Summary, Policy Issues, and Options for Congressional Action

Chapter 1

Summary, Policy Issues, andOptions for Congressional Action

CONTENTSPage

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. 6 0 i e k i . l o N. k . A c. t i. 6 N

Boxes

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

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

34489

12131519192122

Page. . . . . . . . . . . . . . . 5

l-13. MPTP and Parkinson’s Disease ......+..........++.. . .. .. .. .+ . . . . . . . . . . . . . . . . . . 6l-C. had: A Continuing Threat to the Nation’s Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8l-1). Cocaine and the Developing Fetus . . . . . . . . . . . . . . . . . . .+ . . . . . . . . . . . . . . . . . . . . . . . . 10l-E. Neurotoxic Pesticides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26l-F. Limitations of FDA’s Postmarked Monitoring System for

Adverse Drug Reactions: Halcyon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29I-G. Organic Solvents in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..+.. 30

FiguresFigure 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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5l-3. Neurotoxic Effect of MDMA on Serotonin Nerve Fibers in the Cerebral Cortex

of the Monkey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + . . . . . +........ . . . . . . . . . . . . . . 9l-4.Neurotoxic Substances Are Prominent Among the Toxics Release Inventory’s

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

TablesTable Pagel-1. Federal Funding for Civilian Neurotoxicity-Related Research . . . . . . . . . . . . . . . . . . . .l-2+ Major Federal Laws Controlling Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1116

Chapter 1

Summary, Policy Issues, and Options for Congressional Action

SUMMARYChemicals are an integral part of our daily

lives and are responsible for substantially im-proving them. Chemicals can also endanger ourhealth, even our survival. This assessmentfocuses on neurotoxic substances, those chemi-cals that adversely affect the nervous system.Included among such substances are industrialchemicals, pesticides, therapeutic drugs, abuseddrugs, food, food additives, cosmetic ingre-dients, and naturally occurring substances. Whethera substance causes an adverse health effectdepends on many factors, including the toxicityof the substance, the extent of exposure, and theage and state of health of an exposed individual.Minimizing public health risks requires infor-mation about the properties and mechanisms ofaction of potentially toxic substances to whichhumans may be exposed. This informationprovides the foundation for safety standards.

More than 65,000 chemicals are in the U.S.Environmental Protection Agency’s (EPA) inven-tory of toxic chemicals; and the Agency annu-ally receives approximately 1,500 notices ofintent to manufacture new substances. Since fewof these chemicals have been tested to determineif they adversely affect the nervous system, noprecise figures are available on the total numberof chemicals in existence that are potentiallyneurotoxic to humans. Some estimates havebeen developed, however, based on analyses ofcertain subsets of chemicals. These estimatesvary considerably, depending on the definitionof neurotoxicity used and the subset of sub-stances examined. For example, some 600active pesticide ingredients are registered withEPA, a large percentage of which are neurotoxicto varying degrees. One investigator estimatedthat 3 to 5 percent of industrial chemicals,excluding pesticides, have neurotoxic potential.Another investigator found that 28 percent ofindustrial chemicals for which occupationalexposure standards have already been devel-oped produce neurotoxic effects. In addition, a

substantial number of therapeutic drugs haveneurotoxic potential.

In recent years, concern about the neurotoxiceffects of chemicals has increased as evidencehas become available linking exposure to chem-icals and drugs with long-term changes in thenervous system. Some scientists believe thatneurotoxic substances play a role in triggeringsome neurological disorders, including Parkin-son’s disease, Alzheimer’s disease, and amyotro-phic lateral sclerosis. For example, investigatorsrecently found evidence that the incidence ofmotor neuron disease (primarily amyotrophiclateral sclerosis) is increasing particularly in theelderly (figure 1-1 ). Exposure to toxic chemicalsmay be one of the factors contributing to thisincrease. More research is necessary to confirmthis trend and to determine the underlyingcausative factors.

Human exposure to significant concentra-tions of most known neurotoxic substances isnormally quite limited. Consequently, the num-ber of substances that pose an actual threat topublic 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 population12

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 FromMotoneuron 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 signifi-cant risk to public health and the extent ofthat risk are unknown because the potentialneurotoxicity of only a small number ofchemicals has been evaluated adequately.

Scope of This Study

This study examines many, but not all, of theclasses of neurotoxic substances. The assess-ment includes discussion of industrial chemi-cals, pesticides, therapeutic drugs, substancedrugs, foods, food additives, cosmetic ingre-dients, and such naturally occurring sub-stances as lead and mercury. It does notinclude radioactive chemicals, nicotine (fromcigarette smoke), alcohol (ethanol), biologicaland chemical warfare agents, microbial, plant,and animal toxins, and physical agents such asnoise.

What Is Neurotoxicity?

The nervous system comprises the brain, thespinal cord, and a vast array of nerves andsensory organs that control major body func-tions. Movement, thought, vision, hearing,speech, heart function, respiration, and numer-ous other physiological processes are controlledby this complex network of nerve processes,transmitters, hormones, receptors, and channels(figure 1-2).

Every major body system can be adverselyaffected by toxic substances, but the nervoussystem is particularly vulnerable (see box l-A).Many toxic substances can alter the normalactivity of the nervous system. Some produceeffects that occur almost immediately and lastfor several hours. Examples include an alcoholicbeverage or fumes from a can of paint. Theeffects of other neurotoxic substances mayappear only after repeated exposures over weeksor 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

VkL \ A x o nterm[nal

Cell body

2 /

/// -- SynapseMyelin

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 withnormal function.

● Even minor changes in the structure or function of the nervous system may have profound consequencesfor 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 eatingfood or drinking water contaminated with lead.Some substances can permanently damage thenervous system after a single exposure-certainorganophosphorous pesticides and metal com-pounds such as trimethyl tin are examples (boxl-B). Other substances, including abused drugssuch as heroin and cocaine, may lead toaddiction, a long-term adverse alteration ofnervous system function. Many neurotoxic sub-stances can cause death when absorbed, inhaled,or ingested in sufficiently large quantities.Neurotoxic substances play a significant causalrole in the development of some neurologicaland psychiatric disorders; however the pre-cise extent of the contribution is unclear.

Care must be taken in labeling a substanceneurotoxic because factors such as dose and

intended effects must be taken into considera-tion. A substance may be safe and beneficial atone concentration, but neurotoxic at another.For example, vitamins A and B6 are required inthe diet in trace amounts, yet both causeneurotoxic effects in large doses. In other cases,a substance that is known to be neurotoxic mayconfer benefits that are viewed as outweighingthe risk of adverse side-effects. For example,thousands of individuals suffering from schizo-phrenia have been able to live relatively normallives because of the beneficial effects of antipsy -chotic drugs. However, chronic use of pre-scribed doses of some of these drugs may giverise to tardive dyskinesia—involuntary move-ments of the face, tongue, and limbs—side-effects so severe that they may incapacitate apatient.

Box 1-B—MPTP and Parkinson’s Disease

In recent years, the hypothesis that Parkinson’s disease and other neurological disorders might be triggered byenvironmental factors has become more widely accepted. Although toxic substances have long been consideredpossible contributors to the cause of some disorders of the nervous system, the MPTP incident has focused moreattention on this environmental hypothesis.

MPTP is the abbreviation for l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, a compound that can be createdduring the production of synthetic heroin. Remarkably, in just 5 to 15 days, this highly neurotoxic substance caninduce a syndrome virtually identical to Parkinson’s disease—a disease that usually occurs late in life and developsslowly over a period of years. Both Parkinson’s disease and the MPTP-induced syndrome are characterized bytremors and lack of muscular control that stem from degeneration of neurons in the substantial nigra, a region deepin 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 ofresearch on this disease. Much work has focused on MPP+, a metabolize of MPTP that is responsible for the adverseeffects on the brain. Recently, researchers discovered that a monoamine oxidase inhibitor, a type of drug sometimesused to treat depression, blocks the conversion of MPTP to MPP+. Other researchers have shown that themonoamine 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 ofdegeneration 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 ofneurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis. Therelative contributions of environmental and genetic factors to the causes of these diseases are not understood andare the subject of considerable research and debate within the scientific community. Although the extent to whicha neurotoxic substance contributes to the cause of Parkinson’s disease is unclear, the MPTP story serves as anexample of how neurotoxicological research can lead to abetter understanding of the causes of neurological diseaseand ways to treat it.

SOURCES: I.J. Kopin and S.P. Markey, ‘‘MPTP Toxicity: Implications for Research in Parkinson’s Disease,’ Annual Review o~~ewoscknce11:81-96, 1988; J.W. Langston, P. Ballard, J.W. Tetrud, et al., “Chronic Parkinsonism in Humans Due to a Product ofMeperidine-Analog Synthesis, ” Science 219:979-980, 1983; R. Lewin, “Big First Scored With Nerve Diseases,” Science245:467468, 1989.

Chapter 1-Summary, Policy Issues, and Options for Congressional Action ● 7

Broadly defined, a substance is considered tohave neurotoxic potential if it adversely affectsany of the structural or functional components ofthe nervous system. At the molecular level, asubstance might interfere with protein synthesisin certain nerve cells, leading to reduced produc-tion of a neurotransmitter and brain dysfunction.At the cellular level, a substance might alter theflow of ions (charged molecules, e.g., sodiumand potassium) across the cell membrane, therebyperturbing the transmission of information be-tween nerve cells. Substances that adverselyaffect sensory or motor function, disrupt learn-ing and memory processes, or cause detrimentalbehavioral effects are neurotoxic, even if theunderlying molecular and cellular effects on thenervous system have not been identified. Expo-sure of children to lead, for example, leads todeficits in I.Q. and poor academic achievement;however, the mechanisms by which this occursare not understood. In addition, researchersrecently found evidence that phenobarbital, adrug prescribed to children to prevent seizuresassociated with fevers, reduces intellectual abil-ity. But as is the case for lead, the underlyingmechanism is unknown.

For the purposes of this study, the Office ofTechnology Assessment (OTA) defines neurotoxic-ity or a neurotoxic effect as an adverse changein the structure or function of the nervoussystem following exposure to a chemicalagent. This is the definition currently used byEPA. However, as the preceding discussionillustrates, this definition should be used inconjunction with information on the in-tended use of the substance, the degree oftoxicity, and the dose or extent of exposure ofhumans or other organisms. The definitionhinges on interpretation of the word "ad-verse,” and there is disagreement amongscientists as to what constitutes “adversechange.” Determining whether a particularneurological or behavioral effect is adverserequires a comprehensive analysis of allavailable data. Although certain effects are

clearly adverse (e.g., hallucinations, convul-sions, loss of memory, permanent neurologicaldamage, death) others are more difficult todefine (e.g., temporary drowsiness, a briefheadache). The circumstances of exposure anda variety of other factors must be taken intoaccount in borderline cases. For example, drows-iness in the evening at home may be of littleconsequence, but drowsiness during the daywhile operating machinery in the workplacemay 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 affectedby neurotoxic substances, but individuals incertain age groups, states of health, and occupa-tions face a greater probability of adverseeffects. Fetuses, children, the elderly, work-ers in occupations involving exposure torelatively high levels of toxic chemicals, andpersons who abuse drugs are among those inhigh-risk groups.

The developing nervous system is particu-larly vulnerable to some neurotoxic substances,for several reasons. It is actively growing andestablishing cellular networks, the blood-brainbarrier that protects much of the adult brain andspinal cord from some toxic substances has notbeen completely formed, and detoxificationsystems are not completely developed. Lead isa potent neurotoxic substance that is particularlyharmful to children (box l-C). Toxic substancescan contribute to neuropsychiatric disorders inchildren. The National Academy of Sciences

recently reported that 12 percent of the 63million children under the age of 18 in theUnited States suffer from one or more mentaldisorders, and it identified exposure to toxicsubstances before or after birth as one of theseveral risk factors that appear to make certainchildren vulnerable to these disorders.

The elderly are more susceptible to certainneurotoxic substances because decline in thestructure and function of the nervous systemwith age limits its ability to respond to orcompensate for toxic effects. In addition, de-creased liver and kidney function increasessusceptibility to toxic substances. Aging mayalso reveal adverse effects masked at a youngerage. Persons who are chronically ill, especiallythose suffering from neurological or psychiatricdisorders, are at risk because neurotoxic sub-stances may exacerbate existing problems. Also,many elderly Americans take multiple drugsthat may interact to adversely affect nervoussystem 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 andtherefore 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 ingasoline and food have been largely successful, but some sources of exposure remain, and some sources that arenot 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, particularlyamong children, who are both more sensitive to lead’s neurotoxic effects and more likely to be exposed to certainsources, such as paint chips from older houses, school water coolers containing lead-lined tanks, and home watersupplies contaminated with lead from old piping. According to the Department of Health and Human Services, 17percent of the Nation’s children (in standard metropolitan statistical areas) have levels of lead in their blood thatmay be adversely affecting their nervous systems. The percentage is much higher for urban children from poorfamilies. As tests become more sensitive, neurotoxic effects become apparent at progressively lower levels of leadin children’s blood. In addition, relatively low exposures to lead in early years appear to have developmental andneurobehavioral effects that persist into young adulthood. Because of the widespread nature of the problem, it wouldbe 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, andit is unclear whether water suppliers or property owners bear the responsibility for removing lead plumbing. Thesame problem of responsibility exists for the removal of lead-based paint from older houses. Without any centralreporting system, it is difficult to ascertain the extent of lead poisoning in individual States; and since funding forlead poisoning prevention was placed under the block grant umbrella, it is difficult to determine the extent to whichFederal 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,” NewEnglandJournalofh4edicine 322:83-88, 1990. K.L. Florini, G.D. Krumbhaar, Jr., and E.K. Silbergeld, “Ugacy of Gad: America’sContinuing 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), peopleage 60 and older represent 17 percent of theU.S. population but account for nearly 40percent of drug-related hospitalizations andmore than half the deaths from drug reac-tions. Common adverse effects include de-pression, confusion, loss of memory, shakingand twitching, dizziness, and impairedthought processes.

Workers in industry and agriculture oftenexperience substantially greater exposures tocertain toxic substances than the general popula-tion does. Neurotoxic pesticides and solventsare common sources of exposure in theworkplace. The National Institute for Occupa-tional Safety and Health (NIOSH) has identifiedneurotoxic disorders as one of the Nation’s 10leading causes of work-related disease andinjury. Other leading causes of work-relateddisease and injury include noise-induced hear-ing loss and psychological disorders, both ofwhich are mediated by the nervous system.NIOSH has estimated that several million work-ers are exposed to neurotoxic substances on aregular basis.

Persons who abuse psychoactive drugs mayface particularly severe neurotoxic effects. TheNational Institute on Drug Abuse (NIDA) re-ported that in 1986 drug abuse led to more than119,000 emergency room visits and 4,138deaths. Some drugs can permanently damagethe nervous system. Damage may be so severeas to cause personality changes, neurologicaldisease, mental illness, or death. Persons whoabuse drugs are often not aware of, or do not takeseriously, the threat these substances pose totheir health. Drugs such as cocaine, heroin,MDMA (ecstasy), and phencyclidine (PCP) areneurotoxic and threaten the health of manyAmericans. Figure 1-3 illustrates how oneabused drug, MDMA, can destroy nerve fibersin the brain. Abuse of psychoactive drugs bypregnant women poses a major risk to thedeveloping nervous system of the fetus (seebox l-D).

Figure 1 -3--Neurotoxic Effect of MDMA on SerotoninNerve Fibers in the Cerebral Cortex of

the Monkey

A. Control

B. MDMA

Repeated administration of MDMA (5mg/kg, 8 doses) to aCynomolgus monkey produced degeneration of most serotoninnerve fibers in this region of the cortex, which is involved in theperception of touch and position sense. Similar toxic effects areseen 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 sub-stances is conducted primarily at the NationalInstitutes of Health (NIH), the Alcohol, DrugAbuse, and Mental Health Administration(ADAMHA), and EPA. Limited research pro-grams are under way at the Food and DrugAdministration (FDA), the Centers for DiseaseControl (CDC), the Department of Energy, theDepartment of Agriculture, and other agencies.


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 otherfactors, 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 yearas many as 375,000 infants may be adversely affected by substance abuse, Maternal substance abuse is frequentlynot recognized by health-care professionals during pregnancy. Consequently, treatment or prevention programsoften come too late. According to the National Institute on Drug Abuse, approximately 6 million women ofchildbearing age (15 to 44) are current users of an illicit drug, about 44 percent have tried marijuana, and 14 percenthave used cocaine at least once.

A recent study of 50 women who used cocaine during pregnancy revealed a 31 percent incidence of pretermdelivery, 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 todocument, but they are just as real. Early research indicates that cocaine babies suffer abnormal development of thenervous 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 onepregnant crack addict put it: “The lowest point is when I left my children in a park for like 3 or 4 days. I had leftmy kids with a girl that I know and told her. . . ‘watch them. . . I’ll be back’ and I didn’t come back. So that waslike—when I finally came down off of that high, I realized that I needed help. ” Sick and abandoned children ofcocaine mothers have placed a heavy burden on a number of the Nation’s hospitals. During a l-week period at onehospital, 1 in 5 black infants and 1 in 10 white infants were born on cocaine. Taxpayers usually end up paying thehealth-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 ofMatemat 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 CivilianNeurotoxicity-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

26.63.9

0.71.80.50.4

66.5aTotals 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 fundingfor civilian neurotoxicology -related research(excluding research related to nicotine andsmoking, alcohol and alcoholism, and radiation)is about $67 million. The bulk of this funding(89 percent) is through ADAMHA and NIH andtends to focus on the toxicity of drugs and thebiochemical mechanisms underlying neurologi-cal and psychiatric disorders. A number of otherFederal agencies and organizations providelimited funding for research related to neurotox-icity as well. Given the threat that neurotoxicsubstances pose to public health and the lackof knowledge of the mechanisms by whichthese substances exert adverse effects, OTAfound that, in general, Federal researchprograms are not adequately addressingneurotoxicity concerns.

Research related to environmental neurotoxicol-ogy is confined primarily to the intramuralprogram at EPA and the extramural program atthe National Institute of Environmental HealthSciences (NIEHS) within NIH. The NIEHSextramural grants program supports a substan-tial number of research projects in academia.However, OTA found that, with the exception ofthe neurobehavioral section of the Laboratory ofMolecular and Integrative Neuroscience withinNIEHS, NIEHS intramural research programsare focused on the basic neuroscience ratherthan on environmental neurotoxicology, result-ing in a prominent intramural research gap at

NIH in the environmental neurotoxicology field.Of the approximately $3 million NIEHS spenton intramural research in the neuroscience infiscal year 1988, OTA found that only aboutone-fourth was devoted to studies in whichneurotoxicology was the primary focus.

Academic research in neurotoxicology issupported almost exclusively by NIH andADAMHA. Most extramural research fundedby NIH is through NIEHS and the NationalInstitute of Neurological Disorders and Stroke(formerly the National Institute of Neurologicaland Communicative Disorders and Stroke),although several other Institutes have substan-tial programs. The extramural grants program atNIEHS has been particularly effective in fund-ing research grants in the neurotoxicity field.ADAMHA funds grant programs through NIDAand the National Institute of Mental Health.

EPA has a relatively large intramuralresearch program in neurotoxicology whichhas been limited in recent years by lack offunding for supplies and equipment. EPAlacks an extramural grants program in neu-rotoxicology. The Agency has only a smallgrants program that has rarely funded neurotoxi-cology-related projects. Traditionally, Federalagencies have supported both intramural andextramural efforts to ensure a balanced, compre-hensive, and cost-effective program.

In recognition of the need to expand itsresearch programs in the neurotoxicology area,EPA recently submitted to the Office of Man-agement and Budget (OMB) a request to expandits research budget by $1.5 million. Approxi-mately $1.0 million was requested for thedevelopment of in vitro neurotoxicology tests;another $0.5 million was requested to examineadverse effects associated with cholinesteraseinhibition and the utility of cholinesterase inhibi-tion as a biomarker for exposure. However,OMB allowed no funding for either researcheffort. In vitro test development is often cited asa high-priority research need because of therequirement to rapidly screen toxic chemicals

12 ● Neurotoxicology: Identifying and controlling Poison of the Nervous System

and to try to minimize the use of animals inresearch. A technical EPA panel recently recom-mended that the Agency initiate studies toexamine the relationship between cholinesteraseinhibition and other adverse effects on thenervous system.

FDA funds a small number of researchprojects related to neurotoxicology, primarilythrough its intramural research programs. TheNational Center for Toxicological Research isconducting a number of intramural researchprojects related primarily to developmentalneurotoxicology. The Center for Food Safetyand Applied Nutrition has a small in-houseprogram and is supporting three extramuralresearch projects.

Within CDC, NIOSH has small intramuraland extramural programs devoted to the identifi-cation and control of neurotoxic substances inthe workplace. CDC’s Center for Environ-mental Health and Injury Control conductsepidemiological investigations of human expo-sure to environmental hazards, but few studiesfocus on neurotoxic effects.

Industry supports neurotoxicology -related re-search through several mechanisms, includingin-house scientists, contract laboratories, con-sortia, contracts with universities, and grants touniversities. Toxicity evaluations conducted aspart of internal applied research are necessary todevelop safe and effective products, to protectemployees, to protect the environment, and tocontrol liability costs. Research programs varyconsiderably depending on the types of productsmanufactured and various economic considera-tions.

OTA found that education of researchscientists in the neurotoxicology field islimited, in part, by inadequate Federal sup-port for training programs. Part of the diffi-culty in obtaining funding is due to the nature ofneurotoxicology-the intersection of neuroscienceand toxicology. Few academic departmentsdevote significant resources to neurotoxicology,and few Federal research organizations devotemajor efforts to it. NIEHS supports training in

the neurotoxicology field; however, fundinglimitations allow for support of only a relativelysmall number of trainees.

Millions of American workers are exposed toneurotoxic substances in the workplace, butillness stemming from these exposures oftengoes undetected and untreated. The subtlety ofneurotoxic responses is one reason for thissituation; for example, complaints of headacheand nervousness are often ascribed to othercauses. Another reason is the lack of adequatelytrained health-care professionals to diagnoseand treat neurotoxic disorders. Medical schools,in general, devote little of their curricula tooccupational health issues. After medicalschool, physicians may undertake residencytraining in occupational medicine, but in 1987only about 1 in every 1,000 residents wasspecializing in occupational medicine. Nursesare also needed in the occupational health fieldto provide emergency services, to monitoremployee health, and to provide counseling andreferral to physicians. In addition, industrialhygienists are needed to evaluate and controlhealth hazards in the workplace.

Testing and Monitoring

Controlling toxic substances is a two-partprocess. The first step is to identify existingsubstances that adversely affect the nervoussystem and take action to minimize humanexposure to them. The second step is to identifynew neurotoxic substances in use and eitherprevent their manufacture (if they cause seriousneurotoxic effects) or limit human exposure tothem and release of them into the environment.Very few new and existing chemicals havebeen evaluated specifically for neurotoxicity.

The effects of toxic substances on the nervoussystem may be evaluated through animal tests,cell and tissue culture (in vitro) tests, and humantests. Each approach has advantages as well aslimitations. The best way of predicting adverseeffects on human health is to test potentiallytoxic substances directly on human subjects.However, this approach is often difficult and inmany situations is unethical. Therefore, it is


usually necessary to rely on animal and in vitrotests to predict effects on human health. In somecases, in vitro tests can be used to detectneurotoxic effects; at present, however, animaltesting is used to obtain a neurotoxicologicaland behavioral evaluation. As more in vitrotesting techniques become available and arevalidated, they may be used in the initialscreening process or to complement animaltests.

Several industrial and Federal organizationshave developed animal tests to evaluate theeffects of known and potential neurotoxic sub-stances. In industry, several testing methods arecurrently used on a limited basis to assess theneurotoxic potential of some toxic substances.In the Federal arena, EPA recently developedguidelines for a series of neurotoxicity tests tosupplement its general toxicological tests. Coreneurotoxicological tests used in initial screeningfor toxicity include the functional observationalbattery (a series of rapid neurological tests toevaluate toxic effects on animals), tests of motoractivity, and neuropathological examinations.Additional tests that may be used includeschedule-controlled operant behavior tests, acuteand subchronic delayed neurotoxicity tests fororganophosphorous substances, and developmentalexaminations. Neurophysiological evaluationsare also useful in identifying neurotoxic sub-stances and in evaluating their adverse effects.

Several human tests are in use to determinethe neurotoxic potential of suspected and knowntoxic substances. These include neurobehav-ioral evaluations and various neurophysiologi-cal tests. In addition, computer monitoringdevices are rapidly advancing to aid in studies ofneurotoxicity.

Monitoring the release of toxic substances iscritical to regulatory programs. In 1986, Con-gress enacted the Federal Emergency Planningand Community Right-to-Know Act, whichmandated that EPA develop a Toxics ReleaseInventory of more than 300 toxic chemicalsreleased by industry into the environment. Thefirst data were published in 1989, and the

inventory will be updated annually. Such adatabase will undoubtedly prove to be veryuseful in monitoring releases of neurotoxicsubstances. As indicated in figure 1-4, 17 of thetop 25 toxic substances released into the envi-ronment have neurotoxic potential.

Monitoring exposure to neurotoxic substancesis a critical component of public health andenvironmental protection efforts. Monitoringmay be conducted by regularly surveying con-taminants in the food supply, banking animalspecimens, and collecting biological data onhumans. Biological specimens can be used tomeasure contamination levels over periods ofmany years and to document adverse effects.Human biological monitoring programs can beundertaken to detect exposure to toxic sub-stances and to aid in making decisions abouthealth risks. Such programs may be particularlyuseful in monitoring exposures in the workplace.

Risk Assessment

Risk assessment is the analytical process bywhich the nature and magnitude of risks areidentified. Risk, as it pertains to the healtheffects of toxic substances, is the probability ofinjury, disease, or death for individuals orpopulations undertaking certain activities orexposed to hazardous substances. It is some-times expressed numerically (e.g., 1 in 1 mil-lion); however, quantification is not alwayspossible, and risk may sometimes be expressedin qualitative terms such as high, medium, orlow risk. Risk management, a process guided byrisk assessment, and by political, social, ethical,economic, and technological factors as well,involves developing and evaluating possibleregulatory actions and choosing among them.

Some degree of risk is associated with almostevery aspect of modern living. For example,traveling in an automobile involves a risk ofaccidental death of 1 in 4,000, a relatively highrisk. In contrast, the risk of being killed bylightning is 1 in 2 million. Whether a risk isacceptable or not depends on many factors,including benefits. Defining acceptable risk isthe 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

_ A n g e r end Johnson ( 1985], orsu bje cl to TSCA Sect Ion 4 les I r u I etor neurotox IC subs l a n c e s

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

Dlm_lAM 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 M K - 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 t i d e

BE - Benzene

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

AC - AcetoneDI - Dlch Ioromethane P R - P ropy I ene CL - Ch Iorotor mCH - 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 - A l um inum Ox ide NA - N-Bu 1 y I A lcoho l 5A - Sul fur IC Ac8d

ch Ioroethane ET - E thy lene 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. Everyoneevaluates risks on a daily basis and makesindividual choices depending on experience andother factors.

Risk assessment practices are the subject ofongoing debate within the regulatory and scien-tific communities, and in the last two decadesstrategies to regulate toxic substances havechanged considerably. In the early 1970s, envi-ronmental legislation focused on regulating arelatively small number of pollutants of knowntoxicity. Today, concern is focused on thou-sands of toxic substances, for many of whichlittle information is available. This change hasbeen forced in part by improved methods ofdetecting toxic substances in the environment,

improved capabilities for identifying the ad-verse effects of these substances, and thedifficulty of determining threshold levels belowwhich no adverse effects occur.

Policies regarding risk assessment have beencontroversial. Some people believe that Federalagencies overestimate risk by making overlyconservative assumptions in developing riskassessments. Others feel that risk assessmentpractices do not take into account the complexinteractions of multiple pollutants that oftenoccur in the environment. Still others point outthat risk assessments focus primarily on adverseeffects on human health and devote little atten-tion to other organisms and the environment ingeneral. Critics of established risk assessment

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

w.

IIllustrated by: Ray Driver

procedures believe that too little attention isbeing paid to the potential effects of toxicsubstances on children, infants, and the unborn.Regardless of the various viewpoints, riskassessment has become an integral componentof regulatory strategies, and it is important toappreciate the scientific issues underlying thisprocess in order to understand how toxic sub-stances are controlled.

Concerns about carcinogenicity have domi-nated discussions about the risks posed bytoxic substances. However, the adverse ef-fects on organs and organ systems, particu-

larly the nervous system, may pose an equalor greater threat to public health. Conse-quently, it is important to devise risk assess-ment strategies to address noncancer healthrisks. An important difference between neuro-toxicity and carcinogenicity is the extent towhich the effects are reversible. The endpoint ofcarcinogenicity is considered to be irreversible(although some argue that, strictly speaking, a‘‘cure’ would render the effect reversible),whereas the endpoints of neurotoxicity may beeither reversible or irreversible, depending onthe specific effect, the duration and frequency ofexposure, and the toxicity of the substance.Reversibility requires the introduction of a newvariable into the risk assessment equation.

Since the nervous system is perhaps the mostcomplex organ system of the body, evaluatingthe neurotoxic potential of environmental agentsis a particular challenge. For example, testingfor a toxic effect on one component of thenervous system (e.g., hearing), may or may notreveal a toxic effect on another component (e.g.,vision). Furthermore, an effect on one nervoussystem function is not necessarily predictive ofan effect on another nervous system function.

The results of toxicological analyses arestrongly influenced by the age of the organismbeing examined. For example, mice exposed tomethylmercury during prenatal developmentmay not exhibit adverse effects until late in theirlives. With age, the functional capacity of thebrain declines significantly, and chronic expo-sure to some neurotoxic substances is thought toaccelerate this process. Hence, some scientistsand regulatory officials believe that risk analy-ses should consider adverse effects over a rangeof ages and should take into account latenteffects.

Federal Regulatory Response

It is the task of regulatory agencies to limitpublic exposure to toxic chemicals throughprograms mandated by law. Because of the greatdiversity of toxic substances, many statutes existto control their use. These laws are administeredby various Federal agencies, but primarily by


Table 1-2--Major Federal Laws ControllingToxic Substances

Agency primarilyAct 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

EPAFDA

OSHA

EPAEPA

EPAEPAEPA

CPSCCPSCFDA

MSHA

EPACPSCHHS

CPSCKEY: CPSC-Consumer Product Safety Commission; EPA-Environ-

mental Protection Agency; FDA-Food and Drug Administration;HHS--Department of Health and Human Services; MSHA—MineSafety and Health Administration; OSHA-Oocupational Safety andHealth Administration.

SOURCE: Office of Technology Assessment, 1990.

EPA, FDA, and the Occupational Safety andHealth Administration (OSHA) (table 1-2).OTA found that very few substances have beenregulated as a result of neurotoxicity concerns.

New and existing industrial chemicals areregulated by the Toxic Substances Control Act(TSCA). Pesticides are controlled by the FederalInsecticide, Fungicide, and Rodenticide Act(FIFRA), and toxic substances in the workplaceare regulated by the Occupational Safety andHealth Act (OSH Act). The Federal Food, Drug,and Cosmetic Act (FFDCA) regulates food andfood additives, drugs, and cosmetics. Theselaws address the vast majority of toxic sub-stances, and more than a dozen other acts focuson other substances and sources of exposure.Although neurotoxicity is generally not explic-itly mentioned in legislation mandating theregulation of toxic substances, it is implicitlyincluded as a toxicity concern.

Under the authority of this diverse frameworkof legislation, regulatory agencies have promul-gated equally diverse regulations for protecting

human health. Some regulatory programs re-quire substantial testing of chemicals to screenfor toxic effects; others are not empowered torequire any such testing. Some regulations callfor screening substances before they are allowedto enter the marketplace; other regulations arereactive, coming into effect only when evidenceindicates that an existing chemical can or doescause harmful effects.

Federal laws governing toxic effects can bedivided into three general categories:

1.

2.

3.

licensing and registration laws for newand existing chemicals, which entail ex-plicit review processes and may includerequirements for toxicity testing;standard-setting laws for chemicals usedin specific situations, under which regula-tory agencies determine recommended orrequired limits on toxic substances invarious environmental media (air, water,or soil) or emitted by a given source, ordictate appropriate labeling of productsthat contain toxic substances; andcontrol-oriented measures for dealingwith chemicals, groups of chemicals, orchemical processes that are explicitly iden-tified in the laws as targets of concern.

Distinctions among the three categories are notabsolute—there is more of a continuum than adiscrete grouping in the legislative language—but this classification indicates the basic types ofapproaches that have been developed to protectthe public and the environment from the adverseeffects of toxic substances.

Consistency of the Federal Regulatory Effort

There are numerous differences in regulatorypractice under different laws, even within thegroup of Incensing laws (TSCA, FIFRA, FFDCA).These differences do not, for the most part,apply specifically y to the regulation of neurotoxiceffects, but rather to regulation of all toxiceffects. Thus, consistency of regulation forspecific neurotoxic effects hinges on consis-tency of regulation in a more general sense.

Chapter 1-Summary, Policy issues, and Options for Congressional Action ● 17

Statutory requirements for chemical regula-tory programs differ in several important re-spects, among them the number of chemicalsevaluated, the time available for review, theamount and type of data available at thebeginning of the review process, the ability ofthe reviewer to acquire additional data afterreview has begun, and the burden of proofregarding safety. For example, the Premanufac-ture Notice (PMN) process under TSCA neces-sitates review of hundreds of chemicals everyyear; each review is allotted only 90 days(although an extension is possible), and substan-tive toxicity data are rarely submitted. EPA canobtain additional data or impose controls onchemicals only if it finds that there may be anunreasonable risk associated with use of thechemical. Without significant toxicity data,predicting risk is difficult and must rely onhypothetical relations between chemical struc-ture and biological activity. However, little isknown about structure-activity relationshipswith respect to neurotoxicity. Applicants forregistration of a pesticide under FIFRA mustsubmit extensive general toxicological dataaccording to specified test protocols, the reviewprocess extends over a period of years, theapplicant is required to submit additional data ifthe basic data raise concerns, and the applicantmust establish that the pesticide will be both safeand effective under the proposed conditions ofuse. Few data relating to neurotoxicity concernsare presently required. However, the agency isconsidering expanded testing requirements.

That there are differences in the degree ofregulatory scrutiny under the various Federalregulatory programs is widely acknowledged.Often, these disparate regulatory requirementsreflect real differences in the potential risksrepresented by the chemicals each programregulates. It may be that the more intensescrutiny reserved for some types of chemicals isan appropriate reflection of the likelihood thatthey will threaten human health or the environ-ment.

Current laws are generally based on thepremise that chemicals for which there is a

greater probability of exposure should meet ahigher standard of safety. This is most clearlyillustrated by the prohibition of carcinogenicsubstances as direct food additives and ofpesticides that concentrate in foods (the Delaneyclause of FFDCA). No such general prohibitionapplies to general industrial or commercialchemicals under TSCA or the OSH Act.

The stringency of the evaluation process fornew chemicals under the various laws generallymatches the presumption of risk—the combina-tion of hazard and exposure potential-posed byeach class (in the view of regulatory officials)and the number of new class members intro-duced each year. Thus, drugs are not to bepermitted on the market until proven safe andeffective in clinical trials. New pesticides andfood additives are evaluated nearly as strin-gently; however, human trials are not per-formed. Commercial chemicals, whether in-tended for industrial or consumer use, receivethe least scrutiny.

There are two exceptions to these trends, oneminor and one significant. Consumer chemicalshave not received any procedurally differentscrutiny than those intended for industrial use,despite the fact that larger numbers of personsmay be exposed as consumers than as industrialworkers. Moreover, FFDCA does not requirethat cosmetics and cosmetic ingredients undergopremarket toxicity testing. Industry voluntarilytests cosmetic ingredients for acute toxic effects,but few are examined for chronic toxicity. Somehave been found to have acute and chronicneurotoxic effects on laboratory animals.

While many scientists find some comfort inthe observation that the stringency of review ofa chemical matches its presumptive risk (exceptfor cosmetics), public interest groups havevoiced concerns over such odds playing. Forexample, the chemicals regulated under TSCAmake up the largest classes of chemicals, yetthey receive relatively little scrutiny by EPA.TSCA does offer options for selecting high-riskchemicals for further scrutiny, but the vastmajority of chemicals receive only a limited

18 ● Neurotoxcity: Identifying and Controlling Poisons of the Nervous System

review. Critics of EPA argue that regulatoryresource considerations and a desire not toburden industry, rather than presumptiverisk, are in fact driving chemical reviewcriteria. They raise the question of whetherthe minimal screening given to the majorityof chemicals is adequate to deal with high-risk chemicals that are not members ofknown risk categories.

Regulation of New v. Existing Chemicals

Existing chemicals are subject to varyingdegrees of review and reevaluation. In contrastto procedures for reviewing new chemicals,however, procedures for reexamining existingchemicals do not necessarily reflect the inherentrisks of the chemical classes involved.

EPA attempts to ensure the adequacy of thedata supporting continued pesticide registrationthrough a regular review process. The registra-tion standards program, which examines 25chemicals per year, has thus far addressed onlya small portion of the active ingredients ofregistered pesticides and has been the subject ofconsiderable concern. At the present rate, activepesticide ingredients would be reviewed on anaverage of only once every 12 years or more.The 1988 FIFRA amendments mandated thatthe review schedule be accelerated so that allactive ingredients are reviewed by 1997. Tomeet this goal, EPA will need to streamline itsexisting review process.

Under section 4 of TSCA, existing chemicalsare ranked for probable risk or high exposuresprior to entering the test rule or consent orderregulatory process. In the period from 1977 to1988, final rules were issued on only 25chemicals or related sets of chemicals, con-sent agreements were reached on three, withnine proposed rules pending. Clearly, theserules address only a very small fraction of the60,000 chemicals in the TSCA inventory.

FDA’s various procedures for reviewingexisting drugs and food and color additives areless formal than those for pesticides or toxicsubstances. FDA tracks physicians’ reports of

adverse drug reactions and reports them to theoriginal evaluators of the drugs. Food and coloradditives have been notable exceptions to thereview of existing chemicals. Until recently,once an additive was registered, there was nomonitoring of adverse reactions. For aspartame,FDA established voluntary reporting programs,but most food additives are not the subject offormal reporting programs. Although FDA doesnot require reporting on the use of approvedfood and color additives, i t could track suchinformat ion and use i t to assess the r i sksassociated with approved uses.

Specific neurotoxicological Considerations

Regulatory differences in general strategiesfor eva lua t ing toxic i ty en ta i l cor respondingd i f f e r e n c e s i n t h e e v a l u a t i o n o f n e u r o t o x i ce f f e c t s . T h u s f o r h u m a n d r u g s , p r e c l i n i c a ltoxicity tests are only used to guide observationson c l in ica l t r ia l s and to e luc ida te poss ib lemechanisms of toxicity, rather than to directlyassess toxic potential. For pesticides and foodand color additives, in contrast, animal toxicitydata are used directly in predicting human risk.H o w e v e r , e v e n w i t h i n p r o g r a m s t h a t h a v eessentially similar approaches to assessing toxicr isks , there are d i f ferences wi th respect toconsideration of neurotoxic risks.

Regula tory programs have adopted one ofthree basic approaches to toxicity evaluation,depending on which of three under ly ing as-sumptions they hold. One approach is based onthe assumption that general toxicity tests usinghigh doses a re adequate to de tec t neurotoxicpotent ia l and tha t neuro toxicologica l eva lua-tions are needed only if general tests, data onstructural analogues, or other specific knowl-edge about a chemical indicate a potential forneurotoxicity. Among these are FDA’s preclini-cal testing program for drugs and its currentp r o g r a m f o r a p p r o v i n g f o o d a d d i t i v e s . T h esecond approach, represented by the pesticider e g i s t r a t i o n p r o g r a m u n d e r F I F R A , a c c e p t smore general structural information in guidingneurotoxic i ty tes t ing . Al l organophosphorouscompounds are evaluated for the potential to

Chapter l-Summary, Policy Issues, and Options for Congressional Action ● 19

induce delayed neuropathy, but nonorgano-phosphorous compounds are not specificallyevaluated for neurotoxic potential. All pesti-cides undergo a general toxicity screen; how-ever, specific neurotoxicity tests are not pres-ently required. Finally, under section 4 ofTSCA, specific neurotoxicity testing is requiredfor any chemical with high exposure potential,as well as for chemicals specifically suspectedof being neurotoxic. Such testing presumes thatstandard toxicity tests are not adequate toevaluate neurotoxic effects.

OTA found that Federal efforts to controlneurotoxic substances varied considerably be-tween agencies and between programs withinagencies. Improving the Federal response willrequire increased neurotoxicity testing, im-proved monitoring programs, and more aggres-sive regulatory efforts.

Federal Interagency Coordination

Interviews with toxicologists and neurotoxicolo-gists in various Federal agencies indicated thatthere is little formal coordination among agen-cies, although neurotoxicologists at differentagencies maintain regular informal contacts.There are also several coordinated researchefforts mediated by interagency agreements andby personal contac t .In the spring of 1989,OTA and EPA cosponsored a workshop onFederal interagency coordination at whichAgency representatives decided to establishan Interagency Working Group on Neu-rotoxicology to foster increased interactionamong Federal agencies responsible for re-search and regulatory programs.

neurotoxicologists at different agencies main-tain regular informal contact, but this contacthas not fostered a consensus on the bestapproach to regulating neurotoxic hazards. Realdifferences of scientific opinion remain, anddata that would resolve these differences havenot been developed by the agencies involved.Restrictions on revealing confidential businessinformation hinder the transfer of potentiallyuseful toxicological information, both to thepublic and between Federal agencies. Moreover,

even wi th in agencies , neurotoxicologis t s andother toxicologists sometimes disagree on theproper role of neurotoxicity in safety evalua-tions.

An agency’s approach to neurotoxicity evalu-a t i o n o f t e n c o r r e s p o n d s t o t h e p r e s e n c e o ra b s e n c e o f n e u r o t o x i c o l o g i s t s o n t h e s t a f f .Al though th is presumably ref lec ts personnelconsiderations—if an agency is not evaluatingneurotoxicologica l da ta , i t does not requi rep e o p l e t r a i n e d t o d o s o - i t d o e s r a i s e t h eq u e s t i o n o f w h e t h e r p e r s o n s w h o e v a l u a t egeneral toxicological data understand the contribu-tions of directed testing to the prediction ofneurotoxic ef fec ts . Genera l toxicologis ts a reessential to the review process; however, indi-v iduals wi th specia l ized exper t i se are of tennecessary to ensure a comprehens ive evalua-tion. Variations in the hiring of neurotoxicolo-gists by Federal agencies reflect a more generalproblem of toxicologica l assessment , tha t ofd e t e r m i n i n g t h e a p p r o p r i a t e d e g r e e o f s p e -cialization required to evaluate the many organsys tems potent ia l ly a f fec ted by a toxic sub-stance. OTA found that effectiveness in ad-dressing neurotoxicological concerns at Fed-eral agencies is dependent on the presence ofneurotoxicologists in regulatory program of-fices. Improving Federal programs will re-quire increased employment of neurotoxicol-ogists trained in risk assessment and regula-tory procedures.

The Federal regulatory response to neurotox-icity is fragmented not only by differences inscientific judgment, but also by differences inregulatory responsibility. The decision to evalu-ate drugs, pesticides, and food additives bystricter standards than are applied to commercialchemicals is based not only on the views ofscientists, but also on national consensus. Thus,the perception of risk by the public can stronglyinfluence regulatory policies related to toxicsubs tances .

Economic Considerations in Regulation

Regula t ing neurotoxic subs tances involvesconsideration of both the economic benefits of

20 Neurotoxicity: ldentifying and Controlling Poisons of the Nervous System

using these substances and their actual orpotential costs. The problem of balancing bene-fits, costs, and risks of regulation is not uniqueto the control of neurotoxic substances; it arisesin all forms of health, safety, and environmentalregulation. Regulations that are designed toreduce or prevent neurotoxic risks can benefitsociety through improvements in public healthand environmental amenities. In most cases,however, society incurs costs to achieve theseregulatory ends. The costs of complying withhealth and safety regulations may also result inincreases in market prices, reductions in indus-try profits, and declines in new product innova-tion.

Many of the key Federal laws under whichneurotoxic substances are regulated requireagencies to ascertain the positive and negativeeconomic consequences of regulation. In imple-menting these laws, Congress has generallyintended that agencies prepare regulatory analy-ses and document the balancing of benefits,costs, and risks of proposed alternatives.

The Costs and Benefits of neurotoxicity Testing

Experience with neurotoxicity testing is stillrelatively limited, creating uncertainty regard-ing the available cost estimates for this type oftesting. Because of the uncertainty regardingthese costs, OTA obtained estimates of the costsof several types of neurotoxicity tests from anumber of individuals in government, industry,and academia.

The median estimates derived from OTA’ssurvey indicate that a complete set of neurotox-icity tests, including a functional observationalbattery, motor activity, and neuropathology,may add from 40 to 240 percent to the costs ofconventional toxicity tests currently required byEPA. By far the largest portion of the added costcomes from the neuropathology evaluations,which are needed to determine whether struc-tural change in the nervous system has occurredand the nature and significance of the change.Based on its survey, OTA found that acuteneurotoxicity tests (including EPA’s functionalobservational battery, motor activity test, and

neuropathology evaluations) may add a total ofabout $50,000 to standard toxicity test costs.Subchronic neurotoxicitytests may add $80,000,and chronic tests may add about $113,000. TheEPA subchronic schedule-controlled operantbehavior test may add about $64,000. However,the functional observational battery alone wouldadd only $2,500 to the cost of a conventionalacute toxicity test. A conventional acute test oforal exposure presently costs about $21,000.

Testing costs should be viewed in the contextof the health benefits of minimizing publicexposure to neurotoxic substances, the total costto industry of marketing a new product, poten-tial profits resulting from the sale of the product,and the impact high initial costs have on theinnovation process.

The benefits of regulating neurotoxic sub-stances can be measured in terms of the humanand monetary values placed on reduction of risk.A number of approaches have been used toassign monetary values to reduction of the risksof mortality, morbidity, and disability. Lead hasbeen the subject of an in-depth economicanalysis. A 1985 study estimated that the totalhealth benefits of reducing the neurotoxiceffects of lead on U.S. children would amountto more than $500 million annually between1986 and 1988. If adult exposure to lead,including workers’ exposure, were included,the benefits would be considerably larger.Although the health and economic benefits oflimiting public exposure to neurotoxic sub-stances are more difficult to estimate than thecosts of regulation, the example of leadillustrates the importance of considering thepotentially large monetary benefits of regula-tory actions. Like other toxicity testing, neuro-toxicity testing is conducted to prevent adversehealth effects; hence, the benefits of such testingmay not be readily apparent and may accrue wellinto the future. Often, the immediate costs oftesting receive considerable attention by regula-tory officials, but the sizable potential economicbenefits of preventing public exposure to ahazardous substance receive comparatively lit-tle attention.

Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 21

As indicated earlier, neurotoxic substances, inparticular abused drugs, play a significant,causal role in the development of neurologicaland psychiatric disorders; however, the preciseextent of the contribution remains unclear.Mental disorders and diseases of the nervoussystem contribute substantially to healthcosts in the United States. In 1980, theyranked as the third and fifth most expensivemedical conditions in terms of personalhealth-care expenditures. The estimate ofnearly $40 billion (1980 dollars) for these twocategories of morbidity does not include valuesfor lost productivity, restricted activity, andother social costs (e.g., criminal activity, lawenforcement, and rehabilitation for drug andalcohol abuse) that frequently accompany men-tal illness or other forms of mental impairment.

International Issues

Like most environmental concerns, neurotox-icity is a problem that is not limited by nationalboundaries. Pollutants readily cross nationalborders, hazardous chemicals are frequentlyimported and exported between industrializedand developing nations, and adulterated foodand commercial products enter the United Statesdespite current regulatory efforts. Strategies tolimit human exposure to neurotoxic substancesshould be devised in the context of both nationaland international regulatory and research initia-tives.

International Regulatory Activities

Despite numerous regulations governing theexport and import of neurotoxic chemicals andproducts containing them, some countries do nothave the regulatory framework and resources toadequately protect human health and the envi-ronment from these substances. Many nations,including the United States, have policies andprocedures in place, but too often they workonly on paper. In practice, they may allowneurotoxic substances to slip through the regula-tory cracks. Some developing nations haveregulations to protect workers and consumersfrom the adverse effects of neurotoxic sub-stances, but these nations often lack the re-

sources to enforce them. This lack of effectiveregulation and enforcement in developing na-tions has a negative impact not only on publichealth and environment in the user country, butalso in industrialized nations, including theUnited States, where people process and con-sume products imported from developing na-tions.

Both TSCA and FIFRA contain provisionsexempting certain U.S. products produced forexport from the requirements that apply toproducts sold for use in the United States. Inmost instances, the requirements of TSCA donot apply to substances manufactured, proc-essed, or distributed for export. The require-ments will, however, apply if it is determinedthat the mixture or article will present anunreasonable risk of injury to health within theUnited States or to the environment of theUnited States. In addition, because pesticidesintended solely for export are exempt from thepublic health protection provisions of FIFRA,pesticide manufacturers can legally exportbanned, severely restricted, or never-registeredsubstances that have been deemed too hazardousfor use in this country. Companies that do so arerequired to notify the importing country that thepesticides in question have been banned, se-verely restricted, or never registered for use inthe United States. Sometimes such pesticidesare used on food crops that are imported backinto the United States for consumption. Criticsof this practice have termed it the ‘‘circle ofpoison. ’

On January 15, 1981, several days before theend of his term, President Jimmy Carter issuedan Executive Order that set controls on exportsof substances that were banned or severelyrestricted in the United States. Several days afterbecoming President, Ronald Reagan revokedthis order.

International Research Activities

Active interest in neurotoxicity began in theUnited Kingdom during and after World War II.Since that time, research efforts in the UnitedStates have gradually increased. The United


States is now the world leader in environmentallegislation and government funding of neuro-toxicology research.

International research activities tend to focuson the heavy metals (lead and mercury), organicsolvents, and pharmaceutical agents. Scandi-navian countries have been active in research onthe neurotoxicity of organic solvents. OtherEuropean countries have supported research oncompounds of particular concern in occupa-tional settings, such as pesticides and heavymetals. Foreign neurotoxicology -related scien-tific papers published in international journalsmost often originate from authors in Canada,England, Italy, Australia, and Japan. A numberof papers originate from authors in France,India, Sweden, Finland, and Mexico, as well.

neurotoxicology research has been primarilyan intranational effort. In recent years, someinternational cooperation has been initiated bythe World Health Organization and the U.S.National Toxicology Program, but thus farcooperation has occurred only in specific areassuch as lead toxicity, solvent toxicity, and thedevelopment of testing methodologies. Thelimited scope of international cooperation islargely due to the lack of funds available forsuch efforts.

In some European countries, notably theFederal Republic of German and Sweden,environmental movements are becoming in-creasingly influential. It is likely that thesenations will play leading roles in supportingresearch and in developing regulations to con-trol toxic substances. The Federal Republic ofGermany has already acted to remove lead fromgasoline and to fund studies of lead toxicity inchildren. All of the Scandinavian countries(Sweden, Denmark, Norway, and Finland) havetraditionally supported research on solvents.These patterns are likely to continue and maybroaden to include the investigation of othertoxic substances as environmental movementsgrow. Political events in the Soviet Union haveled to the emergence of an environmentalmovement, and it appears that the Soviet

government will also take a more active role inthese issues. Finally, in the Far East, both thePeople’s Republic of China and Japan are facingmajor pollution problems and are becomingincreasingly involved in toxicological issues.

POLICY ISSUES AND OPTIONS FORCONGRESSIONAL ACTION

Six broad policy issues related to the identifica-tion and regulation of neurotoxic substanceswere identified during the course of this assess-ment:

1.

2.

3.

4.

5.

6.

adequacy of the Federal regulatory frame-work,adequacy of Federal and federally spon-sored research programs,coordination of Federal regulatory andresearch programs,availability of adequately trained researchand health-care professionals,communication of information to workersand the public, andadequacy of international regulatory andresearch programs.

Associated with each policy issue are severaloptions for congressional action, ranging in eachcase from taking no action to making substantialchanges. Some of the options involve directlegislative action. Others involve the executivebranch, but with congressional oversight ordirection. The order in which the options arepresented does not imply any priority. More-over, the options are not, for the most part,mutually exclusive; adopting one does notnecessarily disqualify others within the samecategory or in any other category. A carefulcombination of options might produce the mostdesirable effects. It is also important to keep inmind that changes in one area may haverepercussions in other areas.

ISSUE 1: Is the current Federal regulatoryframework addressing neurotoxicity ade-quately?

The Federal regulatory framework has beenbuilt on the foundation established by four


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major Acts: 1) Toxic Substances Control Act; 2)Federal Insecticide, Fungicide, and RodenticideAct; 3) the Federal Food, Drug, and CosmeticAct; and 4) Occupational Safety and Health Act.At least a dozen other acts address generaltoxicological concerns. Many of them explicitlyor implicitly mandate regulation of neurotoxicsubstances. Options related to this issue areorganized around the Federal agency with leadresponsibility for implementing a particular law.

Environmental Protection Agency

EPA is responsible for implementing two ofthe major acts, TSCA and FIFRA, and several

others pertaining to neurotoxic substances, in-cluding the Clean Air Act; the Federal WaterPollution Control Act and Clean Water Act; theSafe Drinking Water Act; the ComprehensiveEnvironmental Response, Compensation, andLiability Act; the Marine Protection, Research,and Sanctuaries Act; and the Resource Conser-vation and Recovery Act.

Option 1: Take no action.

If no congressional action is taken, EPA willcontinue to be responsible for carrying out theprovisions of the existing statutes, which implic-itly address neurotoxicity in the context ofgeneral toxicological concerns. The degree towhich neurotoxic substances are regulated willvary according to program priorities, resources,the expertise of Agency personnel, and interpre-tation of pertinent laws by Agency officials. Todate, few toxic substances have been regulatedon the basis of known or suspected adverseeffects on the nervous system. Even in theabsence of congressional action, this situation islikely to change, given greater public andAgency awareness of neurotoxicological con-cerns and the institution of new neurotoxicitytesting guidelines under TSCA and FIFRA. Forexample, EPA is actively considering requiringfunctional observational battery, motor activity,and neuropathological tests for all new pesti-cides and for all existing pesticides undergoingreregistration.

Option 2: Mandate more extensive neurotoxicity“ testing under TSCA and FIFRA.

neurotoxicity test guidelines developed byEPA to support regulatory programs mandatedby TSCA and FIFRA will allow the Agency torequire neurotoxicity testing of a wide range ofindustrial chemicals and pesticides. The extentand frequency of testing EPA may require is notclear at this time.

If it wishes to mandate additional neurotoxic-ity testing, Congress could require EPA to testnew and existing chemicals if certain productionvolume and human exposure levels are reachedand if structure-activity relationships or other


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information suggests that the substance may beneurotoxic. Volume and exposure levels can beeffective triggers for testing. Production volumeis currently being used as a trigger by the FederalRepublic of Germany, and this testing approachhas been considered by EPA in the past.However, triggered testing does have importantlimitations-some substances may have potentneurotoxic effects at low doses. Congress mayalso wish to request that EPA consider novel

approaches to obtaining more extensive datafrom industry under TSCA, perhaps through theuse of economic incentives. EPA could workwith industry representatives to devise incen-tives for voluntary neurotoxicity testing. EPAcould also work more closely with scientists inindustry and academia to develop and validateneurotoxicity tests.

Congress could amend FIFRA, mandatingthat new and existing pesticides being consid-ered for registration undergo neurotoxicity test-ing under the newer, more extensive guidelines.This would formalize EPA’s pending policy andwould underscore congressional concern re-garding the potential adverse effects of neuro-toxic pesticides on public health. Currently,EPA plans to require the use of three neurotoxic-ity tests: the functional observational battery,motor activity, and neuropathological evalua-tions. Congress could also mandate that certainclasses of inert ingredients undergo neurotoxic-ity evaluations as well. Congress may wish torequest that EPA consider developmental neurotoxi-cological and behavioral tests in addition to thethree core neurotoxicity tests for certain pesti-cides. Such tests are considered by some scien-tists to be particularly important in evaluatingthe effects of neurotoxic substances on children.Congress could also mandate that risk assess-ments devote increased attention to the potentialadverse effects of pesticides on children.

Option 3: Require that EPA and other Federalagencies revise the confidential businessinformation provisions of various toxic sub-stances control laws and regulations to allowgreater access to toxicological information.

Under TSCA, for example, much of theinformation submitted to EPA by chemicalmanufacturers or processors can be claimed tobe confidential business information. Informa-tion covered by such a claim cannot be divulgedto anyone outside the small group of EPAemployees who have been granted a specialclearance, primarily selected EPA staff andcontractors. The aim of confidentiality provi-sions is to prevent commercially valuable infor-

Chapter 1-Summary, Policy Issues, and Options for Congressional Action . 25

mation from being disclosed to the submitter’scompetitors. Other environmental statutes con-tain similar provisions regarding confidential ortrade secret information.

Toxicity data per se cannot be claimed asconfidential under TSCA, but much of the otherinformation relevant to assessing toxic riskscan—including the identity of the chemical forwhich toxicity data are presented, its physical-chemical properties, and its intended uses. Thisrenders the health and safety data of little use toanyone without a special clearance.

The strong confidentiality provisions in TSCAcan present significant barriers to efficientregulation. The requirement for a special clear-ance prevents the use of confidential data byanyone without a clearance, even if they areEPA officials or officials of other Federalagencies who are attempting to regulate thesame chemical or closely related chemicalsunder different laws. The limited exchange ofinformation can lead to duplication of effort,particularly when several agencies are con-strained by confidentiality provisions.

The inability to share information, eitherinside the government or with outside parties,often interferes with research efforts. For exam-ple, much of the information on a chemical’sstructure-activity relationship is covered byclaims that it is confidential business informat-ion. Scientists in industry, academia, and othergovernment agencies cannot gain access to thisinformation, even when it might contain valua-ble data for developing improved methods ofpredicting neurotoxicity and other toxic effects.At the same time, claims of confidentiality mayprevent EPA from obtaining expert advice orconsensus opinions from academic or industrialscientists.

Public interest groups and other interestedindividuals do not have access to informationthat would allow them to question-or toaccept—EPA’s actions on many toxic sub-stances. Nor can individuals take action toprotect themselves if they do not have access toinformation regarding the identity of toxic

chemicals or the products that might containthem.

Few persons would dispute the need for someform of protection for trade secrets. However,many persons believe that there is good reasonto question whether the burden imposed bystrong confidentiality provisions and similarstatutes on the government, the public, andindustry is justifiable.

Congress could disallow certain kinds ofinformation, including the precise chemicalidentification of a substance and all toxicologi-cal data on a substance, from claims of confiden-tiality. It could mandate that more informationabout the chemical properties, potential adverseeffects, and production and release of toxicsubstances be made available to the public. Itcould amend existing laws or write new laws toenable sharing of information between Federalregulatory programs. Congress could also createa centralized confidential database, admini-stered by one designated agency, or a consor-tium of agencies, and divert all reporting to thedesignated agency. In addition, it could requiremore extensive labeling of the contents ofchemical products.

Option 4: Take action to provide agriculturalworkers with greater protection from theadverse effects of pesticides.

Congress could amend FIFRA, giving EPAgreater regulatory authority to protect farm-workers and others from the adverse effects ofpesticides (see box l-E).

Option 5: Mandate that neurotoxicity concernsbe addressed in regulatory activities undervarious other laws for which EPA has regula-tory responsibilities.

Congress could mandate that neurotoxicityreceive greater attention under any or all of thefollowing laws: the Clean Air Act; the CleanWater Act; the Safe Drinking Water Act; theComprehensive Environmental Response, Com-pensation, and Liability Act; and the ResourceConservation and Recovery Act. Each lawaddresses toxicological concerns in a different


Box l-E—neurotoxic Pesticides

Organophosphorous and carbamate insecticidesare the most neurotoxic classes of pesticides used inthe United States and are the most common causes ofagricultural poisoning. They pose a significant threatto a substantial portion of the 4 to 5 million Americanswho work in agriculture. At the biochemical level, theymay affect humans in the same manner that they affectthe insects for which they are intended-throughinhibition of the enzyme that breaks down the neuro-transmitter acetylcholine. The acute health effects oforganophosphorous and carbamate insecticides in-clude hyperactivity, neuromuscular paralysis, visualproblems, breathing difficulty, restlessness, weakness,dizziness, and possibly convulsions. The organo-chlorine class of pesticides is also very toxic becausethese substances accumulate in the body and causepersistent overstimulation of the central nervous sys-tem. Acute or subacute intoxication from organo-chlorines produces excitability, apprehension, dizzineweakness, 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 existingprotective measures. The Environmental Protection Agency (EPA) is aware of the shortcomings of the protectionscurrently in effect for farmworkers and others who work with pesticides. The Agency has proposed regulations toimprove them, but critics have already deemed the proposals inadequate. EPA claims to be restricted by the FederalInsecticide, Fungicide, and Rodenticide Act, which grants the Agency only limited regulatory power. Inadequatefunding has also contributed substantially to the weaknesses of Agency programs.

The possible occurrence of neurobehavioral disorders after chronic low-level exposure or acute poisoningdeserves 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 toassess the length of impairment. Field studies have not provided sufficient data on levels of pesticides in children’sblood 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 andpharmacological agents (including ethanol and common medications).


reamer. Congress could take action as these levels of pesticide residues in foods. Potentiallaws are amended, as funds are appropriated,and/or through various oversight activities.Such action might include making specificreference to neurotoxic substances or the ad-verse effects of chemicals on the nervoussystem, or both, in legislation addressing toxicsubstances and requiring that neurotoxic poten-tial be considered when conducting risk assess-ments. With respect to FIFRA specifically,Congress could mandate that neurotoxic poten-tial be carefully considered in setting tolerance

adverse effects of pesticides on the developingnervous system could be cited as a particularconcern.

Congress could also request that EPA reviewthe effectiveness of agency programs in regulat-ing neurotoxic substances and examine ap-proaches to improve existing activities.

Food and Drug Administration

The Federal Food, Drug, and Cosmetic Actcovers a wide range of substances. It authorizes


FDA to require submission of specific toxicitytest data before permitting food additives, drugs,and other substances to be marketed. Thisauthority could be used to incorporate neurotox-icity evaluations in FDA test guidelines or torequire neurotoxicity testing during the applica-tion process if initial toxicological data indicatepotential neurotoxic effects. FDA does not haveauthority to require premarket toxicity testing ofcosmetic ingredients.


If Congress chooses to take no action, FDA islikely to continue to address the potentialneurotoxicity of food additives, drugs, and othersubstances in the context of general toxicologi-cal concerns. FDA does not routinely requirespecific neurotoxicity testing for food additivesand drugs; instead, it evaluates the potential forneurotoxic effects in the context of a broadtoxicological profile. Some scientists, includingmost FDA officials, believe that specific neuro-toxicity testing of drugs and food additives is notnecessary and that existing general toxicologicaltesting approaches adequately detect adverseeffects on the nervous system. Other scientistsbelieve that existing general toxicological ap-proaches are not sensitive enough to detectmany neurotoxic effects and that specific neuro-toxicity tests are essential for a complete toxico-logical evaluation.

Option 2: Commission an independent study bythe National Academy of Sciences to deter-mine whether specific neurotoxicity testsshould be routinely required by FDA inevaluating the safety of drugs, food additives,and other substances regulated under FFDCA.

This option would address the issue of theadequacy of existing testing approaches. Such astudy could include a retrospective analysis todetermine whether conventional toxicologicaltests have failed to detect neurotoxic effects. Itcould also include a symposium at whichscientists from academia, industry, government,and elsewhere could present varying views onthis subject and attempt to reach a consensus onthe proper course of action.

Option 3: Mandate more extensive neurotoxicitytesting under FFDCA for drugs, food addi-tives, and other substances.

Congress could mandate that FDA revise its‘‘Toxicological Principles for the Safety Assess-ment of Direct Food Additives and ColorAdditives Used in Food,” commonly referred toas the ‘Red Book, ’ to require routine neurotox-icological screening of new food additives andto formulate improved processes for postmarkedsurveillance of new and existing additives.Congress could also require that some generallyregarded as safe (GRAS) compounds undergoneurotoxicity testing. It could require that newdrugs, particularly psychoactive drugs, undergoincreased neurotoxicity testing through the useof specific neurotoxicological tests. In particu-lar, Congress could mandate that FDA requirecomplete neurotoxicity testing of psychoactivedrugs that may be prescribed to children andpregnant women. Choosing this option wouldinvolve agreeing with scientists who believe thatpresent toxicological testing practices at FDAdo not adequately address potential adverseeffects on the nervous system and that specificneurotoxicological tests are necessary to estab-lish the safety of food additives and drugs.

Option 4: Amend FFDCA to require premarkettoxicity testing of cosmetics and cosmeticingredients.

FDA does not have the statutory authority torequire premarket toxicity testing of cosmeticsand cosmetic ingredients. Industry voluntarilyconducts general testing of many products. IfFDA finds that a cosmetic product has not beenadequately tested, it can require that it bepackaged with a warning label stating that ‘thesafety of this product has not been determined. ’In addition, FDA can take regulatory actionagainst any poisonous or deleterious substancein cosmetics. Congress could amend FFDCA torequire that cosmetics and cosmetic ingredientsundergo premarket toxicity tests consistent withthose required of drugs. Testing requirementscould include a screen for neurotoxicologicaleffects. A general toxicological evaluation, at

28 ● neurotoxic@: Identifying and Controlling Poisons of the Nervous System

least, would ensure a degree of safety compara-ble to that of other products regulated underFFDCA.

Option 5: Mandate more extensive postmarkedsurveillance and monitoring of the adverseeffects of drugs, food additives, cosmetics,and other substances and require that suchinformation be made more readily availableto the public.

Congress could mandate that FDA substan-tially expand postmarked surveillance and moni-toring of the adverse effects, particularly neuro-toxic effects, of drugs, food additives, cosmet-ics, and other substances. Congress could man-date that health-care professionals report ad-verse effects directly to FDA. Congress couldmandate that surveillance and monitoring databe made more readily available to the public. Itcould also mandate expanded patient packaginginformation in drug products. Additional infor-mation could be provided to patients on poten-tial adverse neurotoxic effects of drugs, particu-larly at higher than recommended doses, and onadverse effects that should be reported to ahealth-care professional (box l-F).

Occupational Safety and Health Administration

OSHA is authorized under the OSH Act toregulate toxic substances in the workplace inorder to ensure that no employee suffers mate-rial impairment of health or functional capacity.Recently, OSHA promulgated a far-reachingrevision and update of existing standards. Thenew standards affect 428 chemicals, loweringexisting permissible exposure limits for 212substances and establishing new exposure limitsfor 164 others. However, in devising the newstandards, OSHA relied to a large extent on therecommendations of the American Conferenceof Governmental Industrial Hygienists, a privateorganization, instead of NIOSH, the Federalscientific advisory organization on occupationalhealth issues. The advisability of this approachis likely to be a subject of continuing contro-versy in the occupational health field (box l-G).The adequacy of OSHA’s efforts to protect theNation’s workers from toxic substances in

general and neurotoxic substances in particularis a controversial issue. There are varying viewson the extent to which OSHA regulatory actionstake into account neurotoxicological concernsand the adequacy of industrial programs tomonitor worker exposure to neurotoxic sub-stances. There is also the question of whyfarmworkers, a segment of the work force thatregularly comes into contact with pesticideswith neurotoxic properties, are not afforded thesame legal protections as most other U.S.workers.


If no congressional action is taken, OSHAwill continue to be responsible for carrying outthe existing provisions of the OSH Act, whichassure that no employee suffers “materialimpairment of health or functional capacity. ”Under these provisions, neurotoxic effects areimplicitly, but not explicitly, covered. There-fore, the limited attention given to neurotoxicitywill continue to be determined by agencypriorities, resource considerations, public con-cerns, and the expertise of regulatory officials.

Option 2: Mandate that neurotoxicity concernsreceive greater attention under the OSH Act.

Congress could use the authorization andappropriations process to communicate to OSHAits concern regarding neurotoxicity. The currentlaw could be strengthened by incorporating anexplicit reference to neurotoxic substances orthe adverse effects of chemicals on the nervoussystem, or both. Congress could mandate thatMaterial Safety Data Sheets clearly describepotential adverse affects on the nervous system.Congress could encourage industry to assurethat health-care professionals, safety officers,and employee supervisors are aware of theneurotoxic potential of the chemicals to whichemployees are exposed. In addition, Congresscould request that the General AccountingOffice evaluate the effectiveness of OSHA’senforcement program with respect to neurotoxicsubstances.


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 late1982 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 reactionmonitoring system recorded an excess of adverse reports for Halcion in comparison to other benzodiazepinehypnotics--even after correcting for market share of the drug. In 1987, as a result of the reports and the apparentdose-relatedness of some adverse effects, several labeling and marketing changes were made. The usual adult dosewas changed to 0.25 mg, two paragraphs mentioning the apparent dose-relatedness of some side-effects were addedto 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 program20/20 in February 1989. The number of adverse reports received, which was expected to decline as a result of thelabeling changes and Halcion’s status as an “older” drug (the number of adverse reports associated with a drugnormally decreases over time), rose. In September 1989, FDA convened an expert panel to review the reporting dataon 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 adversereporting process. In a comparison of adverse reports for Halcion (45 million prescriptions written since 1982) withadverse reports for Restoril (35 million prescriptions written since 1980), a drug prescribed to patients with similarsleeping problems, the following data were presented:

Total number of reports received by FDAAdverse event Halcion RestorilAmnestic events 267 4Hallucinations, paranoid behavior 241 12Confusion and delirium 304 17Hostility and intentional injury 48 2

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

These seemingly dramatic results, however, were tempered by myriad complicating variables. The influenceof publicity, differences in reporting rates by manufacturers, lack of dosage information in about one-half of theadverse reports for Halcion, and ‘‘new drug’ v. ‘‘older drug’ effects all obscured the significance of differencesbetween the sets of data. The 4-week period following the 20/20 episode, for example, produced twice as manyadverse reports for Halcion as the 4-week period preceding the show. The FDA panel finally concurred that the datawere 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 FDAreview to premarket trials. Unexpected interactions with other medications or long-term side-effects may easily bemissed. This is particularly disturbing from the standpoint of neurotoxicity, since drugs not expected to haveneuropharmacological effects are not necessarily subjected to specific neurotoxicity testing. Changes which couldimprove the present system might include a requirement that all adverse report forms be sent directly to FDA aswell 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 isimportant that physicians and patients be aware of the possible adverse effects of the medications they prescribeand consume. Drugs are approved for use under certain conditions and at certain doses, and complicating factorssuch as age, other medications, or illness may significant y alter the effects of these drugs. In most cases, the decisionto take any medication is a personal choice for the patient; an individual cannot make an informed decision withoutaccess to information about potential adverse effects.

SOURCES: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, PsychopharmacologicalDrugs Advisory Committee, Transcript o~l’roceedings, Thirty-First Meeting (Rockville, MD: September 1989); “When SleepBecomes 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 usedin the workplace. Millions of workers come into contact with solvents every day through inhalation or contact withthe skin, Some solvents profoundly affect the nervous system. Acute exposure to organic solvents can affect anindividual’s manual dexterity, response speed, coordination, and balance. Chronic exposure of workers may leadto reduced function of the peripheral nerves and such adverse neurobehavioral effects as fatigue, irritability, lossof 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 andeducate workers about the materials to which they are exposed, potential health risks involved, and work practicesdesigned to minimize exposure to these substances. NIOSH also recommends that employers assess the conditionsunder 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 theeffectiveness of control methods being employed.

The Occupational Safety and Health Administration has recently updated the permissible exposure limits forapproximately 428 substances, including many solvents. The new ruling established lower exposure limits forapproximately 212 substances already regulated by the agency. Permissible exposure limits are established for thefirst time for another 168 substances, while existing limits for 25 substances are reaffirmed. This marks the first timein 17 years that a new set of exposure standards has been established. For many companies, meeting the newstandards may require stricter engineering controls or more frequent use of respirators and other personal protectivedevices, or both. Continued education of workers, improved methods of preventing exposure, and plans orprocedures to maintain compliance with the new ruling are required.


Option 3: Mandate increased efforts to monitor which they are exposed, access to exposure andadverse neurological and behavioral effectsof substances in the workplace.

Congress could mandate increased monitor-ing of adverse neurological and behavioraleffects of toxic substances in the workplace.This would include enhanced efforts to detecttoxic chemicals and improved reporting ofknown or potential adverse effects of chemicalson the nervous system, including the incidenceof neurological or psychiatric disorders ordiseases. Congress could mandate improvedpostmarketing surveillance of new products.

Congress could also mandate that OSHAconduct a review of its regulatory programs andexamine ways to more effectively protect work-ers from neurotoxic substances.

Option 4: Mandate the extension to farmwork-ers of legal rights under the OSH Act.

Congress could mandate the OSH Act toinclude farmworkers under its provisions. Thiswould give workers the right to know about thetoxicity of pesticides and other chemicals to

medical records, and protection against retalia-tion by employers for taking steps to protecttheir health. Congress could consider extendingthese rights without preempting the more exten-sive standards that now exist in some States.

Consumer Product Safety Commission

The Consumer Product Safety Commission(CPSC) is an independent regulatory commis-sion charged with protecting the public from“unreasonable risks of injury associated withconsumer products.’ Risk of injury is defined as‘‘risk of death, personal injury, or serious orfrequent illness.’ The Federal Hazardous Sub-stances Act provides for the protection of publichealth by requiring that hazardous substances belabeled with various warnings, depending on thenature of the hazard. The Poison PreventionPackaging Act requires that CPSC preventinadvertent poisoning of small children byspecially packaging hazardous substances tomake it “significantly difficult for childrenunder 5 years of age to open or obtain a toxic or


harmful amount of the substance therein withina reasonable time. ’


Present laws treat neurotoxic substances inthe context of general toxicological concerns.Therefore, the degree to which CPSC specifi-cally addresses neurotoxic substances dependson program priorities, resources, and the exper-tise of regulatory officials. Views regardingCPSC’s current degree of concern about neuro-toxic effects vary.

Option 2: Mandate that neurotoxicity concernsreceive greater attention under various Fed-eral laws for which CPSC has regulatoryresponsibilities.

Congress could mandate that a private commis-sion or organization examine the effectivenessof CPSC’s present regulatory activities in pro-tecting the public, especially high-risk groupssuch as children, from neurotoxic and othertoxic substances. In addition, congressionalauthorization and appropriations committeescould request that CPSC programs place ahigher priority on concerns related to theadverse effects of toxic substances on thenervous system, including a requirement that theCommission ensure that products with neuro-toxic potential be clearly labeled.

Department of Housing and Urban Development

The Lead-Based Paint Poisoning PreventionAct of 1971 required that the Department ofHousing and Urban Development (HUD) elimi-nate as far as practicable the hazards of leadpaint in existing houses, and mandated that theDepartment promulgate necessary regulations.However, the General Accounting Office re-ported in 1981 that HUD had not fulfilled itsresponsibility to eliminate lead-based paint inFederal housing. Following litigation and acourt order, HUD revised its regulations in 1986and 1987, and in 1988 Congress amended thatAct requiring that HUD promulgate additionalregulations to address the problem.


HUD is making progress in meeting congres-sional mandates to address lead-based paint inhousing, however, the pace of progress is slow.In the absence of congressional action, HUDwill continue to move forward, but large num-bers of children will continue to be exposed tolead-based paint in older homes.

Option 2: Amend the Lead-Based Paint Poison-ing Prevention Act to better address theproblem of lead paint in older homes.

If Congress wished to take action to expediteremoval of lead-based paint from older homes,it could amend the had-Based Paint PoisoningPrevention Act establishing new programs toaddress the problem and providing funds to support paint removal efforts.

Option 3: Establish a major new program toprovide findingfor the removal of lead-basedpaint from older homes.

Congress may wish to enact a new law tofacilitate removal of lead-based paint from olderhomes. One proposal recently developed by theEnvironmental Defense Fund (EDF) recom-mends establishment of a trust fund financed byan excise fee on the production and importationof lead. The EDF proposal calls for a programjointly administered by EPA and the Depart-ment of Health and Human Services.

ISSUE 2: Is the current Federal researchframework addressing neurotoxicity ade-quately?

The current Federal research framework foraddressing neurotoxicity is composed of majorextramural programs sponsored by NIH andADAMHA. A sizable intramural program islocated at EPA, and more limited intramuralprograms are under way at ADAMHA and NIH.FDA has a substantial developmental neurotoxi-cology program at its National Center forToxicological Research, but research effortselsewhere are very limited in scope. OTA foundthat, in general, Federal research programs arenot adequately addressing neurotoxicologicalconcerns.

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

Environmental Protection Agency

EPA has a large intramural research programdevoted to environmental neurotoxicology. Al-though the Agency has a small extramural grantsprogram, it is not currently supporting anyprojects in which neurotoxicology is a majorfocus. EPA supports intramural program initia-tives through a small number of contracts andcooperative agreements.


Without congressional action, EPA intramu-ral programs will continue at moderate levels.However, in the absence of an Agency policychange, lack of funding for supplies and equip-ment may continue to hamper some researchefforts. Failure to expand EPA’s intramuralprogram will make it difficult to move into new,priority areas such as the development of in vitroneurotoxicity testing approaches and the analy-sis of structure-activity relationships of chemi-cals.

Option 2: Provide funding for expansion ofintramural research programs.

Congress could choose to provide greatersupport to EPA’s Office of Research andDevelopment to fund additional research in theenvironmental neurotoxicology field. Budgetincreases would also alleviate problems associ-ated with the lack of funds for supplies andequipment. Substantial increases would allowEPA to move into new areas of research thatwould strengthen its regulatory capabilities,including its efforts to understand the relation-ship between chemical structure and neurotoxiceffects and further development and validationof neurotoxicity testing protocols, particularlyin vitro and developmental tests.

Option 3: Provide funding for extramural grantprograms to support neurotoxicological andneuroepidemiological research.

EPA’s total extramural grants program forenvironmental issues is small; fiscal year 1989funding for the entire program (addressing allenvironmental concerns) was $8.2 million to

support individual academic investigators and$4.5 million to support eight EnvironmentalResearch Centers (in addition, the Superfundprogram provides $2.5 million in grants toinvestigators and $5.0 million to support fivehazardous substances research centers). Cur-rently, EPA is funding no neurotoxicology-related research grants to individual investiga-tors through its extramural program. Federalresearch programs are normally composed ofboth intramural and extramural efforts: extra-mural programs enable talented investigators inacademia and elsewhere to carry out research ofinterest to the sponsoring agency. They alsoallow an agency to complement its short-termintramural efforts, required to meet regulatoryneeds, with long-term studies that will helpguide future research.

EPA is considering substantial expansion ofits extramural programs. Congress could sup-port such expansion or mandate programs thatgo beyond EPA’s plans, or both. A grantsprogram in neurotoxicology would greatly im-prove the scientific foundation of the Agency’sregulatory decisionmaking. Areas that wouldparticularly benefit from increased support aremonitoring and neuroepidemiology, which aidin tracking the contribution of environmentalcontaminants to adverse human effects, includ-ing neurological and psychiatric disorders. Inaddition, extramural research designed to im-prove the Agency’s ability to predict neurotoxiceffects (e.g., through a better understanding ofchemical structure-activity relationships) wouldgreatly benefit regulatory programs. Researchon the neurotoxicological properties of specificsubstances would aid in regulatory decision-making, and would enhance the Agency’sability to understand and predict the neurotoxic-ity of other substances.

National Institutes of Health

NIH supported more than 200 neurotoxicology-related research projects in fiscal year 1988.Most of the projects were extramural competi-tive grants to investigators in public and private


institutions. A few intramural projects wereconducted.


In the absence of congressional action, NIHwill continue to conduct limited intramuralresearch related to neurotoxicology, primarily atthe National Institute of Neurological Disordersand Stroke (NINDS) and the National Instituteon Deafness and Other Communication Disor-ders (NIDCD). The very small intramural re-search effort in environmental neurotoxicologyat NIEHS might be enhanced. Institute manag-ers could require that existing basic neuro-science research efforts change their focus toneurotoxicological concerns.

Extramural programs that fund neurotoxicologi-cal research projects are sponsored by severalInstitutes, particularly the three mentioned above.Without congressional action, these programswill continue to fund a core group of neurotoxi-cologists in academia at moderate levels. It isunlikely that the number of individual researchprojects funded would increase significantly.

Option 2: Enhance National Institutes of Healthresearch efforts related to neurotoxicology,

If Congress wishes to enhance the NIH effort,it could mandate development of a 5-year planto address neurotoxicological concerns. Such aplan could include an analysis of current NIHintramural and extramural programs, as well asdevelopment of an integrated and comprehen-sive approach to neurotoxicological research inthe years ahead. NIH would also benefit from anoutside review of the missions of individualInstitutes and the current intramural and extra-mural programs supporting those missions.Increased interaction among Institutes and be-tween Institutes and other Federal agencieswould improve NIH’s response to neurotoxicityconcerns. Congress could expand the 5-yearplan to include all relevant programs in theDepartment of Health and Human Services.This would include NIH, ADAMHA, FDA,NIOSH, the Agency for Toxic Substances andDisease Control, and other organizations. De-

velopment of such a plan would lead to acoordinated Federal effort to address the neuro-toxicity issue.

Congress could provide additional funding toNIH to expand extramural grant programs,allowing various Institutes to enhance researchefforts on such subjects as the mechanisms bywhich drugs cause adverse neurotoxic effects,the mechanisms by which environmental con-taminants adversely affect the nervous system,and the extent to which toxic substances contrib-ute to neurological and psychiatric disorders.High-priority research goals might include thestructure-activity relationships of toxic chemi-cals, the vulnerability of developing and agingnervous systems to toxic substances, and thevariation in sensitivity of individuals to thesesubstances.

Congress could fund additional intramuralresearch into high-priority areas of neurotoxi-cology research. It could also mandate rees-tablishment of an intramural neurobehavioraltoxicology program at the National Institute ofEnvironmental Health Sciences and request thatthe National Toxicology Program give a higherpriority to neurotoxicity concerns.

Alcohol, Drug Abuse, and Mental HealthAdministration

ADAMHA funds extensive neurotoxicity re-search at all three of its Institutes (OTA hasexcluded research on alcohol and alcoholismfrom this study). The National Institute on DrugAbuse (NIDA) and the National Institute ofMental Health (NIMH) both fund a substantialnumber of extramural research grants. Intramu-al research programs related to neurotoxicol-ogy are somewhat limited in size and scope.


If Congress chooses to take no action,ADAMHA programs will continue at moderatelevels. However, without budget increases orsignificant reprogramming of funds, it will bedifficult for these institutes to expand researchefforts in the neurotoxicology field.

34 ● Neurotoxicity : Identifying and Controlling Poisons of the Nervous System

Option 2: Encourage greater research empha-sis on the impact of abused drugs on thenervous system and on the potential contribu-tions of toxic substances to neuropsychiatricdisorders.

Congress may wish to encourage ADAMHAto devote increased resources to the potentiallong-term and permanent adverse effects of drugabuse, particularly the effects of maternal drugabuse on the developing nervous system of thefetus. Congress could also encourage greateremphasis on research to understand the mecha-nism by which psychoactive drugs and othertherapeutic drugs act on the central nervoussystem, and particularly on how to preventmoderate to severe adverse side-effects of thesedrugs. ADAMHA could also focus more atten-tion on neurotoxicity issues associated with theuse of multiple psychoactive drugs for longperiods of time by the elderly. Research ad-vances in these areas would promote the devel-opment of safer, more effective drugs. Congresscould support expanded research on the bio-chemical processes underlying addiction toabused drugs at NIDA’s Addiction ResearchCenter.

Food and Drug Administration

Research programs within FDA are con-ducted at the National Center for ToxicologicalResearch (NCTR) in Jefferson, Arkansas, and atthe Center for Food Safety and Applied Nutri-tion in Washington, D.C. Research programsrelated to neurotoxicology are very small, withthe exception of the intramural developmentalneurotoxicology research program at NCTR.


Without congressional action, neurotoxicol-ogy research programs within FDA will remainvery limited in scope. Relatively little researchis currently devoted to neurotoxicological con-cerns. This is of particular significance becauseso many substances regulated under the Food,Drug, and Cosmetic Act have neurotoxic poten-tial. Although some funds, particularly at NCTR,could be redirected to this area, present fiscal

limitations on FDA research leave little roomfor flexibility.

Option 2: Provide funding to expand or initiateintramural and extramural research pro-grams related to the adverse effects on thenervous system of drugs, cosmetics, foodadditives, naturally occurring toxic substancesin food, and other substances.

Congress could choose to provide FDA withfunds to support both intramural and extramuralresearch related to the potential neurotoxiceffects of substances regulated under FFDCA. Asizable research effort in this area would sub-stantially improve FDA’s ability to protectpublic health through an improved understand-ing of the effects of toxic substances on thenervous system. To promote substantive re-search efforts in critical areas, Congress couldconsider establishing research centers at aca-demic institutions to focus on specific neurotoxi-cological concerns (e.g., structure-activity rela-tionships, development of neurotoxicologicaltests, epidemiological studies, mechanisms ofaction). Congress could also provide funds tosupport a major neurotoxicology research unitwithin FDA.

National Institute for Occupational Safetyand Health

NIOSH, located within CDC, has identifiedneurotoxic disorders as one of the Nation’s 10leading causes of work-related disease andinjury. To aid in understanding the extent andnature of this problem, NIOSH supports a smallnumber of intramural and extramural researchactivities. The intramural program is devotedprimarily to evaluation of testing approachesand to analysis of selected neurotoxic sub-stances found in the workplace. The NIOSHextramural program funds a very small numberof grants devoted to understanding the mecha-nisms by which toxic substances adverselyaffect the nervous system.


If no action is taken, NIOSH research pro-grams 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 problemof exposure to neurotoxic substances in theworkplace, the present level of effort will notensure an adequate database to support theanticipated needs of the Occupational Safetyand Health Administration.

Option 2: Expand intramural and extramuralneurobehavioral research programs at NIOSH.

This option would lead to improvements inunderstanding the extent to which workers areexposed to neurotoxic substances, the mecha-nisms by which these substances exert adverseeffects, and means of preventing exposures inthe workplace. Substantive increases in fundingfor research would provide a better foundationfor OSHA’s regulatory activities related toneurotoxicity. Priority research needs include abetter understanding of dose-response relation-ships, mechanisms of action, and structure-activity relationships. Methods for evaluatingworker exposures need to be developed, im-proved, and validated. Epidemiological studiesare needed to reveal the extent of workplaceexposure to neurotoxic substances and thecontribution of such exposure to neurological,psychiatric, and other disorders and injuries.More research is needed on latent neurologicaldisorders that may result from chronic, low-level exposure to neurotoxic substances.

Substantially increased NIOSH funding ofextramural neurotoxicology and neurobehav-ioral research would improve scientific under-standing of workers’ exposure to toxic chemi-cals. Such an increase would encourage researchscientists to enter the field of environmentalneurotoxicology by supporting laboratories thatfocus on occupational health issues. It wouldalso be an important source of training forphysicians.

Other Federal Agencies and Organizations

Other Federal agencies and organizations thatundertake neurotoxicity-related research includethe Center for Environmental Health and InjuryControl and the National Center for HealthStatistics within CDC, the Agency for Toxic

Substances and Disease Registry, the Depart-ment of Energy, the Department of Agriculture,the Department of Veterans Affairs, and theNational Aeronautics and Space Administra-tion. The Department of Defense conductsneurotoxicology -related research, particularlyas it relates to chemical warfare; however,defense-related research is not included in thisreport. The National Science Foundation pres-ently supports very little research in this area.


If Congress chooses to take no action, smallresearch programs in these organizations arelikely to continue. In some of them, limitedefforts may be appropriate; in others, particu-larly those within DHHS, small efforts mayhamper the ability of other agencies and individ-uals to address neurotoxicity-related issues. Forexample, the National Center for Health Statis-tics provides most of the current information onthe prevalence, mortality, and morbidity associ-ated with neurological and other diseases in theUnited States. Because of budget cuts in recentyears, neuroepidemiologists have had difficultyin obtaining the statistical information neces-sary for studies of how neurotoxic substancescontribute to neurological and psychiatric disor-ders.

Option 2: Mandate that various Federal organi-zations and agencies undertake or expandresearch programs addressing neurotoxicity -related concerns.

Several organizations could support researchefforts in neurotoxicology that would enhancetheir own programs and those of others. Con-gress could mandate that these agencies adjustprogram priorities to better address neurotoxicity-related concerns, it could selectively provideincreased funds for these programs, or it coulddo both. For example, enhanced efforts at theCenter for Environmental Health and InjuryControl, National Center for Health Statistics,and Agency for Toxic Substances and DiseaseRegistry would benefit many Federal and Stateagencies and would provide support to academicinvestigators. The Department of Energy has

36 ● neurotoxici~: Identifying and Controlling Poisons of the Nervous System

recently reemphasized research on the toxico-logical effects of chemicals. Its existing pro-grams are focused on nuclear-related healthconcerns; support of nonnuclear, neurotoxicity -related research is minimal. Studies of theneurotoxic substances generated by energy-producing technologies would be beneficial.The National Science Foundation could spuracademic research into the mechanisms bywhich toxic substances adversely affect thenervous system by providing support for basicresearch in the neurotoxicology field,

ISSUE 3: Should Congress take steps toimprove interagency coordination of Fed-eral research and regulatory programsrelated to neurotoxicity?

Until recently there was little coordination ofFederal research and regulatory programs re-lated to neurotoxic substances. At a workshopsponsored by OTA and EPA, representatives ofvarious Federal agencies decided to establish anInteragency Working Group on neurotoxicol-ogy l to aid in interagency coordination.


Without congressional action, the new inter-agency coordinating group may succeed inenhancing the exchange of regulatory and re-search information among Federal agencies.The success of an initiative of this kind is largelydetermined by the willingness of senior agencyadministrators, program managers, and tech-nical personnel to participate and voluntarilyshare information. Whether an adequate level ofinterest will be maintained is not clear. Anotherimportant question is whether the group willhave sufficient support at the senior manage-ment levels to carry out research and regulatoryinitiatives.

Option 2: Mandate and formalize the establish-ment of an organization to foster coordina-tion of Federal interagency research and

regulatory programs related to neurotoxicol-ogy.

Congress could formalize the existing inter-agency coordinating group by mandating establish-ment of an organization to ensure maximum useof U.S. research and regulatory resources.Congress could mandate that all significantFederal programs be represented in the organi-zation, and it could require the submission of areport every 5 years on the state of the Federalneurotoxicology research and regulatory effort.This interagency organization would benefitfrom a board of advisors from academia, indus-try, and elsewhere who could evaluate existingprograms and provide guidance on future direc-tions. Choosing this option would require theredirection of existing agency funds or theappropriation of new funds.

ISSUE 4: Are current Federal educationaland research policies and programs ensur-ing an appropriate number of adequatelytrained research and health-care profes-sionals to address neurotoxicity concerns?

A significant portion of our current under-standing of the effects of toxic substances on thenervous system comes from application of basicresearch to environmental health problems.However, too few scientists are trained in bothneuroscience and toxicology to provide anadequate supply of neurotoxicologists. In addi-tion, other environmental health professionalsare needed to address neurotoxicological con-cerns, including neuroepidemiologists, occupa-tional physicians, and nurses with training inneurotoxicology.


Without congressional action, the focus offederally supported training programs will con-tinue to be determined by individual agencies,and funding will continue at low levels. Inade-quate Federal support of training is partlyresponsible 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.


trained research and health-care professionals inthe field of neurotoxicology.

Option 2: Take steps to encourage individuals toestablish careers in research and health-carefields that address toxicological, particularlyneurotoxicological, concerns.

If Congress wishes to take this approach, itcould mandate expansion of pre- and post-doctoral research training programs in neurotox-icology by increasing the number of traininggrants to individuals and/or research centers.This would primarily involve expansion ofexisting programs supported by NIH and NIOSH.Congress could encourage training of medicalstudents in occupational medicine, includingcourse work in neurotoxicology. It could pro-mote training of graduate students in neurotoxi-cology by providing additional funds to NIH,ADAMHA, and NIOSH for this purpose or byfunding a new training program that would beadministered by EPA. It could also encouragephysician residency training in occupationalmedicine by increasing the funds (through TitleVII of the Health Professionals Education Act)for establishing such programs. Finally, it couldencourage training of occupational safety andhealth specialists through continued or in-creased funding of the NIOSH training grantsprogram, in particular the Educational ResourceCenters.

ISSUE 5: Are workers and the public receiv-ing sufficient information to allow them tomake informed decisions about exposureto neurotoxic substances?

Preventing adverse effects of exposure toneurotoxic substances depends largely on un-derstanding the threat that neurotoxic sub-stances pose to human health and knowing howto limit exposure to these substances. In recentyears, Congress has taken steps to increase thequantity and quality of information available tothe public concerning health risks posed by toxicsubstances. For example, the Federal Emer-gency Planning and Community Right-to-KnowAct of 1986 has resulted in a large database,

Photo credit: UnitedAutomobik, Aerospace, and Agricultural ImplementWorkers of America-UAW Public Relations Department

Respirators may be useful in minimizing exposure tosolvent vapors when engineering or work practice controls

are inadequate.

accessible to the public, on the release of morethan 300 toxic chemicals at facilities throughoutthe United States. In 1987, the Department ofLabor expanded the OSHA hazard communica-tion standard. This standard gives employees theright to know what chemicals they may encoun-ter in the workplace. In general, information istransmitted through hazard communication pro-grams, which use labels on containers and otherwarning signs; post appropriate safety informa-tion, including material safety data sheets; andtrain and educate employees about the chemicalproperties and hazardous effects of the toxicsubstances to which they are or may be exposed.


38 . neurotoxicity: Identifying and Controlling Poisons of the Nervous System

In the absence of congressional action, exist-ing hazard communication and right-to-knowlaws will provide the public and workers withuseful information about the health risks posedby neurotoxic substances. The relevance of thisinformation to neurotoxicity concerns will con-tinue to be determined to a large degree by theperceptions and priorities of officials in thevarious agencies with regulatory responsibili-ties. Federally mandated worker informationprograms tend to focus on the carcinogenic andteratogenic potential of toxic substances; non-cancer health risks such as neurotoxicity tend toreceive less attention, even though they maypose an equal or greater health threat.

Option 2: Take action to ensure that the risksposed by neurotoxic substances are explicitlydescribed to the public through hazard com-munication and right-to-know laws.

Choosing this option will result in enhancedcommunication of neurotoxic health risks to thepublic. Congress could require that informationprovided to workers under the Hazardous Communi-cation Standards of the Occupational Safety andHealth Act include a description of significanthazards posed by neurotoxic substances, and itcould mandate improved enforcement of thehazardous communication provisions of thisAct. Congress could also require that neurotox-icity concerns be explicitly addressed in infor-mation developed and released under the Fed-eral Emergency Planning and Community Right-to-Know Act. Information on trends in annualdata would also be useful in monitoring pro-gress, in limiting releases, and in minimizingpublic exposure.

Option 3: Take additional steps to inform thepublic of the short- and long-term adverseeffects of abuse of psychoactive drugs on thenervous system.

Congress could provide NIDA with fundingfor an aggressive campaign to inform the publicof the potential long-term consequences of drugabuse on the nervous system. Congress couldmandate that particular attention be devoted tothe abuse of psychoactive drugs by pregnant

women and the severe effects these substancesmay have on the nervous system of the develop-ing fetus.

Option 4: Mandate improved labeling of con-sumer products with respect to potentialneurotoxic effects.

Congress could take steps to assure thatsubstances purchased by consumers that haveneurotoxic potential are appropriately labeledand contain appropriate warnings when neces-sary. Congress could request that agenciesdevote particular attention to substances that

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may adversely affect the developing nervoussystem.

In addition, Congress could mandate that alltoxic product ingredients, including those some-times referred to as ‘inert’ substances, be listedon product labels. This is particularly importantwith respect to pesticide products.

ISSUE 6: Should the United States moreactively encourage and participate in inter-national regulatory and research programsrelated to neurotoxic substances, andshould the United States revise its policieswith regard to the export of neurotoxicsubstances?

The adverse effects on the nervous system ofoccupational and environmental exposure totoxic chemicals are a major problem in thedeveloping regions of the world. The UnitedStates is the leader in the international researcheffort to understand the health risks posed byneurotoxic substances. Because of this exper-tise, many persons believe that the United Statesshould participate more actively in cooperativeinternational efforts to address the problem. Inaddition, many question current U.S. policiesregarding the export of neurotoxic substancesthat have been banned, severely restricted, ornever registered for domestic use.


At the present time, U.S. scientists activelyparticipate in international conferences pertain-ing to toxic substances and human health risks.To a more limited extent, public and privateagencies in the United States and foreigncountries cooperate in research and regulatoryactivities. In the absence of congressional ac-tion, informal international activities will con-tinue, but significant formal arrangements forcoordinating research and regulatory efforts areunlikely.

Even though the United States is capable oftraining individuals from foreign countries inthe fields of neurotoxicology and neuroepidemi-ology, it is very difficult for U.S. academic

institutions to obtain funds to support suchefforts. In the absence of congressional action,little funding will be available for training of thiskind.

Without congressional action, the UnitedStates will continue to export neurotoxic sub-stances that are banned, severely restricted, ornever registered for use in this country. Personswho support current export policies believe thatsuch practices are appropriate as long as thehealth risks posed by the chemical are communi-cated to the receiving country. Persons whooppose these policies believe that, despite ef-forts at hazard communication, many receivingnations do not have the expertise to judge thenature of the health risks; further, they argue thatrisk-related information is often not adequatelycommunicated to users. The use of banned,severely restricted, or never-registered pesti-cides in developing countries is often cited as aparticular problem.

Option 2: Encourage Federal agencies to initi-ate and participate in joint internationaltesting efforts to evaluate the toxicity of newand existing chemicals.

Because so many chemicals have not beenadequately tested for neurotoxicity, some per-sons believe it would be advantageous to testcertain chemicals under joint international agree-ments. If standardized testing procedures couldbe agreed on, such an approach might result ina more equitable sharing of the chemical testingburden throughout the international community.The International Program on Chemical Safety(a joint venture of the United Nations Environ-ment Program, the International Labor Organi-zation, and the World Health Organization) hassponsored efforts to develop methods for assess-ing the neurotoxic effects of exposure to chemi-cals. Congress could encourage and supportinternational programs of this kind. It could alsoencourage the development of an internationaltoxicity database accessible to developing coun-tries at minimal cost.

Option 3: Provide or redirect finding to encour-age neurotoxicological and epidemiological

40 . Neurotoxicity: Identifying and Controlling Poisons of the Nervous System

research and information exchange betweenpublic and private U.S. organizations andthose offoreign nations.

This option would promote internationalprograms to evaluate the health risks posed byneurotoxic substances and would encouragecooperative efforts to minimize human exposureto chemicals and naturally occurring substancesthat pose a public health risk. It is currentlydifficult for U.S. researchers to obtain grantsupport for projects involving internationalcollaboration. Modest funding to encouragesuch collaboration would lead to mutuallybeneficial research efforts. U.S. neurotoxicolo-gists and other scientists have few contacts inThird World countries, where their expertisecould promote research and training of foreignpersonnel. Creation of a grants program to fosterthese relationships would not only respond tothese needs, but also enlarge the perspective ofU.S. scientists and promote international coop-eration.

This option would encourage Federal agen-cies to provide grant support to academicinstitutions for partial sponsorship of interna-tional conferences and working groups onneurotoxicological questions. In addition, Con-gress could encourage continued U.S. participa-tion in international toxicological research andpolicy planning activities. In particular, it couldencourage the design and implementation ofeducational programs to inform people in devel-oping countries about the risks posed by expo-sure to neurotoxic substances.

Option 4: Allow academic institutions receivingFederal funds for training grants to use adesignated percentage of funds to supportnon-U.S. residents.

At the present time, NIH can support foreignresearch fellows through various mechanisms;however, Federal funds are not available to helpsupport foreign students at U.S. academic insti-tutions. Allowing U.S. institutions to use adesignated percentage of training funds tosupport non-U.S. nationals and residents would

facilitate the exchange of graduate students andpostdoctoral fellows and aid foreign nations indeveloping their own research and regulatoryprograms. Congress could also make Federalfunds available to encourage public and privateinstitutions to sponsor research and training ofpersons in developing countries by U.S. person-nel working in those countries.

Option 5: Revise existing laws governing theexport of hazardous substances.

Congress could take action under variouslaws to ensure that regulations limiting theexposure of U.S. citizens to toxic substances areextended to individuals in foreign nations. Thiscould involve prohibiting or limiting the exportof neurotoxic substances that are banned, se-verely restricted, or never registered for domes-tic use. Such action would address the ethicalconcerns of persons who believe that currentpolicies place the United States in a position ofprofiting from the export of chemicals that areconsidered to be too hazardous for domestic use.It would also help to minimize the exposure ofU.S. citizens to hazardous chemicals through theimport of foods, food products, and otherconsumer goods containing toxic substancesthat have been banned, severely restricted, ornever registered in the United States.

Specifically with respect to pesticides, Con-gress could take steps to ban or restrict theexport of those products that are not registeredin the United States. It could prohibit or restrictthe export of particularly hazardous pesticidesto countries that do not have adequate regula-tory, monitoring, and public and worker healthprotection programs. Congress could also re-quire proper labeling of all exported pesticideproducts, including clearly written warnings inappropriate languages. Warning labels could berequired to include the use of generally under-stood poison and health protection symbols.Steps could be taken to prohibit or restrict theimport of food products containing the residuesof pesticides not registered for use in the UnitedStates.

Documents

Summary, Policy Issues, and Options for Congressional Action