholinesterase.

Chronic exposure: See duration of exposure, frequency

of exposure.

Classical neurotransmitter: See neurotransmitter.

Clinical test: Experimental use (as of drugs) on humans.

Cloned cells: Asexually produced cells, all of them

genetically identical to the original cell.

Commodity chemical: A compound produced by several

companies. Compare specialty chemical.

Consent decree: A legally binding mutual agreement

between EPA and the manufacturer of a chemical

under which the manufacturer will conduct EPAspecified tests and EPA will not require further testing,

Cost-benefit analysis: A determination of whether the

costs of regulating a toxic substance exceed the

benefits in reducing risk to health or the environment.

Both costs and benefits are measured in monetary

units. Compare risk-benefit analysis, cost-eelectiveness analysis. See risk.

Cost-effectiveness analysis: A determination of whether

the costs of regulating a toxic substance exceed the

effectiveness in reducing risks to health or the environment. Costs are measured in monetary units, effectiveness in natural units such as years of life saved,

incidence of disease averted, and days of work loss

avoided. Compare cost-benefit analysis. See risk.

Dementia: Loss of intellectual function.

Demyelination: Destruction of the myelin sheath of a

nerve. See myelin sheath.

Dendrite: Any of the branched extensions, or processes,

of the neuron along which nerve impulses travel

toward the cell body.

Developmental neurotoxicity tests: Studies of the offspring of animals exposed to toxic substances during

pregnancy and lactation in order to determine the

nature and extent of structural or functional damage to

the nervous system of the offspring.

Differentiation: The process of cells and tissues acquiring distinct characteristics during development.

Discounting: Relating costs or benefits that occur at

different times to a common basis.

Dopamine: See neurotransmitter.

-336-
Appendix F--Glossary of Terms and List of Acronyms ● 337

Dosage: The amount, frequency, and number of doses

administered in a test.

Dose: The amount of a substance absorbed in a unit

volume or in an individual. Dose rate is the dose

delivered per unit of time.

Dose-response: The quantitative relationship between

exposure to a substance, usually expressed as a dose,

and the extent of toxic injury or disease.

Duration of exposure: The length of time a person or test

animal is exposed to a chemical. Duration of exposure

is divided into four categories: acute (exposure to a

chemical for less than 24 hours), subacute (exposure

for 1 month or less), subchronic (exposure for 1 to 3

months), and chronic (exposure for more than 3

months). See frequency of exposure.

Economic efficiency: The ‘state in which the greatest

direct and indirect gains (benefits) are derived from the

resources expended (costs) to achieve a stated objective. Compare net efficiency.

Efficiency: See economic efficiency.

Electromyography, EMG: Recording and measuring

the electrical activity of muscles by means of an

electromyograph. Electromyography is used in testing

the effects of neurotoxic substances on humans.

Electroneurography, ENG: Recording and measuring

the electrical signals generated by nerves by means of

an electromyograph. Electroneurography is used in

testing the effects of neurotoxic substances on humans.

Electrophysiology: Measuring and recording the electrical activity of the brain or nerve cells by means of

electrodes.

Encephalopathy: Degeneration of the brain.

Endpoint: The disease, conditions, or adverse effect

resulting from exposure to a toxic substance (e.g.,

memory loss, paralysis, dizziness, anxiety).

Engineering controls: Methods of controlling worker

exposure by modifying the source or reducing the

amount of contaminants released into the workplace.

These include process design and modification, equipment design, enclosure and isolation, and ventilation.

Environmental hypothesis: The theory that exposure to

toxic substances contributes significantly to neurological disorders such as Parkinson’s disease, Alzheimer’s

disease, and amyotrophic lateral sclerosis (Lou

Gehrig’s disease).

Epidemiology: The study of the distribution of diseases

and their precursors in human populations.

Evoked potentials, sensory evoked potentials (EPs):

Electrical signals generated by the nervous system in

response to a stimulus, whether auditory (brainstem

auditory evoked responses, BAERs), visual (visual

evoked potentials, VEPs, which include flash evoked

potentials, PEPs, and pattern reversal evoked potentials, PREPs), or somatosensory (somatosensory evoked

potentials, SEPs). EPs can be measured and the

measurements used to identify which senses are

affected by neurotoxic substances and how they are

affected. See electrophysiology.

Explant culture: Tissue taken from its original site and

placed in an artificial medium for growth.

Experimental use permit (EUP): An application to EPA

by a manufacturer for permission to conduct fieldtests

on a pesticide.

Exposure: The accidental or intentional contact of a

person or animal with a substance, specifically a toxic

substance. Exposure is measured by the amount of the

substance involved (dose), how often and for how long

contact took place (frequency and duration of exposure), and the means through which contact occurred

(route of exposure). See dose, duration of exposure,

frequency of exposure, route of exposure.

Frequency of exposure: The number of times a person or

test animal is exposed to a chemical. Acute exposures

“are generally single exposures, whereas subacute,

subchronic, and chronic exposures are repeated exposures. See duration of exposure.

Functional observational battery (FOB): A collection

of noninvasive tests to evaluate sensory, motor, and

autonomic dysfunction in test animals exposed to

substances or whose nervous systems have been

damaged, FOBS are generally used to screen for

neurotoxic substances. See screening test.

Ganglion: A collection of nerve cells outside the brain or

spinal cord.

Glia, glial cells: The second basic cell type of the nervous

system. Glia perform support functions for neurons:

namely, nutrition, insulation (through the production

of myelin), and structural support. Compare neuron.

Hazard: The likelihood that a pesticide will cause

immediate or short-term adverse effects or injury

under ordinary circumstances of use.

Hen test: An observational assay in which the observer

ranks the animals’ motor ability.

Hydrophilic: Having an affinity for water; that is, soluble

in water. These substances may also be termed

lipophobic, or insoluble in lipids.

Hydrophobic: Insoluble in water; these substances may

also be termed lipophilic.

Inert ingredient (of a pesticide): The solvent or “inactive” solid that dilutes or carries a pesticide; inert

ingredients are so called because they have no effect on

the targeted pest, not because they are inherently

inactive. An inert ingredient as defined by EPA can, in

some cases, cause adverse effects on human health.

Inorganic: Matter generally not containing carbon (i.e.,

not animal or plant matter). Compare organic.

Integrated pest management (IPM): A system for

controlling pests in which pesticides are used in

conjunction with biological controls (natural predators

and parasites, disease-causing microorganisms, pheromones, pest-resistant plants) and cultural controls

(crop rotation, removal of pest-harboring crop residues
338 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

after harvest).

Investigational new drug (IND): Application to FDA by

a manufacturer for permission to conduct clinical trials

on a drug.

In vitro test: Experiment using cells, tissues, or explants

grown in a nutritive medium as a model system in

toxicity testing rather than using living animals or

human beings. Toxicity is assessed by adding a test

substance to the culture and observing any changes

that occur. See cell culture, tissue culture, explant

culture.

In vivo: Literally, in the living; pertaining to a biological

process or reaction taking place in a living cell or

organism.

Latent effect: A reaction to a toxic substance that is not

immediately evident but that appears later in life; also

referred to as a silent effect.

Lipids: Fat-like substances that are an important constituent of cell structure; the nervous system is composed

of high concentrations of lipids.

Lipophilic: Having an affinity for lipids; that is, soluble

in fat-like material, These substances may also be

termed hydrophobic, or insoluble in water. Many toxic

substances are lipophilic, making them especially

dangerous to the nervous system. See lipids.

Margin of exposure: See margin of safety.

Margin of safety: Division of the NOEL or NOAEL by

the current, desired, or most feasible human exposure

level. See NOEL, NOAEL.

Maximum allowable concentration (MAC): The limit

on atmospheric contaminants in manned spacecraft for

missions of up to 7 days; set by the National

Aeronautics and Space Administration.

Maximum contaminant level (MCL): An enforceable

standard set by EPA for pollutants in drinking water,

to be set as close as possible to the maximum

contaminant level goals. See maximum contaminant

level goals, recommended maximum contaminant

level.

Maximum contaminant level goal (MCLG): Nonenforceable goal set by EPA for pollutants in drinking

water. MCLGs for carcinogenic pollutants are set at

zero; goals for noncarcinogenic pollutants are set by

establishing the lowest dose at which harmful effects

can be observed, compensating for uncertainties, and

calculating predicted human exposure from food and

air. See maximum contaminant level.

Me-too registration: A practice by which subsequent

products that are identical to an initial, registered

product can be registered without undergoing regulatory tests.

Mixed cell culture: A culture of more than one type of

cell.

Mixed neuropathy: Degeneration of both sensory and

motor neurons.

Motor activity tests: Observation and evaluation of the

movements of test animals after acute or subchronic

exposures to a substance; used as a screen for

neurotoxic substances. See screening test.

Motor neuron: See neuron.

Mutagenic: Causing increases in the mutation of genes.

Myelin: A fatty substance (of which the myelin sheath

surrounding axons is made) that acts as an electrical

insulator to speed the conduction of nerve impulses.

Myelin is formed in the peripheral nervous system by

Schwann cells and in the central nervous system by

glial cells.

Myelin sheath: Concentric layers of myelin surrounding

the axons of some neurons. The myelin sheath speeds

the conduction of electrical impulses.

Myopathy: Degeneration of muscle fiber.

Narcosis: Nonspecific, reversible depression of central

nervous system function, marked by stupor or unconsciousness and produced by drugs.

National primary drinking water regulations (NPDWRs):

Enforceable standards for contaminants in drinking

water set by EPA that include maximum contaminant

levels or required treatment techniques, or both. See

maximum contaminant level.

Net efficiency: The difference between direct benefits and

direct costs, generally in regard to regulation.

Neuromuscular junction: The site at which chemical or

electrical information is transmitted from a nerve cell

to muscle fiber. Compare synapse.

Neuron, nerve cell: The basic functional unit of the

nervous system. The neuron is typically composed of

a relatively compact cell body containing the nucleus,

several short radiating processes (dendrites), and one

long process (the axon) with branches along its length

and at its end. Information in the form of electrical

impulses travels from the cell body along these

processes to other cells. Sensory neurons send information to the brain and spinal cord; motor neurons

send instructions to the muscles. See axon, dendrite.

Neuronopathy: A primary damage to the nerve cell body

which results in a rapid, but secondary, degeneration of

nerve processes.

Neuropathological tests: Postmortem examination of

test animals in order to determine changes in the

structure and function of the nervous system as a result

of exposure to a toxic substance. These tests may be

used to screen for toxic substances. See screening test.

Neuropathy: Degeneration of nerve cells; a general

description for any disease of the peripheral or central

nervous system.

Neuropeptide: See neurotransmitter.

Neurophysiological tests: Techniques for measuring the

electrical signals, or evoked potentials, of charged

ions; the measured potentials reflect the functioning of

the neuron or neurons that generated them. See

electrophysiology, evoked potentials.

Neurotoxic esterase (NTE) assay: A procedure for
Appendix F--Glossary of Terms and List of Acronyms ● 339

measuring the inhibition of the enzyme NTE in the

brain or spinal cord of hens exposed to organophosphates. The test can be used to determine the

delayed effects of acute and subchronic exposures to

organophosphates. See organophosphates.

Neurotoxicant, neurotoxic substance: A chemical that

adversely affects the nervous system.

Neurotoxicity, neurotoxic effect: An adverse change in

the structure or function of the nervous system

following exposure to a toxic substance.

Neurotoxicology: Study of the effects of toxic chemicals

on the nervous system, including the modes by which

neurotoxic substances enter the body, the effects these

substances have on the nervous system, the biochemical and physiological mechanisms through which the

effects occur, the prevention of damage to the nervous

system, and the treatment of neurological and psychiatric disorders caused by exposure.

Neurotransmitter: Specialized chemical messenger synthesized and secreted by neurons to convey information from one nerve cell to another (serotonin, norepinephrine, dopamine) or from a nerve cell to muscle

fiber (acetylcholine). Neurotransmitters act on the

receptors of other cells: classical neurotransmitters

(e.g., the four mentioned above) typically interact with

receptors of adjacent cells; neuropeptides (e.g., the

endorphins and vasopressin) may transmit messages to

receptors on distant cells. See receptor.

New drug application (NDA): Submission of evidence,

including results of clinical trials, to FDA by a

manufacturer that a drug is both safe and effective.

Approval of the NDA is required before the drug can

be marketed. Compare investigational new drug.

NOAEL, no observed adverse effect level: That dose

below which no adverse effect is observed. Compare

NOEL.

No-effect levels: See NOEL, NOAEL, threshold.

NOEL, no observed effect level: That dose below which

no effect of any sort is observed. Compare NOAEL,

threshold.

Norepinephrine: See neurotransmitter.

No-threshold: The situation in which any dose greater

than zero increases risk. Compare threshold.

Oligodendrocyte: A type of glial cell that appears to play

a role in myelin formation in the central nervous

system. Compare Schwann cell. See glia.

Opportunity cost: The value of alternative endeavors

that might have been undertaken with the resources

used for the particular endeavor chosen.

Organ culture: A type of tissue culture in which a whole

organ is maintained in vitro.

Organic: Matter containing carbon (i.e., animal or plant

matter). Compare inorganic.

Organic farming, organic production: Farming without

the use of or with limited use of chemical pesticides or

fertilizers.

Organic solvents: Generic name for a group of simple

organic liquids that are volatile (that is, in the presence

of air they change from liquids to gases) and therefore

are easily inhaled.

Organoleptic: Stimulating any of the organs of sensation

or susceptible to a sensory stimulus.

Organophosphates, organophosphorous pesticides: A

class of pesticides with neurotoxic properties; organophosphates have also been used as nerve gases.

Organotypic culture: A type of primary tissue culture in

which the structure of the original organ is maintained

in vitro. This method is useful in neurotoxicity studies

because the connections and spatial relations between

neurons and glia can be maintained.

Pattern of exposure: The dose, duration, frequency, and

route of exposure; used in risk assessment. See dose,

duration of exposure, frequency of exposure, route of

exposure.

Peripheral nervous system: One of the two major

divisions of the nervous system, made up of the nerves

connecting the spinal cord and sensory organs, glands,

blood vessels, and muscles. Compare central nervous

system.

Permissible exposure limit (PEL): The maximum exposure to a given chemical that an industrial worker is

allowed during an 8-hour workday and 40-hour

workweek, set by the Occupational Safety and Health

Administration. Compare reentry interval.

Personal protective equipment: Equipment and clothing designed to control hazards: it includes hard hats,

safety shoes, protective eyewear, and various types of

respirators.

Pesticide: A generic term referring to toxic substances

developed to control pests; it includes insecticides,

fungicides, rodenticides, and herbicides.

Potentiation: The process through which a nontoxic

substance increases the toxicity of another substance.

Preclinical test: Experimental testing (as of drugs) on

animals.

Presumption of risk: The probability that an existing

hazard, combined with the potential for human exposure to it, creates risk. Compare risk assessment.

Primary culture: Cell, tissue, or organ culture initiated

directly from an organism rather than from another

culture. Compare explant culture.

Prior informed consent (with respect to pesticides):

Agreement on the part of one government to import a

pesticide banned or severely restricted by another

government in full knowledge of the reasons for that

ban or restriction.

Processes, nerve processes: Extensions of the neuron,

whether axons or dendrites, along which nerve impulses travel. Compare cell body.

Receptor: Sensory neuron terminal; also, a molecule in

the cell membrane that recognizes and combines with

a specific chemical substance, such as a neurotransmit-
340 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

ter. See neurotransmitter.

Recommended exposure limit (REL): Standard for

maximum exposure of industrial workers to toxic

substances, set by the National Institute for Occupational Safety and Health. Compare permissible exposure limit, threshold limit value.

Recommended maximum contaminant level (RMCL):

Nonenforceable goals set by EPA for pollutants in

drinking water; renamed maximum contaminant level

goal. See maximum contaminant level goal, maximum

contaminant level.

Red Book: Guidelines for toxicological testing of direct

food additives and color additives used in food under

the Federal Food, Drug, and Cosmetic Act published

by the Center for Food Safety and Applied Nutrition of

FDA,

Reentry interval: The time that must elapse between

application of a pesticide and the return of agricultural

workers to the treated area without special protection.

Reference dose (RfD): A term used to characterize risk

and derived by applying safety factors to NOELs or

NOAELs. If human exposure to a substance is below

the RfD, no risk is assumed to exist; if exposure

exceeds the RfD, risk is assumed to exist. The term

may be used interchangeably with acceptable daily

intake, although EPA uses the term RFD. See NOEL,

NOAEL.

Reuptake: Process by which neurotransmitters and their

metabolizes are recycled.

Right-to-know laws: State and local laws requiring

companies to inform workers and communities of the

chemical names and hazards of their products.

Risk: The probability of injury, disease, or death for

persons or groups of persons undertaking certain

activities or exposed to hazardous substances. Risk is

sometimes expressed numerically (as a fraction) and

sometimes qualitatively (e.g., high, moderate, or low).

Risk assessment: The analytical process by which the

nature and magnitude of risk are identified. Four steps

make up a complete risk assessment: hazard identification, dose-response assessment, exposure assessment

and risk characterization. Compare risk management,

presumption of risk. See risk, exposure, doseresponse.

Risk-benefit analysis: A determination of whether the

risks to health and the environment of using a chemical

or drug exceed the economic benefits that accrue from

its use. In the case of pesticides, benefits are measured

in terms of the monetary value of crop yields; in the

case of drugs, benefits are measured in terms of

therapeutic efficacy.

Risk management: The process of determining whether

or how much to reduce risk through regulatory action.

Decisions depend on data from risk assessments and

may also depend on political, social, ethical, economic, and technological factors.

Route of exposure: The means by which a person or

animal comes into contact with a chemical: namely,

intravenous (injected into the bloodstream), inhalation

(through the lungs), oral (through ingestion), and

dermal (through the skin).

Safety factor: Division of the NOEL or NOAEL and

succeeding measures by a factor, typically 10, to yield

a reference dose; used interchangeably with uncertainty factor. Safety factors account for uncertainties in

the extrapolation of data from, for example, short- to

long-term exposures, and animals to humans.

Scaling factor: Weighting disparate measures of health

outcomes for cost-effectiveness analysis on the basis

of value judgments concerning their relative worth.

Schedule-controlled operant behavior (SCOB): A test

in which an experimental animal’s response to a

stimulus is reinforced on a predetermined schedule in

order to produce a predictable pattern of behavior.

SCOB is used to evaluate the effects of acute or chronic

exposure to toxic substances on the rate and pattern of

the animal’s responses.

Schwann cell: A glial cell in the peripheral nervous

system that produces myelin for the myelin sheath.

Compare oligodendrocyte.

Screening test: Broad-based initial test of a chemical

designed to detect adverse health effects. Screening

can help determine what further tests should be

performed to evaluate a substance’s toxicity.

Sensitivity analysis: Deliberately varying the uncertainties in an assessment in order to examine their effects

on the decision taken.

Sensory neuron: See neuron.

Serotonin: See neurotransmitter.

Silent effect: See latent effect.

Specialty chemical: A compound produced by only one

company. Compare commodity chemical.

Structure-activity relationship: The relationship between a chemical’s structure and the biochemical

changes it induces.

Subchronic exposure: See duration of exposure, frequency of exposure.

Synapse: The site at which chemical or electrical

information is transmitted from one nerve cell to

another, typically by a neurotransmitter. Compare

neuromuscular junction. See neurotransmitter.

Synaptic cleft: A narrow gap between two adjacent

neurons into which neurotransmitters are secreted. See

neurotransmitter.

Synergism: The state in which the combined adverse

effects of a chemical exceed the sum of the effects of

each chemical acting alone.

Teratogenic: Producing defects in the developing embryo. (A substance that causes physical defects in the

offspring.)

Test rule: A statement written by EPA of what chemical

or chemicals in a compound must be tested by the
Appendix F-Glossary of Terms and List of Acronyms . 341

manufacturer and how they are to be tested. Test rules

are written under the Toxic Substances Control Act

when it can be shown both that inadequate data on the

effects of a compound exist and that testing is required

to obtain such data.

Threshold: The highest dosage at which no effect is

observed. Compare no-threshold.

Threshold limit value (TLV): That concentration (by

volume in air) of a hazardous substance to which the

majority of industrial workers may be repeatedly

exposed every day without adverse effects; set by the

American Conference of Governmental Industrial

Hygienists. Compare reference dose.

Tiered testing: A strategy for identifying the toxicological effects of a substance by proceeding from general

toxicity tests to progressively more specific and

sophisticated tests.

Time-weighted average: An average over a given

(working) period of a person’s exposure, as determined by sampling at given times during the period.

Tissue culture: The maintenance or growth of tissue,

organs, or cells in vitro. Tissue culture can be

subdivided into cell culture and organ culture. See cell

culture, organ culture.

Tolerance level: The maximum permissible concentration of a toxic substance in or on food, water, or air, as

set by a regulatory agency. Compare action level.

Toxicology: The study of adverse effects of natural or

synthetic chemicals on living organisms.

Uncertainties: Questions involved in risk assessment,

ranging from fundamental questions (e.g., How useful

are animals as predictors of toxicity in humans?) to

specific questions arising from incomplete or imperfect data on a particular substance (e.g., Do responses

differ with route of exposure? What exposures are

likely for various populations?).

Uncertainty factor: See safety factor.

List of Acronyms

ACGIH —American Conference of Governmental

Industrial Hygienists

ADAMHA —Alcohol, Drug Abuse, and Mental Health

Administration

ADI —acceptable daily intake

AETT —acetylethyl tetramethyl tetralin

ALS —amyotrophic lateral sclerosis

ATSDR —Agency for Toxic Substances and Disease

Registry

AZT —azidothymidine

BAER —brainstem auditory evoked response

BHC —benzene hexachloride

BHMH —Lucel-7

BPI —Bureau of Plant Industry (Philippines)

CAA -Clean Air Act

CAP -Consumers Association of Penang

(Malaysia)

CBI

CDC

CEH

CERCLA

CFSAN

CIIT

COHb

CPDA

CPSA

CPSC

CSA

CSPI

CWA

DBCP

DHHS

DOE

EDB

EEC

EEG

EMG

ENG

EP

EPA

EPN

EUP

FAO

FDA

FEA

FEP

FFDCA

FHSA

FIC

FIFRA

FIOH

FLT

FMSHA

FOB

FPA

FWPCA

GAO

GFAP

HCH

HHANES

HUD

IND

IPM

IRIS

-confidential business information

-Centers for Disease Control

—Center for Environmental Health

-Comprehensive Environmental Response,

Compensation, and Liability Act

—Center for Food Safety and Applied

Nutrition (FDA)

—Chemical Industry Institute of Toxicology

-carboxyhemoglobin

-central-peripheral distal axonopathy

—Consumer Product Safety Act

—Consumer Product Safety Commission

—Controlled Substances Act

—Center for Science in the Public Interest

—Clean Water Act

-dibromochloropropane

—Department of Health and Human

Services

—Department of Energy

--ethylene dibromide

—European Economic Community

-electroencephalograph

-electromyography

-electroneurography

-evoked potential

—Environmental Protection Agency

-ethyl-p-nitrophenyl phosphonothionate

—Experimental Use Permit

—Food and Agriculture Organization

(United Nations)

—Food and Drug Administration

—Federal Environmental Agency (West

Germany)

—flash evoked potential

—Federal Food, Drug, and Cosmetic Act

—Federal Hazardous Substances Act

—Fogerty International Center

—Federal Insecticide, Fungicide, and

Rodenticide Act

—Finland Institute of Occupational Health

—fenvalerate

—Federal Mine Safety and Health Act

—functional observational battery

—Fertilizer and Pesticide Authority

(Philippines)

—Federal Water Pollution Control Act

—General Accounting Office

—glial fibrillary acidic protein

—hexachlorocyclohexane

—Hispanic Health and Nutrition

Examination Survey

—Department of Housing and Urban

Development

—investigational new drug

—integrated pest management

—Integrated Risk Information System
342 ● Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

ITC

LBPPPA

LMIN

MA

MAC

MCL

MCLG

MCPA

MNAF

MnBK

MND

MOE

MOS

MPRSA

MSHA

MPTP

MTBE

NAPARE

NAS

NASA

NBS

NBT

NCHS

NCTB

NCTR

NDA

NFPA

NHANES

NHLBI

NIA

NIAAA

NIAID

MDA

NIEHS

NIGMS

NIMH

NINCDS

—Interagency Testing Committee

—had-Based Paint Poisoning Prevention

Act

—Laboratory of Molecular and Integrative

Neuroscience (NIEHS)

—motor activity

—maximum allowable concentration

—maximum contaminant level

—maximum contaminant level goal

—2-methyl-4-chlorophenoxyacetic acid

—Ministry of Nutrition, Agriculture, and

Forest (West Germany)

—methyl-n-butyl ketone

—motor neuron disease

—margin of exposure

—margin of safety

—Marine Protection, Research, and

Sanctuaries Act

—Mine Safety and Health Administration

—l-methyl-4-phenyl- 1,2,3,6-

tetrahydropyridine

—methyl-tert-butyl ether

—National Association for Perinatal

Addiction Research and Education

—National Academy of Sciences

—National Aeronautics and Space

Administration

—National Bureau of Standards

—Neurobehavioral Toxicology Team

—National Center for Health Statistics

—Neurobehavioral Core Test Battery

—National Center for Toxicological

Research

—new drug application

—National Food Processors Association

—National Health and Nutrition

Examination Survey

—National Heart, Lung, and Blood Institute

—National Institute on Aging

—National Institute on Alcohol Abuse and

Aging

—National Institute of Allergy and

Infectious Diseases

—National Institute on Drug Abuse

—National Institute of Environmental

Health Sciences

—National Institute of General Medical

Sciences

—National Institutes of Health

—National Institute of Mental Health

—National Institute of Neurological and

Communicative Disorders and Stroke

NIOSH

NLM

NOAEL

NOEL

NPDWR

NRC

NRDC

NTD

NTE

NTP

OECD

OPP

OSH Act

OSHA

OTA

OTS

PAN

PCB

PCP

PDDP

PEL

PIC

PMN

PPPA

PREP

RCRA

REL

RfD

RMCL

RQ

SAP

SARA

SCOB

SDWA

SEP

SMSA

SNUR

STEL

TDM

TLV

TRI

TSCA

TWA

USDA

USDJ

WHO

—National Institute for Occupational Safety

and Health

—National Library of Medicine

—no observed adverse effect level

—no observed effect level

—national primary drinking water

regulations

—National Research Council

—Natural Resources Defense Council

—Neurotoxicology Division (EPA)

—neurotoxic esterase assay

—National Toxicology Program

-Organization for Economic Cooperation

and Development

-Office of Pesticide programs (EPA)

-Occupational Safety and Health Act

-Occupational Safety and Health

Administration

-Office of Technology Assessment

-Office of Toxic Substances (EPA)

—Pesticide Action Network

—polychlorinated biphenyl

—phencyclidine; pentachlorophenol

diisodecyl phenyl phosphite

—permissible exposure limit

—prior informed consent

—premanufacture notice

—Poison Prevention Packaging Act

—pattern reversal evoked potentials

—Resource Conservation and Recovery Act

—recommended exposure limit

—reference dose

—recommended maximum contaminant level

—reportable quantity

—Science Advisory Panel

—Superfund Amendments and

Reauthorization Act

—schedule-controlled operant behavior

—Safe Drinking Water Act

—somatosensory evoked potential

—Standard Metropolitan Statistical Area

—significant new use rule

—short-term exposure limit

—triadimeform

—threshold limit value

—triphenyltin

—Toxics Release Inventory

—Toxic Substances Control Act

—time-weighted average limit

—U.S. Department of Agriculture

—U.S. Department of Justice

—World Health Organization
Index

abused drugs

addiction, 6, 52,74, 75

designer drugs, 51

effects on nervous system, 6,9, 51–53, 71

health costs of, 20,53,232

psychoactive drugs, 6, 10,27,44,50

withdrawal from, 74

see also specific drugs

academic research

cooperative agreements with government, 94

factors influencing directions of, 92-94

acetaldehyde, 297

acetone, 14, 136,296, 297,303

acetylcholine, 26, 66, 109, 124,294, 336

acetylcholinesterase, 11,50,74,84,187,203, 289,290-292,336

acetylethyl tetramethyl tetralin (AETT)

exposure route, 108

incidents of poisoning, 47, 54

neurological effects of, 54

acrylamide, 73, 120

neurotoxicity testing, 166, 175

regulation for neurotoxicity, 178

risk assessment approaches, 150, 151,216

research on neurotoxicity, 258

acrylates, 175

acrylonitrile, 203

neurotoxicity testing, 166, 173

OSHA health standards, 185

action levels for contaminants in foods, 164, 241–242, 336

“Adam,” 51

Administrative Procedure Act, 162

age/aging

and exposure to neurotoxic substances, 269

as a factor in animal studies, 107

nervous system effects of, 8, 15, 54, 67, 152

and neurobehavioral tests, 126

and toxicity of chemicals, 15, 63, 152

see also children; elderly

Agency for Toxic Substances and Disease Registry, 135–136

research activities of, 9, 11, 89, 188, 271, 322

Agent Orange, 295

Agricultural Pesticide Institute of the Philippines, 252

air pollutants

hazardous, defined, 181

lead, 273–274, 276,281

standards for, 181, 182, 185

see also Clean Air Act

Alar, 291

Alaskan Marine Mammal Tissue Archival Project, 133

alcohol and alcohol abuse, 4,44, 115

axonopathic effects, 73

effects on fetus, 70, 124

research on, 9, 11

thiamine deficiency and toxicity of, 71

Alcohol, Drug Abuse, and Mental Health Administration

(ADAMHA), research

-i

activities of, 33, 81, 88, 322

aldicarb, 47, 173,251

aldrin, 250,252,292

allyl chloride, 303

aluminum, 48

and Alzheimer’s disease, 54-55

oxide, 14, 136

Alzheimer’s disease

effects on hippocampus, 71

environmental cause, 3, 6, 54-55, 70, 72

research on, 259

American Academy of Pediatrics, 189

American Conference of Governmental Industrial Hygienists,

28, 151, 185, 186,203,302-303

American National Standards Institute, 185

ammonia, 14, 136

amphetamines, 74

amyotrophic lateral sclerosis

characteristics of, 54

environmental cause, 3, 6, 54-55, 70, 72

incidence of, 54, 55

research on, 259

anencephaly, 70

anilines and substituted anilines, 179

animal tests, 13

accuracy and reliability, 106, 115

advantages and limitations of, 105, 106, 111, 112, 114, 116,

120-121, 136, 137

alternatives to, 121–125; see also in vitro neurotoxicity tests

of BHMH, 55–56

biochemical markers, 117

choice of animals, 106-107, 109-110, 121, 152

in combination with in vitro tests, 13, 122, 124

cost factors, 106-107, 110, 222–225, 226227

cross-species comparisons, 115–1 16, 121, 148

design, 105, 106-109,222

developmental neurotoxicology, 110, 111, 114-116, 137,

165-166, 178

dosing regimen, 107, 110, 147-148

comparability with human testing, 115

EPA guidelines, 110

evaluating chemicals for neurotoxicity, 109-110

extent and duration of exposure, 108, 222, 225, 226

extrapolation to humans, 18,82, 105, 121, 147, 148, 149, 153,

204

of food additives, 52

functional observational battery, 110,11 1–1 12,136,137,178,

224-225,226

hazard identification with, 147

housing conditions, 108-109

innovation impacts of, 226-227

longitudinal, 107

of MDMA, 51–52

motor activity, 110, 11 1–1 14, 136, 137, 178,224-225, 226

Motron Electronic Mobility Meter, 113

multispecies, 107

-343-
344 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

neuropathological examination, 110, 111, 114, 136, 137, 178,

224-225,226

neurophysiology techniques, 118–121

neurotoxic esterase assay, 111, 136-137, 178

nutritional status of animals, 108

observational methods, 112–1 13

for organophosphorous pesticides, 110, 117-118

quality assurance in, 222-223

route of exposure, 108, 121, 222, 225

schedule-controlled operant behavior, 110, 111, 116–1 17,

136, 137, 178,224-225

temperature of environment, 109

tiered approach, 109-110

types of, 110-121

validation of, 109

antagonism, 65

antibiotics, 45, 70, 123, 125

anticancer drugs, 51, 73

antipsychotic drugs, 44, 50

Apiol (with TOCP), incidents of poisoning, 47

Argentina

research on neurotoxicity, 258

use of banned pesticides in, 239

arsenic, 133, 182, 183, 185

aryl phosphates, 179

asbestos, 176, 180, 182

aspartame, 166, 198

application process, 315–318

claims of adverse effects, 18, 318–319

postmarketing surveillance, 318

aspartate, 71

Association of People for Practical Life Education, 252

astrocytes, 117

attentional disorders, 70, 229, 273

auditory system

substances affecting, 49, 119, 131, 135,272

testing of, 119

Australia, use of banned pesticides in, 239

axonopathy

causative agents, 73–74

defined, 67,336

axons, 72

development of, 67

effects of toxic substances on, 67, 69, 73, 295

functions of, 65-66,336

azidothymidine, 167

barium, 183

Basic Document on Regulations of Registration, Marketing and

Control of Agricultural Chemicals for Countries of

Central America, 253-254

Bayley Scales of Infant Development, Mental Development

Index, 155

behavioral effects, 70

Collaborative Behavioral Teratology Study, 115

defined in TSCA, 174

duration of exposure and, 70

EPA research on, 82

examples of, 46

of lead, 46, 229–230, 272, 273

of organic solvents, 298–299

of pesticide poisoning, 285

research needs on, 154

tests for, see neurobehavioral tests

see also operant behavior

behavioral teratology, 70, 114-116

Belgium, regulatory policies in, 246-247

Benton Visual Retention Test, 127

benzene, 14, 135, 136, 182,297,303

beryllium, 182

BHC, 252

BHMH, incidents of poisoning, 47,55-56

biochemical markers, 11,82, 84, 117

biological monitoring, 133-134

blood-brain barrier

drug passage through, 66-67

fetal, 70

structure and function, 336, 66-67, 73

blood vessels, neurotoxic substances acting on, 74,76

botulinum toxin, 45

Bourdon Wiersma Vigilance Test, 127

brain

aging, and structure of, 15, 67, 152

congressional resolution on Decade of the Brain, 330–331

development of, 67

opioid receptors, 74

regional differences in sensitivity to toxic substances, 68

structure and function, 66

brain damage

from abused drugs, 51,70

from lead, 271

from mercury, 131

from pesticides, 291

brainstem auditory evoked responses, 119, 128

Brazil, pesticide misuse in, 251

buckthorn (Karwinskia humboldtiana), 74

B-bungarotoxin, 124

Bureau of Community Environmental Management, 277

n-butyl alcohol, 14, 136

cadmium, 48, 68, 74

monitoring of, 133, 134

research on, 257

California Birth Defects Prevention Act of 1984,289-290

camphechlor, 250

Canada

human tissue monitoring, 132

regulatory policies and practices in, 245

research on neurotoxicity, 258

carbamate insecticides, 26,49,74, 175,287, 289–291, 293,295,

336

carbon disulfide

exposure limits for, 187, 303

neurological effects of, 73, 108, 298, 299

poisoning incidents, 256

releases, 14, 136

carbon monoxide

air quality standards, 181, 182

central nervous system effects, 181, 187

poisoning, 64,69, 181

research on neurotoxicity, 258

carbon tetrachloride, 297

carbonyl sulfide, 14, 136

carcinogenicity, 56
Index ● 345

cassava (Manihot esculenta), 55

cell cultures

defined, 123,336

mixed, 338

monolayer, 124

muscle cells, 124

retinal neurons, 124

cell lines, 124, 125, 336

Center for Environmental Health, research activities of, 90-91

Center for Science in the Public Interest, 192

Centers for Disease Control

acceptable levels for lead, 271

human monitoring program, 133

lead poisoning prevention program, 277

research activities of, 9, 11, 12, 81, 322

central distal axonopathy, 74

central nervous system, 336

degeneration, 72

depression of activity, 108

lead effects on, 272

pesticide effects on, 284-285

structure, 66

central-peripheral distal axonopathy, 67, 73–74

cerebellum, 67, 70, 72, 336

cerebral palsy, 49

cerebrum, 70, 336

charitable organizations, research by, 97

Chemical Industry Institute of Toxicology, 123-124

Chemical Specialties Manufacturing Association, 220

chemicals

commercial, see industrial chemicals

consumer, 17

diversity of new products, 227

high production, high exposure, 17, 178-179, 195, 197,202,

204,227

licensing and registration of, 174-180, 197,202

low production, low exposure, 178,227-228

neurotoxic, classes of, 175

neurotoxicity tests and innovation in, 227–228

new v, existing, consistency of regulation, 17, 18, 196-198

patent protection, 226

premanufacture notices, 17, 174-176, 194, 196, 197, 201-

202,219-220,227,247

priorities for testing, 178

reporting of harmful effects of, 180, 197

significant new use rule, 174

subject to neurotoxicity evaluation under TSCA, 179, 202

testing of, 174-175, 232

see also neurotoxic substances; organic solvents; and specific

chemicals

chemoreceptors, 65

children

lead poisoning in, 7,8,46,70,72-73,181, 229,267,268-271,

273,275,278

mental disorders in, 8, 45, 70, 73

number exposed to lead, 269, 271

pesticide risks to, 25,283,284,293,295

vulnerability to neurotoxic substances, 8, 45, 267, 268, 283

chlordane, 238–239, 250, 252, 292

chlordecone, incidents of poisoning, 47, 50, 293

chlordimeform, 120, 250

chlorine, 14, 136

chlorofluorocarbons, neurotoxicity testing, 166

chloroform, 14, 136, 303

chloroquine, 124

chlorphenoxy herbicides, 294-295

cholinesterase inhibitors, see acetylcholinesterase; organophosphorous pesticides

chromium, 133

Clean Air Act, 135

1970 amendments, 180

amendments proposed, 26, 182, 280

cost-benefit analysis under, 216

definition of hazardous air pollutant, 181

lead regulation under, 273

regulatory authority, 23, 160, 162

risk assessment approach, 160

standard setting under, 180-182

toxic substances regulated by, 160

Clean Water Act, 26

regulatory authority, 16, 23, 160

risk assessment approach, 160

standard setting under, 180, 182–183, 187

toxic substances regulated by, 160

clioquinol, incidents of poisoning, 47, 74

cocaine, 9, 44, 115

effects on nervous system, 6, 52, 74-75

fetal effects of, 10,53,70,74

Codex Alimentarius Commission, 242

cognitive effects

of carbon monoxide poisoning, 181

detection of, 70

examples of, 46

of lead poisoning, 44, 70, 181, 269,273

of pesticide poisoning, 285

Cognitive Scanner, 128

Colombia, use of banned pesticides in, 239,243

Color Additive Amendments of 1960, 165

color additives, see food and color additives

Comprehensive Drug Abuse Prevention and Control Act, 188

Comprehensive Environmental Response, Compensation, and

Liability Act (CERCLA), 26, 198

control measures under, 187–188, 280-281

regulatory authority, 16, 23, 161

risk assessment approach, 161

toxic substances regulated by, 161,280-281

see also Superfund Amendments and Reauthorization Act

computer-based testing, 127–128, 137

confidentiality, trade secret protection and testing, 19, 25, 176,

202,218,226,288

Consumer Product Safety Act (CPSA), 172

regulatory authority, 16, 160

reporting requirements for adverse effects, 204

risk assessment approach, 160

standard setting under, 180, 184

toxic substances regulated by, 160

Consumer Product Safety Commission (CPSC), 176

in vitro testing by, 122

policy issues and options for, 31

regulatory authority of, 160, 161, 184, 190, 191, 268

research activities of, 323

risk assessment applications, 150

standard setting by, 184, 276

Consumers Association of Penang, 252
346 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

control-oriented measures

under CERCLA, 187–188

under Controlled Substances Act, 188

economic incentives, 161

features of laws, 159, 161

under bad-Based Paint Poisoning Prevention Act, 189–191

under Marine Protection, Research, and Sanctuaries Act,

188-189

under Poison Prevention Packaging Act, 189–191

regulatory approach, 16, 159

under Resource Conservation and Recovery Act, 191

Controlled Substances Act

control measures under, 187, 188

regulatory authority, 16, 161

risk assessment approach, 161

toxic substances regulated by, 161

cosmetics

antidandruff shampoos, 108

color additives in, 165

dermal exposure to toxic substances, 108

fragrances, 108

incidents of neurobehavioral toxicity, 54

licensing and registration of, 168

regulation of, 54

testing, 17,28, 52,54, 168, 196

cost-benefit analysis

competing interests in, 56

costs defined, 214, 215

defined, 336

economic principles of, 221

effect on environmental policymaking, 220-221

Executive Order 12291 requirements, 212,214-216,220,231

under FIFRA, 216, 286

health costs in, 228–230

knowledge requirements for estimating benefits, 228

for lead, 216

net efficiency, 215, 338

risk reduction, measures of, 215

in standard setting, 181

under TSCA, 216

unit of value in, 221

cost-effectiveness analysis, 214,220, 221,336

Costa Rica regulatory issues in, 253-254

costs of testing

in animal studies, 20, 106-107, 110, 111, 112, 116, 222–225

drug and pesticide development and, 225–227

estimates of, 20, 224-225,231

fees, 223

financial determinants, 106,223-224

general and administrative rates, 223

in vitro methodologies, 122

and innovation, 217–218, 225–228

labor rates, 222,223-224

laboratory automation and, 116,223

laboratory capabilities and, 223

overhead rates, 223

personnel, 223

protocol and, 222

quality assurance, 222-223

reregistration of pesticides, 241

scientific determinants, 222–223

under TSCA, 217

unit test costs, 217 n.10

Council on Environmental Quality, 177

cresols, 179, 303

cumene, 179

cutaneous receptors, 65

cyanide, 55

cycad, 54, 74

cyclamates, 166

cyclohexane, 179,297

cyclohexanone, 179

2,4-D, 183,294,295

DDT, 50,72, 134,250,252,255,292

deltramethrin, 251

dementia, 229,259,299,336

dendrites, 72

development of, 67

functions of, 65-66, 336

Department of Agriculture

monitoring programs, 135

regulatory authority of, 160, 161, 171, 241, 242

research activities, 9, 11, 81, 92

Department of Commerce, 177

Department of Defense, research activities of, 90,324

Department of Energy, research activities of, 9, 11,81,91,323

Department of Health and Human Services, 8,45

human research regulations, 130

neurotoxicology -related activities, 321

Department of Housing and Urban Development, 276

Department of Justice, regulatory authority of, 161, 188

Department of Labor, research activities of, 323–324

Deprenyl, 6,72

designer drugs, 51

detoxification systems, in humans, 44,45,64

developing counties

famine in, 243,245

imports of pesticides, 237, 242

manufacture of banned or restricted pesticides in, 243, 253,

255

pesticide misuse in, 50,239,248-249,253

poisonings and deaths from pesticides in, 250-251,260,283

regulatory issues in, 21–22, 237–238, 248–256, 2260

screening test for, 126

susceptibility to neurotoxicity in, 71

use of pesticides, 250, 260

see also specific countries

developmental neurotoxicity, 110, 111

animal tests for, 13, 114–1 16, 137, 165-166, 247–248, 336

biochemical markers, 117

of pesticides, 172

testing guidelines, 153, 165–166, 178, 179, 192,248

di-tert-butylphenyl phosphite, 166

1,2-dibromo-3-chloropropane, 185,250

dichloromethane, 14, 136

1,2-dichloropropane, 179

dichloropropene, incidents of poisoning, 47

dichlorvos, 173

dieldrin, 250,252,292

N,N-diethyl-m-toluamide, 172

diethylene glycol butyl ethers, testing guidelines, 115, 179

diisodecyl phenyl phosphite, 179

Dimecron, 284
Index ● 347

dioxin, 180,294

diphenylhydantoin, 115

diphtheria toxin, 74

Dominican Republic, use of banned pesticides in, 239

domoic acid, incidents of poisoning, 47

dopamine, 66,72,336

depletion of, 6, 109

effects of cocaine on, 52,74

dose

acceptable daily intake, 148, 336

behaviorally effective, 116

defined, 337

extrapolation from high to low, 148, 154, 200

reference (RfD), 116, 148–149, 150, 153, 340

regimen in animal tests, 107, 110

threshold, 14, 147, 151, 153, 162, 185,203,341

and toxicity, 6, 44, 70, 108, 150, 283, 290

see also no observed adverse effect levels; no observed effect

levels

dose-response assessment

from automated motor activity measures, 113

defined, 63,337

extrapolation of doses, 147

issues in, 107, 153–154

methods, 111, 118, 147–148

NOAEL versus NOEL, 147-148, 153

in risk assessment, 147–148

safety factors, 147, 148, 149, 153–154, 155

thresholds and RfD approach, 153, 155

Down’s syndrome, 71

doxorubicin, 73

drinking water

hazardous wastes in, 198

lead in, 216,230,269,277-279

regulations to control contaminants, 183–184, 216, 277–279

from water coolers, 279,280

Drug Price Competition and Patent Restoration Act, 226

drugs

axonopathy from, 73

color additives in, 165

development, 219,225-226,231-232

neurotoxic potential, 43

neurotoxicity testing and innovation in, 226-227

passage through blood-brain barrier, 67

see also abused drugs; therapeutic drugs; and specific drugs

economic issues, 56

analysis of regulations, 213–221, 230

benefits of regulating neurotoxic substances, 20, 228-231,

232

cost-benefit analyses, 20,211, 214-215,220-221, 337

cost-effectiveness analyses, 214-215, 220, 221, 337

in design of animal experiments, 106, 222–223

economic efficiency, 56, 214-216

innovation incentives and disincentives, 20, 218–220, 225–

228

market prices and profitability and costs of regulation,

217-218

opportunity costs, 221, 228

regulatory analyses, 20,211, 214-215,218 n.11, 220-221

regulatory impact analyses, 211, 214, 231

risk assessments, 211, 231

risk-benefit analyses, 20, 211, 216-217, 218 n.11, 340

in standard setting, 199

see also costs of testing; health costs of neurotoxicity; risk

assessment

“ecstasy,” 9, 51

Ecuador

pesticide import problems, 243

regulatory issues in, 255–256

education

of health-care professionals, 97-100

of research scientists, 97, 259

of workers, 30, 287

Egg Products Inspection Act, 241,242

elderly, vulnerability to neurotoxic substances, 8, 45

electroencephalograph, 119

electromyography, 128, 337

electroneurography, 128, 337

electrophysiological testing, 82, 337

electroencephalograph, 119

macroelectrode, 118

rnicroelectrode, 118

multiunit electrode, 118

of muscle cells, 124

encephalitis, 74

encephalopathy, 74, 181, 337

endorphin, 66, 74

endpoints, 337

for emission standards for hazardous air pollutants, 182

in risk assessment, 15, 149, 150, 151, 152, 153

for toxicity testing, 109, 116, 125, 150, 152, 178

for water quality criteria, 182-183

endrin, 47, 183, 250, 255, 292

enkephalin, 66, 74

environmental hypothesis, 54-55, 70, 72, 337

Environmental Protection Agency (EPA), 56, 177

Clean Air Scientific Advisory Committee, 271

coordination of regulatory efforts within, 191–192, 198

core test battery, 13,20, 23–24, 110-111, 114, 137, 152, 178,

179,224,231,287

definition of neurotoxicity, 44

developmental neurotoxicology workshop, 115

economic assessment of regulations, 213, 218

health advisories, 183-184

impact analysis of regulations, 220-221

Integrated Risk Information System, 198

labeling criteria, 172

monitoring activities, 132, 133

Neurotoxicology Division, 81–84

Office of Drinking Water, 183

Office of Environment Criteria and Assessment, 187

Office of Mobile Sources, 182

Office of Pesticide Programs, 110, 135, 170-172, 191-192,

203,216,287

Office of Program Planning and Evaluation, 198

Office of Solid Waste Management, 198

Office of Toxic Substances, 110,152,174,176,177, 191-194,

197, 198,200,201,216

Office of Water Regulations and Standards, 182

pesticides registered with, 49

policy issues and options relevant to, 23-27,31-32

policy on neurotoxicity testing, 178

regulatory authority of, 15–16, 26, 23, 160-162, 164,
348 ● neurotoxicity: Identifying and Controlling Poisons of the Nervous System

170-177,179-182,187, 189,197,212,227 n. 16,241,267

research activities, 9, 11, 31–32, 81–84, 323

Risk Assessment Forum, 11

risk assessment guidelines, 116, 146, 150, 192, 216

Science Advisory Board, 81,82,84

Scientific Advisory Panel, 110-111, 115, 173,288

standard setting, 180-183

testing guidelines, 13,110-112,114-118, 136,137, 177–179,

191-193,200,201,222, 287

Tolerance Assessment System, 135

Toxics Release Inventory, 3,43, 122, 134-136, 195

epidemiological studies, 337

advantages and limitations of, 125, 128

computer-based neurobehavioral tests for, 127

geographical isolates of neurological conditions, 259

hazard identification with, 147

industry-government cooperation on, 96

international activities in, 259

need for, 55, 154

occupational, 129–120

of pesticide poisoning, 285, 295

specimen banking for, 132

erythrosin, 166

ethanol, see alcohol and alcohol abuse

ethical issues

exports of toxic substances, 56-57, 243, 245, 261

human testing and monitoring, 125, 130, 136

manufacturers’ duty to follow products to consumers, 249

Ethiopia

lathyrism in, 55

research on grass pea neurotoxicity, 259

ethyl acetate, 297

ethyl ether, 297

ethyl nitrate, 297

ethyl parathion, 250, 251

ethyl toluenes, 179

ethylene, 14, 136

ethylene dibromide, 250

ethylene dichloride, 303

ethylene glycol, 297

ethylene oxide, 185

ethyl-p-nitrophenyl phosphonothionate, 203

risk assessment approaches, 150, 151, 173

European Economic Community, testing guidelines, 115

evoked potentials, 337

brainstem auditory, 119

flash, 119

pattern reversal, 119

somatosensory, 118–1 19, 120-121

visual, 119–120

excitotoxicity, 71

Executive Order 12264, control of exports of hazardous

substances, 57, 240-241, 260

Executive Order 12291

cost-benefit analyses under, 212, 215–216, 220

inflation considerations in, 217 n.9

requirements of, 213–214

exports of toxic substances

consent requirements, 240

Executive Order 12264,57,240-241

famine as justification for, 243,245,261

international effects of U.S. practices, 21–22, 242–245

labeling violations, 242–243

notification requirements, 22, 239–240, 247, 261, 339

pesticides, 56-57,237, 241–245, 249–250, 261

repackaging problems, 243

testing requirements, 240

U.S. laws, 239-241,261

exposure to neurotoxic substances

acute, 26, 108, 111, 114, 116, 125, 148, 222, 224,272, 292,

294,296,336

additive effects, 44

in animal tests, 107–108

assessment of, 132, 148; see also Monitoring of toxic

substances

chronic, 26,44, 114, 116, 125; 148, 152,222,224,256,257,

272,291,294,296,336

defined, 337

dermal, 107, 108,292-293,294-295, 296,298

extent and duration, 4,44,67-68,73, 107, 108,125, 133,148,

152,222,337

human studies of, 128-131

inhalation, 107, 108, 269, 292,293, 296, 298

margin of (MOE), 149

oral, 107, 269, 292, 298

OSHA limits for mercury, 131

pattern of, 148, 178, 339

prevention of, 130-131

risk to humans, 43

routes of, 6, 63, 64, 107–108, 121, 125, 131, 148, 222, 224,

231,269,283,290,293, 298,340

subacute, 108

subchronic, 108, 111, 114, 148, 149, 340

see also dose; occupational exposures; and specific

substances

Eysenck Personality Inventory, 127

famine, and pesticide use, 243,245,253,261

Faroe Islands, 259

Federal Emergency Planning and Community Right-to-Know

Act of 1986, 13, 134

Federal Environmental Pesticide Control Act, 170,213

Federal Food, Drug, and Cosmetic Act (FFDCA), 56, 172,213

1962 amendments, 217,219

amendments proposed, 168

color additive regulation, 164-166

cosmetics regulation, 17, 168

Delaney clause, 17, 195

drug review and regulatory process, 16, 29, 51, 166-169,

221-222

economic balancing provisions of, 212

environmental contaminants of food, 163–164

food additive regulation, 52, 164-166

licensing and registration under, 27,29, 161, 163–169

notification requirements, 218

pesticide residue standards, 164,241

regulatory authority, 16, 160, 213

reporting requirements for adverse reactions, 167,203

risk assessment approach, 160

risk-benefit analysis under, 216

tolerance setting, 216

toxic substances regulated by, 160

Federal Hazardous Substances Act, 172

definition of hazardous substance, 184
Index 349

regulatory authority, 16, 160

risk assessment approach, 160

standard setting under, 180, 184

toxic substances regulated by, 160, 190

Federal Insecticide Act, 168

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA),

56, 172,213

1972 amendments, 170,219,285-286

1988 amendments, 18, 171, 192, 197,217, 287,288

amendments proposed, 24, 26

coordination of TSCA neurotoxicity evaluations with, 191–

192

definition of pesticide, 281-282

economic balancing provisions of, 212,216, 286

export controls, 21–22, 239, 240,261

extent of testing under, 17, 18, 24, 203, 221–222, 287

generic testing guidelines, 115, 136, 171, 192

licensing and registration under, 17, 16, 29, 161, 169-173,

194, 199,201,203,204

new pesticide registration, 17, 164, 170-171, 194

notification requirements, 218, 238, 240

pesticide residues in food, 241

protection of workers under, 285-287

regulatory authority, 16, 23, 26, 160

reregistration of existing pesticides, 17, 171–173, 286, 287

risk assessment approach, 160

risk-benefit analysis under, 216, 286

Science Advisory Panel, 192

tolerance setting, 27, 164

toxic substances regulated by, 160

Federal Interagency Hazardous Substances Export Policy Task

Force, 57

Federal Meat Inspection Act, 241,242

Federal Mine Safety and Health Act

regulatory authority, 16, 161

risk assessment approach, 161

standard setting under, 180, 185, 186

toxic substances regulated by, 161

Federal Republic of Germany

human tissue monitoring, 132

neurotoxicity testing approach, 24

regulatory policies in, 22, 245–246, 260,261

researcher mining, 259

Federal Water Pollution Control Act

regulatory authority, 16, 23, 160

risk assessment approach, 160

standard setting under, 180, 182–183

toxic substances regulated by, 160

Federation of American Societies for Experimental Biology,

testing recommendations of, 114, 193

fenvalerate, 113

fetuses

alcohol effects, 70, 124

antibiotic effects, 70

cocaine effects, 9, 10, 52, 53, 70, 74

lead effects, 272

nervous system development, 67

mercury poisoning, 49, 152

steroid effects, 70

therapeutic drug effects, 51,73

vulnerability to neurotoxic substances, 8, 45, 49, 70, 269

Finland, Institute of Occupational Health neurotoxicity test, 126

flash evoked potentials, 119, 128

food

action levels for contaminants in, 164

adulterants, 241

imports, 239, 241–242, 250

lead in, 274-275

pesticide residues in, 241-242,250,260

regulation of environmental contaminants of, 163–164

Food Additives Amendment of 1954, 164

food and color additives

adverse effects claims, 318

appeals of decisions, 31&317

application, 315

approval process, 315–3 19

lead in, 275

licensing and registration process, 52, 164-166

postmarketing surveillance, 318

preapplication, 315

regulation of, 17, 52, 161, 195, 204

review, 203, 315

testing for neurotoxicity, 18,27,52, 166, 199,204

Food and Drug Administration (FDA), 56

analytical methods for pesticide detection, 50

Center for Biologics Evaluation and Research, 167

Center for Drug Evaluation and Research, 167,168, 198,201

Center for Food Safety and Applied Nutrition, 12, 165-166,

192–194

color additive regulation, 192–194

cosmetic regulation, 54

drug review and regulatory process, 51, 199

economic assessment of regulations, 213

food additive regulation, 52, 192-194

interpretation of safety, 165

monitoring system for adverse drug reactions, 29, 168, 169,

198

neurotoxicity testing by, 27, 166

policy options for, 27-28,33-34

Priority-Based Assessment of Food Additives Program, 198

Red Book for food and color additives, 27–28, 166-167,

192-194,340

regulatory authority of, 15–16, 54, 160, 161, 163–167, 171,

188,200,241-242,267

research activities of, 9, 12, 33–34, 81, 88-89, 122, 323

risk assessment applications, 150

testing guidelines, 27, 51, 167–168, 192–194, 199-200,204

Total Diet Study, 135

Food and Drugs Act of 1906, 163

Food Safety Amendments of 1989, 168

France

regulatory policies in, 247, 259

research on neurotoxicity, 258

Freon 12, 166

Freon 113, 14, 136

fufuryl alcohol, 303

fumigants, neurotoxic, 293-294

functional observational battery

advantages and limitations, 11 1–112

costs of, 20, 224-225, 226, 231

defined, 337

in EPA core test battery, 13, 111, 136, 204

EPA guidelines for, 110, 111, 178

FDA approach, 193
350 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

OECD guidelines, 194

fungicides, mercury, 48,257

Galecron, 250

Gammalin 20,252

ganglion, 124, 337

General Accounting Office, 220

Generally regarded as safe (GRAS) compounds, 27

Ghana

Lake Ghana pesticide poisoning incident, 252

regulatory issues in, 248

Ginger-Jake syndrome, 47,69

glial cells

development of, 67

effects of toxic substances on, 67

function of, 65, 124,337,339

neurotoxic substances acting on, 74

glial fibrillary acidic protein (GFAP) radioimmunoassay, 117

Global Environment Monitoring System, 134

glue-sniffing, 48; see also inhalant abuse

glutamate, 71, 124

glycol ethers

releases of, 14, 136

toxicity of, 175

testing of, 115, 135

grass pea, 55,259

Guam ALS-Parkinson’s dementia, 54,70,74,259

Halcion, FDA monitoring of adverse reactions to, 29, 169

hazard identification, 147, 152, 154

hazardous wastes

defined, 187, 191

in drinking water, 198

registry of persons exposed to, 135–136

health-care professionals

education of, 97-1OO

see also nurses; industrial hygienists; physicians

health costs of neurotoxicity

dementia, 229

of drug abuse, 20, 53

exposure to lead, 20, 229–230

mental disorders and nervous system diseases, 229

personal health-care expenditures, 20-21,229

health effects

“adverse” defined, 7, 4445, 115–1 16, 145, 162, 167, 170,

212,228

delayed, 50,54,70, 107, 117, 118, 151-152, 155, 194

“harmful,” 145, 147

nutritional status and, 70, 72

reversibility of, 15,46, 69, 71, 107, 108, 151, 152, 290

secondary, 45, 72

health status, and neurotoxicity, 8,70-71, 108,290

heavy metals

assessment of effects of, 119, 124

effects on nervous system, 74

monitoring of, 135

research on, 256, 258

toxicity of, 46, 71; see also specific metals

hen test, see neurotoxic esterase assay

heptachlor, 238,250,292

heroin, 6,9,44,72,74

hexachlorobenzene

effect on nervous system, 74

incidents of poisoning, 47

hexachlorocyclohexane, 250

hexachlorophene, 45

n-hexane, 73, 124, 297, 299

incidents of poisoning, 47

neurotoxicity testing, 179

regulation of, 184

risk assessment approaches, 150, 151

2,5-hexanediol, 124

hippocampus

functions and structure of, 68,71

PCP effects on, 71

trimethyltin damage to, 68, 74

Hispanic Health and Nutrition Examination Survey, 132

Honduras, pesticide-contaminated exports, 238-239

Human Nutrition Information Service, 135

human testing and studies, 105,336

computerized techniques, 13, 127–128, 137

confidentiality, 130

consent and disclosure requirements, 130

examiner-subject interaction, 128-129

exposure studies, 128–131, 256

extrapolation of results to other populations, 147, 153

of food additives, 52

Institutional Review Boards, 130

for lead exposure, 270

legal and ethical considerations, 12, 125, 130

limitations of, 147

neurobehavioral, 13, 125–126, 137

neurophysiological techniques, 13, 128, 137

selection of study populations, 105, 129

of therapeutic drugs, 52

types of, 125-128, 137

workplace research, 129

see also epidemiological studies

hydrocarbons, 182

hydrochloric acid, 14, 136

hydroquinone, 179

imidazoles, 175

imports

and “circle of poison,” 22,57,238,250,260,261

controls in developing countries, 250-255

see also exports of toxic substances

in vitro tests, 338

advantages and limitations of, 12–13, 56, 105, 118, 122,

124-125, 136

application to neurotoxicity testing, 122, 123–124

cell lines, 124

costs of, 122

development of, 11, 12-13, 84, 122, 137

primary cultures, 123-124

screening with, 13, 110

validation of, 123–124

see also tissue culture, 122, 123

incinerator ash

exports of, 240

lead in, 268,279-280

India

Bhopal accident, 243

grain surpluses, 243
Index ● 351

regulatory activities in, 253

research on neurotoxicity, 258

Indonesia, pesticide misuse in, 251

industrial chemicals

axonopathy from, 73

incidents of poisoning, 47,48-49

licensing and registration of, 16,161,174-180,195,196, 204;

see also Toxic Substances Control Act

neurotoxic potential, 3,43, 48,259

see also chemicals; organic solvents; and specific chemicals

industrial hygienists, education of, 99

industrial research, 12

by consumer product industry, 95

government-industry consortia, 96

industry consortia 96

by pesticide industry, 94

by pharmaceutical industry, 95

industrialized countries

imports of contaminated food, 238

regulatory policies in, 245–248, 260

see also specific countries

inert ingredients, neurotoxicity evaluations, 24,288

inhalant abuse, 48, 49, 296, 299-300

innovation

chemical R&D, 219–220, 227–228

costs of neurotoxicity testing and, 225–228

drug R&D, 219,225-226

input measures, 219

output measures, 219

pesticide R&D, 219,226-227

regulation and incentives for, 20, 218–220

integrated pest management, 243, 290, 291, 295, 337

Inter-American Institute for Cooperation on Agriculture, 253-

254

interaction of toxic substances

additive effects, 44, 64

antagonism, 65

drugs, 8-9,29,45, 169

potentiation, 65

synergistic effects, 64, 65

sources of complex mixtures, 65

Interagency Testing Committee, 177–178, 202

Interagency Working Group on Neurotoxicology, 19

International Code of Conduct on the Distribution and Use of

Pesticides, 242,243,249-251,253-256

International Group of National Associations of Manufacturers

of Agrochemical Products, 243, 255

international issues, 21, 56-57

effects of U.S. export practices, 242–245

monitoring of toxic substances, 132, 134

neurotoxicological research, 256-260

pesticide residues in domestic and imported food, 241-242

regulatory activities, 21–22, 115, 237–256

regulatory issues in developing countries, 248–256

regulatory policies in other industrialized countries, 245–248

testing guidelines, 191

U.S. export laws, 239-241

U.S. regulation of neurotoxic substances, 239-245

see also developing countries; exports of toxic substances;

imports

International Neurotoxicology Association, 256,258

International Program on Chemical Safety, 242

International Rice Research Institute, 252-253

ion channels, 7, 66, 72, 118, 295

Iraq, mercury poisoning in, 47,48,49,243,257

isopropanol, 179

Italy

research on neurotoxicity, 258, 259

researcher training, 259

Japan

human tissue monitoring, 132

mercury poisoning in Minamata Bay, 47,48,247, 257

regulatory policies in, 247–248, 259

research on neurotoxicity, 258, 259

kainic acid, 124

Kenya, regulatory issues in, 256

Kepone, incidents of poisoning, 47,50,293

Kuhnburg Figure Matching Test, 127

labeling, 29,44, 169, 171

of cosmetics, 28

effectiveness of regulatory requirements, 172

of exported pesticides, 171, 172, 240, 242–243, 247, 248,

253-255

of hazardous substances, 184, 187, 247, 248

incidents of poisoning resulting from violations of, 242–243

with pictograms, 243–244

WHO requirements, 249

latent effects, 50,54, 70, 107

acute delayed neurotoxicity, 118

defined, 338

of organophosphates, 117–1 18, 194, 199,204,284,290-291,

295

and risk assessment, 15, 151–152, 155

subchronic delayed neurotoxicity, 118

lathyrism, 55

lead

in air, 273–274, 276, 281

cost-benefit analyses, 20, 216, 230-231,232

in drinking water, 8,216, 221,230,231,267,269, 277–279,

281

effects on human body, 229–230, 271–273

estimates of exposure, nationally, 230

Federal regulation of, 8,46, 182, 183

in food, 267, 269, 274-275, 281

in gasoline, 216,221,230,231,257, 267,269, 273–274, 275,

281

health benefits of reducing neurotoxic effects in children, 231,

232

in incinerator ash, 279–280

levels of exposure, 270-271,274,281

MCLs, 183

monitoring programs, 133, 134

neurological effects of, 6,8,46,56,72-73,74, 150, 162, 181,

185

occupational exposures, 269,276

OSHA health standards, 185

in paint, 8, 184, 189–191, 257, 267–269, 276-277

PELs, 276

in pesticides, 274

regulatory activity, 211,213, 267, 273–281

research on toxicity, 256-257, 258, 259
352 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

risk assessment approaches, 150, 151

routes of exposure, 269

screening method for humans, 270

sites of accumulation in the body, 64

in soil, 269, 280-281

sources of exposure, 8, 267,46, 267–269, 273

standard setting, 181–181, 184, 189, 276, 277, 281

threshold for, 162,267,270-271,281

water quality standards, 183, 281

see also lead poisoning

Gad-Based Paint Poisoning Prevention Act (LBPPPA)

amendments, 189, 190

control measures under, 187, 189–191, 276-277, 280

regulatory authority, 16, 161

risk assessment approach, 161

toxic substances regulated by, 161

Lead Industries Association, Inc., 162, 182 n.8

lead poisoning, 45, 115

case studies, 267–281

chelation treatment, 271–272

in children, 7, 8,46,70, 72–73, 155, 181, 184,229,260,267,

268–271, 273,275,276,281

cognitive development and, 7, 8, 44,46, 70, 73, 155, 273

costs of, 229–230

duration of exposure and, 44,270-271

economic status and, 271

historical perspective on, 268

incidents of, 47

mortality from, 271–272

prevalence of, 267,268

prevention of, 8, 189-190,277,278,280, 281

research on, 260

sources of, 256-157

learning disorders, 46,70, 181,230,283,293

tests of, 193

legal issues

challenges to EPA standard-setting authority, 162

in human testing and monitoring, 130

labeling requirements, 172

legislation

diversity of, 159,211,213

export, 237–241

interpreting language of, 162

key features of laws regulating toxic substances, 160-161

major statutes, 23; see also specific statutes

see also control-oriented measures; licensing and registration;

regulations and regulatory issues; standards and standard

setting

leptophos, incidents of poisoning, 47

levodopa, 72

licensing and registration

application and review processes, 161, 163

chemicals, 161, 174-180

of color additives, 164-166

of cosmetics, 168

of drugs and biologics, 29, 161, 166-169

environmental contaminants of food, 163–164

features of laws, 159-160

under Federal Food, Drug, and Cosmetic Act, 29, 161,

163-169, 194,218

under Federal Insecticide, Fungicide, and Rodenticide Act,

161, 168, 170-173, 194,218

of food additives, 161, 164-166

implementation of, 159

neurotoxicity testing for, 161, 163

of pesticides, 164, 161, 170-173

regulatory approach, 16, 159

risk-benefit analyses, 216

under Toxic Substances Control Act, 173-180, 194

lindane, 183,250,252,292

lipophilicity of chemicals, 44,64,298,338

locus ceruleus, 67

Lou Gehrig’s disease, 54,70

LSD, 51,74

Lucel-7, 47, 55–56, 73

malathion, 251, 284

Malaysia, regulatory issues in, 250-252

manganese, 47, 48, 257

manganese madness, 48

mania, 71

margin of safety, 338

EPA interpretation, 180–181

risk assessment approaches, 149, 162

marijuana, 10, 53

Marine Protection, Research, and Sanctuaries Act (MPRSA)

control measures under, 187, 188–189

regulatory authority, 16, 23, 161

risk assessment approach, 161

toxic substances regulated by, 161

Maternal and Child Health Services Block Grant, 277,280

maximum contaminant levels (MCLs) and maximum

contaminant level goals (MCLGs), 183, 198, 278-279,

338

MDMA, effects on nervous system, 9, 51–52

mental disorders

in children 45, 70

costs of, 20, 229

exacerbation of, 71

retardation, 70, 73, 272

meperidine, 51, 106

2-mercaptobenzothiazole, 179

mercury

delayed effects of, 152

effects on nervous system, 72, 74

emission standards, 182

incidents of poisoning, 45, 4649, 131, 247, 257

MCLs, 183

monitoring programs, 133

ocean dumping restrictions, 189

OSHA exposure limit, 131

research on toxicity, 257

routes of exposure, 131

symptoms of exposure, 48, 49, 131

testing for, 124

and water quality standards, 183

mescaline, 74

methadone, 115

methanol, 14, 136, 186-187, 203

methomyl, 284

methoxychlor, 183

methyl alcohol, 296, 297

methyl bromide, 255, 294

methyl chloride, 166
Index ● 353

methyl chloroform, 303

methyl ethyl ketone, 14, 136

methyl ethyl ketoxime, 179

methyl tin, 166

methyl-n-butyl ketone, 299

incidents of poisoning, 47, 49

releases of, 14, 136

route of exposure to, 108

2-methyl-4-chlorophenoxyacetic acid, 294

methyl-tert-butyl ether, 179

methylcyclohexane, 299

methylcyclopentane, 299

methylene chloride, 296, 298

methylmercury, 15, 48,49, 115, 152, 243, 257, 258

mevinphos, 284

Mexico

pesticide import problems, 243

regulatory issues in, 254-255

research on neurotoxicity, 258

MicroTox System, 128

Milan Automated Neurobehavioral System, 127

Minamata Bay, Japan, methylmercury poisoning, 47,48,247

Mine Safety and Health Administration, 161, 185

Minerals Management Service, 133

Mira Test, 127

mirex, 292

monitoring toxic substances

adequacy of regulatory structure determined through, 203–

204

animal tissues, 132

biological programs, 13, 132, 133-134, 137

for cholinesterase inhibition, 84,287,289

coordination of programs, 325–326

FDA postmarked system for adverse drug reactions, 28, 29,

168, 169, 198

in human tissues, 132, 137

legal and ethical considerations, 130

mechanisms, 13, 203–204

need for, 13, 30, 289

neurophysiological techniques, 128

occupational exposures, 13, 30, 131, 133

pesticides, 132, 133, 134, 135,241,242,251-255, 289,296

purpose of, 133

specimen banking, 132–133, 137

worker safety programs, 131

see also Toxics Release Inventory

monoamine oxidase inhibitor, 6, 72

monohalomethanes, 123–124

mood and personality, effects of neurotoxic substances on, 46,

230,283,285

morphine, 74

mortality

abused drugs, 51, 52

mercury poisoning, 47, 48, 49

motor neuron disease, 54

Parkinson’s disease, 3, 54,55

from pesticide poisoning, 250,251,283,285

motor activity

animal tests of, 13, 20, 110, 111-114, 116, 118, 136, 178,

224-225,226,231,338

defined, 111-112

effects of neurotoxic substances on, 46-50, 53,72, 109, 117,

118, 123, 131,271

as an indicator of neurotoxicity, 112, 116, 194

mechanical recording of, 113

observational analysis, 112–113

sensory systems and, 70

specificity of measures, 114

see also screening

motor neuron disease, 54, 55

motor neurons, 66, 70, 74

MPTP

animal model for experiments, 106

effects on nervous system, 51, 54

incidents of poisoning, 47, 70

and Parkinson’s disease, 6, 51, 54, 72

multiple sclerosis, 70, 120, 259

myelin/myelin sheath

aging and, 67

assessment of effects of neurotoxic substances on, 124

destruction of, 336

effects of toxic substances on, 67

function of, 65,66,338

neurotoxic substances acting on, 74

myelinopathy, 67

National Academy of Sciences, 8,45

proposed study by, 27

risk assessment recommendations, 146-147

testing recommendations of, 114, 116

National Aeronautics and Space Administration, research

activities of, 9, 11,92

National Agricultural Chemicals Association, 255

National Ambient Air Quality Standards, 180-181

National Association for Perinatal Addiction Research and

Education, 10,53

National Bureau of Standards, monitoring activities, 132

National Cancer Institute, 86, 177

National Center for Education in Maternal and Child Health, 277

National Center for Health Statistics

HHANES, 132

NHANES II, 132,230 n.19

NHANES III, 132-133

National Center for Toxicological Research

Collaborative Behavioral Teratology Study, 115

research activities of, 12, 88--89,

National Consumer Health Information and Health Promotion

Act, 190

National Emissions Standards for Hazardous Air Pollutants,

181, 182

National Environmental Specimen Bank, 132

National Food Processors Association, 282

National Health and Nutrition Examination Surveys

II, 132,230 n,19

III, 132–133

National Human Adipose Tissue Survey, 133

National Institute on Aging, research activities, 86

National Institute of Child Health and Human Development,

research activities, 86-87

National Institute on Drug Abuse, 9,53

developmental neurotoxicology workshop, 115

research activities of, 87-88

National Institute of Environmental Health Sciences, 11,85,177

National Institute of Mental Health, research activities, 88
354 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

National Institute of Neurological Disorders and Stroke,

research activities, 11, 84–85

National Institute for Occupational Safety and Health (NIOSH),

45,56, 177

Educational Resource Centers, 99-100

protective measures recommended by, 30,296

research activities of, 12, 34-35, 89–90

standard setting by, 28, 185, 186, 198–199

testing recommendations, 126

National Institutes of Health (NIH)

policy issues and options, 32-33

research activities, 9, 11, 32–33, 81, 84-87, 122, 321–322

see also specific institutes and programs

National Library of Medicine, research activities, 87

National Oceanic and Atmospheric Administration, tissue

monitoring program, 133

National Primary Drinking Water Regulations, 183, 191, 278,

338

National Research Council, 146-147

National Residue Program, 135

National Science Foundation, 177

National Status and Trends Program for Marine Environment

Quality, 133

National Toxicology Program

in vitro test development, 122

research activities, 22, 85–86, 259, 261

Nationwide Food Consumption Survey, 135

Natural Resources Defense Council, 282

naturally occurring toxic substances

in algae, see saxitoxin

in buckthorn, 73–74

cassava, 55

cycad, 54, 74

drought-resistant grass pea, 55

effects of, 54-55

in puffer fish, see tetrodotoxin

scorpion toxin, 72

neostriatum, 68

nerve gas, 50, 74

nervous system

adult-stage modifications, 67

changes with aging, 8, 67

development of, 8,67

diseases, 54, 229; see also specific diseases

effects of toxic substances on, 67–71; see also symptoms of

toxicity

immune system interaction with, 71

functional changes due to toxic substances, 69–70

lesions, 172

pesticide effects on, 283-285

structural changes due to toxic substances, 67-69, 267

structure, 43, 65-67

vulnerability to toxic substances, 4, 5, 8, 44

see also central nervous system; peripheral nervous system;

and other specific elements of the nervous system

Netherlands, pesticide regulation, 249

neural tube, 67, 70

neuritic plaques, 67

Neurobehavioral Evaluation System, 127

neurobehavioral tests

advantages and limitations of, 116, 128

in animals, 82, 112, 116-117, 171

in combination with NTE, 118

computer-based, 127–128

environmental factors in, 126

examiner factors in, 126

Finland Institute of Occupational Health approach, 126, 127

in humans, 70, 125–126, 137

observational, 112

psychological testing, 126

reproducibility of, 128

selection of techniques, 125–126

subject factors in, 126

World Health Organization approach, 126-127

neuroblastoma C-1300 cell lines, 124

neurofibrillary tangles, 67

neuromuscular disorders, exacerbation of, 70

neuromuscular junction, 66, 124, 338

neuronal membrane, 72

neuronal potentials, 118

neurons, 124, 338

anoxia, 67

degeneration, 54,72,203,338

development of, 67

effects of toxic substances on, 9, 67

electrical properties, 118

loss of, 67,68,74, 107

neurotoxic substances acting on, 72–74

regeneration, 44, 67

retinal, 124

structure, 5, 65, 72

neuropathies

defined, 67

delayed, 204

from industrial chemicals, 49, 108

mixed, 70, 338

peripheral, 181

from pesticides, 291–292

neuropathological examination

of animals, 13, 110, 111, 114, 116, 118, 136, 172, 178, 194,

224-225

in combination with NTE, 118

costs of, 20, 224-225, 231

defined, 338

electrophysiological testing with, 119

evaluation of PMN assessment accuracy with, 204

FDA policy on, 194

with glial fibrillary acidic protein radioimmunoassay, 117

with operant behavior studies, 116

sensitivity of, 193

neurophysiologica1 tests, 338

advantages of, 13, 128, 137

in animals, 118–121, 137

brainstem auditory evoked responses, 119, 128

electromyography and electroneurography, 128

EPA research on, 82

in humans, 70, 128, 137

somatosensory evoked potentials, 120-121, 128

visual evoked potentials, 119-120, 128

neurotoxic esterase assay (NTE), 111, 117–1 18, 13&137, 178,

194,339

neurotoxic substances, 339

absorption, distribution, biotransformation, and excretion, 64,

108
Index .355

additive effects, 44, 64, 65

behavioral effects, 70

benefits of regulating, 228-230,232

classes of, 71–76, 175

classification criteria, 175

detectors of, 199

determinants of toxicity, 7,63

effects on nervous system, 12, 67–71; see also symptoms of

neurotoxicity

evaluation in animals, 109–110

export policy, 57

health costs of, 228–230; see also specific conditions

incidents of poisoning, 47 (table)

lipophilicity of, 44,64

multiple, interaction of, 64-65

number of, 3, 4, 43

releases by industry, 135

susceptibility to, 70-71

see also abused drugs; chemicals; industrial chemicals;

pesticides; therapeutic drugs; and specific substances

neurotoxicology

defined, 63,339

developmental, in animals, 114-116

fundamentals, 63–76

principles, 63-65

see also health effects

neurotransmitters

aging and, 67

classical, 66, 336

depletion of, 109

effects of abused drugs on, 51, 52, 74, 74

functions of, 65,66,339

hippocampal, 71

inhibition of, 6, 7, 67

neuropeptides, 66, 74

see also specific neurotransmitters

nicotine, 74

nitrogen oxides, 181, 182, 258

no observed adverse effect levels (NOAELs), 106, 146

defined, 147, 339

in dose-response assessment, 147–148, 153

in risk assessment, 147–149, 150–151

in standard setting, 187

techniques to determine, 114, 115, 118, 147

no observed effect levels (NOELs)

defined, 147, 339

in dose-response assessment, 147–148, 153

norepinephrine, 66, 74, 109

notification of unreasonable risk, 218

nurses, education of, 98–99

nutritional status, and toxicity, 70, 71, 108, 269

occupational exposures, 148

administrative controls, 336

to carbon disulfide, 256

epidemiological studies, 26, 128–129

ethical issues, 130, 131

at fabric production plant, 47, 49

Hopewell, Virginia, chemical plant workers, 50,293

incidence of disease from, 125

to lead, 257, 269,276

mercury removal from thermometers, 131

monitoring, 13, 133, 289

to organic solvents, 30, 257, 296-304

to pesticides, 45, 50, 267, 281–285, 289, 293, 294; see also

pesticide poisonings

at plastic manufacturing plant, 47, 55–56

prevention of, 130-131,267,336

regulation of, 16; see also Occupational Safety and Health Act

research on, 256

vulnerability of workers, 9

Occupational Safety and Health Act, 56

exposure limit for mercury, 131

general duty clause, 302

MCL for lead in air, 278

protection of farmworkers under, 26,250-252,267,284,285,

288–289

regulatory authority, 16, 161

reporting requirements for adverse effects, 204

risk assessment approach, 161

standard setting under, 16, 28, 180, 185–187, 195, 267, 276

toxic substances regulated by, 161

Occupational Safety and Health Administration (OSHA), 177

adequacy of efforts of, 28, 30

economic analysis requirements, 303

enforcement of regulations, 30, 276

Hazard Communication Right-to-Know Standard, 285

permissible exposure limits, 185-187, 199,203,302-304

policy issues and options for, 28-30

regulatory authority of, 15–16, 28, 161, 185, 302

risk assessment applications, 150, 151, 216

occupational safety and health programs, 130

octadecyl phosphite, 166

Office of Management and Budget, 11,84, 159, 162,214,231

oleylamine, 179

Omnibus Budget Reconciliation Act, 277

operant behavior

defined, 116

schedule-controlled tests, 13, 110, 111, 116-117, 136, 137,

178, 192, 224–225, 231,340

optic neuritis, 120, 272

organ cultures, defined, 123, 339

organic farming, 291

organic solvents, 6, 339

classes of, 296, 297

effects of, 30, 119, 267, 296, 298-300

encephalopathy from, 299–300

inhalant abuse, 296

labeling of, 184

occupational exposures, 30, 257, 296-304

OSHA regulations, 267,302-303

PELs, 302–304

protection of workers from, 267,296,300-302

research on toxicity of, 256-259, 260

risk from, 48

route of exposure to, 108, 296, 298

testing for, 119, 126

uptake, distribution, and elimination of, 298

volume of production in U. S., 296

see also specific solvents

Organochlorine insecticides, 49, 292–294

organoleptic effects, 182-183, 339

organophosphites, 166

organophosphorous pesticides, 292–293, 339
356 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

action on nervous system, 26, 50, 74,290

animal tests for, 13, 106-107, 110, 117–1 18, 136-137, 171,

194,290

delayed effects, 117-118, 194, 199,204,284,290-291, 295

duration of exposure and toxicity, 44,67, 107

effects on nervous system, 6, 26, 49-50, 67, 73, 107, 117,

290-292,294,295

ethyl-p-nitrophenyl phosphonothionate, 150, 151

extent of testing of, 18, 171, 199, 204

in vitro tests of, 124

incidents of toxicity, 47,69, 284; see also pesticide poisoning

list of, by level of toxicity, 292-293

monitoring of exposures to, 134, 289

reentry intervals for farmworkers, 287

research needs on, 26, 284

study design for, 178

organotin, 47, 74, 257

ozone, 181

paint

fumes, toxicity of, 4,44,296

lead in, 8, 184, 189-191,257,267-269, 276-277

Papua New Guinea, pesticide import violations, 243,251

paralytic shellfish poisoning, 72

paraquat, 250,251

parathion, 255,284,288

Parkinson’s disease

environmental cause, 3, 54-55, 70, 108

mortality, 3, 55

MPTP as cause of, 3,51,54,72

research on, 259

particulate matter, 181, 182

pattern reversal evoked potentials, 119, 120, 128

pentachlorophenol, 250

People’s Republic of China research on neurotoxicity, 22,258,

260

perhexilline maleate, 74

peripheral nervous system

damage from pesticides, 291-292

function tests, 178

structure, 66, 339

vulnerability of, 73

permissible exposure limits (PELs), 28,30, 185-187, 199,203,

276,296,302-304,339

personality effects, see mood and personality

pest control, new approaches, 243,290,295,337

Pesticide Action Network, Dirty Dozen Campaign, 249-250

pesticide poisoning

and accidents, 285

Agent Orange, 295

of agricultural workers, 45, 50,267, 282–285, 288,289,294,

295

Bhopal, India, accident, 243

case studies of, 281–296

in children, 283, 284, 293

chlordecone (Kepone) in Hopewell, Virginia 47, 50, 293

container recycling and, 251

deaths from, 250,251,283,285,290, 294,295

in developing countries, 250, 260

diagnosis of, 50,289

dose and, 283,290-292,294

effects on nervous system, 6, 26, 49–50, 67, 73, 107, 117,

283-285,290-295

epidemiological studies of, 285,295

exposure route and, 283, 292–293

labeling violations and, 242-243,251

Lake Volta, Ghana, incident, 252

major incidents of, 47 (table)

mercury fungicides, 47-49

from methyl bromide, 294

from misuse in developing countries, 50,239,248-249,251,

252,253

monitoring of, 251–256, 289, 296

from organochlorines, 293

from organophosphates, 47,50,69,284,290-292

prevalence of, 248-249,252,283,284, 295

prevention of, 26,28,30,250-252,267, 284,286-289,295

recovery periods, 284, 290

reentry intervals and, 288

repackaging and, 243, 247,248, 251

reporting of illnesses related to, 50, 283, 289,295

pesticides, 339

active ingredients, 336

in adipose tissue, 133, 292–293

advertising, 251, 255–256

alternatives to use of, 243,290-291,295

banned, restricted, or unregistered, 21-22,173,237-238,240,

242, 249-250, 252, 253, 255, 261, 283, 288, 290,

292–295; see also Exports

Belgian regulatory policies, 246-247

Canadian regulatory policies, 245

cancellation/suspension of registration, 173

chlorphenoxy herbicides, 294-295

cholinesterase inhibitors, 290-292

data call-ins, 172, 173,203

defined, 49,281-282

detection of residues, 50

development, 225-226, 231–232

in developing countries, regulatory issues, 248-256, 260; see

also exports of toxic substances; and specific countries

dioxin contamination of, 294

Experimental Use Permit, 170-171,337

exports of, 56-57, 237, 241–245

Federal Republic of Germany regulatory policies, 245–246

fishing with, 252

fumigants, 293-294

inert ingredients, neurotoxicity evaluations, 24, 288

innovation in, and neurotoxicity testing, 226-227

International Code of Conduct on the Distribution and Use of

Pesticides, 242,243

international effects of U.S. export practices, 242–245

Japanese regulatory policies, 247-248

labeling, 171, 172,240,242-243,247, 248,253-255

market size worldwide, 237

MCLs for, 183

me-too registration, 240, 253,255,338

monitoring of, 132, 133, 134, 135, 241, 242, 251, 253–255,

289

neurotoxic, 43, 172, 183, 290-295

notification requirements, 22, 239–240, 247, 261, 290, 339

occupational exposures to, 281–283

organochlorine, 292–293

prior informed consent, 249,339

protective clothing, 250,283,287-289
index ● 357

pyrethroids, 72,295

reentry intervals for farmworkers, 284, 286-288, 290, 295–

296,340

registered, 3,43,49, 195,237

registration of new compounds, 17, 161, 170-171, 197, 199,

216,241,287-288,295

regulation of (Federal), 16, 17, 56, 164, 170-173, 204,

285-289

reregistration of existing compounds, 17, 171–173, 197, 241,

286,287

research on neurotoxicity, 256, 257–258, 295

residues in domestic and imported food, 241–242, 251, 282

resistance of pests to, 243

risk standards, 25, 168, 241

risk-benefit analysis, 216, 217,296

safety information, 287

safety, measure of, 221–222

special review of, 173, 197, 216

state regulation of, 289–290

testing for neurotoxicity, 17,18,115,119,170-173, 191–192,

194, 199,204,287,295

Tolerance Assessment System, 135

tolerances, 27, 164, 168, 171,216, 241,247, 254, 341

use annually, 282, 295

WHO toxicity classification, 249, 254

see also carbamate insecticides; organophosphorous

pesticides

phencyclidine, 9,52,71

phenylene diamines (unsubstituted), 179

Philippines

pesticide problems in, 251

regulatory issues in, 252–253

phosalone, 284

Phosdrin, ,242,284

phosphamidon, 284

phosphines, 175

Phosvel, incidents of poisoning, 47

photoreceptor cells, 124

physicians, education of, 98

Poison Prevention Packaging Act (PPPA)

control measures under, 187, 190-191

regulatory authority, 16, 161

risk assessment approach, 161

standard setting under, 180

toxic substances regulated by, 161

policy issues and options

for ADAMHA, 33

adequacy of regulatory framework, 23–31

adequacy of research framework, 31–35

confidential business information, 25

cosmetics testing, 28

for CPSC, 31

education and training of research and health-care

professionals, 36

education of workers and public, 37–38

for EPA, 23-27,31-32

for FDA, 27-28,33-34

interagency coordination of research and regulatory

programs, 35-3 6

international regulatory and research programs, 38-40

Material Safety Data Sheets, 30

monitoring of adverse health effects, 28, 30

neurotoxicity testing requirements, 24-25, 27–28

for NIH, 32-33

for NIOSH, 34-35

for OSHA, 28,30

protection of agricultural workers, 26,28,30

statutory scope of neurotoxicity regulation, 26-27

polyaromatic hydrocarbons, 133

polychlorinated biphenyls (PCBs), 115, 180

incidents of poisoning, 47, 247

monitoring of, 133, 134

research on, 258

potentiation, 65,339

Poultry Products Inspection Act, 241,242

premanufacture notices, 17, 174-176, 194, 196, 197,201-202,

219-220,227,247

prevention of exposure

adequacy of measures, 28, 30, 288, 289

educational programs, 30, 130

engineering controls, 13, 30, 267, 276,296, 300, 301, 337

to lead, 8, 189–190, 277, 278,281

medical controls, 130-131, 300

to organic solvents, 30, 296, 300-302

to pesticides, 26,250-252,267,284, 285–290, 295,340

protective clothing and devices, 30, 250, 267, 283, 286,

288-289,295,296,300-302, 339

reentry levels for farmworkers, 284,286, 288, 290, 295, 340

state programs, 289–290

training in handling of pesticides, 252,255,290

in workplace, 130–131, 300-302, 336

see also monitoring toxic substances

propylene, 14, 136

protective clothing and devices, 30, 250, 267, 283, 286,

288-289,295,296,300-302, 339

psilocybin, 74

psycho organic syndrome, 296

psychoactive drugs, 6, 10,27,44,50

psychological testing, 126

psychosis, 71

Public Health Service Act, 167

Purkinje cells, 67

pyramidal cells, 68

pyrethroid pesticides, 72,295

pyridine derivatives, 175

quaternary ammonium compounds, 175

quinone, 179

radionuclides, 182

rat glioma C-6 cell lines, 124

reentry levels for farmworkers, 284, 286, 288, 290, 295, 340

reference dose (RfD), 116, 148-149, 150, 153, 340

registration, see licensing and registration

regulations and regulatory issues

adequacy of regulatory framework, 201–203

administration of laws, 56, 160-161; see also specific

agencies

application and notification procedures, 159; see also

licensing and registration

in behavioral teratology, 115

consistency of protection, 17, 19, 194-196, 199-200

consistency of requirements, 16-17, 194

coordination and cooperation among agencies, 19, 176, 194,
358 ● Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

198-199,200-201,205, 326-327

costs of compliance, 20, 201, 211, 215, 217–218, 220, 230

diversity of, 159

economic benefits of, 228–230

economic impacts of, 213–215

economic incentives, 161

effectiveness of regulatory programs, 203–204, 205,274,281

endpoint basis for, 56

expected and detected neurotoxicity, 201–203

expenditures by government, 215

export laws, 239–241

general toxicological considerations in, 194-199

of human research, 130

impact analyses, 211 n.1, 214, 220, 231

of industrial chemicals, 56

in industrialized countries, 245–248

international regulatory activities, 21–22, 115, 237–256

labeling, 172

for lead, 46, 273–281

measurements of effectiveness, 201

minimal data set, value of, 201

neurological considerations in, 18–19, 178, 199-201, 204

new initiatives, 191–194

new v, existing chemicals, 18, 196-198

nonregulatory factors affecting implementation, 159, 161,

162

for pesticides, 241-242,286-290

redundancy of effort among agencies, 198

risk assessment approaches, 146, 150–151

State regulation of lead, 277, 278

State regulation of pesticides, 289-290

statutory authority, 56; see also legislation; and specific

statutes

tolerance setting, 164

see also cost-benefit analysis; economic issues

regulatory analyses, 20, 211, 218 n.11

institutionalization of, 215, 230

utility in regulatory policymaking, 220-221

regulatory impact analyses (RIAs), 211 n.1, 214, 216, 231

reporting of harmful effects, 180, 197

CPSA requirements, 204

FFDCA requirements, 167,203

OSH Act requirements, 204

pesticide poisoning, 50,283,289,295

of therapeutic drugs, 18, 167, 203

research

academic activities, 92–94, 256–259

adequacy of Federal programs, 31–35, 81

by charitable organizations, 97

under Clean Air Act, 180

comparison of U.S. and foreign programs, 259

coordination of Federal programs, 200, 325

development of methodologies, 81,259

Federal activities, 9, 11–12, 81–92, 321–324; see also specific

agencies

funding, 9, 11-12, 81, 82-84,259

industry activities, 12, 94-95, 256-259

interactions among, government, academia, and industry, 96,

256-259

international efforts, 22, 256–260, 261

journals, 22,256

leadership roles by foreign governments, 260

needs, 3, 11,26,55,76, 137, 154--155, 259–260, 295

pathological changes related to functional impairment, 154

resources, 259

trends internationally, 21,258-259,261

workplace, 129; see also occupational exposures

see also academic research; epidemiological studies;

industrial research

research scientists, education of, 12, 97, 259

Resource Conservation and Recovery Act (RCRA), 135, 176

control measures under, 187, 189–191

export controls, 239, 240

regulatory authority, 16, 23, 161

risk assessment approach, 161

toxic substances regulated by, 161

Restoril, 29, 169

risk

acceptable, 13, 145, 146, 164, 196, 340

characterization of, 148–149

defined, 13

and economic benefit, 216-217

expression of, 13, 145

individual v. societal, 154, 155

negligible, 168

public perceptions of, 145-146

and stringency of evaluation process, 17, 195–196

unreasonable, 212, 241

vulnerable populations, 8–9, 45

zero, 153, 168, 339

risk assessment

for acrylamide exposures, 150, 151,216

approaches for neurotoxic substances, 56, 150-154, 160-161

carcinogen approach, 15, 149, 150, 151, 152, 153

characterization of risk, 56, 105, 106, 148–149, 150, 154; see

also testing

components of, 145, 231

controversial issues in, 14-15, 146

coordination of programs, 326-327

defined, 13, 145,211,340

dose-response relationship, 147–148, 153–154

EPA guidelines, 116, 146, 150, 192

exposure assessment, 148

hazard identification, 147, 148, 152, 154

Integrated Risk Information System, 198

and latent adverse effects, 15, 151-152, 155

limitations of current approaches, 106, 151-152

MOS/MOE approaches, 149, 162, 181

regulatory approaches, 17, 25, 146, 150–151, 160-161

safety factors, 148–149, 153–154

uncertainty in, 149, 153, 154, 340, 341

risk-benefit analysis, 211, 216-217, 218 n.11, 286, 296, 340

risk management

defined, 13, 145,211,340

process of, 145, 149-150

purpose of, 149

risk balancing approach, 149–150

risk only approach, 149

technological control approach, 150

Rorschach Inkblot Test, 127

Safe Drinking Water Act (SDWA), 26

1986 amendments, 183

cost-benefit analysis under, 216
Index ● 359

regulatory authority, 16, 23, 160

risk assessment approach, 160

standard setting under, 180, 183–184, 278

toxic substances regulated by, 160

Santa Ana Dexterity Test, 127

saxitoxin, 72

Scandinavian counties

neurotoxicological research, 22, 256-259, 260,261

regulatory policies in, 260, 261

researcher training, 259

schedule-controlled operant behavior (SCOB) tests, 13, 110,

111, 116-117, 136, 137, 178, 192,224-225,231,340

scorpion toxin, 72

screening, 154, 340

adequacy of, for chemicals, 17

developmental neurotoxicity, 116

computer-assisted, 82, 175

in EPA core test battery, 111

FDA policy on, 194

with functional observational battery, 82, 111, 112, 193

with in vitro tests, 13, 110, 136

for lead exposure, 270,277,278,280,281

with motor activity test, 82, 193

of pesticides, 199, 204

structure-activity relationships, 18, 175, 194, 203, 340

WHO Neurobehavioral Core Test Battery, 126-127

selecron, 251

Senegal, pesticide import violations, 243,251

sensory systems

effects of neurotoxic substances on, 46, 51–52, 272

evoked potentials, 118–1 19, 128, 337

functions of, 66

and motor functions, 70

neuron losses, 74

serotonin, 66

effects of abused drugs on, 9, 51–52, 74

short-term exposure limits, 302

significant new use rule, 174

silicon, and Alzheimer’s disease, 54–55

silver, 133

soil, lead in, 269, 280-281

solvents, see organic solvents

somatosensory evoked potentials, 119, 120–121, 128

South Korea, pesticide import problems, 243

Soviet Union, neurotoxicity research, 22,258,260

specimen banking

domestic and international programs, 132-133

nonhuman tissues, 133

spina bifida, 70

spinal cord

clioquinol effects on, 74

damage from pesticides, 291-292

degeneration, 55

development of, 67

functions, 66

standards and standard setting

action levels for contaminants in foods, 164, 241–242, 336

air quality, 180-181

for airborne contaminants, 181, 182, 185

carcinogenicity -based, 185

challenges to EPA authority, 162, 182 n.8

under Clean Air Act, 180-182

under Clean Water Act, 182–183

under Consumer Product Safety Act, 184

cost-benefit analysis, 181

drinking water, 183-184

economic considerations in, 199

emissions, 181, 182

exposure probability and, 195

features of laws, 159, 160-161

under Federal Hazardous Substances Act, 184

under Federal Mine Safety and Health Act, 185

under Federal Water Pollution Control Act, 182–183

hazard communication, 187

by international groups, 242

for lead, 271,276,278-279

litigation over validity of, 276

margin of safety in, 180-181, 338

maximum contaminant levels and maximum contaminant

level goals, 183, 198,278-279,338

neurotoxicity considered in, 162

under Occupational Safety and Health Act, 185–187

for packaging, 190

permissible daily intakes, 189

permissible exposure limits, 28,30, 185-187, 199,203,276,

296,302-304,339

for pesticide residues, 164

recommended exposure limits, 199, 302–303, 340

reentry intervals for farmworkers, 284, 286-288, 340

regulatory approach, 16, 159, 180

regulatory impact analysis, 181

reportable quantities, 187

under Safe Drinking Water Act, 183–184, 191

threshold limit values, 151, 185, 186, 199,203,341

and toxicity testing requirements, 180

water quality, 182

see also regulations and regulatory issues; and specific

statutes

steroids, 70

stroke research, 259

structure-activity relationships, 17, 18, 25, 175, 194, 203, 340

styrene, 14, 136, 258, 299, 303

substance P, 66

substantial nigra, 6, 67, 72

Sudan, pesticide poisoning in, 251

sudden infant death syndrome, 10,53

sulfur oxides, 181

sulfuric acid, 14, 136

sulfuryl fluoride, 120

Superfund Amendments and Reauthorization Act, 135

confidentiality under, 176

health effects contemplated by, 188

regulatory authority, 161

research authorized by, 188

risk assessment approach, 161

toxic substances regulated by, 161, 198

Sweden

human tissue monitoring, 132

Performance Evaluation System, 127

synapse, 66, 70

chemical communication at, 66

defined, 340

measurement of function at endings, 118, 124

synaptic cleft, 66, 340
360 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

synergism, 64, 65, 340

2,4,5-T, 250,294,295

2,4,5-TP, 183

tardive dyskinesia, 6, 44

TCDD, 294

Telone II, incidents of poisoning, 47

temik, 251

temperature, and toxicity, 109

testing

accuracy of PMN assessments, 204

computerized/automated techniques, 112–1 13

confidentiality issues in, 19, 176, 202, 218, 226

consent decrees for, 177, 197, 201, 202, 336

coordination of programs, 325–326

of cosmetics, 52, 54, 168, 196

criteria, 152

cross-species comparisons, 115-116

current extent of, 12, 16,43, 52, 55, 56, 76, 151, 211

design, factors considered in, 105-109, 178, 199-200

in developing countries, 251–252

disincentives to, 174-175, 176

economic impacts of, 218; see also Costs of testing

endpoints, 109, 116, 125, 150, 152, 178

EPA guidelines, 110-112, 114-118, 136, 137, 191-193

of exports, 240

extrapolation of results to other populations, 147, 153

FDA requirements, 163, 165-167, 192-194, 199

FIFRA guidelines, 115

flexibility in, 193,200

of food additives, 52, 192–194

in industrialized countries (other than U.S.), 245, 246,

247-248

and innovation in drugs and pesticides, 226-227

interpretation of safety, 165

laboratory automation, 223

laboratory capabilities, 223

limitations of current tests, 122, 151-152

needs, identification of, 324

options for changes in requirements for, 24-25

personnel, 223

protocol requirements, 222

quality assurance, 222-223

reliability and sensitivity, 26, 115, 152, 191, 193

research on new methods, 81–84

standardization of, 324-325

statutory authority for, 159

stringency of, 17, 195–196

tiered approach, 18, 109-110, 154, 193,200, 341

triggers for, 24

validation, 109, 111, 123–124, 168

WHO objectives, 106

see also animal tests; in vitro tests; human testing and studies;

risk assessment; screening

tetrachloroethylene, 14, 136

tetraethyl lead, incidents of poisoning, 47, 303

tetrodotoxin, 45, 72

Texas Agricultural Hazard Communication Law, 290

Thailand, pesticide misuse in, 243,251

thalidomide, 73

thallium

effects on nervous system, 74

incidents of poisoning, 47

testing of, 124

toxicity, 48

water quality standards, 183

therapeutic drugs and biologics

adverse effects of, 29, 45, 50-51, 167–169

for animals, 166, 167

benefits assessment, 216

benzodiazepine hypnotics, 29, 169

efficacy and effectiveness, 217

interactions, 8, 29, 45, 169

investigational new drugs, 167–168, 203, 338

labeling, 29, 169

licensing and registration of, 18, 29, 161, 166-169

monitoring reactions to, 29, 168, 169

neuroeffective substances, 168

neurotoxic potential, 3, 45

new drug applications, 166, 167, 188, 339

packaging information on adverse effects, 28

R&D studies, 219

reporting of adverse reactions, 18, 167, 203

research on neurotoxicity, 258

risk assessment, 146, 151, 153

risk-benefit analysis, 217

safety, measure of, 221–222

seizure medication, 44

standard for approval, 166-167

testing of, 17, 18, 26,29, 105, 115, 166-168, 169, 199,204

see also specific drugs

thiamine deficiency, 71

thiocarbamates, 172

threshold limit values, 151, 185, 186, 199,203,341,302-303

time-weighted average limits, 302

tin, 133

tissue culture

antibiotics added to, 123

applications in neurotoxicology, 122

defined, 122,340

embryo, 123–124

expenditures for development of methods, 122

explants, 124, 337

organotypic, 124, 339

see also Cell culture; Organ culture

TOCP, incidents of poisoning, 47

tolerance levels

for contaminants in foods, 164

enforcement of, 241–242

lead in canned evaporated milk, 274-275

for pesticides residues, 27, 164, 171,216,239,241

recommended approach, 27

toluene, 14, 119, 136, 183, 296,299, 303

Total Diet Study, 135

toxaphene, 183, 250, 255,292

toxic substances

general considerations in regulation of, 194-199

see also neurotoxic substances

Toxic Substances Control Act (TSCA), 56, 110

confidential business information under, 19, 25, 176, 202,

218,226

consent decrees, 17, 177, 179, 197, 201, 202, 336

coordination of FIFRA neurotoxicity evaluations with, 191–

192
Index . 361

economic balancing provisions of, 212, 216, 217–218

existing chemicals, 175, 177–180

export controls, 21–22, 239–240, 261

extent of testing under, 17, 18-19, 24-25, 201–202, 204

licensing and registration under, 16, 161, 173-180, 194, 195,

197

new chemicals, 174-175

notification requirement, 218, 239–240

premanufacture notices, 17, 174-176, 194, 196, 197, 201-

202,203-204,215,219-220, 227

regulatory authority, 16, 20, 160, 213

risk assessment approach, 160, 196

significant new use rule, 174

substances regulated by, 160

test guidelines, 150, 191, 199, 224

test rules, 17, 82, 197, 178, 179, 215, 217, 222, 340–341

Toxics Release Inventory, 13, 14, 17,43, 122, 134-136, 197

triadimefon, 113

triazophos, 292

tributyl phosphorotrithioates, 173

1,l,l-rnchloroethane

releases of, 14, 136

testing of, 115, 135, 179

trichloroethylene, 14, 136,299, 303

2,4,5 -trichlorophenoxypropionic acid, 294

triethylene glycol monomethyl ethers, testing guidelines, 115,

179

trimethyl benzenes, 179

trihalomethanes, 183

trimethyltin

biochemical markers for, 117

poisoning, 6,44,68,74

triorthocresyl phosphate, 47, 69

triphenyltin, 113

Tris phosphite, 166

United Kingdom

regulatory policies in, 248

research on neurotoxicity, 21, 256,258, 259, 261

United Nations

Food and Agriculture Organization, 135,242,243, 249–251,

253-256

OECD toxicity testing guidelines, 191, 194

urea-formaldehyde resins, 179

U.S. Public Health Service, 189

vasopressin, 66

vincristine, 73

vinyl chloride, 182

visual evoked potentials, 119-120

visual systems

impairment of, 26, 48, 49, 51, 55, 72, 74, 131, 135, 181

substances affecting, 48, 49, 51, 55,72, 74, 119

testing of, 119

vitamins, toxicity, 6, 44, 74

Walsh-Healy Act, 185, 186

water quality standards, 182–183

Wechsler Adult Intelligence Scale, 127

Wechsler Memory Scale, 127

World Health Organization, 22, 135,242,255

acceptable levels of lead, 271

childhood lead intoxication study, 257, 261

epidemiological study of dementia, 259

objectives of neurotoxicology testing, 106

Neurobehavioral Core Test Battery, 126-128

organic solvent studies, 257

pesticide toxicity classification, 249,254

specimen banking program, 133

testing recommendations of, 114, 115, 116, 150

X-irradiation, 115

xylene, 14, 136, 299, 303

zinc pyridinethionine, 108

Zolone, 284