Identifying and Controlling Immunotoxic

Substances

April 1991

OTA-BP-BA-75

NTIS order #PB91-183145
Recommended Citation:

U.S. Congress, Office of Technology Assessment, Identifying & Controlling immunotoxic

Substances-Background Paper, OTA-BP-BA-75 (Washington, DC: U.S. Government

Printing Office, April 1991).

For sale by the Superintendent of Documents

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

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

Thousands of new chemical substances enter the market annually. Although the public continues to

embrace the benefits of these substances, increasingly wary consumers now inquire about their downside,

particularly health risks. While information about what chemicals are in the air or water and in what

quantities is usually forthcoming, answers about their human health effects are often vague and unsatisfying.

Much of the American public– scientists and laymen alike – finds this uncertainty troubling. A recent

novel described the impacts of an accidental chemical release on a small community. The following exchange

captures the frustration of the townspeople trying to understand the consequences of the chemical exposure:

“Am I going to die?”

“Not as such,” he said.

“What do you mean?”

“Not in so many words.”

“How many words does it take?”

“Let me answer like so. If I was a rat, I wouldn’t want to be anywhere within a two hundred mile

radius of the airborne event.”

“What if you were a human?”

“I wouldn’t worry about what I can’t see or feel.”*

Nowadays, after years of research, answers about potential carcinogens come more readily than those

conveyed in the novel. But noncancer health risks, such as potential, adverse effects of chemicals on the

nervous, immune, or respiratory systems, have received less attention and remain more of a mystery. The

Senate Committee on Environment and Public Works and its Subcommittee on Toxic Substances, Environmental Oversight, Research and Development asked OTA to examine noncancer health risks in the

environment, including the availability of testing technologies, future research needs, and the adequacy of

the current regulatory scheme. This background paper, which describes Federal efforts to identify and

control substances that may harm the immune system, is one response to that request. It builds on previous

OTA work on carcinogenic and neurotoxic substances.

OTA acknowledges the generous help of the workshop participants, reviewers, and contributors who

gave their time to ensure the accuracy and completeness of this study. OTA, however, remains solely

responsible for the contents of this background paper.

~ f ~

A-M ‘ >

JOHN H. GIBBONS

~ Director

*

Don DeLillo, White Noise (New York, NY: Penguin Books, 1986), pp. 140-141.

. . .

111
Workshop on Identifying and Controlling immunotoxic Substances, September 1990

Philip J. Landrigan, Workshop Chair

Chairman

Department of Community Medicine

The Mount Sinai Medical Center

New York, NY

Robert Burrell

Professor

Department of Microbiology& Immunology

Health Sciences Center

West Virginia University

Morgantown, WV

Joy A. Cavagnaro

Special Assistant to the Director

Office of Biologics Research

Center for Biologics Evaluation& Research

U.S. Food and Drug Administration

Rockville, MD

Theodora E. Colburn

Senior Fellow

World Wildlife Fund/The Conservation Foundation

Washington, DC

Earon S. Davis

Environmental Health Consultant

Evanston, IL

Jack H. Dean

Vice President of Drug Safety

Sterling Research Group

Rensselaer, NY

Frank W. Fitch

Albert D. Lasker Professor of Medical Sciences

Department of Pathology

University of Chicago

Chicago, IL

Michael I. Luster

Head, immunotoxicology Group

Systemic Toxicology Branch

Division of Toxicology Research& Testing

National Institute of Environmental Health Sciences

Research Triangle Park, NC

Stephen Mooser

Outreach Coordinator

Mount Sinai School of Medicine

New York, NY

William J. Rea

Director

Environmental Health Center

Dallas, TX

MaryJane K. Selgrade

Chief

immunotoxicolog Section

Health Effects Research Laboratory

U.S. Environmental Protection Agency

Research Triangle Park, NC

Abba I. Terr

San Francisco, CA

Robert F. Vogt

Research Chemist

Division of Environmental Health

Centers for Disease Control

Atlanta, GA

NOTE: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the workshop participants. The

participants do not, however, necessarily approve, disapprove, or endorse this background paper. OTA assumes full responsibility

for the background paper and the accuracy of its contents.

iv
OTA Project Staff - Identifying and Controlling immunotoxic Substances

Roger C. Herdman, Assistant Director, OTA

Health and Life Sciences Division

Michael Gough, Biological Applications Program Manager

Holly L. Gwin, Project Director

Robyn Y. Nishimi, Senior Analyst

Peter R. Andrews, Research Assistant

Monica V. Bhattacharyya, Research Assistant

Timothy E. Sullivan, Intern

Desktop Publishing Specialists

Linda Rayford-Journiette

Carolyn Swarm

support staff

Cecile Parker, Office Administrator

Jene Lewis, Secretary

Contractor

Robert Burrell, West Virginia University, Morgantown, WV
Chapter 1.

Chapter 2.

Chapter 3.

Chapter 4.

Contents

Introduction and Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Immune System and immunotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

immunotoxicologicalTests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Federal Attention to immunotoxicants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

AppendixA. Income Replacement for Individuals Disabled by Immunotoxicants . . . . . . . . . . . . . . . . . .

AppendixB. Reviewers and Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

AppendixC. Glossary of Terms and Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Boxes

l-A. General Principles of Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-A. Cell Surface Receptors of the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-B. “Allergy’’:SomeCommon Misperceptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-A. Polybrominated Biphenyls: The Michigan Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-B. Polychlorinated Biphenyls: The Taiwan Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3-C. Chemical-Induced Autoimmunity: Spanish Toxic Oil Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figures

1-1. Spectrum of Adverse Immune System Effects.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-1. Structure of an Antibody Molecule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-2. White Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-3. Major Organs and Tissues of the Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2-4. Generation of Antibody Forming Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tables

1-1.

1-2.

2-1.

2-2.

2-3.

2-4.

2-5.

3-1.

3-2.

3-3.

3-4.

4-1.

4-2.

4-3.

4-4.

4-5.

4-6.

A-L

Common immunotoxicological Tests . . . . . . . . . . . . . . . . . . . . .

Federal Agencies Engaged in Immunotoxicological Research

Major Cell Classes of Immunological Importance . . . . . . . . . .

Major Functions of T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mechanisms of Cell-Mediated Immunity . . . . . . . . . . . . . . . . .

Some Human Autoimmune Diseases . . . . . . . . . . . . . . . . . . . . .

Some Immunodeficiency Disorders . . . . . . . . . . . . . . . . . . . . . .

Known or Suspected Immunosuppressants . . . . . . . . . . . . . . . .

Common Contact Sensitizers . . . . . . . . . . . . . . . . . . . . . . . . . . .

Industrial Chemicals Associated With Occupational Asthma

Substances Associated With Autoimmune Responses . . . . . .

NTP’s Panel of Tests for Detecting immunotoxicity . . . . . . . .

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

or Regulation . . . . . . . . . . . . . . . . . .

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

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

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

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

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

Substances Tested by NTP for Immunosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Substances Tested by NTP for Hypersensitivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Major Federal Laws Controlling Toxic Substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sensitizers Regulated by OSHA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

EPA’s Revisited Subdivision M Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

State Workers’ Compensation Disability Benefit\ 1989 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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vi

Chapter 1

Introduction and Summary

INTRODUCTION

The potential for substances used in industry,

transportation, and households to be simultaneously

beneficial and toxic to human life creates a legislative and

regulatory dilemma. The challenge of balancing a strong

economy, one that delivers products that people need

and desire, with the health and safety of the populace

sometimes seems to be a tremendous burden.

Technological advances add to the weight of that

burden. Thousands of new, potentially toxic substances

enter the market annually. Advanced instruments help

scientists measure the presence of new and existing substances in minute quantities. Substances formerly unknown or undetected suddenly become worrisome as

technology provides the means to predict human risks

from these substances.

Governmental concern that a substance might create

an adverse health effect historically concentrated on

carcinogenicity. Most Federal legislative and regulatory

efforts to prevent or minimize human exposure to toxic

substances have focused on identifying and controlling

carcinogens. Physicians and researchers now recognize

the noncancer, toxic effects of many substances. Some

of these effects, for instance teratogenicity, have become

the subject of specific legislative concern. Federal

regulatory attention to other types of toxic injury, e.g., to

the nervous system, the immune system, the respiratory

system, depends on the more general mandate to protect

human health. Some observers fear that historical emphasis on carcinogenicity, combined with limited agency

resources, has led to neglect of problems such as

neurotoxicity, immunotoxicity, or pulmonary toxicity–

problems that may be as widespread and severe as carcinogenicity.

The Senate Committee on Environment and Public

Works, and its Subcommittee on Toxic Substances, Environmental Oversight, Research and Development,

asked for assistance from the Office of Technology Assessment (OTA) in evaluating technologies to identify

and control noncancer health risks in the environment.

The committee’s interests include advances in toxicology, research and testing programs in the Federal agencies, and the consequences of exposure to toxic substances.

This background paper, which describes the state-ofthe-art of identifying substances that can harm the immune system, represents one response to the committee’s

request. Chapter 2 provides basic information about the

principal components of the immune system and the

general consequences that stem from perturbations to it.

Chapter 3 describes methods for evaluating chemical

immunotoxicity and reports on some known or suspected

immunotoxicants. Chapter 4 summarizes Federal research and regulatory activities related to immunotoxicity. Appendix A provides a very brief synopsis of

income replacement programs available to persons disabled by toxic exposures.

TERMINOLOGY

This background paper examines a field of study rife

with jargon. Not all specialists in the field of immunotoxicology--which combines the expertise of immunologists and toxicologists — use terminology in

precisely the same manner. The following definitions

explain how OTA applies the terms-of-art essential to

this study.

immunotoxicity, or an immunotoxic effect, is defined

as an adverse or inappropriate change in the structure or

function of the immune system after exposure to a foreign

substance. Foreign substances capable of adversely affecting the immune system may be of synthetic or natural

origin. This study focuses on chemicals, including industrial, transportation, agricultural, and household

chemicals, drugs, and food additives.

immunotoxicity manifests at both ends of a

spectrum— as an enhanced but inappropriate immune

response, and as a failure to mount an appropriate immune response. (See figure l-l.) This background paper

examines three types of adverse effects: immunosuppression, hypersensitivity, and autoimmunity. Immunosuppression is a generalized decrease in immune

responsiveness that may result in increased incidence of

3
4 ● Identifying and Controlling Immunotoxic Substances

Figure 1-1- Spectrum of Adverse Immune System Effects

Hypersensitivity

Autoimmunity

Immunosuppression

SOURCE: Office of Technology Assessment, 1991.

infection or tumors. Immunologic hypersensitivity is allergy-an overreaction of the immune system to a substance. Hypersensitivity is a normal immune response to

a foreign substance, but one with deleterious consequences. Autoimmunity results from a breakdown in the

ability of the immune system to distinguish “self’ from

“nonself.” An autoimmune reaction involves the body

mounting an immune response against some of its own

components.

Substances that provoke an immune response are

called antigens. Antigens trigger beneficial responses,

e.g., destruction of an infectious agent, and adverse

responses, e.g., hypersensitivity. Other substances can

damage the immune system by destroying or inactivating

specific elements within it, thereby suppressing immune

response. Substances that elicit adverse immune responses or damage the immune system are called immu -

notoxic substances, or immunotoxicants.

THE IMMUNE SYSTEM

The immune system is a complex, cooperative effort

among several types of cells, cell products, tissues, and

organs in the body. The simplified description that follows should help the reader comprehend state-of-the-art

immunotoxicology, but by no means represents an exhaustive examination of this complicated organ system.

The immune system involves several cell types. Most

of them belong to the large group of cells commonly

lumped together as white cells. The white cells of principle interest to immunotoxicologists are macrophages

and lymphocytes. Macrophages ingest cellular debris

and infecting organisms, and they process and present

antigens to the lymphocytes. Lymphocytes include B

cells, T cells, and natural killer (NK) cells. B cells secrete

antibodies (immunoglobulins), substances that inactivate antigens in the body. Each B cell makes antibody

specific to a given antigen; the body can make antibodies

to thousands of antigens.

T cells regulate the immune system. T cells must

interact with B cells for antibody production. Some T

cells can directly kill cells presenting antigens. T cells also

secrete cytokines, protein molecules that transmit signals

to modulate (augment or suppress) immune response

between cells of the immune system. (Macrophages also

produce cytokines.) NK cells attack and destroy certain

other cells. Most types of cells are resistant to NK cell

activity, but tumor cells and virus-infected cells appear

to be susceptible.

The organs of the immune system– the lymphoid organs– include the bone marrow, the thymus, the lymph

nodes, and the spleen, as well as the tonsils, the appendix,

and clumps of tissue in the small intestine and the

respiratory tract. The lymphoid organs are compartmentalized collections of lymphocytes, macrophages, and

other immune system cells. They produce, store, and

distribute the immune system cells. The lymphatic vessel

network also circulates lymphocytes.

Foreign substances provoke two basic types of immune response: nonspecific immunity and acquired immunity. Nonspecific immunity, which involves functions

of the macrophages and NK cells, represents the body’s

first line of defense. The nonspecific immune response

occurs without prior exposure to antigens. Acquired

immunity develops after the initial exposure to a foreign
Chapter 1—Introduction and Summary ● 5

substance and can be subdivided into humoral immunity

and cell-mediated immunity. humoral immunity involves antibody production, which generally requires

macrophages (to process and present the antigen), T

cells (to stimulate B cell production), and B cells (to

produce antibodies). The other basic type of acquired

immunity, cell-mediated immunity, also begins with the

microphage but then relies on the T cell functions of

cytotoxicity and cytokine secretion. Although scientists

distinguish between humoral and cell-mediated immunity, most antigens can provoke both types of immune

response.

IDENTIFYING IMMUNOTOXIC

SUBSTANCES

The AIDS epidemic has heightened public interest in

the immune system and its potential for injury. A virus,

not a chemical, causes AIDS, but the disease illustrates

the devastating effects of immunosuppression and suggests to people the importance of protecting the immune

system. In response to increased public awareness, researchers have devoted greater effort in recent years to

developing predictive tests to measure the potential immunotoxicity of chemicals before they enter commerce.

As a result of these efforts, a number of tests now exist

to assess the effects of foreign substances on the components and processes of the immune system. Researchers testing a chemical’s immunosuppressive

potential often start with pathology, an examination of

tissues and organs of the immune system for evidence of

disease. The organs of experimental animals can be

weighed or cells from organs or in peripheral blood can

be counted to get preliminary indications of how a substance may affect the immune system. Other assays of

immunosuppression assess whether exposure to a chemical affects the ability to mount a particular type of immune response. Measures of humoral, cell-mediated,

and nonspecific immunity exist and can be applied in the

laboratory. These tests usually involve experimental

animals but occasionally direct assessment of humans.

The most comprehensive tests of immunosuppression

available to researchers today measure a subject’s ability

to fight infections or tumors after exposure to a suspected

immunotoxicant. Scientists expose experimental animals

to a toxic substance and subsequently expose (challenge)

the animals to an infectious agent or a tumor. If animals

exposed to the suspected toxicant show a significant

increase in the incidence of disease or death following

challenge compared to unexposed animals, the substance is suspected to be immunotoxic.

Researchers and manufacturers also use hypersensitivity assays. Whether a substance can induce hypersensitivity can be assessed using skin and respiratory tests.

Antibodies can also be measured in the blood of animals

or humans who have had an allergic reaction to an antigen. (Table l-l lists common immunotoxicological

tests.)

immunotoxicological testing presents an investigator

with significant challenges in interpretation. Test results

can differ depending on the subject’s age, species, sex, or

recent illnesses. Environmental factors, such as diet or

other chemical exposures, can also affect immune system

performance. Choosing the appropriate test dose and

the means and duration of exposure can prove difficult

when the point of the exercise is to extrapolate from the

test to the predicted consequences of actual human exposure. (See box l-A.) These considerations present

themselves in all types of toxicology, but the complexity

of the immune system compounds these difficulties for

immunotoxicologists. immunotoxicology’s fledgling

status as a field of scientific inquiry and the fact that few

toxicologists have training in immunology further complicate study of immunotoxicity.

The immune system is thought to have a reserve

capacity, although the size of that reserve is as yet undetermined. Thus tests that measure impairment of one

immune system component may not, in fact, indicate

overall immunotoxicity, since other immune components

or processes may compensate for the impairment. Frequently a decrease in a particular immune function is

discerned but no clinical symptoms – certain infections or

cancers, for instance– appear during the test period.

There is still much to be learned about the long-term

consequences of weakening an individual component of

the immune system.

Relatively few data exist on immunotoxicity in humans.

Studies of radiation victims and patients receiving immunosuppressive drugs provide evidence of the consequences of long-term immunosuppression. A few

epidemiologic studies of toxic exposures that appeared

to result in immunosuppression have been attempted,
6 ● Identifying and Controlling Immunotoxic Substances

Table l-l—Common immunotoxicological Tests

Category Test

Pathology . . . . . . . .

humoral

immunity . . . . . . .

Cell-mediated

immunity . . . . . . .

Nonspecific

immunity . . . . . . .

Host-resistance . . .

Hypersensitivity . . .

Hematology

Organ weights

Histology

Cellularity

Antibody plaque forming cell (PFC) response

B cell litogen response

Immunoglobulin levels in serum

Quantitation of splenic and/or peripheral

blood B cells

T cell mitogen response

Cytotoxic T lymphocyte (CTL) cytolysis

Delayed hypersensitivity response

Mixed leukocyte response (MLR)

Quantitation of splenic and/or peripheral

blood T cells

Natural killer cell activity

Microphage counts

Neutrophil counts

Syngeneic tumor cells:

. PYB6 sarcoma (tumor incidence)

. B16F1O melanoma (lung burden)

Bacterial models:

• Listeria monocytogenes (mortality)

● Streptococcus species (mortality)

Viral models:

. Influenza (mortality)

● Mouse cytomegalovirus (mortality)

Parasite models:

. Plasmodium yoelii (parasitemia)

Draize test

Open epicutaneous test

Buehler test

Freund’s complete adjuvant test

Optimization test

Split adjuvant test

Guinea pig maximization test

Mouse ear swelling test

Respiratory rate measurement

Serum lgE measurement

Local lymphnode proliferation assav . .

NOTE: immunotoxicologists seldom perform each test or type of test for a

particular substance. They often divide the tests into tiers, using

tests that indicate immune system damage at a fairly gross level to

screen for potential immunotoxicants, and applying more sensitive

and specific tests only to those substances that indicate possible

toxicity in the primary screen. These tests are described inch. 3.

SOURCE: Office of Technology Assessment, 1991.

but with inconclusive results. On the other hand, workers

and consumers have provided conclusive evidence that

several chemicals can induce hypersensitivity. At least

one epidemiologic study has examined humans for signs

of autoimmunity resulting from chemical exposure.

However, the overall lack of data makes it problematic

to extrapolate from the results of tests of substances in

experimental animals to the likely effects of human exposure.

EXAMPLES OF immunotoxic

SUBSTANCES

Scientists have identified several substances that suppress the immune system, induce hypersensitivity, or

cause autoimmunity in laboratory animals. This is true

despite the fact that testing for immunotoxicity has been

done on very few of the chemical substances, regulated

or unregulated, in commerce.

Substances That Suppress Immune Response

Substances that can suppress immune responses fall

into several general categories, including: therapeutics,

solvents, pesticides, halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, airborne pollutants, and metals. Testing has not been conducted on

all individual substances in any particular category, and

not all substances tested within each of these categories

have been shown to be immunotoxic. Not all categories

of chemicals have been scrutinized.

Therapeutic drugs designed to prevent transplant

rejection or treat cancer or autoimmune disorders are

the most thoroughly studied immunosuppressive chemicals. The most frequently used immunosuppressive

drugs fall into four basic categories-–alkylating agents

(e.g., cyclophosphamide), glucocorticosteroids (e.g.,

prednisolone), antimetabolites (e.g., azathioprine), and

natural products (e.g., cyclosporin A).

Benzene, a solvent commonly used in many industrial

processes, has been linked to immune dysfunction.

Workers chronically exposed to high levels of benzene

(> 100 ppm in the air) experienced increased rates of

agranulocytosis and myelogenous leukemia, accompanied by an increased risk of infection. The immunotoxicity of benzene at levels closer to the current

regulatory level (1 to 5 ppm in the air) has not been

demonstrated.

Animal studies of, pesticides show evidence of immunosuppressive potential, but little analysis of the effects of human exposure has been done. Among the

commonly found halogenated aromatic hydrocarbons

(HAHs), polybrominated biphenyls (PBB), polychlorinated
Chapter l—Introduction and Summary ● 7

biphenyls (PCBs), and dioxin have shown evidence of humans exist. Other airborne pollutants with immuimmune suppression in animal studies. However, the few

human studies on these substances have either been

inconclusive or have contradicted the animal evidence.

Carcinogenic polycyclic aromatic hydrocarbons

(PAHs), the products of fossil fuel combustion, create

clear signs of immunosuppression in animal studies.

Humans are exposed to PAHs in the workplace and as

airborne pollutants, but few data on their effects on

.

nosuppressive potential include ozone, nitrogen dioxide,

cigarette smoke, and trace metals. Metals shown to suppress immune function in experimental animals include

lead, cadmium, mercury, and organotins.

Substances That Induce Hypersensitivity

Contact sensitivity and other immune mediated skin

disorders often arise from exposure to environmental
8 ● Identifying and Controlling Immunotoxic Substances

agents. A variety of substances, including drugs, cosmetics, and certain metals can give rise to allergic contact

dermatitis, which manifests itself with a red rash, swelling itching, and sometimes blisters. Numerous inhalants

cause immune-mediated respiratory disorders, including some types of asthma, hypersensitivity pneumonitis,

allergic rhinitis, bronchopulmonary aspergillosis,

silicosis, asbestosis, coalworkers’ pneumoconiosis, and

possibly byssinosis.

Among the known human allergens are certain

prescription drugs, including penicillin and methyldopa.

Over-the-counter drugs, cosmetics, and the metals found

in costume jewelry can also cause allergic reactions.

Plastics and resins, particularly the isocyanates, cause

both asthma and contact dermatitis. Pesticides, too, have

provoked hypersensitivity under certain conditions.

Substances That Induce Autoimmunity

Several drugs and heavy metals have been implicated

in autoimmune processes. Genetic susceptibility also

plays an important role in autoimmunity. Because of this

strong genetic component and a generally poorer understanding of autoimmunity compared to other immune

responses, deciphering the exact role of toxic chemicals

in the induction of autoimmunity is difficult.

FEDERAL ATTENTION TO

immunotoxic SUBSTANCES

The Federal Government is actively involved in advancing the state-of-the-art of immunotoxicology. The

Environmental Protection Agency (EPA), Food and

Drug Administration (FDA), Centers for Disease Control, and National Institutes of Health have immunotoxicological research programs. Each of these

agencies also contributes to the work of the National

Toxicology Program (NTP), whose immunotoxicological

research program was the first coordinated Federal effort to evaluate toxic substances for adverse effects on

the immune system.

Current Federal research in immunotoxicology is

directed toward developing and validating tests for

evaluating substances for immunotoxic potential. NTP

has published a panel of tests for immunosuppressive

potential that has been validated in the mouse, and it

continues to work on validating immunotoxicity tests in

other species and on improving its current panel of tests.

NTP is also applying the battery of tests for immunosuppressive potential and standard hypersensitivity assays to

various substances. EPA is working independently and

with NTP on developing and validating immunotoxicity

tests using the rat and the mouse, and has undertaken

human inhalation studies on substances regulated under

the Clean Air Act. EPA has also published immunotoxicity testing guidelines for certain pesticides. FDA

considers the immune system an important target of

toxicological assessment and is involved in developing

and applying tests to measure the potential immunotoxicity of foods and drugs. (See table 1-2.)

Few substances have been regulated by the Federal

Government on the basis of immunotoxicity. The Occupational Safety and Health Administration (OSHA)

has issued regulations for certain substances because

they can provoke hypersensitivity. FDA has restricted

the use of sulfites in foods because they can induce

asthmatic attacks insensitive individuals. These agencies

and EPA regulate additional substances that have shown

evidence of immunotoxicity, but other health effects

serve as the basis for those regulations.

Several Federal activities are designed to enhance

public awareness of the hazards of toxic substances,

including immunotoxicants. OSHA’S hazard communication standard requires that workers be provided

with information about known health hazards in their

jobs. However, since so little information is available

regarding immunotoxic effects, and since the standard

cannot be used to compel testing, the standard does little

at present to protect workers from immunotoxic hazards.

Community right-to-know legislation requires EPA to

collect information about substances that pose potential

toxic hazards to local communities and make that information available to the public. As with the OSHA stanTable 1-2—Federal Agencies Engaged in

immunotoxicological Research or Regulation

Consumer Product Safety Commission

Department of Agriculture

Department of Defense

Department of Health and Human Services

Agency for Toxic Substances and Disease Registry

Alcohol, Drug Abuse, and Mental Health Administration

Centers for Disease Control

Food and Drug Administration

National Institutes of Health

Department of Labor

Mine Safety and Health Administration

Occupational Safety and Health Administration

Environmental Protection Agency

SOURCE: Office of Technology Assessment, 1991.
Chapter 1—Introduction and Summary . 9

dard, however, this program does not permit EPA to

require that health effects information be developed

The Federal Government also supports information dissemination activities related to toxic substances undertaken by the National Library of Medicine and the

Agency for Toxic Substances and Disease Registry.

RELATED ISSUES

As a science develops, experts continually disagree on

whether currently available evidence supports a particular conclusion. In the ease of immunotoxicology, a

growing number of medical practitioners are drawing

conclusions regarding the immunotoxicity of chemicals

in the environment that other practitioners and researchers

believe to be unjustiled on the basis of current knowledge.

This disagreement has had at least two interesting effects

on governance in the past few years.

One effect is the increasing public demand for

governmental attention to a problem frequently identified

as multiple chemical sensitivity (MCS) but also called environmental illness and several other names. MCS

remains a poorly defined problem — experts disagree on

what causes the problem and whether it is physical or

mental—but sufferers generally exhibit symptoms that

they attribute to immune system dysfunction when exposed to very low levels of common industrial, environmental, and household chemicals. Two States, Maryland

and New Jersey, commissioned studies of MCS as a

public health problem but have not proceeded with

screening or regulatory programs. California has considered (but not passed) legislation that would encourage

research and education regarding environmental illness

and MCS. Within the Federal Government, EPA is funding a study by the National Academy of Sciences that will

assess the type of research needed to determine whether

MCS exists and its possible causes. Constituents at the

State and Federal level are appearing before their elected

representatives to demand attention to this problem,

which some medical practitioners attribute to immunotoxicity. This background paper does not attempt

to weigh the merits of arguments supporting or denying

the existence of MCS or of claims that MCS is an immune

system dysfunction. The analysis examines state-of-theart methods for identifying substances that may damage

the immune system but does not evaluate diseases of or

involving the immune system.

A second effect is the introduction of immunotoxicological test results to support claims of disability. Individuals

with diseases they believe to be linked to immune system

impairment are making claims against Social Security,

workers’ compensation programs, and in tort suits for

injuries caused by chemicals frequently used in commerce. Here, too, experts disagree on whether available

evidence supports these claims. However, most of the

experts contacted by OTA believe that data currently

available from immunotoxicological testing are limited in

the support they provide to plaintiffs’ claims of immune

system injury from toxic substances. Appendix A provides

a brief description of the compensation programs and a

synopsis of a few claims based on immune system injury

from toxic chemicals.

SUMMARY

immunotoxicology has advanced rapidly as a distinct

field of study over the last several years. Scientists now

recognize the immune system as an important target

organ for toxicity. Tests to determine whether a substance can suppress the immune system or induce hypersensitivity or autoimmunity have been developed and

applied by manufacturers and by regulatory agencies.

Yet the growing database of immunotoxicological information remains insufficient for most regulatory purposes.

immunotoxicology is complicated by several factors:

the complex nature of the immune system, limited (historically) attention to immunotoxicity research, and lack of

human exposure data stand out among them. Regulators at

the FDA have the opportunity to observe the effects of

drugs on humans in clinical trials before they are marketed.

However, when FDA, EPA, OSHA, or the other regulatory agencies try to decide whether a food additive or

pesticide, for instance, poses an undue risk to human

health, they face the problem of trying to extrapolate

from animal test results to the likely consequences of

human exposure to immunotoxic substances. Very few

useful human data are available to support these attempts.

The science of immunotoxicology is sufficiently advanced for regulators to begin to consider use of its

results in the decisionmaking process, but much research

remains to be done. Current law permits Federal agencies

to require immunotoxicological testing-either by the

government or by industry-on substances suspected of

posing a potential threat to the human immune system.

The agencies are devoting resources to developing and

applying immunotoxicological tests in areas where the

potential for human exposure is thought to be significant,
Chapter 2

The Immune System and immunotoxicity
Chapter 2

The Immune System and immunotoxicity

INTRODUCTION

Each day, the human body must defend itself against

a battery of foreign substances (e.g., bacteria and

viruses), as well as against elements from within (e.g.,

cancer cells). This protective capacity arises, for the most

part, from our immune system, which can generally distinguish what is “self’ from what is “nonself,” or foreign.

The stark statistics of acquired immune deficiency

syndrome (AIDS), for example, demonstrate the importance to human health of an appropriately functioning

immune system.

The immune system is a complex, highly regulated,

cooperative effort among several types of cells, cell

products, tissues, and organs. It is not an isolated system,

but operates in concert with other systems within the

body (e.g., endocrine, central nervous, and cardiovascular). Any particular stimulus to the immune system

results in a complex series of events, and any single

response can have a number of consequences. Similarly,

perturbations that primarily affect other body systems

can cascade, resulting in an effect on the immune system.

This chapter briefly describes the principal components of the immune system and the general consequences that stem from perturbations to it. This chapter

also briefly explores one of the practical considerations

of immunotoxic substances and humans: Who is at risk?

Only the most basic and broad concepts of immunology are presented in this chapter. Current knowledge

about the immune system is presented in several sources

(4,19,22). Similarly, a detailed description of toxicological effects on the immune system is beyond the scope of

this report but is presented elsewhere (7,10,11,18,27,28).

COMPONENTS OF THE IMMUNE

SYSTEM

Cells are the basic structural unit of living organisms.

They are the smallest components of plants and animals

that are capable of carrying on all essential life processes.

A single cell is a complex collection of molecules with

many different activities, all integrated to form a functional, self-assembling, self-regulating entity, although

cells in different organs carry out different functions.

Several types of cells comprise the human immune

system, as do units of cells and tissue, i.e., organs.

Together these cells, tissues, and organs respond to challenges to the immune system. This section briefly

describes the major components of the immune system;

a later section examines how these elements coordinate

to mount an immune response.

Antigens and Antibodies

Elements that are capable of eliciting an immune

response are called antigens. Humans are exposed to

antigens primarily through inhalation, direct skin contact, or ingestion. Antigens include, but are not limited

to, chemical compounds and micro-organisms. And,

while antigens are generally substances “foreign” to – i.e.,

originating outside — the human body, in some instances,

the immune system will perceive a normal, self component of the body as foreign and mount an immune

reaction against it. Several types of cells can react with

antigens, depending on the exact nature of the particular

antigen.

One response to antigen stimulation results in the

production of proteins called immunoglobulins, or antibodies. Antibodies have binding sites that are specific

for, and complementary to, the structural features of the

antigen that stimulated their formation. Antibodies

formed by a sheep, for example, in response to injection

of human hemoglobin (the antigen) will combine with

human hemoglobin and not an unrelated protein such as

human growth hormone.

By combining specifically with antigens, antibodies

can neutralize substances, such as toxins. Antibodies also

facilitate the elimination of bacteria and viruses to which

they are bound by recruiting other components of the

immune system (e.g., macrophages and complement).

13
14 ● Identifying and Controlling Immunotoxic Substances

(Complement activation is a rapid, complex process that

is activated by antigen-antibody complexes to destroy

cells, bacteria, or viruses, or cause inflammation.)

The basic unit comprising antibodies consists of four

protein chains– two identical light chains and two identical heavy chains. Heavy chains can vary in type, and the

type of heavy chain in a particular antibody determines

the subclass– i.e., IgM, IgA, IgD, IgG, or IgE–of antibody. These protein subunits are linked in a fixed and

precise orientation to forma “Y’’-shaped molecule (figure 2-l). The forked end of the antibody contains two

variable regions, the sites of the molecule that recognize

and bind with the specific antigen. To accommodate the

many antigens that exist, these variable regions differ

from molecule to molecule. The other end is nearly

identical among all antibodies and is known as the constant, or effecter, region. The constant region is not

responsible for antibody binding specificity, but has

other functions, including promoting efficient attachment of the antigen-antibody complex by certain cells

and activation of the complement cascade.

Cells

In recognizing and reacting to substances it perceives

as foreign, the immune system, or lymphoid system, involves several different cell types. Most of these cells are

commonly referred to as white cells, or leukocytes. FigFigure 2-1 – Structure of an Antibody Molecule

SOURCE: Office of Technology Assessment, 1991.

ure 2-2 presents one simple classification scheme for

white cells.

An exhaustive description of each type of cell involved

in an immune response is beyond the scope of this report.

Rather, this section provides short descriptions of only

the principal cell types –lymphocytes and macrophages-to serve as background for the following section, which describes the interaction of these cell types,

and for chapter 3, which discusses how scientists test for

immunotoxicity by measuring perturbations in these cell

populations. Table 2-1 lists additional cell types that have

immunological importance.

B Cells

A particular subclass of lymphocytes, called B lymphocytes or B cells, recognizes antigens as foreign substances and responds by producing antibodies specific

for a given antigen. Antigen-antibody mediated reactions

are known as humoral immunity. Once a B cell has been

activated by an antigen, it is committed to producing

antibodies that bind to the specific antigen. B cells arise

from precursors in the bone marrow (as do all other

lymphoid and blood cells) . These cells, like macrophages

(described in following section), play important roles in

antigen processing, one sequence of events necessary to

trigger antibody production and other immune responses.

A distinguishing feature of the outer surface of B cells

is the presence of surface antibodies. These surface markers,

along with surface markers on other cells of the immune

system (box 2-A), play critical roles in the activation and

Table 2-l—Major Cells Classes of Immunological

Importance

Primary effecter cells

B lymphocytes

T lymphocytes

NK cells

Antigen presenting cells

B lymphocytes

Macrophages/monocytes

Follicular dendritic cells

Interdigitating dendritic cells

Langerhans cells

Endothelial cells

Accessory cells

Neutrophils

Basophils and mast cells

Eosinophils

Platelets

SOURCE: Office of Technology Assessment, 1991.
Chapter 2—The Immune System and immunotoxicity ● 15

Figure 2-2-White Cells

White

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SOURCE: Office of Technology Assessment, 1991, adapted from S. Sell, Basic Immunology: Immune Mechanisms in Health and

Disease (New York, NY: Elsevier, 1987),

regulation of the immune system. Surface immunoglobulins

define the specificity of the response for that B cell and help

trigger the production of antibodies by that cell.

T Cells

A second broad group of lymphocytes are T cells. Like

B cells, T cells arise from precursors in the bone marrow,

but must circulate to the thymus for maturation. Similary, they have characteristic cell surface markers and can

specifically recognize antigen if it has been processed

and presented to them by other cells of the immune

system. Based on functional and other criteria, T cells

can be divided into several major subpopulations (table

2-2).

T cells can be viewed as the “master regulators” of the

immune system (22). In addition to their required interaction with B cells to produce antibody, various T cell

types are responsible for cell-mediated immunity, a class
16 ● Identifying and Controlling Immunotoxic Substances

of immune responses that does not depend on antibody

production. T cells can be cytotoxic, i.e., directly kill cells

that are expressing a specific antigen. T cells (and macrophages and natural killer (NK) cells) produce a variety

of protein molecules, called cytokines, but they do not

produce antibodies.

Cytokines serve as messengers that transmit signals

between cells to control and modulate an immune

response. For example, some cytokines recruit other

cells to participate in and augment an immune response.

Some stimulate B cells to produce antibodies. Others

suppress the immune reaction or ensure that the system

focuses on the antigen and does not run rampant in a

nonspecific attack that would damage host tissue.

Cytokines are produced in extremely small amounts – on

the order of parts per billion – and act locally at the site

of their release. The interferon are examples of

cytokines. \

Macrophage s

Macrophages (literally “large eaters”) are the largest

cell type in the immune system and play a central role in

the immune system’s response to a foreign agent. Macrophages invade sites of inflammation and serve to clear

the sites of cellular debris; they are also particularly

effective in phagocytizing, or ingesting, infecting organisms.

Macrophages do not produce antibodies. Instead,

they are involved in the first step leading to induction of

an immune response. A microphage ingests and nonspecifically processes antigen, and then presents the

processed antigen on its cell surface so that it can be

recognized by specific antigen reactive cells. Such antigen presentation and processing-which is linked to

genetic elements (3,12,17,24,29) – is a critical part of the

induction of both humoral and certain cell-mediated
Chapter 2—The Immune System and Immunotoxicity ● 17

Table 2-2—Major Functions of T Cells

Abbreviation Function

TD~ . . . . . . . . . . .

TH~ . . . . . . . . . . .

TK~ . . . . . . . . . . .

TS~ . . . . . . . . . . .

T cells responsible for ’’delayed-type hypersensitivity y.’’ After reacting with antigen, TDcells

release cytokines that can kill target cells in

vitro (cytotoxins) and activate macrophages,

inducing inflammation.

T helper cells assist in humoral immunity, i.e.,

antibody production. They are required if a B

cell is to produce antibody. One characteristic

feature of helper T cells is a surface marker

called CD4.

Often referred to as killer T cells, or cytotoxic

lymphocytes, this subclass of T cells, after

being specifically sensitized, directly interacts

with target cells to kill them in vitro. They are

distinguished from NK cells by the requirement

for sensitization and cell surface markers.

T cells that serve to control immune responses

by producing factors that can act on both B

cells and TH cells. Suppressor T cells can be

dis-tinguished from helper T cells because

they exhibit a signature molecule referred to as

CD8.

SOURCE: Office of Technology Assessment, 1991.

immune responses. (B cells also process antigens.) Macrophages also produce important cytokines that regulate

overall immune responsiveness.

NK Cells

Another lymphocyte subclass is natural killer cells, or

NK cells. NK cells derive from the bone marrow, but their

exact relationship to B cell and T cell precursors remains

to be elucidated. NK cells share some properties of T

cells and macrophages, but also share several surface

characteristics with B cells.

NK cells do not play a central role in antigen-specific

antibody responses, but are critical components of

general, nonspecific immune defenses. In vitro, NK cells

lyse, i.e., kill, several types of tumor cells and virus-infected cells, and thus are believed to be important in the

body’s defense against viruses or cancer. Additionally,

these cells likely play an important role in immunity to

certain bacterial and parasitic infections.

Organs

Several organs are responsible for the development

and maintenance of a functioning immune system (figure 2-3), which complicates making assessments of

immunotoxicity. Changes in the circulatory or lymphatic

systems, for example, can affect any number of organs.

Strictly speaking, however, lymphoid organs are the principal organs of the immune system (22). A lymphoid

organ is a compartmentalized collection of lymphocytes,

macrophages, and other immune cells. It maybe part of,

or mixed among, cells of another organ. Lymphocytes

also circulate freely through the blood and lymphatic

vessel network.

Bone marrow, the thymus, and even the fetal liver, in

part, are lymphoid organs. In humans (and most other

species), bone marrow is the predominant organ from

which lymphoid cells originate. Some of the cells that

develop in the bone marrow complete their maturation

before entering circulation. Others, however, must undergo further differentiation in other organs (e.g., the

thymus).

The spleen and lymph nodes are lymphoid organs that

clear the blood of infectious organisms and serve as

repositories for antibody-producing cells. Tonsils, the

appendix, and Peyer’s patches (small aggregates of cells

in the intestine) are also lymphoid organs. Local collections of tissue within both the gastrointestinal tract and

bronchus play a role in certain immune responses–

gastrointestinal lymphoid tissue is thought to play an

important role in immunity to infectious agents entering

the body through the mouth, for example.

IMMUNE RESPONSES

Immune responses can be divided into two categories:

nonspecific and acquired. Nonspecific, or innate, immunity involves those cells (e.g, macrophages and

natural killer cells) and processes (e.g., complement

activation) that do not depend on exposure, followed by

reexposure, to antigen. Generally, nonspecific immune

responses represent the body's first line of defense and

involve a generic, innate reaction to foreign substances.

Acquired, or adaptive, immunity is characterized by antigen specific processes.

There are two broad classifications of acquired immunity that are commonly referred to as humoral immunity and cell-mediated immunity. Both require the

coordination of multiple cell-types of the immune system. And, while one type of immune response can sometimes dominate after exposure to a particular antigen, for

the most part, both play roles when foreign substances

are presented. This section briefly describes the interac-
18 ● Identifying and Controlling Immunotoxic Substances

Figure 2-3 –Major Organs and Tissues of the Immune System

Lymph

L

I

Thymus

des

er's patches

K’JW)AL’11 I \ 1/:’/ I

I Bone marrow

SOURCE: Office of Technology Assessment, 1991, adapted from S. Sell, Basic Immunology Immune Mechanisms in Health and

Disease (New York, NY: Elsevier, 1987).

tions involved in the two classes of acquired immune

responses to provide a background for how perturbations in immune responses can be measured.

As mentioned previously, the immune system functions principally to protect the body. Under some circumstances, however, control mechanisms can be compromised

and the immune system turned against the body, causing

harm. Conditions that arise when this occurs vary from

mild discomfort to fatal disorders. Thus, this section also

examines pathological immune responses.

humoral Immunit y

The production of specific antibodies in response to

exposure to a foreign substance is called humoral immunity. humoral immunity can be particularly important

in protecting the body against certain biological agents.

As illustrated by figure 2-4, three types of immune cells

typically interact during optimum immunoglobulin production. A toxic substance that blocks any step can disrupt

this response in a measurable fashion.

First, an antigen presenting cell, often a microphage,

must process the foreign substance. Macrophages perform this reaction nonspecifically, and in doing so concentrate the antigen as well as release factors that

facilitate subsequent B and T cell cooperation. Second,

T helper cells interact with the antigen-presenting cell to

produce chemical signals, cytokines (interleukins), that

stimulate B cells and additional T cells. Finally, the B cell

can mature into an antibody producing cell, also called a

plasma cell.

This series of reactions is antigen-specific. Each different antigen elicits a unique antibody and there are a
Chapter 2—The Immune System and Immunotoxicity ● 19

Figure 2-4 – Generation of Antibody Forming Cells

Activation Proliferation

\

J J

Bcell

Differentiation

Antibodies

secreted

.

/ + .

.ntigen~~m~ ’

;::;:;::o f

TH activation and proliferation

T-helper ( TH ) cells

Antigen

processing cells

SOURCE: Office of Technology Assessment, 1991, adapted from K. White, Medical College of Virginia, Richmond, VA, 1990.

large number of antigens against which antibodies can be

produced. Additionally, the immune system has a

“memory" whereby re-presentation of a familiar antigen

results in a slightly different, accelerated immune response.

Both B and T cells are involved in immune memory.

In some cases, B cells can be stimulated, by certain

antigens called T cell-independent antigens, to produce

antibodies without the involvement of T cells. B cells can

also be stimulated to proliferate in vitro by mitogens.

Mitogen assays are used as a measure of immunotoxicity

and are discussed in chapter 3.

One potentially adverse consequence involving antibody production is immediate-type hypersensitivity, a

type of allergy response. (Some use the term allergy to

refer only to immediate-type hypersensitivity, and not a

second reaction, delayed-type hypersensitivity. This

background paper uses allergy to denote both responses.) When immediate-type, or anaphylactic, reactions are initiated by certain antigens– e.g., pollens or

animal dander– in certain individuals, mast cells (table

2-1, figure 2-2) release pharmacologically active substances (e.g., histamine, serotonin). These substances can

induce a range of problems, including inflammatory

changes in many tissues that result in hives and wheezing,

or even abrupt changes in blood pressure. In some circumstances, such reactions can be life-threatening. The

predominant immunoglobulin involved in immediatetype hypersensitivity in humans is called IgE.

Cell-Mediated Immunity

As described previously in table 2-2, several subpopulations of T cells can be recognized physically and

functionally. T cells, NK cells, and activated macrophages

carry out the functions of the second broad category of

acquired immune responsiveness, cell-mediated immunity. Again, the interaction of cells in cell-mediated

immunity forms the basis for tests developed to assess

potential immunotoxicants. Cell-mediated immune

responses require antigen processing to specifically sensitize T cells. Table 2-3 summarizes the general types of

cell-mediated immunity. Cell-mediated immunity is particularly important to transplantation rejection, tumor

surveillance, and for protection against infectious agents.

Several different types of cell-mediated immune responses

exist (8). One potentially adverse consequence of cellmediated immunity is delayed-type hypersensitivity

(DTH). Contact sensitization, such as poison ivy and

other skin allergies resulting in inflammation and tissue

damage, is a classic example of DTH. Another delayedtype hypersensitivity called cutaneous basophil sensitivity

also involves the skin, but the predominant cell type

involved differs from that for classic contact sensitivity
20 ● Identifying and Controlling Immunotoxic Substances

Table 2-3-Mechanisms of Cell-mediated Immunity

Direct killing by sensitized TK cells; the cells react directly with

the target cells to Iyse them (cytotoxic T lymphocyte activity).

Indirect killing by sensitized TD cells in combination with

cytokines.

Antibody-dependent cell-mediated cytotoxicity (ADCC) involves a type of lymphocyte without characteristic cell surface markers (“null cells”) in combination with specific antibody.

Direct killing by nonsensitized NK cells; the cells react directly

with the target cells.

Phagocytosis, i.e., digestion, of substances by macrophages.

Release of cytokines.

SOURCE: Office of Technology Assessment, 1991; based on S. Sell, Basic

lmmunology:lmmune Mechanisms in Health and Disease (New

York, NY: Elsevier, 1987).

and the time lag between exposure and the reaction is

shorter (1,8).

Autoimmunity

“Tolerance” is the term applied to the mechanisms that

prevent the immune system from responding to its own–

i.e., self or auto — antigens. Sometimes, however,

tolerance to self antigens is lost, resulting in autoimmune

reactions (table 2-4). When such situations occur,

humoral immunity, cell-mediated immunity, or both can

turn their destructive capabilities against the body, leading to tissue damage and/or inflammation. The presence

of antibodies that react against self antigens (autoantibodies) can sometimes be demonstrated in several

autoimmune diseases (e.g., systemic lupus erythematosus,

rheumatoid arthritis, diabetes). But, the presence of

autoantibodies is not inevitably associated with disease

and, in fact, autoantibodies normally increase with age.

Autoimmune pathologies can be difficult to assess, but

certain features are thought to be indicative of autoimmune phenomena. The induction of autoimmune events

in a few discrete populations have been attributed to

exposure of the individuals to certain toxicants (5,14,15).

WHAT IS immunotoxicITY?

As mentioned, immune responses are complex, multifactorial interactions with different consequences depending on the situation. In some instances, the immune

response will be depressed or suppressed (table 2-5),

which can result in increased susceptibility to disease or

tumor formation. Conversely, the immune system sometimes hyperreacts when presented with certain foreign

substances, which can result in an allergic response, i.e.,

immunologic hypersensitivity, wherein the response is

out of proportion to and more harmful than the initial

threat of the substance. In some of these cases, the

response can be the source of tissue damage, so that

suppressing certain immune reactions actually reduces

tissue injury. Finally, the immune system can become

confused and fail to recognize the body’s own components as “self’ – i.e., the immune system treats a “self’

substance as foreign and mounts an autoimmune

response, which can result in certain characteristic

pathologies.

For the purposes of this study, OTA defines immunotoxicity as an adverse or inappropriate change in the

structure or function of the immune system after exposure to a foreign substance. Adverse effects can be

manifest as immunosuppression, hypersensitivity, or

autoimmunity.

In any of these reactions, the cells, tissues, and organs

of the immune system can be activated, inhibited,

destroyed, or their responses exaggerated. It is the

demonstrated involvement of at least one or more of

these components that defines whether a consequence

results from an actual immune response. For example,

the term allergy should be used only to denote the involvement of immune responses, but is often mistakenly

used to describe other adverse reactions (box 2-B).

An array of biological, physical, and chemical substances can perturb the intricate balance of the immune

system, and this complex system provides several target

sites for immunotoxicants. OTA broadly defines immunotixicant as a substance that leads to undesired effects

on the immune system. The focus of this report is on

immunotoxicants that are chemicals, although important information has been, and continues to be, learned

from studies of biological substances.

Whether a substance causes an adverse effect on the

immune system, which could be permanent or reversible,

depends on many factors, including the nature of the

substance, dose and exposure, route and extent of exposure, the presence of other agents, and an individual’s

sex, genetic predisposition, age, and state of health.
Chapter 2—The Immune System and Immunotoxicity ● 21

Table 2-4-Some Human Diseases in Which Autoantibodies Have Been Detected

Self-antigens (as defined by the autoantibodies

Disease involved or detected)

Guillan-Barré syndrome . . . . . . . . . . . . . . Myelin and other components of the peripheral nerves

Hashimoto’s thyroiditis . . . . . . . . . . . . . . Cytoplasmic or microsomal thyroid antigen, thyroglobulin

Multiple sclerosis . . . . . . . . . . . , . . . . . . . Brain or white matter

Myasthenia gravis . . . . . . . . . . . . . . . . . . Acetylcholine receptor at the neuromuscular synapsis

Progressive systemic sclerosis

(scleroderma) . . . . . . . . . . . . . . . . . . . Various antigens in cell nuclei, especially nucleoli

Rheumatoid arthritis . . . . . . . . . . . . . . . . Heart, muscle, joint, subcutaneous nodules, aggregated

gamma-globulin

Systemic lupus

erythmatosus (SLE) . . . . . . . . . . . . . . Various nuclear antigens, especially double-stranded

DNA, antigens on leucocytes and erythrocytes, liver,

spleen, kidney, muscle

SOURCE: Office of Technology Assessment, 1991; adapted from E. Gleichmann, I. Kimber, and I.F.H. Purchase,

“lmmunotoxicology: Suppressive and Stimulator Effects of Drugs and Environmental Chemicals on the

Immune System,” Archives of Toxicology 63:257-273, 1989; and S. Sell, Basic Immunology: Immune

Mechanisms in Health and Disease (New York, NY: Elsevier, 1987).

Table 2-5-Some Immunodeficiency Disorders

Disorder Immunological defect

Acquired immune deficiency syndrome (AIDS) . . Viral infection of certain T ceils

Congenital thymic aplasia (DiGeorge

syndrome) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thymus absent or small; T cells absent or reduced

Severe combined immune deficiency disease

(SCID; “Bubble Boy” disease) . . . . . . . . . . . . . Lack of T and B ceils

X-linked hypogammaglobulinaemia

(Bruton’s disease) . . . . . . . . . . . . . . . . . . . . . . . . Absence of B cells

SOURCE: Office of Technology Assessment, 1991; adapted from E. Gleichmann, I. Kimber, and I.F.H. Purchase,

“lmmunotoxicology: Suppressive and Stimulator Effects of Drugs and Environmental Chemicals on the

Immune System,” Archives of Toxicology63:257-273, 1989.

Chapter 3 discusses what tests are currently employed to

determine whether a substance is immunotoxic and

describes immunotoxic substances and their effects.

immunotoxicANTS: WHO IS AT RISK?

While exposure to immunotoxic substances can occur

anywhere to anyone, the opportunity to be exposed is

greater for some populations of individuals than for

others. Since immunotoxic effects have been described

for some ambient and indoor air pollutants, some point

out that the magnitude of individuals at risk could be

tremendous (21). Yet others argue that while such effects

have been described for indoor air pollutants, the levels

of these chemicals would generally be low– probably

below the threshold for response (2).

Nevertheless, certain discrete populations are

probably at increased likelihood of exposure, more

amenable for scientific research, or both. For example,

observations of occupational exposures to toxic substances have contributed much of the data pertinent to

immunotoxicological effects — i.e., hypersensitivity,

autoimmunity, and immunosuppression. Similarly, immunosuppressive drugs can be viewed as prototype immunotoxicants, and so patients receiving such drugs to

prevent transplant rejection can be observed. Consumers of cosmetics have also been examined to detect

hypersensitivity to various agents.

Yet even among populations of individuals, not all of

those exposed are affected. Certain individuals may be

more susceptible to developing adverse reactions for a

variety of reasons separate from mere exposure to the

toxicant – even when dose and duration of exposure are

similar for different individuals. For example, the person

could be innately susceptible, i.e., be genetically

predisposed. Age is another important factor in immunotoxicology, since the immune system is not completely functional at birth and might be more vulnerable

to damage then. It also changes appreciably in older

populations–generally to a less responsive level (26).
22 . Identifying and Controlling Immunotoxic Substances

Box 2-B –"Allergy": Some Common Misperceptions

From an immunological standpoint, the term allergy refers to a normal immune response with deleterious

consequences, such as allergic rhinitis, or hay fever (e.g., to grass pollen), or contact sensitivity (e.g., to poison

ivy). True “allergies’’ occur when a human comes in contact with a substance that triggers a predictable response

that involves certain compon-ents of the immune system. Immunological hypersensitivity, or allergy, is not due

to an alteration of the immune system by a foreign substance per se, but is an inappropriate activation of the

immune system. Two exposures, the first involving sensitization to the substance, are needed to demonstrate

allergy.

“Allergy," however, is often improperly used to denote generic adverse reactions or susceptibilities. For

instance, some persons develop, or are born with, an inability to produce the intestinal enzyme lactase. These

lactase-deficient individuals are unable to breakdown the sugar lactose. For them, digestion and absorption

ofordinarylactose-containing milk is quite troublesome and results in gastrointestinal distress. The symptoms,

however, do not arise as a result of perturbations to the immune system. Rather, the problems stem from an

intolerance, not an allergy, to the milk sugar lactose.

In contrast, some problems previously thought to be intolerances might be true immune reactions, or

allergies —e.g., example the condition known as celiac sprue, where an individual has an adverse reaction to

wheat. In this syndrome, the soluble protein of wheat flour, A-gliadin, induces a damaging inflammatory reaction

to the epithelial layer of the gut leading to a malabsorption syndrome. Although once believed to be due to another

enzyme deficiency, growing evidence indicates that A-gliadin shares significant structural homology with an

adenovirus protein. AS a result of earlier presensitization to the adenovirus protein, epithelial lymphocytes respond to

the gliadin with subsequent adverse inflammatory effects — a true immune response, and hence a true allergic

response.

SOURCE: Office of Technology Assessment, 1991.

Finally, the overall state of health is also important in

determining immunotoxicity.

Genetic background, in particular, is an important

consideration in evaluating both potential immunotoxicity and variation in toxic effects. For example,

genetic bases could account for the differential ability of

individuals to produce anti-inflammatory factors, which

in turn would influence how a person would be able to

mount and modulate an immune response to an offending agent (8). Likewise, although almost anyone can

develop an allergy to a given substance, a distinct segment (15 to 20 percent (23)) of the population is clinically

atopic, i.e., individuals who are unusually reactive to a

variety of substances. Several genes have been identified

that could influence this hyperreactivity (16), although

specifics remain to be elucidated.

Not only is there a genetic basis for controlling the

immune response to a particular antigen (as determined

by histocompatibility or human leukocyte antigens (HLA),

which present processed antigens (3,12,17,24,29)), but

other genes are responsible for certain pharmacologic

abnormalities that can predispose an individual to immune

dysfunctions, e.g., hyperreactivity to histamine or acetylmethylcholine. The latter substance is used to detect

people with hyperreactive airways that constrict and

cause wheezing when exposed to antigen. Total IgE

production–central to immediate-type allergic reactions– is regulated by genes (16). Persons could have

genetic differences —singular or in combination— that

might predispose them to allergies to certain environmental and occupational antigens (30). Certain HLA

genes also are associated with increased risk of autoimmune diseases (13,20).

Finally, in addition to intrinsic factors, external risk

factors are critical. Smoking and exposure to tobacco

smoke, for example, are important external risk factors

that must be accounted for in assessing potential immunotoxicity in humans (6). Another potential external

risk factor is the presence of coincidental pulmonary

infection at the time of exposure. The association of viral

(but not bacterial) infection with triggering attacks of

both childhood and adult onset asthma has been documented (9). Such infections can cause bronchial hyperreactivity that may even become permanent. It has been

hypothesized that such an infection occurring in a worker
Chapter 2—The Immune System and Immunotoxicity ● 23

simultaneous with exposure to an industrial substance or

environmental pollutant could result in an enhanced

sensitivity to that substance. A different external factor,

house dust mites, is a precondition for certain childhood

asthmas (25).

SUMMARY AND CONCLUSIONS

A functioning immune system helps protect the

human body from a vast array of chemical, physical, and

biological foreign substances, as well as from problems

that arise from within (e.g., tumor cells). proper reaction

to a stimulus requires the cooperation of several types of

cells and organs, as well as feedback from other systems

in the body.

Two broad types of immune responses exist: nonspecific and acquired. The latter response involves two

different types of reactions: humoral immunity and cellmediated immunity. humoral immunity is characterized

by the production of antibodies that circulate in blood

and lymph fluid. Cell-mediated immunity encompasses

an array of responses that involve different cell types, but

does not involve antibody production.

The complexity of the immune system makes it vulnerable to the effects of toxic substances on many fronts.

immunotoxicity, then, is any alteration in an immune

response — suppression, hypersensitivity, or autoimmunity-- resulting from exposure to a toxic substance.

The science of immunotoxicity, i.e., immunotoxicology, is complicated by several elements: the complex

nature of the immune system, age of subject, genetic

background, and external risk factors, such as smoking.

Genetic factors account, in some instances, for variation

in immune responsiveness to an antigen, and hence need

to be assessed when evaluating potential immunotoxic

affects of a substance.

1.

2.

3.

4.

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Chapter 3

Immunotoxicological Tests

INTRODUCTION

This study defines immunotoxicity as an adverse or

inappropriate change in the structure or function of the

immune system after exposure to a foreign substance. An

overreactive or a suppressed immune system can lead to

certain health effects commonly associated with immune

dysfunction. Skin and respiratory allergies indicate that

the immune system has become overreactive–hypersensitive-to a foreign substance. Increased rates of certain

types of infection or incidence of certain tumors indicate

that parts of the immune system have become suppressed. For example, researchers received an important

clue regarding human immunodeficiency virus when

physicians reported more frequent diagnoses of a rare

infection, Pneumocystis carinii, and a rare tumor,

Kaposi’s sarcoma, in the same individual. Similarly, certain fungal or viral infections point to a suppressed immune system, for these ubiquitous infectious agents rarely

surmount the body’s defense systems.

Evidence accumulated over time indicates that some

chemicals encountered in commerce can alter the structure or function of the immune system. Occupational and

consumer experiences have identified several allergens.

Clinical experience with certain drugs and studies of

accidental exposure to certain industrial substances indicate that some chemicals can lead to disease by suppressing various immune functions or can cause

autoimmune reactions.

Rather than wait for adverse effects to manifest themselves, chemical manufacturers and regulators now seek

means to predict immunotoxicity prior to human exposure. immunotoxicologists have developed in vivo and

in vitro tests, often used in combination, to analyze the

effects of substances on various components and processes of the immune system. This chapter describes methods

for evaluating chemical immunotoxicity. It also provides a

brief explanation of the difficulties entailed in interpreting currently available tests and using their results to

predict immunotoxicity in humans. Finally, it reports on

some known or suspected immunotoxicants.

TEST METHODS

The purpose of toxicity testing is to ascertain the

potential for a substance to adversely affect the structure

or function of an organ system. Toxicological tests must

be valid, i.e., they must actually measure the effect of

interest. They must also be reliable, i.e., it must be possible to duplicate the test in different laboratories with a

minimal number of inaccurate results. Importantly, since

the test results may be used as the basis of regulation, it

must be possible to extrapolate the likely results of

human exposure from data garnered from toxicological

tests on experimental animals.

An immunotoxicity assessment measures quantitative

and functional changes in the immune system following

exposure to the test substance. It measures whether a

chemical alters lymphoid organ weights or histology,

causes qualitative or quantitative changes in humoral,

cell-mediated, and nonspecific immunity, or modifies

susceptibility to infectious agents or tumors. (Ch. 2

details the various functions of the immune system and

its components.) Most tests used in immunotoxicological

assessments are performed on experimental animals,

usually rodents. In the best experiments, animals are

exposed to a putative toxicant in a manner that mimics

human exposure conditions as closely as possible. In

many of the tests, tissue or fluids removed from an animal

that has been killed (sacrificed) are examined in vitro to

detect evidence of toxicity. Some tests, primarily the host

resistance assays, are performed in vivo, but have disease

or death as the endpoint measured.

Because of the harm that most current tests can do to

the test subject, predictive testing for immunotoxicity

using human subjects is quite rare. It is possible to perform some of the common predictive tests on human

peripheral blood, bronchoalveolar lavage fluid, or nasal

27
28 . Identifying and Controlling Immunotoxic Substances

lavage fluid since removal of these fluids does no harm.

Tests similar to those used to predict hypersensitivity are

used on humans in a clinical setting-to determine the

cause of allergic symptoms—but clinical testing is

beyond the scope of this report.

A basic list of immunotoxicity tests and what they

measure is provided in the following sections. The list is

illustrative rather than comprehensive. Descriptions of

basic tests and specific methodology can be found in

several sources (3$8,75).

Pathology

Pathology– the science of disease– is a basic tool of

toxicology. Examination of the organs and cells of the

immune system using routine pathologic tests can yield

evidence of immunotoxicity. Many of the following tests

are applied routinely to new chemicals, and can be interpreted to suggest the need for further study of immune

system effects.

Hematology--A complete blood cell count measures

the total number of blood cells. A differential blood cell

count discriminates between the red blood cells and the

types of white cells (e.g., lymphocytes, monocytes,

neutrophils, basophils, and eosinophils) in the blood.

Alterations in cell counts can indicate potential immunotoxic effects.

Histology-The lymphoid organs – the thymus,

spleen, lymph nodes, and bone marrow — provide information about possible immune alterations when examined at the cellular level. Changes in the thymus may

indicate T cell alterations; B and T cell accumulations in

specific areas of the spleen and the lymph nodes suggest

a potential change in either humoral immunity (B cells)

or cell-mediated immunity (T cells). Bone marrow

evaluation can yield information about pluripotential

stem cells (immune cell progenitors).

Organ weights –T cells complete their maturation in

the thymus. The spleen contains B and T cells. Thymus

or spleen weights outside normal reference ranges are

viewed as important indicators of potential immunotoxicity.

Cellularity– Counts of certain cells in the tissues of the

thymus, spleen, bone marrow, and peripheral lymph

nodes can be used to determine potential immune alteraions, since a change in cell number suggests an immunotoxic effect on that organ.

Quantitation of splenic B and T cells–B and T cells

cannot be distinguished by size or shape, but they do have

distinct surface markers. A variety of specialized

markers can be used to identify cell types and subsets

within type. Marked cells can be counted manually or by

using automated cell counters. Alterations in cell counts

suggest possible immunotoxic effects.

humoral Immunity

humoral immunity involves the production of specific

antibodies by B cells following exposure and sensitization

to a specific antigen (see ch. 2). The following tests of

humoral immunity call for quantitation in vitro of cell

types following exposure in vivo to a test agent. The tests

are performed on organ cells (which come only from

experimental animals) or on peripheral blood (which can

come from animals or humans).

Antibody plaque forming cell (PFC) response–This

test measures the number of B cells capable of producing

antibodies following exposure to an antigen. The test

commonly employs a T-cdl-dependent antigen, such as

sheep red blood cells (SRBC), and can reveal whether B

cells, T helper cells, and macrophages are functioning

properly. This test cannot identify the cell type (or types)

responsible for the abnormal result. This assay can also

be performed following immunization with T-cell-independent antigens to exclude the possibility that alteraPhoto credit: American Type Culture Collection, Rockville, MD

Human T cells surrounded by sheep red blood cells in a PFC assay.
Chapter 3—Immunotoxicological Tests . 29

tions in antibody production to T-dependent antigens

are due to T helper cell dysfunction.

B cell mitogen response –This test measures the ability

of B cells to proliferate (undergo mitogenesis) after

stimulation by a bacterial mitogen. Analysts measure the

amount of DNA synthesis by B cells from the spleen or

peripheral blood after exposure to the suspect chemical.

Reference values are determined in unexposed cells,

and a decrease in synthesis or proliferation below those

values may indicate that the B cells did not respond to

stimulation.

Immunoglobulin (Ig) levels in serum –Several

methods exist to measure serum or body fluid Ig levels.

Changes in a given Ig level are proportional to the number of B cells secreting that particular class of antibody.

The most common techniques for measuring serum Ig

can identify class (e.g., IgG, IgA, or IgE) and subclass

(e.g., IgG has four major subclasses, each of which can

be associated with specific disorders). In the case of IgE,

the radioallergosorbent test (RAST) can be used to

identify antigen specific antibody.

Cell-Mediated Immunity

Cell-mediated immunity describes any immune

response in which antibody plays a subordinate, rather

than a dominant, role (see ch. 2). Most immune responses involve both humoral and cell-mediated immunity,

but the responses can be measured separately.

The test for delayed hypersensitivity response is carried out in vivo. Other tests for cell-mediated immunity

are evaluated in vitro after exposure in vivo. Human

testing is possible if peripheral blood is to be evaluated,

and in some cases human skin testing can be done.

T cell mitogen response –This test measures the ability

of T cells to proliferate after stimulation by mitogens

such as plant lectins. As with the B cell mitogen assay,

analysts measure the amount of DNA synthesis in T cells

from the spleen or peripheral blood. A decrease in synthesis or proliferation (below reference values) may indicate that the T cells did not respond to stimulation.

Cytotoxic T lymphocyte (CTL) assay–This assay

measures the ability of certain T cells, those induced to

differentiate into cytotoxic T cells, to lyse (destroy) cells

of the type with which they were immunized. The

cytolytic activity of these activated cells is assessed by

measuring the amount of radioactivity released from

radiolabeled target cells of the same type used to immunize the animal. Cytolytic activity below reference

values established in the test indicates a possible immunotoxic effect.

Delayed hypersensitivity response– This assay

measures the ability of the immune system to mount a

delayed hypersensitivity response after injection with an

antigen. Measurement of swelling and redness at the site

of antigen injection can be used to evaluate the response,

as can other types of assays using radioisotopic procedures

that measure the influx of macrophages or serum albumin.

Mixed leukocyte response (MLR)—The MLR is a

general test of cell-mediated immunocompetence. The

test measures T cells’ ability to recognize foreign lymphocytes, to transform and proliferate into various effector T cells, and to release cytokines.

Nonspecific immunity

Immunity is considered nonspecific when it develops

without prior contact with antigens. Tests for nonspecific

immunity are most often performed on experimental

animals. However, tests of natural killer (NK) cell activity

can be performed using peripheral blood, and the tests

measuring microphage numbers and functions can be

done using human lavage fluids.

Natural killer (NK) cell activity – NK cells are thought

to lyse (kill) several types of tumor cells and virus-infected cells. The cytotoxic activity of NK cells can be

measured by the amount of radioactivity released from

labeled NK-sensitive targets when they are incubated

together with the NK cells. The release of radioactivity is

an indication that the tumor cells have been attacked and

damaged in a way that would ultimately lead to their

death.

Macrophages– Microphage functions commonly

measured include antigen presentation and cytokine

production (mechanisms used by the microphage for

cell-to-cell communication), phagocytosis (consumption

of debris and invading organisms), intracellular production of oxygen free radicals (substances to kill the or-
30 . Identifying and Controlling Immunotoxic Substances

Photo credit: Medical College of Virginia, Richmond, VA

Flow cytometers are used to count cells

in various immunotoxicity assays.

ganisms the cell consumes), and direct tumor-killing

activities. Macrophages can also be counted in the manner described for B and T cells.

Host Resistance

Assays of host resistance – ability to fight infections or

tumors–are performed on experimental animals. They

test overall immunocompetence. In host resistance assays, animals are first exposed to a potential immunotoxicant and then exposed to — challenged with – a

tumor, bacterium, virus, or parasite. Different components of the immune system can be evaluated by selecting specific challenge agents.

Challenge with one type of tumor cell, a PYB6 sarcoma, assesses the cytolytic activity of T cells (cellmediated immunity) and NK cells (nonspecific

immunity); challenge with cells from another tumor, the

B16F10 melanoma, mainly permits evaluation of the nonspecific immunity afforded by NK cells and macrophages. Influenza virus and Streptococcus bacteria

provoke antibody production and are used generally to

test humoral immunity, though some scientists believe

that no adequate host resistance assay of humoral imunity has been developed. Antibody apparently plays

no role in resistance to Listeria bacteria, which depends

on T cells and macrophages, thus Listeria challenge

measures cell-mediated immunity. These challenge

agents are illustrative and do not represent a complete

list of tests in use.

Hypersensitivity

The assays described above generally test for a suppressed immune system. Tests for hypersensitivity can

also be performed on laboratory animals to screen for a

substance’s allergic potential (or in an allergist’s office to

discern the reasons for an individual’s allergic

symptoms). Several types of tests have been developed

to measure whether chemicals can produce an allergic

response directly or by bonding with proteins in the body.

Tests of skin and respiratory reactions can be performed

in experimental animals and humans.

Skin reactions: Guinea pig sensitization tests-Tests to

determine a substance’s potential to induce delayed-type

hypersensitivity – usually manifest as allergic contact

dermatitis–are conducted most often in guinea pigs.

The tests measure erythema and edema (redness and

swelling). Common tests include the Draize test, the

open epicutaneous test, the Buehler test, the Freund’s

complete adjuvant test, the optimization test, the split

adjuvant test, and the guinea pig maximization test. The

essential difference among these tests is the manner in

which the animal is exposed to the test substance (3,64).

Skin reactions: Mouse tests—In addition to the guinea

pig tests, a mouse ear swelling test (MEST) has recently

been developed and validated. Some researchers believe

the MEST is a sensitive, efficient, and cost-effective

alternative to the guinea pig tests (26). More recently, a

murine (mouse) local lymph node assay has been

developed to identify chemicals that are contact allergens. This test assesses proliferation of T cells in the

Photo credit: Medical College of Virginia, Richmond, VA

The mouse ear swelling test.
Chapter 3—Immunotoxicological Tests ● 31

draining lymph node of the ear after application of the

chemical to the ear. The test developers find the results

of the lymph node assay to be as reliable as results from

guinea pig tests (47,79).

Skin reactions: Human sensitization assays-Skin

tests can also be conducted in humans– either experimentally, to predict sensitization potential (on informed volunteers), or clinically, to determine the cause

of an allergic reaction. Four basic types of predictive tests

are used: a single induction/single challenge patch test;

a repeated insult patch test; a repeated insult patch test

with continuous exposure; and a maximization test. As

with the animal tests, erythema and edema are measured

(64). [Clinical test methods are beyond the scope of this

study.]

Respiratory reactions—Experimental animals, often

guinea pigs, can be tested for pulmonary hypersensitivity

by measuring certain types of pulmonary function after

inhalation exposure (43). Carefully controlled, clinical

studies of human respiratory responses have also been

undertaken (63,67,68,78).

Serum IgE levels--Total IgE levels and IgE levels

specific for a particular antigen can be measured in the

peripheral blood of both humans and experimental

animals.

Test Selection

The time and resources available for testing new and

existing chemicals generally preclude application of all

tests to all chemicals. Therefore researchers try to

develop screening processes that reserve the most comprehensive tests for the chemicals considered most likely

to engender problems. Toxicologists often examine a

chemical’s structure-activity relationship to known toxicants

as a preliminary step. They compare the test chemical’s

molecular structure to previously studied substances. If

a chemically analogous substance is identified, its effects

on the body– its activity-will be presumed for the test

substance, to the extent the substances are similar. An

evaluation of the structure-activity relationship of a new

chemical can indicate whether it might affect the immune

system and whether an immunotoxicity assessment is

desirable. Determinations based on structure-activity

relationships are not fool-proof, however, since structurally similar compounds can have quite different levels

of toxicity.

Pathologic tests of immune system organs are fairly

standard in general toxicologic testing. These tests can

reveal structural changes in immune system organs,

which can be used to determine whether additional immunotoxicity testing is warranted. The main drawback to

these tests is that they assess only structure, not immune

function.

Interest in screening chemicals for possible immunotoxic effects has led some chemical manufacturers

and regulatory agencies to develop standardized testing

tiers. Testing regimes for possible immunosuppressants

are generally divided into two or more tiers. The first tier

is limited to a screening-type effort intended to assess, as

efficiently as possible, the integrity of the major components of the immune system. Subsequent tiers represent more in depth evaluation of those responses and also

include assays that evaluate host ‘resistance to challenge

with infectious agents or transplantable tumors.

There is also some interest in developing a tier testing

method for hypersensitivity assessment. One approach

to assessing the potential for low molecular weight compounds to act as respiratory allergens calls for a literature

search on the compound, followed by an evaluation of its

ability to bind with serum proteins (required for allergenicity), followed in turn by skin tests, and, if warranted,

respiratory tests (77).

Tier testing is not appropriate for all needs. FDA, for

instance, eschews standardized tests in favor of a casespecific evaluation of substances intended for human

consumption.

immunotoxicology is still a developing field. Selection of

immunotoxicological tests for chemicals remains discretionary. The tests applied to a particular substance are

those considered most efficacious in a particular instance

by the manufacturer and the regulator.

EPIDEMIOLOGIC EVALUATION OF

immunotoxicIT Y

Environmental epidemiology, which attempts to associate disease or other adverse outcomes with an en-
32 ● Identifying and Controlling Immunotoxic Substances

vironmental exposure, measures health effects in

humans at exposure conditions that are by definition

realistic (4). Epidemiologic studies can identify possible

associations that should be tested in laboratory environments and can be used to evaluate human health risks

suggested by laboratory exposures (17).

Some epidemiologic studies of suspected immunotoxicants have been performed. Contact hypersensitivity and asthma are known hazards of many

occupations because of the experience of exposed

workers (29,42,57). Accidental exposure to industrial

chemicals outside the workplace has occasionally

yielded opportunities to study health effects in humans,

as with polybrominated biphenyls (PBBs) (see box 3-A),

polychlorinated biphenyls (PCBs) (see box 3-B), and

dioxin (36). Some of the studies on PBBs, PCBs, and

dioxin have shown evidence of quantitative immunosuppression, but none has shown evidence of actual health

effects, and followup studies have sometimes contradicted the original studies. A recent study of the effects of passive smoking on children did reveal an

immune-mediated effect on lung function corresponding

to elevated prevalence of asthma and chest colds (12).

Current epidemiologic research on immunotoxicity includes examination of the correlations between asbestos

exposure and the development of immune system dysfunction (30,54,97). Some experts believe that increased

immunological evaluation of asbestos workers may eventually explain the long latency between asbestos exposure

and disease (14).

Epidemiologic research on any substance is complicated by the lack of good exposure data (4). Efforts to

improve this situation are underway, however. In May

1990, the Board on Environmental Studies and Toxicology of the NAS and the Agency for Toxic Substances and

Disease Registry cosponsored a meeting on Frontiers in

Assessing Human Exposures to Environmental

Toxicants. This meeting signaled increased emphasis on

developing improved epidemiologic evaluation

measures and increased coordination of Federal,

academic, and industrial research efforts in this area.

Confounding factors, such as diet and exposure to chemicals other than the one under study, make epidemiology

a challenging field for researchers.

Idiosyncrasies of the immune system compound the

difficulties for epidemiologic studies of immunotoxicants.

The range of “normal” immune responses and “normal”

conditions of immune system components varies greatly

within the population, thus it is hard to define a “suppressed” human immune system in the absence of disease

(18). Since epidemiologic studies do not permit challenging the study population with infectious agents, satisfactory evidence of immunosuppression may not be

available during the study period, particularly if immunosuppression is transient.

Epidemiologic investigations of immunotoxicity are

complex undertakings that require much time and many

resources. Few epidemiologic studies have specifically

examined environmental or occupational exposure to

immunotoxic substances (33,49). They are likely, however, to be the only means of gaining realistic data on the

human health effects of nontherapeutic substances.

PROBLEMS WITH PREDICTING AND

INTERPRETING IMMUNOTOXICIT Y

The immune system is a complex toxicological target.

As with other organ systems, its response to chemical

insults has features that complicate the interpretation of

experimental findings. For instance, test agents commonly show variations in impact on test subjects that can

be attributed to species, strain, or sex differences (e.g.,

hexachlorobenzene stimulates the immune system in rats

but suppresses the immune system in mice (103); chloral

hydrate in drinking water significantly depressed

humoral immune function in female mice, but male mice

showed no alterations (45,108)).

immunotoxicological studies often reveal complex

dose-response relationships as well. A specific test agent

can stimulate the immune system at one dose and suppress the immune system at another. Problems with interpreting dose-response relationships also manifest as

problems with evaluating the immune system’s reserve or

redundant capacity. Scientists cannot accurately predict

whether exposure to a test agent that reduces one cell

type will impair immune function or whether that same

test agent will stimulate another component of the immune system, which will then compensate for the irnpaired component (e.g., dimethylnitrosamine (DMN)

reduced B and T cell function in mice, but susceptibility

to Listeria was reduced because DMN stimulated macrophage function (37,108)).

Experimental conditions also influence immune

response. Reaction to exposure in vivo often differs significantly from reaction to exposure in vitro (e.g.,

estradiol benzoate decreased NK cell activity in mice in

vivo, but not in vitro (39)). Acute and chronic doses can

render different results (e.g., acute doses of dichloroethane
Chapter 3-Immunotoxicological Tests . 3 3

Box 3-A– Polybrominated Biphenyls: The Michigan Case

Industrial incidents allow scientists to examine human immunotoxicity in “real-life” situations. One incident

involving polybrominated biphenyls (PBBs) in Michigan “frustrates some of the problems in assessing immunotoxicity in humans.

In the 1970s, a commercial preparation of PBB was accidentally used in place of an inorganic ingredient in

preparing a feed supplement for lactating cows, and the supplement was subsequently used throughout

Michigan in 1973 and 1974. Toxic manifestations in the cattle included reduced milk production, joint swelling,

hyperkeratosis, persistent mastitis, cutaneous and subcutaneous infections, abscess formation on back legs and

udder-, and various reproductive anomalies, but did not involve indications necessarily related to infection. It

took 9 months from initial contamination to identify the toxicant.

Many people consumed the contaminated products-– milk, milk products, meat, eggs, and poultry— and

PBB was found in serum and adipose tissues of individuals at least through 1980, Clinical symptoms included I

fatigue, a striking decrease in the ability to do physical or mental work, and an unusual requirement for sleep.

Reduced memory and energy were also noted. Arthritic changes and other symptoms affecting the liver,

neurological, and musculoskeletal systems were detailed. Increased susceptibility to infections or tumors,

however, was not described.

Two studies, in 1977 and 1980, of farm residents exposed to PBB examined immunological parameters.

These individuals were compared to age-matched controls: dairy farm residents living in nearby Wisconsin,

who had not been exposed to the contaminated products, and New York City residents. Total B and T cell

counts, functional mitogenic assays, immunoglobulin content, and NK cell abnormalities were studied. For at

least 18 of 45 Michigan residents examined, a statistically significant decrease in the absolute number of T cells

(about 60 percent of the amount in nonexposed control subjects) and a decreased mitogenic response to both

T and B cell mitogens. The absolute number of B cells was unchanged. In a follow-up study, the researchers

concluded that the immunological dysfunction reported in the first study had persisted, lasting at least 5 years.

Elevated levels of IgG, IgA and IgM were also reported.

Two other studies of a different, larger cohort of exposed Michigan residents, however, found no significant

differences in an array of immune parameters. The first found significantly higher levels of circulating

lymphocytes in the PBB-exposed group when tested in 1976 to 1977, but found no decrease in the absolute

numbers of T or B cells. The second study reported no significant differences in B or T cells among exposed

Michigan residents, PBB workers, and unexposed individuals. The researchers reported depressed mitogenic

responses to certain mitogens in PBB-exposed individuals v. unexposed persons, but considered the values

within the normal range of their laboratory, and thus did not attach any significance to the finding.

In all studies, the individuals exposed had not exhibited an unusual increase in infections or tumors, two

widely accepted and applied indicators of suppression-type immunotoxicity. Although the lack of clinical

manifestations might indicate that it was and is too early to predict or extrapolate immunotoxicit y of PBB based

on the Michigan accident, the conflicting laboratory values and conclusions of these studies, derived with

different methods on different populations, underscore the problems associated with evaluating human

epidemiologic studies, Clearly PBB affected many organ systems, but its immunotoxicological significance is

difficult to discern.

SOURCE-S: Office of Technology Assessment, 1990 based on J.G. Bekcsi, J.F. I Iolland, I I.A. Anderson, et al., “Lymphocyte Function

of Michigan DaiV Farmers Exposed to Polybrominated Biphenyls,” Science 199:1207-1209, 1978; J.(3. Bckesi, J. Roboz,

A. Fisehbein, et al., “Immunological, Biochemical, and Cl inical Consequences of Exposure to Polybrominated Bipheny]s,”

Immunoto.nscology and I)nmnop)lanmco[og), J. I 1. Dean, M.I. Luster, A.E. Munson, et al., (eds.) (NewYork, NY: Raven

Press, 1985); J.G. 13ekesi, J.P. Roboz, S. Solomon, et al., “Altered Immune Function in Michigan Residents Exposed to

Polybrominated Biphenyls,” Immunolo.xicolcyy, G.G. Gibson, R. IIubbard, and D.V. Parke (eds.) (New York, NY:

Academic Press, 1983); R. Burrcll, “Identifying and Controlling Irnmunotoxic Substances,” contract paper prepared for

the Office of Technology Assessment, U.S. Congress, April 1990; PJ. L,andrigan, K.R. Wilcox, Jr., J. Silva, Jr., et al.,

“Cohort Study of Michigan Residents Exposed to Polybrominated Iliphenyls: Epidemiologic and Immunologic Findings,”

Annab of the New York Acu&wy of Scknccs 320:284-294, 1979; J. Roboz, J. Grcavcs, and J.G. Bekesi, “Polybrominated

Biphenyls in Model and Environmentally Ccmtaminatcd Iluman Blood: I’rotcin 13inding and immunotoxicological

Studies,” Ent’ironmmuai }lealdl Pwspcc[hics 60:107-1 13, 1985; and J.K. St ross, LA. Smokier, J. Isbistcr, et al., “The I Iuman

IIealth Effects of Exposure to Polybrominated Biphenyls,” Toxicology and Applied Pharmdcolqy 58;145-150,1981.
34 ● Identifying and Controlling Immunotoxic Substances

Box 3-B – Polychlorinated Biphenyls: The Taiwan Case

In February 1979, rice bran oil poisoned over 2,000 people in Taiwan. The oil had been accidentally

contaminated by polychlorinated biphenyls (PCBs), which were detectable in oil samples at concentrations of

from 4.8 to 204.9 ppm, and in the blood of poisoned patients from 3 to 1,156 ppb. Subsequent analyses

convinced most scientists that the toxic effects were associated with the chlorinated dibenzofurans (chemicals

closely related to dioxin) that contaminated the PCBs. Patients experienced headaches, ocular disturbances,

diarrhea, mylagia, arthritis, and general malaise.

The syndrome, which was first seen in Japan in 1%8, where it is called the “Yusho Syndrome;" is often

referred to as "Yu-Cheng,” literally “oil disease.” Yu-Cheng is characterized mostly by distinctive acneiform

eruptions and pigmentation, as well as other symptoms involving nonimmune organ systems. An increase in I

infections per se was not detailed, and infections that were reported seemed to be largely confined to superficial

skin infections not usually associated with immunodeficiency.

For the most part, in vitro lymphocyte mitogen assays of patient lymphocytes showed enhanced stimulation.

T cell loss was reported, particularly helper cells, and increased skin reactivity (delayed-type hypersensitivity)

to tuberculin and streptococcal enzymes was also documented. Tuberculin reactivity seemed to persist into

the fourth year. These people were probably tuberculin sensitive before the accident and carried the bacteria

in an inactive state. One possible future consequence of the PCB and furan exposure could be reactivation of

tuberculosis, although to date this has not been reported.

SOURCE: Office of Technology Assessment, 1991; based on R. 13urreli, “Identifying and Controlling immunotoxic Substances,”

contract paper prepared for the Office of Technology Assessment, L’.S. Ckmgre.ss, June 1990; Y.-C. Lu, Y.-C. Wu, “Clinical

Findings and Imml~nologic Abnormalities in Yu-Cheng Patients,” Environrnentul Ifeuhh Perspectives 59:17-29, 1985; and

Wilson, J. D., “A Dose-Response Curve for Yusho Syndrome,” Rebwla[oy Toxicolog and Phannacolog 7:364-369, 1987.

suppressed the mouse immune system, but chronic ad- clusion that many results can be extrapolated from

ministration in drinking water had no effect (62)). An

oral dose can have no effect while injection of the same

substance provokes a response. Thus the route of exposure can affect the tests results (e.g., as with chlordimeform exposure in mice (81)). The age or

maturational status of the test animal may also affect

results. with prenatal or neonatal exposure to immunotoxicants often provoking a much stronger reaction

than adult exposure (e.g., as with DES (38)). Nonspecific environmental factors can also affect the immune system. For instance, even moderate dietary

restrictions in mice can reduce spleen cellularity. However, the effects of cell reduction are unpredictable (e.g.,

the reduction in spleen cellularity was accompanied by

an increase in PFC response (66,108)).

Even when toxicologists overcome the difficulties in

interpreting results from tests on laboratory animals, the

question remains as to whether animal responses correspond to human responses. Experience with

therapeutic drugs provides evidence to support a conlaboratory animals to humans. However, little direct

evidence exists with regard to industrial or environmental exposures to immunotoxicants. Purposely exposing

humans to suspected toxicants generally is considered

unethical clinical practice. Epidemiologic studies have

posed serious problems for researchers since reliable

exposure data have usually been lacking, though there

has been some improvement in this area (102).

Perhaps the greatest problem with extrapolating test

results from animals to humans is evaluating the clinical

significance of altered immune responses, particularly

the significance of suppressing humoral, cell-mediated,

or nonspecific immunity. Observational experience is

based mainly on severe and long-lasting immunosuppression resulting from therapeutic drug treatments, and

scientists do not know the clinical relevance of moderate

and transient perturbations of the immune system. Conversely, changes in the immune system may not be immediately apparent, i.e., biologically significant changes in

immune function could occur with few morphological
Chapter 3—Immunotoxicological Tests ● 35

correlates and remain subclinical until the animal or

human is subjected to a particular stress or insult.

Comprehensive and reproducible testing schemes

exist to evaluate immunotoxicological potential of

chemicals in experimental animals. However, few chemicals have been tested in this manner, and the immunotoxicological findings in experimental animals can

only serve as indicators of concern in humans. Historically, the immune system has received little attention as

a target organ for toxicity, and immunology has not been

an integral part of the toxicology curriculum (61). Increased education and research integrating immunology

and toxicology would benefit scientists and policymakers

interested in identifying and controlling immunotoxicants.

EXISTING DATA ON immunotoxicITY

Few of the chemical substances now marketed have

undergone immunotoxicological testing. This section

describes some of the research that has been done on

substances or classes of substances to determine whether

they can suppress the immune system or cause hypersensitivity or autoimmune reactions. Most of the referenced

studies have been performed on laboratory animals since

human studies on nontherapeutic substances are

notoriously difficult. Specific note is made of the origin —

animal or human— of the data.

Immune Suppression

Several substances clearly exhibit a toxic effect on the

immune system by suppressing normal immune responsiveness. Table 3-1 lists several substances and classes of

substances thought to be immunosuppressive toxicants.

This subsection further analyzes the effects of some of

these substances.

Therapeutic Drugs

Therapeutic drugs designed to prevent transplant

rejection or to treat autoimmune disorders and cancer

are the most thoroughly studied immunosuppressive

substances. They are listed here as immunotoxicants

because of the clearly demonstrated association between

the therapeutic use of immunosuppressants and the increased incidence of infections and cancer (59). For

instance, 50 percent of transplant patients get cancer

within 10 years (65).

Table 3-l—Known or Suspected Immunosuppressants

Halogenated aromatic hydrocarbons (HAHs)

PCBs

PBBs

Dioxins

Immunosuppressive drugs

Azathioprine

Glucocorticosteroids

Cyclophosphamide

Cyclosporin A

Pesticides

Organophosphates (e.g., malathion)

Organochlorides (e.g., DDT)

Carbamates (e.g., aldicarb)

Polycyclic aromatic hydrocarbons (PAHs)

3-methylcholanthracene

Benzo[a]pyrenes

Benzene

Illegal drugs

Cannibinoids (e.g., marijuana)

Phencyclidine (PCP)

Opiates (e.g., heroin)

Heavy metals

Lead

Nickel

Cadmium

Mercury

Organotins

Air pollutants

Nitrogen dioxide

Ozone

Cigarette smoke

SOURCE: Office of Technology Assessment, 1991.

The most frequently used immunosuppressive drugs

fall into four basic categories –alkylating agents,

glucocorticosteroids, antimetabolites, and natural

products. Research remains to be done on exactly how

these drugs produce immunosuppression, but each appears to act through a different mechanism. Alkylating

agents disrupt cell functions, particularly mitosis. They

are, therefore, highly toxic to rapidly proliferating cells,

such as lymphoid cells. Cyclophosphamide is representative of this type of drug, and is used as a pretreatment in bone marrow transplant recipients to prevent

graft rejection and is also used as a cancer treatment and

to reduce symptoms of certain autoimmune diseases (91).

Treatment with cyclophosphamide, while very effective, carries with it an increased risk of certain cancers (95).

Glucocorticosteroids alter phagocytosis and depress

T and B lymphocyte function, though the exact mechanisms

for these immunosuppressive effects remain unknown. Prednisolone and methylprednisolone,

glucocorticosteroids, are therapeutic for transplant

recipients and for individuals suffering from extreme

allergic reactions (91). Glucocorticosteroids are as-
36 ● Identifying and Controlling Immunotoxic Substances

sociated with enhanced susceptibility to infection (95).

Azathioprine is a widely used antimetabolite and acts

chiefly by inhibiting protein synthesis (71). It is used

clinically in transplant patients and also as an anti-inflammatory agent. A common side effect of azathioprine treatment is bone marrow suppression (95). Cyclosporin A,

a natural product derived from fermentation products of

two fungi, appears to act through modulation of mechanisms

regulating immune responsiveness. Cyclosporin A suppresses cell function but spares B cell function, and has

proved successful with transplant patients, though longterm use has been shown to lead to higher infection rates

and incidence of non-Hodgkins lymphoma (55).

Benzene

Benzene, a basic industrial chemical, serves as a solvent or feedstock in the synthetic chemical, printing,

lithograph, rubber cement, rubber fabricating, paint, varnish, stain remover, adhesive, and petroleum industries.

Benzene has been causally linked to several health

problems, including immune dysfunction, and it is subject to stringent workplace regulations because of its

proven carcinogenicity (1 ppm TWA; 5 ppm STEL (29

CFR 1910)). High dose exposure to benzene results in

decreased immune cell function and increased lethality

of infections. Acute exposure studies in rats have

demonstrated bone marrow toxicity and depressed immune function. Benzene metabolizes remain in bone

marrow after exposure ceases, and may lead to long-term

immunotoxic effects.

Workers chronically exposed to benzene ( >100 ppm)

experienced increased rates of agranulocytosis and

myelogenous leukemia, accompanied by an increased

risk of infection (22). Depressed levels of some immunoglobulins in humans exposed to benzene have been

reported (21), but a 1988 study showed no change in

lymphocyte function in workers exposed for long periods

to benzene concentrations of 1 to 5 ppm with peaks up

to 100 ppm (107). There have been major disparities

between studies of individuals that experienced shortterm, high dose exposure, and studies of individuals

subjected to long-term, low dose exposure. Benzene is,

therefore, considered immunotoxic, but the magnitude of

effect and the exposure threshold remain to be established.

Pesticides

Pesticides have been the subject of numerous animal

studies of immunosuppression in recent years. Rodent

studies of organophosphates, such as malathion; organochlorides, such as DDT; and carbamates, such as

carbofuran, showed evidence of immunosuppression

(93). However, none of these pesticides has been submitted to a systematic evaluation for immunotoxicity. In

addition, it appears that intentionally added inert ingredients or other contaminants maybe responsible for

the observed suppressive effects (83,93). Many experts

consider the animal studies indicative of potential immunotoxicity in humans, though certainly not conclusive

evidence, and recommend prudence when dealing with

pesticides, particularly the organochlorides, which

remain stable in the environment and become concentrated in the food chain.

Most studies of the immunosuppressive effects of pesticides in workers indicate no decrease in resistance to

disease even where changes in immune system components were measurable (43,48,106). However, one

study of workers handling organophosphate pesticides

did find an increase in upper respiratory tract infection

(35). Epidemiologic evidence of the effects of pesticide

exposure outside the workplace is quite sparse (23). A

study of women who drank aldicarb-contaminated

groundwater showed altered numbers of T cells, but the

biological significance of the alteration was not

demonstrated (25,93).

Halogenated Aromatic Hydrocarbons

Among the most infamous halogenated aromatic

hydrocarbons (HAHs) are polybrominated biphenyls

(PBB), polychlorinated biphenyl (PCBs), and dioxins.

PCBs (now banned) has been used as plasticizers and as

a heat transfer medium; PBB as a fire retardant. Dioxin

appears as a contaminant in some commercial substances. Studies of the effects of HAHs on experimental

animals indicate that they can have adverse effects on the

immune system (94). Findings in laboratory animals exposed to PCBs or PBB at levels higher than most human

exposures include severe atrophy of primary and secondary lymphoid organs, lower circulating immunoglobulin levels, and decreased specific antibody

response (85,%). Evidence from epidemiologic studies is

inconclusive regarding immunotoxicity of these substances in humans. Studies of human exposure have

shown abnormal laboratory values for immune

parameters, but no conclusive clinical evidence of immune aberration (see boxes 3-A and 3-B).

The name dioxin is assigned to 75 chemicals with

similar composition. The most widely studied dioxin,
Chapter 3—Immunotoxicological Tests ● 37

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), affects

young animals more severely than adults and leads to

severe thymic atrophy and moderate atrophy of the

peripheral lymph nodes at doses that cause other toxic

effects as well (94). Recent animal research indicates that

genetic predisposition plays a major role in susceptibility

to the effects of dioxin (76,82). A study of mobile home

park residents exposed to TCDD yielded abnormal in

vitro test results in about 25 percent of the exposed

population, but uncovered no reports of clinical disease

due to demonstrated cellular immunity (36). These effects were not detectable upon reexamination of the

same population, and the authors of the second paper

consider the possibility that the first paper was in error

(24). Some data on children accidentally exposed to

TCDD show normal immunoglobulin levels and elevated

lymphocyte responsiveness, but the only clinical

evidence of disease is chloracne (70). The position of the

majority of scientists who have examined human health

effects of dioxin is that little or no harm has been done

by its dissemination in the environment (31,73).

Polycyclic Aromatic Hydrocarbons

Fossil fuel combustion produces polycyclic aromatic

hydrocarbons (PAHs), and distillates from these products

are widespread in the chemical industry. Exposure occurs in the workplace and in the environment generally.

Many PAHs are carcinogenic, and a growing body of

evidence indicates that they may also be immunotoxic. A

1980 study showed that mice exposed in utero to

benzo[a]pyrene (BaP), a PAH, experienced significant,

persistent suppression of humoral immunity(99). A later

study by the same author showed inhibition of the PFC

response and the MLR when spleen cells were exposed

to concentrations of BaP (100). Another PAH, 7,12-

dimethylbenz[a]anthracene (DMBA), significantly increased susceptibility to murine cytomegalovirus (80).

Noncarcinogenic PAHs do not appear to produce immune alterations (104). The immunotoxic effects of PAHs

have not been widely studied in humans.

Oxidant Gases

The transportation system and many industrial processes produce airborne pollutants. Two air pollutants that

have been studied for their immunotoxic effects are

ozone and nitrogen dioxide, oxidant gases regulated

under the Clean Air Act (CAA). Studies on experimental animals reveal increased susceptibility to infection

after exposure to low levels of ozone and nitrogen

dioxide. Pulmonary NK cell activity in rats was significantly suppressed following continuous exposure to

ozone, but after 10 days, NK cell activity returned to

normal, even in the continued presence of ozone (13).

Dutch researchers found that ozone suppressed or enhanced pulmonary NK cell activity in the rat depending

on the exposure level (101). Mice exposed to 2.5 to 5.0

ppm of nitrogen dioxide showed increased susceptibility

to bacterial infection (40).

Ozone has been shown to cause immediate short-term

changes in lung function and increased respiratory

symptoms among healthy adults and children who exercise moderately or heavily during periods of elevated

ozone concentrations. Some studies suggest that there

may be some persistent effects associated with long-term

exposure to ozone, although understanding of such effects, including whether they are immune-mediated, is

currently limited (98). Government researchers recently

summarized the results of several epidemiologic studies

of nitrogen dioxide exposure (32). The studies reveal an

increased prevalence of respiratory infections among

individuals, particularly children, exposed to nitrogen

dioxide, but small sample sizes and poor exposure data

tend to lessen the significance of the findings. EPA has

set national primary ambient air quality standards for

ozone (0.12 ppm) and nitrogen dioxide (0.053 ppm)

based on health effects other than immunotoxicity (40

CFR 50).

Indoor Air Pollutants

Some air pollutants become particularly concentrated

indoors. Some of the epidemiologic evidence of the

health effects of nitrogen dioxide comes from studies of

individuals in homes with gas stoves. Sidestream cigarette

smoke, in one study of children, increased the incidence

of respiratory infections through immune-mediated

mechanisms (12). Concerns have been raised about offgassing from products containing formaldehyde, but

animal (20) and human (69) studies of immune functions

following inhalation of formaldehyde indicate that it is

not immunosuppressive.

Metals

Heavy metals are ubiquitous – in the air and water, at

work and at home — and a few of them have been studied

for immunotoxicity. A 1982 study of the effects of lead on

macrophage function in mice indicated a significant immunosuppressive effect (46). A more recent study of

lead’s effects on host resistance in mice yielded conflicting results depending on time and amount of exposure,
38 . Identifying and ControllingImmunotoxic Substances

making it difficult to draw any conclusions about lead’s

immunotoxicity (50). The latter study also evaluated the

effects of nickel and selenium. Nickel’s effects on host

resistance varied significantly with time and amount of

exposure; selenium uniformly increased resistance to

infection. Other studies of nickel indicate that it suppresses NK activity in mice and rats (86,87,89) but that

nickel chloride does not adversely affect the immune

system of the developing mouse (88). One study of cadmium showed that it significantly depressed NK cell

activity in mice but had no effect on mortality due to

infection (19). A study of cadmium in aged mice showed

no immunosuppressive effects (10). The evidence for

immunosuppressive effects of mercury on animals is conflicting (52). Organotins, used as heat stabilizers, catalytic

agents, and antifungal/antimicrobial compounds, have

been widely studied, but show highly variable effects

depending on the species, times. and amount of exposure

involved in the test (11,84,85,90).

Hypersensitivity

This report defines immunologic hypersensitivity as

allergic response (see ch. 2). Delayed-type hypersensitivity manifests as allergic contact dermatitis and is the

result of a T cell mediated inflammatory response. Immediate hypersensitivity is an antibody-mediated

response that manifests as allergic rhinitis, asthma, or

anaphylaxis. This section describes some problems with

hypersensitivity resulting from environmental exposures.

Contact Sensitivity and Skin Disorders

The skin is an excellent route for toxic agents to enter

the body. Workers engaged in leather tanning and finishing poultry/egg processing, manufacturing sealants, adhesives, or abrasives, fish packing, boat building and

repairing, and landscaping are at risk for skin manifestations of immunotoxicity called occupational dermatoses.

Cell-mediated hypersensitivity causes 20 to 30 percent of

occupational dermatoses (14).

A number of therapeutic and cosmetic materials

provoke various types of skin reactions. Oils used as

bases in many ointments for either medical or cosmetic

purposes can induce contact sensitivity. If substances

(e.g., perfumes) are dissolved in solvents, cutaneous absorption is greatly facilitated. One type of immunologic

hypersensitivity, “underarm anti-perspirant granuloma,"

occurred when compounds containing the element zirconium were introduced. Although excellent antiperspirants they induced cell-mediated hypersensitivity,

which over along period of application led to pathological manifestations of granuloma formation. Once the key

ingredient was identified, the compounds were either

eliminated or modified to avoid the condition.

Some common metals also cause hypersensitivity

responses. The nickel in costume jewelry can cause contact sensitivity 5 percent of all contact dermatitis can be

attributed to nickel-containing compounds (14). Exposure to platinum, chromium, mercury, and gold can

also lead to skin sensitization. Table 3-2 lists a number of

agents known to induce types of contact sensitivity.

Respiratory Disorders

Numerous inhalants cause immune-mediated respiratory

disorders, including some types (but not all) of bronchial

asthma, hypersensitivity pneumonitis, allergic rhinitis,

bronchopulmonary aspergillosis, silicosis, asbestosis,

coalworkers’ pneumoconiosis, and possibly byssinosis

(60). Some of these conditions result from a humoral

immune response, as in the case of IgE-mediated,

bronchial asthma, while others have cell-mediated immune involvement, as with the mineral pneumoconioses.

Hypersensitivity pneumonitis is a respiratory disease

of immune origin. The exact mechanism of its pathogenesis

is controversial, but the involvement of several immune

components, including nonspecific complement activaTable 3-2—Common Contact Sensitizers

Another skin disease of immunologic significance is

atopic dermatitis (eczema). This condition is a chronic,

periodic skin disorder, primarily of infants and children, that

depends on a complex interrelationship of genetic

predisposition, and an imbalance of immunologic and

pharmacologic mediators in the skin (53). Environmental agents, including jewelry and cosmetics, may provoke

initial attacks or recurrences (14).

Plant

Poison ivy

European primrose

Synthetic compounds

Benzocaine

Epoxy resins

Mercaptan

Picric acid derivatives

C-1 Hydrocarbons

Ethylenediamine

Paraphenylenediamine

Thimerosol

Minerals

Beryllium

Nickel

Cadmium

Chromates

Silver

Zirconium

Cutting oils

SOURCE: Office of Technology Assessment, 1991.
Chapter 3—Immunotoxicological Tests . 39

tion, T and B lymphocyte stimulation, and microphage

activation, has been reported (15,72). Hypersensitivity

pneumonitis is caused by allergy to specific microbial or

organic substances. However, the dusts that cause the

condition are sometimes mixtures of many potentially

inflammatory or bio-active agents.

Asthma is the leading chronic disease of childhood

(27). Occupational asthma is the most common occupational respiratory ailments in the Western world (16).

Numerous agents can induce asthma, and they are generally

divided into two groups: large molecular weight substances, usually proteins, that cause classical, IgE-mediated

asthma; and low molecular weight materials that cause

non-IgE-mediated, longer lasting types of asthma. Occupational asthma is often of the non-IgE-mediated type;

table 3-3 presents a list of the some common incitants for

occupational asthma.

Table 3-3—industrial Chemicals Associated With

Occupational Asthma

Platinum salts Ethylenediamine

Nickel salts Phthalic anhydrides

Pyrethrum Colophony resins

Diisocyanates Exotic wood dusts

SOURCE: Office of Technology Assessment, 1991.

Substances That Are Allergenic

Some commonly used drugs cause allergic reactions

in users. Penicillin produces an allergic reaction in 1 to

10 percent of users (less than 1 percent are of the lifethreatening anaphylactic variety) (l). Some drugs used

to treat hypertension are also suspected of producing

allergic reactions in patients using the drug for extended

periods (l), although the exact mechanism of the reaction remains unknown. Over-the-counter medications

are also allergenic for some users and bear warnings to

that effect. It should be noted that not all adverse drug

reactions are immune-mediated though the reaction may

be called “allergic” (see box 2-B). For instance, aspirin

produces an allergy-like reaction in some users, but the

weight of the evidence now indicates a non-immunologic

basis for aspirin intolerance (21).

Formaldehyde has historically been used to increase

wrinkle resistance and fabric durability, and many garment industry workers were believed to develop an allergic reaction to free formaldehyde (21). However, recent

challenge studies on patients with asthma yielded no

evidence that formaldehyde could cause or aggravate

symptoms, and attempts to measure serum antibody and

skin reactions yielded no adverse reactions (69). OSHA

regulates formaldehyde as a carcinogen.

Toluene diisocyanate (TDI) is used in plastics manufacture and reportedly has induced asthma and contact

dermatitis in occupationally exposed individuals. Some

patients with ‘I”DI-induced asthma remain symptomatic

even years after cessation of exposure, and some observers believe that TDI may cause airways to become

hyperreactive to agents such as smoke or air pollutants.

Most individuals with TDI-induced asthma react similarly to other diisocyanates (42). OSHA now regulates TDI

at levels below those demonstrated to induce hypersensitivity in humans (0.005 ppm TWA; 0.002 ppm STEL).

Definitive data demonstrate that Occupational exposures to some pesticides (e.g., some carbamate and

organophosphorous esters) can induce contact hypersensitivity. While animal studies indicate that antibody

response to pesticide derivatives is possible (93), no

reports of IgE sensitization of humans to pesticides have

been confirmed. Some scientists believe reported reactions may be irritative rather than allergic in nature.

Autoimmunity

Autoimmune diseases are aberrations of the immune

system resulting in an organism attacking a part of itself

as a foreign substance. Certain toxic substances that are

biological in nature can increase the risk of certain

autoimmune conditions. For example, it is well known

that certain streptococcal infections, when left untreated,

may lead to rheumatic fever and post-streptococcal

glomerulonephritis. However, the evidence for chemical-induced autoimmune disorders is ambiguous

(2,34,41).

A growing list of pharmaceuticals have been shown to

induce autoantibody formation (antibodies against self

antigens) or actual autoimmune pathologies (table 3-4;

box 3-C; 9,28,41). Genetic susceptibility also plays an important role in immunotoxicology and autoimmunity. Because of the strong genetic component and a generally

poorer understanding of autoimmunity compared to other

immune responses, deciphering the exact role of toxic

chemicals in the induction of autoimmunity is difficult.

SUMMARY AND CONCLUSIONS

Scientists have developed a number of tests that assess

the various components and processes of the immune

system. Pathologic evaluations and certain assays of
40 ● Identifying and ControllingImmunotoxic Substances

Table 3-4-Substances Associated With

Autoimmune Responses

Antihypertensive drugs

Hydralazine

Methyldopa

Anti-arrhythmia drugs

Procainamide

Practolol

Quinidine

Anticonvulsant drugs

Phenytoin

Ethosuximide

Primidone

Antimicrobial drugs

Penicillin

Sulfonamides

Isoniazid

Nitrofurantoin

Metals

Lithium

Gold

Mercury

Cadmium

Other substances

Penicillamines

Chlorpromazine

Propylthiouracil

Griseofulvin

Oxyphenisatin

Vinyl chloride

Methylcholanthrene

SOURCE: Office of Technology Assessment, 1991; based on P.E. Bigazzi,

“Mechanismsof Chemical-induced Autoimmunity,” Immunotoxicologyand Immunopharmacology J. H. Dean, Ml. Luster, A.E.

Munson, et al. (eds.) (New York, NY: Raven Press, 1985).

humoral, cell-mediate~ and nonspecific immunity have

been validated in one experimental animal, the mouse,

and validation efforts are underway for other species.

Tests that measure immune cell numbers have advanced

more quickly than tests that measure functional immunity, but tests to evaluate specific immune functions

are available.

immunotoxicological testing–like all toxicology–

presents an investigator with significant challenges. The

results of tests on experimental animals often differ

depending on the test subject’s age, species, or sex. Environmental factors, such as diet or smoking, also affect

immune system performance. Choosing the appropriate

test dose and the means and duration of exposure can

prove difficult when resources are limited and the point

of the exercise is to extrapolate from the test to the

consequences of human exposure.

Scientists believe that the immune system has a reserve

capacity, although the size of that reserve is as yet undetermined. Thus tests that measure impairment of one

immune system component may not, in fact, indicate

overall immunotoxicity, since other immune components

or processes may compensate for the impairment. In

several of the studies cited in the preceding text, a chemical produced a discernible decrease in a specific immune

function without producing a measurable decrease in host

Box3-C-Chemical-InducedAutoimmunity

Spanish Toxic Oil Syndrome

Understanding of autoimmune responses to

chemical exposure lags far behind hypersensitivity and immunosuppression. Following a

poisoning episode in Spain, scientists made one

of the few attempts to examine whether an

autoimmune mechanism could explain the

symptoms experienced after toxic exposure.

In May 1981, an unknown disease affecting

approximately 20,000 people was reported in

Madrid and northwest of the city. About 3

months after the acute phase of the outbreak, a

subpopulation of individuals developed a severe

neuromuscular and scleroderma-like syndrome,

causing at least 350 deaths. Epidemiologic evidence

supported a conclusion that adulterated

rapeseed oil, sold as olive oil, was responsible

for the disease.

Kammuller, et al., reported that a contaminant, l-phenyl-5-vinyl-2-imidazolidinethione (PVIZT), was isolated in certain

case-associated oil samples. Because the chemical structure of PVIZT is closely related to

hydantoins and thioureylenes, which can cause

autoimmune-like disorders in man, the researchers conclude that PVIZT could account

for the syndrome. Patients with toxic oil

syndrome presented symptoms similar to those

found in known human autoimmune diseases.

In addition, the researchers measured immunological changes, including high nonspecific

IgE antibody levels, marked eosinophilia,

decreased T suppressor cells, and several types

of autoantibodies.

SOURCE: Office of Technology Assessment, 1991; based

on M.E. Kammuller, N. Bloksma, and W.

Seinen, “Chemical-Induced Autoimmune

Reactions and Spanish Toxic Oil Syndrome:

Focus on Hydantoins and Related Compounds”

Clinical Toxicology 26(3&4):157-174, 1988.

resistance to disease. Many scientists believe that without

increased incidence of infection or cancer, there is no

evidence of immunotoxicity. There is still much to be
Chapter 3—Immunotoxicological Tests . 41

learned about the long-term consequences of weakening

individual components of the immune system.

Immunotoxicologists have identified many substances

that have demonstrable immunotoxic effects in

laboratory animals, and in a few instances, the effects of

these substances have been observed in humans as well.

Drugs developed to control graft rejections and cancer

definitely suppress the human immune system, and

patients receiving these drugs provide good human data

on the consequences of prolonged immunosuppression.

Occupational experience (see table 3-3) has provided

some evidence of substances’ inadvertent immunotoxic

effects in humans. Accidental exposures to suspected

immunotoxicants have, in a few cases, provided the opportunity for gathering human data (see boxes 3-A and

3-B). For the most part, however, data are sparse on the

effects of general exposure to immunotoxicants in the

environment. The scientific community recognizes that

the immune system is an important target organ for toxicity.

Most scientists agree that the lack of human test data

should not preclude efforts to control human exposures

to suspected immunotoxicants, but the absence of data

will ensure continued disagreement about suitable

means and levels of control.

1.

2.

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“Immunologic Effects of Nickel, I: Suppression of
Chapter 3—Immunotoxicological Tests . 45

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46 ● Identifying and ControllingImmunotoxic Substances

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Chapter 4

Federal Attention to Immunotoxicants
Chapter 4

Federal Attention to Immunotoxicants

INTRODUCTION

A diverse framework of laws authorizes several Federal

agencies to control human exposure to toxic substances,

including immunotoxicants. This chapter describes

Federal research activities designed to enhance the base

of knowledge about immunotoxicology and to support

regulatory efforts. This chapter also provides a brief

summary of the power of the Federal regulatory agencies

to license, register, set standards, or otherwise control

immunotoxic substances. Several previous OTA studies have

described Federal programs to regulate toxic substances in

much greater detail (24,26,27,28,29,30,31,32). Finally, this

chapter describes Federal programs that enable workers

and the general public to obtain information about the

presence of toxic substances as a means to control exposure.

FEDERAL RESEARCH ACTIVITIES

Federal immunotoxicology programs focus on research, development, and validation of test methods to

assess the impact of substances on the immune system.

Researchers seek improved methods for assessing the

toxicological bases of hypersensitivity, autoimmunity, and

immune suppression. This section discusses Federal efforts

to evaluate substances that may present immunotoxic health

risks and to develop immunotoxicological tests for use in

regulation.

The National Toxicology Program

The Secretary of the U.S. Department of Health and

Human Services(HHS) established the National Toxicology

Program (NTP) in 1978 to coordinate and strengthen the

Department’s activities in characterizing the toxicity of

chemicals. NTP is charged with:

● broadening the spectrum of toxicologic information obtained on selected chemicals;

● increasing the numbers of chemicals studied,

within funding limits;

. developing and validating assays and protocols

responsive to regulatory needs; and

● communicating NTP plans and results to

governmental agencies, the medical and scientific communities, and the public.

NTP consists of four charter agencies of HHS: the

National Cancer Institute (NCI), the National Institute

of Environmental Health Sciences (NIEHS), the National Center for Toxicological Research (NCTR), and the

National Institute for Occupational Safety and Health

(NIOSH). NTP coordinates the relevant programs,staff, and

resources from those Public Health Service agencies relating

to basic and applied toxicological research, An executive

committee consisting of the heads of the Environmental

Protection Agency (EPA), the Food and Drug Administration (FDA), the National Institutes of Health (NIH),

NIEHS, the Agency for Toxic Substances and Disease

Registry (ATSDR), the Consumer Product Safety Commission (CPSC), NCI, NIOSH, and the Occupational Safety

and Health Administration (OSHA) oversees NTP.

Nominations of chemicals for toxicology studies are made by

all participating agencies and are encouraged from all

sectors of the public.

The objectives of NTP’s immunotoxicology Program

are to systematically: 1) evaluate and examine the influence of selected chemicals on the immune response;

2) relate alterations in immunologic functions to both

general toxicity and specific organ toxicity; 3) relate

changes in immunologic functions to altered host resistance; and 4) refine and employ a panel of immune and

host resistance test procedures in order to better define

in vitro and in vivo immunotoxicit y. The immunotoxicology Program seeks to correlate laboratory immunologic

findings with altered host susceptibility and to extrapolate animal findings about chemically induced effects to

estimates of human risk (17).

NTP researchers conceived a tier approach to testing

for immunosuppression (12; see ch. 3). Tier I (see table

4-1) includes assays for pathology, humoral immunity,

49
50 . Identifying and Controlling Immunotoxic Substances

Table 4-1—NTP’s Panel of Tests for Detecting immunotoxicity

Parameter Procedures

Screen (Tier 1)

Immunopathology . . . . .

humoral-mediated

immunity . . . . . . . . . .

Cell-mediated

immunity . . . . . . . . . .

Nonspecific immunity . .

Comprehensive (Tier 11)

Immunopathology . . . . .

humoral-mediated

immunity . . . . . . . . . .

Cell-mediated

immunity . . . . . . . . . .

Nonspecific immunity . .

Host resistance

challenge model

(endpoints) . . . . . . . .

Hematology-complete blood count and differential

Weights-body, spleen, thymus, kidney, liver

Cellularity—spleen

Histology-spleen, thymus, lymph node

Enumerate lgM antibody plaque forming cells to T-dependent

antigen(SRBC)

LPS mitogen response

Lymphocyte blastogenesis to mitogens (Con A) and mixed Ieukocyte

response against allogeneic leukocytes (MLR)

Natural killer (NK) cell activity

Quantitation of splenic B and T cell numbers

Enumeration of lgG antibody response to SRBCs

Cytotoxic T lymphocyte (CTL) cytolysis. Delayed hyper-sensitivity

response (DHR)

Microphage function-quantitation of resident peritoneal cells, and

phagocytic ability (basal and activated by MAF)

Syngeneic tumor cells

PYB6 sarcoma (tumor incidence)

B16F1O melanoma (lung burden)

Bacterial models

Listeria monocytogenes (mortality)

Streptococcus species (mortality)

Viral models

Influenza (mortality)

Parasite models

Plasmodium yoelii (parasitemia)

SOURCE: Ml. Luster, A.E. Munson, P.T. Thomas, et al., “Methods Evaluation—Development of a Testing Battery to

Assess Chemical-Induced immunotoxicity: National Toxicology Program’s Guidelines for immunotoxicity

Evaluation in Mice,” Fundamental and Applied Toxicology 10:2-19, 1988.

cell-mediated immunity, and nonspecific immunity. The

tests included in Tier I function as a basic immunotoxicity

screening mechanism and cannot predict whether a substance will reduce the immune system’s ability to fight disease.

However, they can detect immune alterations that suggest

the need to evaluate the compound further, using one or

more of the specialized tests listed under Tier II. Tier II

assays include pathologic tests and measures of humoral,

cell-mediated, and nonspecific immunity, and employ

host resistance challenge models that test the ability of

an animal (usually a mouse) to prevent infection or tumor

growth after exposure to a suspected immunotoxicant.

NTP’s battery of tests does not include measures of a

substance’s potential to induce hypersensitivity. NTP’s

methods cannot measure tolerance or reversibility of

effect, since animals are evaluated at a single point in

time, or specific sites of immune responsiveness, such as

lung or intestinal immunity.

Since 1985, when validation of the NTP tiers was

completed, more than 50 chemicals have been evaluated for

immunosuppression (see table 4-2). NTP has also tested

2 of those chemicals and 15 additional chemicals using

standard hypersensitivity assays (see table 4-3). Among

the agents tested by NTP are the AIDS treatment, AZT;

nitrophenylpentadien — spy dust; methyl isocyanate, the

primary causative agent of the Bhopal disaster; and silicone fluid used in surgical implants.

The mouse has been the experimental animal of

choice at NTP because its immune system is well characterized. Efforts are underway to validate immunotoxicity
Chapter 4-Federal Attention to Immunotoxicants . 51

Table 4-2—Substances Tested by NTP for Immunosuppression

Substance Use/Industry immunotoxicity

acetonitrile . . . . . . . . . . . . . . . . . . .

aldicarb oxime . . . . . . . . . . . . . . .

allyl isovalerate . . . . . . . . . . . . . . .

arsine . . . . . . . . . . . . . . . . . . . . . .

azathioprine. . . . . . . . . . . . . . . . . .

benzidine . . . . . . . . . . . . . . . . . . . .

benzo (a) pyrene . . . . . . . . . . . . . .

benzo (e) pyrene . . . . . . . . . . . . . .

o-benzyl- p-chlorophenol . . . . . . . .

t-butylhy roquinone . . . . . . . . . . . yd

cadmium chloride . . . . . . . . . . . . .

chemical mixture . . . . . . . . . . . . .

4-chloro-o-phenylenediamine . . .

cyclophosphamide . . . . . . . . . . . .

2,4-diaminotoluene . . . . . . . . . . .

dideoxyadenosine . . . . . . . . . . . . .

diethylstilbestrol . . . . . . . . . . . . . .

dimethylbenz(a) anthracene . . . . .

dimethyl vinylchloride. . . . . . . . . .

diphenylhydantoin . . . . . . . . . . . . .

ethyl carbamate . . . . . . . . . . . . . .

ethylene dibromide . . . . . . . . . . . .

formaldehyde . . . . . . . . . . . . . . . .

gallium arsenide . . . . . . . . . . . . . .

ginseng . . . . . . . . . . . . . . . . . . . . .

hexachlorobenzo-p-dioxin . . . . . .

indomethacin . . . . . . . . . . . . . . . . .

interferon-alpha . . . . . . . . . . . . . .

lithium carbonate . . . . . . . . . . . . .

methyl carbamate. . . . . . . . . . . , ,

methyl isocyanate . . . . . . . . . . . . .

nickel sulfate . . . . . . . . . . . . . . . . .

nitrobenzene . . . . . . . . . . . . . . . . .

nitrofurazone . . . . . . . . . . . . . . . . .

n-nitrosodimethylamine . . . . . . . .

m-nitrotoluene ... , . . . . . . . . . . . .

p-nitrotoluene . . . . . . . . . . . . . . . .

ochratoxin a . . . . . . . . . . . . . . . . .

oxymetholone . . . . . . . . . . . . . . . .

pentachlorophenol . . . . . . . . . . . .

pentamidine isethionate. . . . . . . .

o-phenylphenol . . . . . . . . . . . . . . .

phorbol myristate acetate. . . . . . .

ribavirin . . . . . . . . . . . . . . . . . . . . .

silicone polymers . . . . . . . . . . . . .

2,3,7,8 -tetrachlorodibenzop-dioxin

tetraethyI lead-

.

- ~~~.’.’ ~.’ ~.’ ~ ~; ~; j

tetrahydrocannibinol. . . . . . . . . . . J

4,4-thiobis(6-t-butyl-m-cresol) . . .

toluene . . . . . . . . . . . . . . . . . . . . . .

tris(2,3-dichloropropyl) phosphate.

vanadium pentoxide . . . . . . . . . . .

4-vinyl-1- -cyclohexene diepoxide .

catalyst; solvent

insecticide

fragrance; flavoring agent

dopant for microelectronics

chemotherapeutic agent

drycleaning fluid; dye manufacturing

fossil fuel combustion byproduct

veterinary antiseptic

germicide

antioxidant in cosmetics

photography; dyes; lubricants

mix of 26 groundwater contaminants

hair dyes; curing agent

cancer therapeutic

photography

potential AIDS therapeutic

formerly a hormone therapy; cattle growth promoter

induces malignant tumors (research)

organic synthesis

anticonvulsant therapeutic

anesthetic; co-solvent; anti-neoplastic

fumigant; gasoline additive

disinfectant; tissue fixative; textiles; photography;

wood products

semiconductors; electronics; microwave

generation

medicinal and research purposes

chemical byproduct

analgesic; anti-inflammatory

cell product with antiviral activity

glazes; antidepressant drug

chemical intermediate

synthesis of pesticides

fabrics; plating; catalyst

dyes; shoe polish; leather; paint; soaps

antibacterial agent; food additive

solvent; rocket fuels; antioxidant

explosives; dyes

explosives; dyes

metabolize from mold

therapeutic; synthetic androgen

wood preservative

antiprotozoal used to treat pneumonia

fungicide; cleaning; rubber; preservative

tumor promoter (research)

antiviral therapeutic

semiconductor manufacture; surgical implants

herbicide production byproduct

chemical intermediate

constituent of marijuana

antioxidant and stabilizer

solvent; denaturant

flame retardant

catalyst; glass; ceramics; photos; textiles

resins

—

+

+

+

+—

—

+

+

+

+

+

+

+

+

+

+

+

—

+

+

+

+

+

+—

—

+—

+

+

+

+—

+

—

+

+—

+

+—

+—

—

—

+

NOTE: Positive (+) compounds demonstrated a significant dose-response effect for any one parameter in the NTP

Tiers or showed significant effects in multiple parameters at a high dose level. The designation indicates

potential immunosuppresive chemicals, not definitive immunotoxicants.

SOURCE: Office of Technology Assessment, 1991; based on Ml. Luster, National Institute of Environmental Health

Sciences, Research Triangle Park, NC, personal communication, July 1990.

testing in rats because they are used most frequently in to identify the most suitable test subjects for particular

general toxicological testing. The goal of toxicological immune functions.

testing on experimental animals is to be able to extrapolate from test results to human health effects. Thus re- in fiscal year 1990, NTP had a budget of almost $2.6

searchers may proceed with testing and test validation in million for immunotoxicological research (19). NTP conother species (e.g., dogs, swine, and primates) in order tinues to work on refining and improving the immu-
52 ● Identifying and Controlling Immunotoxic Substances

Table 4-3-Substances Tested by NTP for Hypersensitivity

Substance Use/industry immunotoxicity

benzothonium chloride . . . . . . . . . . . . . . .

benzyl-p-chlorophenol . . . . . . . . . . . . . . .

4-chloro-o-0-phenylenediamine . . . . . . .

cobaltous sulfate . . . . . . . . . . . . . . . . . . .

crotonaldehyde . . . . . . . . . . . . . . . . . . . . .

2,4-diaminotoluene . . . . . . . . . . . . . . . . .

dinitrofluorobenzene . . . . . . . . . . . . . . . .

ethylene thiourea. . . . . . . . . . . . . . . . . . .

glutaraldehyde. . . . . . . . . . . . . . . . . . . . .

isobutyraldehyde . . . . . . . . . . . . . . . . . . .

isophorone diisocyanate . . . . . . . . . . . . .

2-mercaptobenzothiazole . . . . . . . . . . . .

nitrophenylpentadien. . . . . . . . . . . . . . . .

oleic acid diethanolamine . . . . . . . . . . . .

polydimethylsiloxane fluid. . . . . . . . . . . .

triethanolamine . . . . . . . . . . . . . . . . . . . . .

xylenesulfonic acid . . . . . . . . . . . . . . . . .

veterinary medicine

disinfectant germicide

hair dyes; curing agent

electroplating; glazes

solvent; warfare

photography

reagant

electroplating; dyes; rubber

disinfectant; fixative

perfumes; rubber; antioxidants

polyurethane

rubber; fungicide; oil

spy dust

surfactant

water repellant; resin; surgical implants

dry cleaning; cosmetics; textiles

shampoos;cleaning compounds

+

+

+—

+

+

+

+

+

. ,

NOTE: Positive (+) indicates statistically significant contact hypersensitivity response observed in mice and/or guinea

pigs.

SOURCE: Office of Technology Assessment, 1991; based on Ml. Luster, National Institute of Environmental Health

Sciences, Research Triangle Park, NC, personal communication, July 1990.

notoxicity test battery, and is currently engaged in

reviewing data to determine whether the Tier I and Tier

II assays can predict the immunotoxicity of compounds

and the potential for use of the test data in risk assessment (34).

The Environmental Protection Agency

EPA’s primary immunotoxicological research efforts

are located in the Office of Health Research (OHR). In

fiscal year 1990, OHR had 6 principle investigators

engaged in immunotoxicological research and funded

$345,000 of intramural research and $324,000 of extramural research (22).

EPA’s research program in immunotoxicology has

four primary goals:

●

●

●

to develop tier testing methods in the rat similar

to those used by NTP in the mouse. This effort,

which is coordinated with NTP, supports

guideline development for the Office of Pesticide Programs and the Office of Toxic Substances;

to develop host resistance assays for both the

mouse and rat that can be included in test

guidelines, which would facilitate use of immunotoxicity testing data for risk assessment purposes;

to develop methods for assessing immune

responses in the lung (including development

of appropriate host resistance models) in order

to improve the ability to assess immunotoxic

effects of inhaled compounds. These methods

are used to evaluate National Ambient Air

Quality Standard (NAAQS) pollutants as well

as other compounds covered by the Clean Air

Act. Such methods are needed because of the

diffuse nature of the immune system and because many of the inhaled compounds assessed

primarily affect the lung rather than the spleen

from which cells are usually obtained for immune function tests. Effects of certain air pollutants on markers of immune dysfunction in

the lung are also being assessed in human clinical studies; and

● to develop improved methods for assessing allergenic potential of compounds, including

methods development in both contact sensitivity

and pulmonary hypersensitivity (22).

In addition to work in the immunotoxicology program

of OHR, EPA scientists have established an oral reference dose for tributyltin oxide (an antimicrobial/antifungal

pesticide) based on immunotoxic concerns. The reference dose may eventually be used by regulatory offices

within the agency to set exposure standards.

The Food and Drug Administration

FDA has contributed substantially to the field of immunotoxicology and held one of the first scientific conferences on inadvertent modification of immune

response. Four centers of the FDA, the Center for Food
Chapter 4—Federal Attention to Immunotoxicants . 53

Safety and Applied Nutrition (CFSAN), the Center for

Drug Evaluation and Research (CDER), and the Center

for Biologics Evaluation and Research (CBER), and

NCTR are currently engaged in basic immunotoxicity

research and test development.

FDA uses different immunotoxic testing strategies

depending on the substance tested and its intended uses,

thus a standardized testing scheme is unsuited to FDA’s

needs. CFSAN has been involved in immunotoxicological research since the mid-1970s, when it began to

develop in vitro studies to screen for potentially immunotoxic food constituents and contaminants. Current

research efforts involve methods development as well as

actual studies of the immunotoxic potential of food additives and contaminants. CFSAN is trying to integrate

immunotoxicity with conventional toxicity testing and

may soon issue guidelines for evaluating the immunotoxic potential of direct food additives (11).

immunotoxicology research efforts at CBER are

aimed at better understanding the clinical relevance of

compromised immune function (5). CDER evaluates

drugs on a case-by-case basis and encourages immunotoxicity testing by manufacturers where it is warranted (14). The NCTR initiated an immunotoxicity

research program in 1975, and the major focus of

NCTR’S research program has been on development of

in vivo testing (2). FDA states that much of its workload

is directly related to identifying possible toxic effects on

the immune system, and the agency was unable to

respond to OTA’s inquiry about budget and personnel

devoted specifically to immunotoxicology (3).

Other Federal Research Efforts

The NIH allocated approximately $27 million to immunotoxicological research in fiscal year 1989 (some of

which went to NTP) (16). Funds for intramural and

extramural research have been available at varying levels in

each of the Institutes. Much of the immunotoxicity research

was incidental to other research efforts, but immunotoxicology received some direct attention. For instance, the National Institute of Allergy and Infectious

Diseases has supported dermatotoxicological studies of

allergenic plants, assessment of how chemical additives

in foods and medications can trigger asthmatic attacks,

and animal studies on the causal role of workplace

chemicals in asthma.

NIEHS spent approximately $7.5 million on immunotoxicological research in fiscal year 1989. NIEHS is

actively involved in developing and validating immunotoxicological test methods, and provides funding

for NTP’s immunotoxicity testing program. NIEHS,

working independently and through NTP, also performs

basic research, seeking to better define the relationship

between immune function changes and altered host

resistance, particularly at the low end of the doseresponse curve, as well as provide data that should support a framework to allow better extrapolation from

animal immunotoxicity data to human health risks.

The Centers for Disease Control (CDC) also conduct

immunotoxicity research. The Center for Environmental

Health and Injury Control allocated $175,000 and two

full-time equivalent staffers (FTEs) to a study of immunology measurements for human exposure assessment in fiscal year 1990. NIOSH conducted an

assessment of immunological markers of herbicide exposure in fiscal year 1990, and provided basic support to

immunotoxicological research for a total budget of over

$300,000 and four FTEs. The Agency for Toxic Substances and Disease Registry (ATSDR) also provides

financial support to much of CDC’S immunotoxicology

research (8).

The Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA) carries out research to determine the effects of alcohol and abused drugs on the

immune system. ADAMHA has a particular interest in

the interaction between the nervous system and the immune system (6). The Department of Defense reported

that it funded, in fiscal year 1990, one extramural immunotoxicity research project designed to develop a

model for studying the toxicity of dioxin (15). The

Department of Agriculture reported that it does not

single out immunotoxic substances for research, but indicated significant research attention to aflatoxin, which

has shown evidence of immunotoxicity (21).

Because of significant differences in data collection

and reporting among the agencies, OTA could not arrive

at an exact budget for federally supported immunotoxicological research for this background paper.

Most of the agencies charged with protecting human

health have some ongoing immunotoxicological research

activities, much of it devoted to developing and validating

tests that can be applied to substances of concern to the
54 ● Identifying and Controlling Immunotoxic Substances

agencies. There is strong interest among the Federal

agencies–particularly FDA, NIH, CDC, and EPA– to

organize a Federal interagency committee on immunotoxicology to foster increased interaction among

the agencies responsible for immunotoxicity research

programs (4).

FEDERAL REGULATORY ACTIVITIES

OTA identified 12 laws with mandates broad enough

to encompass immunotoxicological concerns that

authorize Federal agencies to regulate toxic substances

(table 4-4). None of these laws spells out a specific duty

to regulate immunotoxicants, but the duty to protect

human health included in each law places immunotoxicants within the regulatory reach of the administering agencies.

The Occupational Safety and Health

Administration

OSHA administers the Occupational Safety and

Health Act (OSH Act) of 1970 (29 U.S.C. 651 et seq.).

The Act authorizes OSHA to promulgate new standards

for toxic materials and to modify or revoke existing standards. Section 655(b)(5) states that:

Table 4-4—Major Federal Laws Controlling

Toxic Substances

Agency primarily

Act responsible

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

Federal Insecticide, Fungicide,

and Rodenticide Act . . . . . . . . . . . . . . . . .

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

Occupational Safety and Health Act. . . . . .

Comprehensive Environmental Response,

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

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

Federal Water Pollution Control Act and

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

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

Resource Conservation and Recovery Act..

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

Federal Hazardous Substances Act. . . . . . .

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

EPA

EPA

FDA

OSHA

EPA

EPA

EPA

EPA

EPA

CPSC

CPSC

MSHA

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

MSHA—Mine Safety and Health Administration; OSHA--Occupational Safety and Health Administration

SOURCE: Office of Technology Assessment, 1991.

The Secretary, in promulgating standards dealing with

toxic materials or harmful physical agents under this subsection shall set the standard which most adequately assures, to the extent feasible on the basis of the best available

evidence, that no employee will suffer material impairment

of health or functional capacity even if such employee has

regular exposure to the hazard dealt with by such standard

for the period of his working life.

The Supreme Court has interpreted this language to

require OSHA to enact the most protective standard

possible to eliminate a significant risk of material impairment, subject to the constraints of technological and

economic feasibility (American Textile Manufacturers Institute, Inc. v. Donovan, 452 U.S. 490 (1981)).

OSHA rulemaking can result in requirements for

monitoring and medical surveillance, workplace procedures and practices, personal protective equipment, engineering controls, training, recordkeeping, and new or

modified permissible exposure limits (PELs). In 1987,

OSHA adopted updated standards that had been set by

the American Conference of Government Industrial

Hygienists (ACGIH), a voluntary organization, for

workplace exposure to 428 toxic substances (52 FR 2332;

29 CFR Part 1910). Despite these new standards, OSHA

lacks information on the effects of chronic exposure for

over 90 percent of these substances. Most of the remaining 10 percent, which have been evaluated for chronic

toxicity, have not been evaluated for immunotoxicity

(36). However, an immunotoxic effect, sensitization, was

specifically noted for eight of these substances (table

4-5).

Photo credit: Environmental Protection Agency, Washington, DC

Special clothing, as well as exposure limits,

can help protect workers.
Chapter 4--Federal Attention to Immunotoxicants . 55

Table 4-5-Sensitizers Regulated by OSHA

Substance Use/industry Health effects

Captafol . . . . . . . . . . . . . . . . . . . . fungicide Skin and respiratory sensitization

Cobalt (metal, dust, and fume) . . aircraft; automobile Pulmonary sensitization

Isophorone diisocyanate . . . . . . . housing; automobile Skin and respiratory sensitization

Phenothiazine . . . . . . . . . . . . . . . . veterinary insecticide Skin sensitization

Phenyl glycidyl ether . . . . . . . . . . monomer and surfactant Skin sensitization

production

Picric acid . . . . . . . . . . . . . . . . . . . rocket fuels; steel Skin sensitization

Subtilisins . . . . . . . . . . . . . . . . . . . laundry detergents Respiratory sensitization

Toluene-2,4-diisocyanate. . . . . . . rubber; paints; coal tar Pulmonary sensitization

SOURCE: Federal Register, vol. 53, No. 109, Tuesday, June 7, 1988.

The Food and Drug Administration

FDA regulates chemicals found in foods, drugs, and

cosmetics under the Food, Drug, and Cosmetic Act of

1938 (FDCA; 21 U.S.C. 301-392). FDCA encompasses

several laws passed by Congress since the first Federal

statute regulating food safety, the Food and Drugs Act

of 1906, including the Pesticide Chemical Residues

Amendment of 1954, the Food Additives Amendment of

1958, the Color Additive Amendments of 1960, the Drug

Amendments of 1962, and the Animal Drug Amendments of 1%8.

Food s

FDCA declares it illegal to sell an adulterated food.

A food is adulterated if:

. . . it bears or contains any poisonous or deleterious

substance which may render it injurious to health; but in

case the substance is not an added substance such food shall

not be considered adulterated under this clause if the quantity of such substance in such food does not ordinarily

render it injurious to health (21 U.S.C. 342(a)).

FDA has authority to regulate unavoidable environmental contaminants, pesticide residues, and additives

that appear in food. Added substances are governed by

a stricter standard than naturally occurring substances.

FDA has authority to require premarket submission of

specific toxicity test data. FDA does not currently have

testing guidelines for immunotoxicity in foods, but

CFSAN has proposed some guidelines that are currently

under review (11).

FDA regulates some substances studied as immunotoxicants, such as mercury and polychlorinated

biphenyls (PCBs), based upon other adverse health effects (21 CFR Part 189). FDA regulated Yellow Dye No.

5 based on its association with hypersensitivity. FDA has

also regulated the use of sulfites because they can

provoke life-threatening responses– often severe

asthmatic attacks— in sensitive individuals. Sulfites are

no longer generally recognized as safe for use on fruits

or vegetables intended to be served or sold raw or

presented as fresh to consumers, or on potatoes intended

to be served or sold unpackaged and unlabeled to consumers (21 CFR Part 182).

Drug s

FDCA authorizes FDA to regulate new drugs for

humans and animals. The Public Health Service Act

provides similar authority for biologics (e.g., vaccines,

monoclinal antibodies, cytokines, and growth factors).

New drugs and biologics require pre-marketing approval. In the approval process, applicants must submit

two kinds of applications: 1) an Investigative New Drug

(IND) application, essentially a request to conduct an

investigation; and 2) a New Drug Application (NDA) or

Product Licensing Application (PLA), essentially a request for permission to conduct a more detailed investigation adequate to achieve marketing approval.

The IND application must include chemical,

manufacturing, and control information; pharmacologic

and toxicologic information from animals and in vitro

systems; and a plan of clinical study. An NDA or PLA,

submitted after the research period for the IND, must

include full reports of toxicological studies and clinical

investigations to show that the test agent is safe and

effective; a complete list of the test agent’s composition;

samples of the test agent; information that may be re-
56 ● Identifying and Controlling Immunotoxic Substances

Photo credit: Julios, Washington, DC-- Onrubia

Federal regulations now prohibit the use of sulfites on salad

bars because they evoke hypersensitivity reactions.

quired for monitoring; specimens of proposed labels;

and information on the potential risks of inactive ingredients.

The mechanisms of immunosuppression and its clinical consequences are better understood than those of

immunostimulation, due largely to experience with

immunosuppressive drugs in clinical practice. FDA has

approved the use of several drugs as immunosuppressive

agents, such as cyclosporin A. In addition, FDA has

approved drugs whose known immunotoxic effects, particularly sensitization, are outweighed by their benefits, but

generally requires a warning of sensitization as a possible

side effect. In CDER, each division routinely evaluates immunotoxicity as part of the total safety assessment. Many

of the tests for effects on the immune system are routinely

incorporated into the 28-day toxicity studies that are

usually submitted as part of the IND (14). FDA’s drug

testing guidelines do not specifically require immunotoxicity testing, but require that an applicant convince FDA that its test data are adequate. FDA can suggest

or require immunotoxicity testing where appropriate.

Cosmetic s

FDA cannot, under the law, require a manufacturer

to perform toxicity testing of cosmetic ingredients, However,

products that have not been tested for safety cannot be

marketed unless they bear a label reading “Warning. The

safety of this product has not been determined” (21 CFR

740.10).

FDA has restricted fewer than 20 cosmetic ingredients on

the finding that they were “poisonous or deleterious.”

Among these restricted ingredients, however, are substances known to affect the immune system, such as

mercury and mercurial compounds, potent allergens and

contact sensitizers (21 CFR 700.13), and vinyl chloride, a

contact sensitizer (21 CFR 700.14). Despite FDA’s inability

to compel toxicity testing, the cosmetic and fragrance industries do operate voluntary testing programs for potential skin sensitizers (7).

The Environmental Protection Agency

EPA administers several laws that authorize regulation of toxic substances, including the Clean Air Act

(CAA; 42 U.S.C. y 7401 et seq.), the Clean Water Act

(CWA; 33 U.S.C. 1251 et seq.), the Safe Drinking Water

Act (SDWA; 42 U.S.C. 201, 300f et seq.), the Federal

Insecticide, Fungicide, and Rodenticide Act (FIFRA; 7

U.S.C. 136 et seq.), the Toxic Substances Control Act

(TSCA; 15 U.S.C. 2601 et seq.), the Resource Conservation and Recovery Act (RCRA; 42 U.S.C. 6901 et seq.),

and the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA; 42 U.S.C. 9601 et seq.).

The Clean Air Act

Under the CAA, EPA regulates air pollutants by

setting National Primary and Secondary Ambient Air

Quality Standards as necessary to protect the public
Chapter 4-Federal Attention to Immunotoxicants ● 57

health and welfare. EPA has promulgated primary National Ambient Air Quality Standards for sulfur oxides,

particulate matter, carbon monoxide, ozone, nitrogen

dioxide, and lead (40 CFR 50). None of these standards

was based on consideration of immunotoxic effects, although ozone, nitrogen dioxide, and lead have all shown

evidence of immunotoxicity in animal tests.

The 1970 amendments to the CAA also called for

EPA to set standards limiting hazardous pollutants. Section 112 of the CAA authorizes EPA to set emissions

standards for pollutants that may reasonably be anticipated to result in an increase in mortality or an increase in serious, irreversible, or incapacitating

reversible illness. The list of substances designated by

EPA as hazardous air pollutants includes asbestos, benzene, beryllium, coke oven emissions, inorganic arsenic,

mercury, radionuclides, and vinyl chloride (40 CFR

Part 61). Several of time substances have shown evidence of

immunotoxicity in the laboratory, but serious health effects

other than immunotoxicity served as the basis for these

standards, which set exposure levels far below those used

in the tests.

Amendments to the CAA passed by the 10lst Congress (Public Law 101-549) establish a statutory list of 189

hazardous substances or classes of substances. The EPA

Administrator may add or delete substances based on

evidence of a pollutant’s potential to cause in humans:

(i) cancer or developmental effects, or

(ii) serious or irreversible–

Photo credit: Environmental Protection Agency, Washington, DC

Few data exist on the human health risks from transient,

low-level chemical exposures.

(I) reproductive dysfunctions,

(II) neurological disorders,

(III) heritable gene mutations,

(IV) other chronic health effects, or

(V) adverse acute human health effects.

The 1990 amendments direct EPA to require application of the maximum achievable control technology

(MACT) initially. Following implementation of MACT,

EPA is required to evaluate residual risk from sources of

these substances and decide whether public health is

adequately protected; if not, stricter controls can be required.

The Clean Water Act

Since the Federal Water Pollution Control Act was

first enacted in 1948, it has been amended nine times and

is now generally referred to as the CWA. The 1972

amendments set the goal of achieving “fishable, swimmable” waters by 1983 and prohibiting the “discharge of

toxic pollutants in toxic amounts” by 1985. The 1977

amendments endorsed anew method for regulating toxic

pollutants, and the 1987 amendments continued

Congress’s emphasis on control of toxic pollutants.

The CWA authorizes the EPA administrator to establish and revise a list of toxic water pollutants. EPA may

then issue effluent limitations or effluent standards to

regulate discharges of these substances into the Nation’s

navigable waters. Effluent limitations, established on an

industry-by-industry basis, impose technology-based restrictions on the amount of a toxic substance that can be

directly discharged from a point source. Effluent standards are control requirements based on the relationship

between the discharge of a pollutant and the resulting

water quality in a receiving body of water. Effluent standards can be imposed when, in the judgment of the Administrator, the effluent limitations affecting a particular

source are insufficient to protect the designated use of a

particular water body reflected in the water quality

standard for that body established by the State. This

more stringent effluent standard is employed much less

frequently than the technology-based effluent limitations.

The CWA also requires that EPA establish pretreatment standards for toxic substances discharged from

private pollution sources into publicly owned water treatment facilities. In addition to these legally binding regulations, the CWA authorizes EPA to establish ambient
58 . Identifying and Controlling Immunotoxic Substances

water quality criteria for all pollutants, including toxics,

to be used as water quality goals.

EPA has published a list of hazardous substances

under the CWA (40 CFR 116.4) and has established

reportable quantities for each of these substances (40

CFR 117.3). Under the CWA, EPA has also promulgated toxic pollutant effluent standards for six substances

(40 CFR Part 129), including PCBs (known to be immunotoxic in laboratory animals). immunotoxicity was

not the endpoint of concern in these rulemaking procedures, however.

The Safe Drinking Water Act

The SDWA regulates public waters systems and addresses contaminants “which may have an adverse effect

on the health of persons.” Under the SDWA, EPA

establishes maximum contaminant levels goals for contaminants that may have an adverse effect on health.

These are nonenforceable health goals, which are used

as guidelines for establishing enforceable drinking water

standards. EPA then sets enforceable “maximum contaminant levels” (MCL) that are as close to the goal as

feasible considering the best available technology and

the economic costs of complying with the standard.

MCLs have been set for inorganic chemicals (40 CFR

141.11 and 141.62) organic chemicals (40 CFR 141.12 and

141.61). Immunotoxicity was not a noted consideration in

these actions.

The Federal Insecticide, Fungicide, an d

Rodenticide A c t

FIFRA makes it unlawful to sell or distribute a pesticide that is not registered with EPA. An applicant for

registration of a pesticide must file the following information with EPA: a statement of all claims made for the

pesticide; directions for its use; a description of tests

made upon it; and the test results used to support claims

made for the substance. In addition, the applicant must

supply appropriate health and safety data. EPA must

register the pesticide if its composition warrants the

proposed claims for it, if it will perform its intended

function without unreasonable adverse effects on the

environment, and if, when used in accordance with

widespread and commonly recognized practice, it will

not generally cause unreasonable adverse effects on the

environment. An “unreasonable adverse effect on the

environment” is defined as “any unreasonable risk to man

or the environment, taking into account the economic,

social, and environmental costs and benefits of the use of

any pesticide.” The burden of proof regarding safety is

on the manufacturer. If EPA finds that a pesticide meets

or exceeds any of its specified criteria for risk (40 CFR

154.7), it must initiate a special review process. This

process allows EPA to require additional toxicity testing

including immunotoxicity, if warranted.

A pesticide may be registered for general or restricted

use, and EPA may conditionally register pesticides even

if some test data are unavailable. EPA has concentrated

its attention to date on the active ingredients in pesticides,

but expresses increasing concern about inert ingredients.

EPA has issued no restrictions on pesticide use based solely

on immunotoxicity. The 1988 amendments to FIFRA

require EPA to review 600 active ingredients of existing

pesticides by 1997, which requires reexamination of safety,

including toxicity. The test guidelines for reregistration are

the same as for registration.

In 1982, EPA’s Office of Pesticide Programs (OPP),

which administers FIFRA, published data requirements for

the toxicological evaluation of biochemical pesticides

and for microbial pesticides. Biochemical pesticides include pheromones, hormones, natural insect and plant

growth regulators, and enzymes. Microbial pesticides include bacteria, fungi, protozoa, and viruses. OPP recently

revised the requirements to reflect advances in toxicology

(23). The immunotoxicity study now required for

biochemical pesticides is designed to accommodate

either the rat or the mouse as the test animal. The tiered

testing scheme as revised is presented in table 4-6. The study

is required for biochemical pesticides where uses result in

significant human exposure (e.g., food uses, indoor

aerosols). Tier I tests serve as a screen for immunotoxic

potential, and Tier II tests are designed to provide information necessary to perform risk assessment. Tests to

determine whether biochemical pesticides can induce a

delayed-type hypersensitivity reaction in guinea pigs are

required and are set forth as a separate study in the data

requirements (40 CFR 158.690).

The revisions of the data requirements deleted the

requirement for specific immunotoxicity testing of

microbial pesticides, but the ability of the test animals to

clear the active microbial ingredient after dosing via oral,

pulmonary, and intravenous routes is used as an indicator

of a properly functioning immune system. EPA reserves

the right to require an immunotoxicity study for certain

microbial pesticides, but this study would be reserved for

certain viruses that are related to viruses known to impact

adversely on the human immune system (23). The requirement for a hypersensitivity assessment of
Chapter 4--Federal Attention to Immunotoxicants . 59

Table 4-6-EPA Subdivision M Guidelines: Proposed

Revised Requirements for immunotoxicity Testing of

Biochemical Pest Control Agents

Tier /

A. Spleen, thymus, and bone marrow cellularity

B. humoral immunity-do one of the following:

1. Primary and secondary immunoglogulin (lgG and lgM)

responses to antigen

2. Antibody plaque forming cell assay

C. Specific cell-mediated immunity—do one of the following:

1. One-way mixed Iymphocyte reaction (MLR) assay

2. Effect of BPCA on normal delayed-type hypersensitivity

3. Effect of BPCA on generation of cytotoxic T-lymphocyte

D. Nonspecific cell-mediated immunity:

1. Natural killer cell activity

2. Microphage function

Tier II

A. Tier II studies required if:

1. Dysfunction is observed in Tier I tests

2. Tier I test results cannot be definitively interpreted

3. Data from other sources indicate immunotoxicity

B, General testing features:

1. Evaluate time-course for recovery from immunotoxic

effects

2. Determine whether observed effects may impair host

resistance to infectious agents or to tumor cell challenge

3. Perform additional specific, but appropriate, testing

essential for evaluation of potential risks

SOURCE: Office of Technology Assessment, 1991.

microbial pesticides also has been dropped, with reporting of any observations of allergic reactions being required instead. This is because it is expected that

proteinaceous components of microbial pesticide

preparations (including fermentation byproduct ingredients) would elicit a positive response in test guinea

pigs after subcutaneous induction and challenge; and

would most likely not give a positive response with topical

induction and challenge.

OPP plans to revise its testing guidelines for chemical

pesticides to include immunotoxicity testing Laboratory

studies presently required for registration of chemical

pesticides include a battery of acute toxicity studies (oral,

dermal, pulmonary, eye), subchronic studies, chronic

studies, developmental toxicity studies, reproduction effects study, battery of mutagenicity studies, chronic carcinogenicity study, and metabolism study (23).

The Toxic Substances Control Act

TSCA authorizes EPA to regulate chemicals (specifically excluding pesticides; tobacco and tobacco

products; nuclear materials; foods, drugs, and cosmetics;

pistols, firearms, revolvers, shells, and cartridges, which are

regulated under other statutes) before and after they

reach the market. EPA’s first task under TSCA was to

compile an inventory of all existing chemical substances

that would be subject to the provisions of TSCA that were

manufactured or imported into the United States in 1977.

Any chemical not on that initial list is a “new” chemical

and subject to premanufacture notice (PMN) requirements.

TSCA requires manufacturers to notify EPA in advance of the intended introduction into commerce of a

new chemical with a Premanufacture Notice (PMN).

EPA must also be notified if a chemical is to be used in

away that differs significantly from that proposed in the

original PMN. The PMN contains data on a chemical’s

identity and structure, proposed use, manufacturing

byproducts, and impurities.

TSCA does not require that manufacturers carry out

a specific program of toxicity testing before approval of

a new chemical, thus PMNs are rarely submitted with

toxicity data for each organ system. The extent of toxicity

data submitted with PMNs generally depends on the

projected annual production volume for the compound.

If insufficient or incomplete toxicity data are provided to

support a PMN, EPA requests additional information or

issues a consent order in which the manufacturer agrees

to provide the required information according to an

established timetable.

EPA toxicologists evaluate PMNs by comparing new

chemicals to structurally related existing chemicals. If

toxicity is predicted on the basis of structural analogues,

a chemical maybe subjected to a more detailed examination. If during the detailed review EPA concludes that a

new chemical may present an unreasonable risk of adverse effects on human health or the environment, additional toxicity data can be required. Immunotoxicity has not

been used as the basis for any regulatory action taken by

EPA under the PMN provisions of TSCA.

TSCA also directs EPA to regulate existing chemical

substances that pose an unreasonable risk of injury to

human health or the environment and to act promptly on

substances that pose imminent hazards. An Interagency

Testing Committee reviews substances on the existing

chemicals list and can recommend that EPA require
60 ● Identifying and Controlling Immunotoxic Substances

testing for these substances. In determining whether a

chemical presents or may present an unreasonable risk

to human health or the environment, EPA considers:

●

●

●

●

the effects of a substance or mixture on human

health and the magnitude of the exposure of

human beings to it;

the effects of a substance or mixture on the

environment and the magnitude of the exposure of the environment to such substance or

mixture;

the benefits of such substance or mixture for

various uses and the availability of substitutes

for such uses; and

the reasonably ascertainable economic consequences of the rules, after consideration of the

effect on the national economy, small business,

technological innovation, the environment, and

public health.

If EPA can show that there is inadequate information

on the effects of a chemical and that testing is necessary

to obtain that information, it may issue a test rule defining

the substances to be tested and how they should be

tested. EPA has developed general guidelines for toxicity

testing (40 CFR 796), but each test rule contains requirements specific to the chemical under scrutiny. Chemical

manufacturers and processors are responsible for

developing these test data, but EPA bears the burden of

proof in establishing that a substance is an unreasonable

risk to human health or the environment.

For either new or existing chemicals, EPA regulatory

efforts may include steps to: prohibit their manufacture,

processing, or distribution in commerce; limit their uses

or amounts; require certain labeling; require maintenance of records and monitoring; prohibit or regulate

any manner or method of commercial use; prohibit or

regulate their disposal. Manufacturers or processors are

required to notify EPA of any unreasonable risks posed

by new or existing chemicals. immunotoxicity has been a

noted concern in evaluations of chemicals under TSCA,

but has not served as the health effect of primary concern

in any regulatory action.

The Resource Conservation and Recovery Act

RCRA defines solid and hazardous wastes, authorizes

EPA to set standards for facilities that generate or

manage hazardous waste, and mandates a permit program for hazardous waste treatment, storage, and disposal facilities. Hazardous waste is defined as any solid

waste that may cause death or serious disease, or may

present a substantial hazard to human health or the

environment if it is improperly treated, stored, transported, or disposed of. Lists of wastes subject to RCRA

regulation can be found at 40 CFR 261.31, .32, and .33.

The list contains known immunotoxicants, but immunotoxicity has not been the basis for any chemical’s

appearance on this list.

The Comprehensive Environmental Response,

Compensation, and Liability Act

CERCLA (sometimes referred to as Superfund) requires anyone who releases significant amounts of hazardous substances into the environment to notify EPA.

CERCLA defines hazardous substances as substances

identified as toxic by the CWA, RCRA, CAA, or TSCA,

and any substance which “when released into the environment may present substantial danger to the public

health or welfare or the environment.” CERCLA also

requires that hazardous waste sites be cleaned up to a

standard that ensures the protection of human health

and environment. Reportable quantities (RQ) were set

for each hazardous substance on the basis of aquatic

toxicity, mammalian toxicity, ignitability, reactivity,

chronic toxicity, and potential carcinogenicity. Immunotoxicity has been a consideration but not a primary

factor in setting RQ standards.

Other Federal Regulatory Activity

EPA, FDA, and OSHA exercise the main regulatory

authority over toxic substances, including immunotoxicants.

Other agencies also administer laws that could be used

to control these substances, however. The Consumer

Product Safety Commission (CPSC), for instance, enforces the Consumer Product Safety Act (CPSA) (15

U.S.C. 2051 et seq.) and the Federal Hazardous Substances Act (FHSA) (15 U.S.C. 1261 et seq.).

The CPSA authorizes regulation of consumer

products (except for foods, drugs, and cosmetics; pesticides; tobacco and tobacco products; motor vehicles;

aircraft and aircraft equipment; and boats and boat accessories) that pose an “unreasonable risk” of injury or

illness. CPSC may set safety standards that specify requirements for product performance or design, requirements for consumer instructions or warnings, or both. A
Chapter 4--Federal Attention to Immunotoxicants ● 61

product c-an be banned if adequate safety standards are

not feasible. No products have been regulated under

CPSA on the basis of immunotoxicity.

The FHSA covers hazardous substances (excluding

pesticides, foods, drugs, cosmetics, certain radioactive

materials, and tobacco and tobacco products) in general

use in the home, and is meant particularly to protect

children from hazardous toys and products. A hazardous

substance is a substance or mixture that may cause substantial personal injury or substantial illness as a

proximate result of any customary or reasonably foreseeable handling or use, including reasonably foreseeable

ingestion by children. A product can be required to bear

a hazard label or it can be banned if labeling is inadequate to protect health. No products have been regulated

under FHSA on the basis of immunotoxicity.

The Mine Safety and Health Administration (MSHA)

regulates the exposure of miners to toxic substances

under the Federal Mine Safety and Health Act Amendments of 1977 (30 U.S.C. 801 et seq.). Much of MSHA’s

regulation of toxic exposures involves incorporating by

reference the lists of ACGIH. Some observers question

use of the standards set by ACGIH since they historically

have been set without reference to adequate research

(36). On the other hand, as demonstrated by the very few

standards that have been enacted by OSHA, hardly any

workplace chemical exposures would be regulated if the

ACGIH standards were not adopted by MSHA and

OSHA (28).

FEDERAL INFORMATION PROGRAMS

Some Federal programs incorporate the assumption

that an informed public is one means to decrease toxic

exposures. Worker Right-to-Know programs, established by OSHA’s hazard communication standard, and

Community Right-to-Know programs, established by the

Emergency Planning and Community Right-to-Know

Act of 1986 (EPCRA), require that workers and other

citizens be provided with knowledge about the toxic

substances in their work or local environment. The

Federal Government funds a national database at the

National Library of Medicine that helps distribute information collected under EPCRA nationwide. Federal law

also established the Agency for Toxic Substances and

Disease Registry (ATSDR), which maintains a nationally available list of toxic substances and their health effects. The following section briefly describes each of

these programs.

Worker Right-to-Know

In 1983, OSHA first established its hazard communication standard (29 CFR 1910.1200). This standard

requires each employer to have a written hazard communication program for each workplace, including a list

of all hazardous chemicals in the workplace. The

employer is permitted to rely substantially on manufacturers and importers of chemicals to prepare the necessary information.

There are four basic elements of a hazard communication program. First, each manufacturer or importer of a

chemical must determine whether that chemical is hazardous. A health hazard is defined as a chemical for which

there is “statistically significant evidence based on at least

one study conducted in accordance with scientific principles that acute or chronic health effects may occur.”

Second, each manufacturer or importer must prepare a

material safety data sheet (MSDS) containing comprehensive information on the chemical, including all its

hazards, precautions for safe handling and use, and control measures. These MSDS must be available to

employees and customers. Third, employers must label

containers to alert workers to the identity and significant

hazards of the chemical. Finally, each employer must

provide its workers with education and training in the

handling of hazardous chemicals (13,20).

The standard requires disclosure of immunotoxic effects, where known. The standard does not permit OSHA to

compel testing to determine unknown health effects,

however. It should be noted that many MSDS contain

very limited information on known toxic hazards (32),

and those hazards that are described may be expressed

in terminology unintelligible to the lay public (10).

Community Right-to-Know

Congress enacted EPCRA (42 U.S.C. 110001-11050)

in response to releases of chemicals at Bhopal, India.

EPCRA requires EPA to establish and maintain a list of

“extremely hazardous substances.” The current list includes 420 substances set out in 40 CFR Part 355 Appen-
62 ● Identifyingand Controlling Immunotoxic Substances

dix A. EPA has developed a threshold planning quantity

(TPQ) for each substance on the list.

This law requires owners and operators of facilities

that store, use, or release extremely hazardous substances in amounts in excess of the TPQ to report to EPA

information about those chemicals, their amounts, and

their locations. EPCRA requires facility owners and

operators to report releases of these chemicals into the

environment whether from accidental spills or normal

operations. The statute does not limit use or release of a

substance; it merely requires that the public be informed

(9).

Local community organizations must be notified of

any offsite spills or any releases of a “reportable quantity"

(RQ) of an extremely hazardous substance or a hazardous substance as defined in CERCLA. The RQ’s for

extremely hazardous substances are set out in 40 CFR

Part 355, Appendix A. The list of hazardous substances

and their RQ’s under CERCLA are set out at 40 CFR

302.4. This emergency notification must include the

chemical’s common name, the lists on which it appears,

the quantity released, the time and duration of the

release, the media into which the release occurred, any

acute or chronic health risks presented by the release,

precautions to be taken, and the persons to contact for

further information (l).

EPCRA community right-to-know provisions also require the public availability of material safety data sheets

similar to those prepared under OSHA’s hazard communication standard. The MSDS must contain the

chemical and common names of the chemical, the

chemical’s physical and chemical characteristics, its

physical and health hazards, its routes of exposure,

precautions and emergency response procedures, exposure limits, and possible carcinogenic effects. If immunotoxic effects are among the known health hazards,

they must be listed (35). Some research indicates that the

MSDS, which were developed to convey information

about workplace exposures, are unsuited to a community

information program and that better means to communicate information about risk to the general public are

needed (10).

National Library of Medicine: Toxicology

Information Program

The National Library of Medicine (NLM) is the

Nation’s principal resource for the collection, organization, and retrieval of scientific literature in the health and

biomedical fields (25). It has provided data about toxic

chemicals and their hazards to the public for over 20

years. To enhance the accessibility of this information,

NLM established the Toxicology Data Network (TOXNET). This database contains several files, including the

Toxic Chemicals Release Inventory (TRI), which contains data on the estimated releases of toxic chemicals to

the air, water, or land, as well as amounts transferred to

waste sites. Current law requires U.S. industrial facilities

to report the TRI information to EPA, which in turn

provides it to NLM for public access. Searches of this file

can be performed by region, company, chemical, but the

file does not contain information on the health effects of,

or human exposure to, these chemicals.

Another TOXNET file, the Hazardous Substances

Data Bank (HSDB), covers chemical toxicity, as well as

emergency handling procedures, environmental fate,

human exposure, detection methods, and regulatory requirements. This file contains information on 4,200

chemicals. Most of the data in this file is taken from

peer-reviewed journals. TOXNET also includes the

Registry of Toxic Effects of Chemical Substances

(RTECS), which covers 100,000 chemicals, and contains

information on their acute and chronic effects, carcinogenicity, mutagenicity, and reproductive consequences. This file is not peer reviewed.

NLM also maintains the TOXLINE group of

databases, outside TOXNET, which contains references

to journal articles dealing with hazardous chemicals and

other areas of toxicology and environmental health. At

present, interested parties must contact a health science

library or information center to request a TOXLINE
Chapter 4-Federal Attention to Immunotoxicants ● 63

search. In the future, more public libraries may tie in to

NLM. Individuals can request an application form to use

NLM’s system on a personal computer (33,18).

The Agency for Toxic Substances and

Disease Registry

Congress created ATSDR in 1980, and its mission is

to prevent or mitigate adverse human health effects and

diminished quality of life resulting from exposure to

hazardous substances in the environment. As part of its

mission, ATSDR prepares toxicological profiles for hazardous substances which are most commonly found at

facilities on the CERCLA National Priorities List and

which pose the most significant potential threat to human

health.

Each toxicological profile must include:

●

●

●

an examination, summary, and interpretation

of available toxicological information and

epidemiological evaluations on the hazardous

substance;

a determination of whether adequate information on the health effects of each substance is

available or in the process of development; and

an identification of toxicological testing

needed to identify the types orlevel

s of exposure that may present significant risk of adverse health effects in humans.

ATSDR also has a Division of Health Education

which coordinates health communication and education

activities for the Agency; coordinates development and

educational activities for emergency response personnel;

develops and disseminates to physicians and the health

care providers materials on the health effects of toxic

substances; establishes and maintains a list of areas

closed or restricted to the public because of contamination with toxic substances; and initiates research. In addition, ATSDR has regional staff, located throughout the

United States, who offer consultation on environmental

health issues, including emergency response.

SUMMARY AND CONCLUSIONS

The Federal Government is actively involved in advancing the state-of-the-art of immunotoxicology. EPA,

FDA, and NIH have immunotoxicological research

programs, and each of these agencies contributes to the

work of the NTP. Much of the ongoing Federal research

is directed toward developing and validating tests for

evaluating substances for immunotoxic potential. NTP

has published a panel of tests for immunotoxicity testing

that has been validated in the mouse. NTP continues to

work on validating immunotoxicity tests in other species

and on improving its current panel of tests. NTP is also

applying the tests to various substances. EPA is working

on developing and validating immunotoxicity tests using

the rat as the test species, and has published immunotoxicity testing guidelines for certain pesticides.

Immunotoxicity is a major concern of FDA researchers

when evaluating new products for human and animal

consumption.

Few substances have been regulated by the Federal

Government on the basis of immunotoxicity. OSHA has

issued regulations for eight substances on the basis of

their ability to provoke hypersensitivity. FDA has

restricted the use of Yellow Dye No. 5 and sulfites in

foods because of their association with hypersensitivity.

These agencies and EPA regulate other substances that

have shown evidence of immunotoxicity in a few animal

tests, but other health effects serve as the basis for those

regulations.

Several Federal activities are designed to enhance

public awareness of the hazards of toxic substances,

including immunotoxicants. OSHA’s hazard communication standard requires that workers be provided

with information about known health hazards in their

jobs. However, since so little information is available

regarding immunotoxic effects, and since the standard

cannot be used to compel testing, the standard does little

at present to protect workers from immunotoxic hazards.

Community right-to-know legislation requires EPA to

collect information about substances that pose potential

toxic hazards to local communities and make that information available to the public. As with the OSHA standard, however, this program does not permit EPA to

require that health effects information be developed,

therefore available information on immunotoxicity is

very limited. ATSDR is disseminating information about

health risks, including immunotoxicity, to the public.

CHAPTER 4 REFERENCES

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Canrnunitk Emergency Response, Community Rightto-Know, and Prevention of Chemical Accidents,”

Hm-vardEnvironmentalL awReview 14:135-188, 1990.

2. Bass, B.F., Muir, W. R., and Rose, N.R., “Irnmunotoxieology Strategy— Review of Major Scientific

Conferences, Federal Activities and Federal Policies
64 ● Identifyingand Controlling Immunotoxic Substances

3.

4.

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Washington, DC, personal communieatio~ October 1990.

Cavagnaro,J.A., Center for BiologiesEvaluation and

Research Food and Drug Adrninistratio~ Rockville, MD, personal communicatio~ May 1990.

Cavagnaro,JA., Center for BiologiesEvaluation and

Research Food and Drug Administratio~ Rockville, MD, personal ammmnieatio~ July 1990.

Condon, T.P., Alcoho~ Drug Abuse, and Mental

HealthAdminis@atioq Washingto~ ~personalcommunication, May 1990.

Domans~ JJ., Lehn & Fink Products Technical

Center, MontVale, NJ, personal communication, July

1990.

Dowdle, W.R., Centers for Disease Contro~Atkmt~

GA, personal communication, February 1990.

Finto, KJ., “Regulation by Information Through

Epm” N~id h~~ and EntiOnmenl 4(3):13-

48, Winter 1990.

Hadden, S. G., “Providing Citizens With Information

About Health Effects of Hazardous Chemi~’’Joumal

of &cupationdMdiche 31(6):528-535, June 1989.

Hinton, D.M., Center for Food Safety and Applied

Nutritio~FoodandDrugAdministratio~ Washingto~

DC, personal communication, August 1990.

Luster, M.I., National Institute of Environmental

Health Sciences Research Triangle Park NC, personal cmmnunicatio~ July 1990.

Mar% Dv “OSHA’S Expanding Hazard cOITUIWl&

tion Requirement~’’NaturalResources and Environment 4(3):19-50, Winter 1990.

Mielac~ F.A., Center for Drug Evaluation and Research, Food and Drug Administratio~ Washingto~

DC, personal communication, September 1990.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

Millburq G.P., Office of Defense Research and Engineering Department of Defense, Washingto~ DC,

personal communication, March 1990.

Moskow@JqNationalInstitutes ofHeal@ Washingto~

DC, personal communication, March 1990.

National Toxicology Program Annual Plan for Fiscal

Year 1989, NTP-89-167, June 1989.

OMB Watch “TRI Gains in Use and Popularity;

lhe OMB Watcher 8(1):10-11, 1990.

Phelps, B., National Toxicology Program, Research

Triangle Par~NC, personal communicatio~ August

1990.

Piecio@ R., “Indust@s Response to OSHA’S Hazardous Communication Standard: Is the LawWorking as Intended?” Chemical Times and Trends, pp.

31-36, April 1990.

Plowma~ R. D., Agricultural Research Serviee, U.S.

Department of Agriculture, Washingto~ DC, personal communicatio~ February 1990.

Selgrade, M., Health Effects Research Laboratory,

Environmental Protection Agency, Research Triangle Park NC, personal communicatio~ July 1990.

Sjobla~ R.D., Office of Pesticides and Toxic Substan~Environmental ProtectionAgeney, Washingto~

DC, personal cmmm.micatio~ July 1990.

U.S. Congress, Office of Technology Assessment,

Assessment of Technologies for Determining Cancer

Risks From the Environment, OTA-H-138

(Washingto~DC: U.S. Government Printing Office,

June 1981).

U.S. Congress, Office of Technology Assessment,

MEDLARS and Health Information Po!iqy, OTATM-H-11 (Washington, DC: Government Printing

Office, September 1982).

U.S. Congress, Office of Technology Assessment,

Acid Rain and TrampotiedAirPollutants: Inlplications

fmPubh2Policy OTA-O-204 (Washingto~ DC: U.S.

Government Printing Office, June 1984).
Chapter 4—Federal Attention to Immunotoxicants . 65

27.

28.

29.

30.

31.

U.S. Congress Offke of Technolog Assessment,

%tectigtiNtils Groundw@rFm Con@rukati@ OTA-O-233 (Washingto~ DC: U.S. Government Printing Office, October 1984).

U.S. Congress Offke of Technology Assessment,

PreventingIlihm andInjuyh the Wix@~ OTA-H256 (Washingto~ DC: U.S. Government Printing

Offi~ April 1985).

U.S. Congress, Oflke of Technology Assessment

Superjimd Strate~, OTA-ITE-252 (Washington,

DC: U.S. Government Printing Office, April 1985).

U.S. Congress, Offke of Technology Assessment,

Identi~gandRegulating Carcinogens, OTA-BP-H42 (Washington, DC: U.S. Government Printing Office, November 1987).

U.S. Congress, Office of Technology Assessment,

Catching Our Breath: Next Steps for Reducing Urban

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33.

34.

35.

36.

Ozone, OTA-O-412 (Washington, DC: U.S. Government Printing Offke, July 1989).

U.S. congress Offke of Technology Assessment,

Neurotoxicity: Identifying and Controlling Poisons of

the Nervous Systerq OTA-BA-436 (Washingto~DC:

U.S. Government Printing Office, April 1990).

Wexler, P., “Finding and Using Toxics Information;’

J7?mle Earth Review, pp. 120-121, Spring 1990.

White, KL., Jr., Medical College of Virgini~ Richmon~ VA personal communicatio~ July 1990.

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US” The Whgton Lawyr 4:(4):24-57, March/April

1990.

Zie~ G. Baltimore, MD, personal communicatio~

July 1990.
Appendices
Appendix A

Income Replacement for Individuals Disabled

by Immunotoxicants

INTRODUCTION

Even the best efforts to prevent harmful exposures to

toxic substances are imperfect. When regulations or

other precautions fail to prevent toxic exposure, permanently or temporarily disabling illnesses sometimes

result. Federal and State level programs have evolved to

provide a continuing source of income for disabled individuals. This appendix presents a brief overview of

Social Security, State workers’ compensation programs,

and toxic tort. The initiatives described in this appendix

were not specifically designed to compensate individuals for

exposure to toxic substances, but they are available, within

certain limits, to immunotoxicant exposure victims.

SOCIAL SECURITY BENEFITS

If an illness or injury interferes with a person’s ability

to work and lasts, or is expected to last, for more than a

12-month period, it can give rise to full Social Security

benefits, either disability benefits (SSDI; 42 U.S.C. 423)

or Supplemental Security Income (SSI; 42 U.S.C. 1381-

1383a). To secure these benefits, a claimant must prove

inability to work. It is not necessary for a Social Security

claimant to prove that illness or injury occurred because

of a work-related incident.

SSDI benefits are available to persons who would

otherwise be qualified for Social Security benefits had

they paid into the system for the requisite number of

quarters (as established by 20 CFR 404.130). The SSI

program guarantees a minimum level of cash income to

needy aged, blind, and disabled persons who may not

otherwise be eligible for Social Security.

A Social Security claimant files an application with the

Social Security Administration (SSA), which then turns

it over to the State administering agency. The State assesses the claim and medical evidence presented against a

standard set by law, which defines disability as the inability to do any substantial gainful activity by reason of

any medically determinable physical or mental impairment which can be expected to result in death or which

has lasted or can be expected to last for a continuous

period of not less than 12 months (4).

For purposes of SSDI and SSI benefits, a medically

determinable diagnosis of an immune-system injury– including an injury or illness caused by an immunotoxicant – would be compensable. A diagnosis should

be supported by a medical history, clinical findings,

laboratory findings, and information regarding treatment and prognosis. Well known immune system disorders, such as a severe allergy, asthma, or autoimmune

disease (e.g., rheumatoid arthritis) could be medically

determinable to result in a disability.

More problematic for Social Security claimants and

the SSA is the issue of environmental illness. In its Program Operations Manual System (POMS), SSA now recognizes the claim of some medical practitioners that

exposure to toxic substances can damage the immune

system, and the SSA identifies this claim as environmental illness (POMS 24515.065, Evaluation of Specific Issues-Environmental Illness). In the POMS, the SSA

states that while there is no evidence that claimants with

this type of claim have immune deficiency, immune complex disease, autoimmunity, or abnormal functioning of

their immune systems, evaluation should be made on an

individual case-by-case basis to determine if the impairment, whether or not immune system related, prevents

substantial gainful activity. Some legal and medical practitioners claim that this standard should increase

claimants’ success in obtaining Federal benefits after exposure to immunotoxic substances.

WORKERS’ COMPENSATION

Workers’ compensation laws vary among the States,

but all laws share the requirement that the injury or

illness occur on the job and that the claimant be temporarily or permanently disabled as a result. This section

briefly describes worker’s compensation programs and

concludes with a short summary of some workers’ com69
70 ● Identifying and Controlling Immunotoxic Substances

pensation claims based on damage to the immune system, and a synopsis of recent congressional interest in

workers’ compensation.

Basic Workers’ Compensation Law

State workers’ compensation programs represent a

compromise reached 80 years ago between labor and

business, before many of the chemicals in common use

today were developed or their hazards understood.

Under the common law, the basic duty of employers was

to act with due care for employee safety, as a reasonably

prudent person would, and to furnish a sufficient number

of safe tools and equipment, as well as a sufficient number

of qualified employees to do the work. Employers were

responsible for issuing and enforcing rules for workplace

safety, rules that with ordinary care would prevent

reasonably foreseeable accidents. Finally, employers had a

duty to warn workers of unusual hazards.

In theory, if the employer failed to live up to this

standard of conduct, an injured employee could sue for

damages under the common law. This was seldom easy,

however. The first difficulty was simply proving the

employee’s case. Other employees might be crucial witnesses, but when few governmental or union job protections existed, anyone who testified against an employer

risked being fired. The common law also established three

powerful defenses that employers could use against lawsuits

brought by employees: negligence of other servants or

co-workers; knowledgeable assumption of risk by the

employee; and cent.tlmtory negligence by the injured

employee. Just prior to enactment of the workers’ compensation statutes, however, some States began to ease

the claimant’s burden of proving employer negligence,

and a few workers began to win sizable judgments (16).

Workers’ compensation substituted a regular, fixed,

and predictable compensation payment, previously unavailable to most workers, for uncertain, potentially

ruinous liability judgments, which were becoming uncomfortably frequent for employers. The first State law

to withstand challenge passed in the State of Wisconsin

in 1911; all States had worker compensation laws by 1948.

Initially workers’ compensation laws only covered accidental injury and excluded occupational disease. However, all States covered occupational disease by 1%7.

Three basic approaches to occupational disease coverage

have been adopted. States generally elect either to:

● establish a schedule of covered diseases (which

minimizes problems of proof but excludes unlisted diseases);

● establish a schedule and a residual clause that

allows claims for unlisted disease to be made,

with the burden of proof on the claimant; or

● cover diseases “peculiar to” or “characteristic

of” relevant trades.

Most States exclude coverage of the ordinary diseases

of life (even where risk of ordinary disease maybe notably increased by an occupation) and require that a

worker face a hazard greater than that to which the

general public is exposed.

Disease claims that are readily connected to workplace

exposure and are relatively inexpensive (e.g., acute dermatoses) are compensated like accidental injuries. Disease claims involving serious disabilities that are less

clearly linked to workplace exposures (e.g., chronic

respiratory disease) are marked by extended controversy

and long waiting periods between the time a claim is filed

and a decision on that claim. For these claims, the system

retains many of the undesirable features of the tort system that workers’ compensation was supposed to supplant.

Some observers believe that workers’ compensation

systems have failed to keep pace with knowledge of the

hazards of chemical agents (9,11). According to OSHA,

occupational diseases from chemical exposures represent a continuing complex problem for workers’ compensation programs. Disabilities resulting from occupationally

induced illness often are less clearly defined than those from

occupationally induced injury. As a result, OSHA finds

that workers’ compensation is often a weak remedy in the

case of occupational disease (52 FR 26843). This finding

is used as partial justification for OSHA’s decisions to

regulate certain chemical exposures rather than rely on
Appendix A-Income Replacement for Disabled Individuals . 71

market-based incentives or other Federal programs to

ensure worker health and safety.

Table A-l-State Workers’ Compensation Disability

Benefits, 1989

Disease claimants face extended conflict over the issue of

causality, in part due to meager scientific evidence to show

a relationship between exposure and disease. The fact

that many years often intervene between exposure and

disease also plays a role (19). In addition, proof of

causality may be ambiguous where cases are aggravated

by lifestyle choices (e.g., smoking) or other nonworkplace exposures to hazardous substances. Some

States have opted for a statutory presumption that a

claimant’s disease is work-related, but that is not the

prevalent approach. One study found that 60 percent of

occupational disease claims are contested, and 15 percent of challenged claims result in an award for the

worker (9).

Occupational disease now accounts for about 1 percent of all workers’ compensation claims. The insurance

industry expects the number of occupational disease

claims to rise significantly during the 1990s if medical

research more clearly shows a link between illness and

workplace exposure to harmful substances (18). Thus the

results of future research on immunotoxicity could greatly affect the number and success of workers’ compensation claims based on exposure to immunotoxicants.

Even if a claimant establishes a right to workers’ compensation, the amount collected may not be perceived as

adequate recompense for the illness. In a majority of

States, the maximum amount paid a temporarily disabled

worker is at least 100 percent of the State’s average wage,

but 22 States pay less than that. Table A-1 shows the

maximum weekly benefits paid by each State and the

percentage of the State’s average wage this amount represents. These temporary disability benefits are paid in

addition to medical expenses, but obviously represent a

substantial decline in income for many workers (18). While

this problem is not peculiar to claims based on exposure

to toxic substances, it may serve to discourage claims that

have less than a certainty of success, like toxicant-caused

illnesses, since the rewards for the claimant and a legal

representative are relatively low.

immunotoxicity Claims

The legal literature includes some published eases of

workers’ compensation awards to individuals claiming an

immune system disorder following exposure to a toxic

substance. In Grayson v. Gulf Oil Company, 357 S.E. 2d

The first column shows the maximum weekly benefit paid to

workers whose disability is total but temporary. The second

column shows that payment as a percentage of the State’s

average weekly wage.

Maximum Maximum benefit as

weekly percentage of State’s

benefit average weekly wage

Alabama . . . . . . . . . . . . . . .

Alaska. . . . . . . . . . . . . . . . .

Arizona . . . . . . . . . . . . . . . .

Arkansas . . . . . . . . . . . . . .

California . . . . . . . . . . . . . .

Colorado . . . . . . . . . . . . . . .

Connecticut . . . . . . . . . . . .

Delaware . . . . . . . . . . . . . .

District of Columbia. . . . . .

Florida . . . . . . . . . . . . . . . .

Georgia . . . . . . . . . . . . . . . .

Hawaii . . . . . . . . . . . . . . . . .

Idaho . . . . . . . . . . . . . . . . . .

Illinois. . . . . . . . . . . . . . . . .

Indiana . . . . . . . . . . . . . . . .

Iowa . . . . . . . . . . . . . . . . . .

Kansas . . . . . . . . . . . . . . . .

Kentucky . . . . . . . . . . . . . .

Louisiana . . . . . . . . . . . . . .

Maine . . . . . . . . . . . . . . . . .

Maryland .., , . . . . . . . . . .

Massachusetts . . . . . . . . .

Michigan . . . . . . . . . . . . . . .

Minnesota . . . . . . . . . . . . .

Mississippi . . . . . . . . . . . . .

Missouri . . . . . . . . . . . . . . .

Montana . . . . . . . . . . . . . . .

Nebraska . . . . . . . . . . . . . .

Nevada . . . . . . . . . . . . . . . .

New Hampshire. . . . . . . . .

New Jersey . . . . . . . . . . . .

New Mexico . . . . . . . . . . . .

New York . . . . . . . . . . . . . .

North Carolina. . . . . . . . . .

North Dakota. . . . . . . . . . .

Ohio . . . . . . . . . . . . . . . . . .

Oklahoma . . . . . . . . . . . . . .

Oregon . . . . . . . . . . . . . . . .

Pennsylvania . . . . . . . . . . .

Rhode Island . . . . . , . . . . .

South Carolina. . . . . . . . . .

South Dakota. . . . . . . . . . .

Tennessee . . . . . . . . . . . . .

Texas . . . . . . . . . . . . . . . . .

Utah . . . . . . . . . . . . . . . . . .

Vermont . . . . . . . . . . . . . . .

Virginia . . . . . . . . . . . . . . . .

Washington . . . . . . . . . . . .

West Virginia . . . . . . . . . . .

Wisconsin . . . . . . . . . . . . . .

Wyoming . . . . . . . . . . . . . .

357.98

700.00

276.15

209.08

224.00

371.28

671.00

280.64

513.00

362.00

175.00

358.00

193.80

604.73

274.00

684.00

271.00

343.02

267.00

471.83

407.00

444.21

409.00

391.00

206.60

289.75

318.00

245.00

368.82

600.00

342.00

283.70

300.00

376.00

313.00

400.00

231.00

388.99

399.00

360.00

334.87

289.00

252.00

238.00

347.00

544.00

393.00

389.32

367.89

363.00

354.00

104

130

74

67

51

94

144

71

102

102

47

101

60

142

73

207

77

100

75

143

102

103

92

100

68

78

103

78

99

162

75

85

63

110

102

102

66

108

103

100

102

103

72

61

101

161

105

102

103

100

99

SOURCE: U.S. Department of Labor, based on laws in effect on July 1,

1989.

479 (South Carolina Court of Appeals, 1987) total disability benefits were awarded under south Carolina’s workers’
72. Identifyingand Controlling Immunotoxic Substances

compensation statute on the basis of petrochemical hypersensitivity, which led, according to the claimant's physician,

to a cascade of dysfunction of the claimant's immune system..

The treating physician wrote that,"... the constant exposure

over 19 years to the petrochemicals in her workplace dysregulated [the claimant’s] immune system resulting in an allergic

or hypersensitivity cascade to her total environment, including all foods, chemicals, and her own microbiological

flora.’’ The court found that the plaintiff’s hypersensitivity was

created by her workplace and left her unable to function

properly in any environment.

A Florida appeals court also upheld a workers’ compensation award based on an immune injury. In Dayron

Corporation v. Morehead 509 So. 2d 930 (Florida 1987),

the claimant developed a permanent sensitivity to a

coolant used in his workplace. Although the claimant

showed no signs of illness when outside of the workplace,

the sensitivity was deemed a permanent disability for

purposes of entitlement to workers’ compensation.

Workers’ compensation benefits were also awarded in

Kyles v. Workers' Compensation Appeals Board (California Court of Appeals, 1st Appellate District, Division 4,

1st Civil No. A037375, Oct. 21, 1987), where long-term

PCB exposure was found to have led to chemical hypersensitivity.

These cases indicate that courts will entertain a claim

for workers’ compensation based on an immune injury if

the claimant establishes a work-related cause. Some

States, most notably California, are considering an insurance system that would compensate employees

regardless of the work-relatedness of their illness or

injury, but such plans remain in a very preliminary stage

at this time.

The cases also indicate, however, that such claims

often proceed to court after they fail to be settled at the

administrative level. This increases the costs of the system and delays workers’ receipt of benefits. If the inability to work extends for a prolonged period, workers

can quickly become impoverished. Most State workers’

compensation statutes also foreclose a worker’s ability to

bring a tort case against the employer unless the worker

can reasonably claim that the employer intentionally

caused the injury or illness.

Congressional Interest in Workers’

Compensation

Congress has been concerned with the workers’ compensation system for many years. In 1970 Congress

created a National Commission on State Workmen’s

Compensation Laws, which concluded, in a 1972 report,

that State laws in general were “inadequate and inequitable.” The Commission urged Congress to impose national standards if the States did not act quickly on the

Commission’s key recommendations. On average, States

now comply with just over 12 (out of 19) of these recommendations (18). No Federal standards have been

enacted.

Hearings were held in 1979 on the National Workers’

Compensation Standards Act, which would have guaranteed minimum compensation levels nationwide and

created an advisory panel to look at causation issues.

Then Secretary of Labor Raymond Marshall, and several

other witnesses, testified to the peculiar problems of

compensating occupational disease, especially issues of

causation and long latency (24). Hearings were also held

in 1981 and 1983 on bills that would have created Federal

standards of compensation for work-related exposure to

toxic substances (21,22). None of those bills was enacted.

No bills introduced in the 101st Congress attempted to

reform the workers’ compensation system as it relates to

toxic exposures.

TORT CLAIMS

This section briefly describes how tort law provides

compensation for injuries due to exposure to toxic substances. It also summarizes a few cases based on evidence

of immune system damage, and briefly discusses recent

congressional activity related to tort law.

Basic Tort Law

Tort law is part of the common law system. Its purpose

is to compensate persons injured as the result of the

conduct of another. In order to receive compensation for

an injury through the tort system, a claimant, or plaintiff,

files suit alleging tortious (wrongful) conduct on the part

of the defendant. To prove a case, the plaintiff must show
Appendix A-Income Replacement for Disabled Individuals .73

that he or she has suffered damage, that the damage was

caused by the defendant, and that the defendant had no

sufficient justification or legal right to cause this damage

(13). If the plaintiff convinces the jury (or the judge in a

non-jury trial) that the defendant was more likely than

not the cause of the plaintiff’s damages, compensation is

awarded to the plaintiff.

Claims for damages based on exposure to hazardous

substances are called toxic torts. As part of the required

proof, the plaintiff must show that the defendant caused

him or her to be exposed to a toxic substance, that the

substance is capable of causing the type of damage suffered by the plaintiff, and that the particular exposure

caused by the defendant was, more likely than not, the

cause of plaintiff’s damage. Toxic tort cases are difficult

to prove in general, and present special difficulties when

immune-system impairment is claimed since immunotoxicology has only recently been developed, some

of its methods remain controversial, and agreement has

not been reached about what constitutes immune system

damage.

immunotoxicity Claims

Cases involving damage to the immune system began

appearing in the early 1980s and have increased in the

intervening years. Some attorneys now estimate that

hundreds, and perhaps thousands, of cases incorporating claims of immune system damage now stand in State

and Federal court systems. Since the immune system is

intimately connected with the body’s capacity to respond

to foreign substances, a large range of cases exist for

which a claim of immune damage maybe relevant.

Despite the difficulties of proving a case, several tort

suits have claimed damages from exposure to immunotoxicants. OTA found the following cases in published databases. These cases are not presented as an

exhaustive listing of immunotoxicity case law, but as

illustrative of the circumstances in which individuals can

be exposed, the damages alleged, and the compensation

recovered.

It should be noted that many of the plaintiffs in these

cases claim to have a disease or syndrome commonly

referred to as multiple chemical sensitivity (MCS). MCS is a

poorly understood and controversial phenomenon. Its

proponents claim that exposure to certain chemicals, even at

very low levels, can create immunological, neurological,

and other problems for its sufferers. Its opponents argue

that no scientific evidence supports such claims.

Proponents and opponents agree that additional research will be required to prove or disprove the existence

of MCS and its cause or causes. This background paper

does not attempt to weigh the merits of claims by MCS

proponents or opponents and presents these cases solely

because of their use of immune system evidence.

CASE: Woodrow Sterling et al. v. Velsicol Chemical

Corp., 647 Fed. Supp. 303 (W.D. Term. 1986); affirmed

in part, reversed in part, 855 F 2d 1188.

Claim: Plaintiffs (community residents) claimed that

immune system injury accounted for present disorders

(including pulmonary disease, respiratory problems,

seizures, and learning disabilities) and increased the

future risk of developing disease. Immune system injury

was claimed to have been caused by exposure to various

chemicals, including carbon tetrachloride and chloroform, in well water contaminated by Velsicol.

Evidence: Immunological tests consisted of a white

blood cell count, a lymphocyte count, a total T cell count,

a B cell count, a null cell count, and a breakdown of the

T cell count into T helper and T suppressor cell counts.

(See chapters 2 and 3 for descriptions of the immune system

and immunotoxicological tests.) Plaintiffs’ experts testified

that the data was consistent with a diagnosis of chemically induced immune dysregulation.

Outcome: The trial court awarded damages of $75,000

to four of the five plaintiffs for impairment of the immune

system and $500,000 to the fifth plaintiff, a child. The

appeals court reversed the district court’s award of

damages for immune system impairment, finding that the

plaintiffs’ experts’ opinions were insufficient to sustain

the burden of proof. The award for immune system

damage constituted only a portion of the total award

($5,273,492 in compensatory damages; $7,500,000 in punitive damages; interest on compensatory damages at 8 percent annually). The case has now been settled (5).

CASE: Elam v. Alcolac, 765 S.W. 2d 42,4 TXLR 167

(W.D. Mo. Ct. of Appeals)

Claim: The plaintiffs (community residents) claimed

that immune system injury was partially responsible for
74. Identifyingand Controlling Immunotoxic Substances

numerous adverse health conditions. Injuries were attributed to exposure to toxic waste originating in an

Alcolac chemical plant.

Evidence: Tests of immunological parameters included a mitogen challenge, total T cell counts, total T

helper and T suppressor cell counts, and natural killer

cell counts. The plaintiffs’ expert witness testified that

each of the 31 plaintiffs was suffering from immunosuppression.

Outcome: The jury awarded a $49 million verdict to

the plaintiff for claims including immunotoxicity. The

trial court judge set aside this verdict; an action affirmed

by the appeals emu-t (which found that the term “chemical

AIDS” used in association with the plaintiffs’ condition

was inflammatory). The case was then settled out of court

for an undisclosed amount (25).

CASE: Barth v. Firestone Tire and Rubber Co. ,673 F.

Supp. 1466 (N.D. Cal. 1987).

Claim: The plaintiff (a worker at the Firestone plant)

claimed that he suffered injury to his immune system and

onset of diseases in their latency stage as a result of

Firestone’s fraudulent concealment of hazardous substances at the workplace and lack of required safety

devices and protective clothing. He also claimed emotional distress. The plaintiff alleged exposure to benzene,

heavy metal compounds, and other industrial chemicals used

in the manufacturing of tires. Plaintiff sought creation of a

medical monitoring fund as remedy for the class.

Evidence: The case has not reached the trial stage and

no evidence has been presented.

Outcome: The Federal district court denied a motion

by defendant to dismiss the claim on grounds that there

was no legally cognizable the injury. The California Superior Court has ruled that the class is unascertainable

(17).

CASE: Moore v. Polish Power, Inc., 720 S.W. 2d 183

(Tex. Ct. App. 1986).

Claim: The plaintiff (who purchased a carpet from the

defendant) claimed neurological and muscular problems

as a result of exposure to formaldehyde off-gassing from

Polish Power’s carpet.

Evidence: The plaintiff’s expert witness testified that

the plaintiff suffered from damage to her immune system

from exposure to formaldehyde, which led to the

neurological and muscular problems.

Outcome: The trial court excluded evidence from the

medical expert witness relating to characteristics, formaldehyde content, formaldehyde emission rate, and

dangerousness of carpet and carpet pad based on his lack

of expertise on the chemistry of carpets. The court allowed the expert’s opinion that formaldehyde was cause

of carpet buyer’s physical problems. The jury brought in

a verdict for Polish Power. The Court of Appeals

reversed the trial court’s exclusion of the carpet

evidence, and the case was sent for a new trial on the

merits.

CASE: Higgens v. Aerojet-General Corp., 1986 Env’t

Rep. (BNA) 1183 /Nos. 287147, 290449, 290450 (Cal.

super. Ct. 1986).

Claim: The plaintiff alleged immune system damage,

among other injuries, resulting from defendant

company’s disposal of tricholoroethylene (TCE) and

other solvents in unlined ditches on his property.

Evidence: Plaintiff’s experts testified that the plaintiff

suffered from immune system damage, basing their finddings on a blood sample from the plaintiff. Defendant’s expert countered that since there was no base line

measurement, the blood tests were inconclusive. Two

immunologists testified for the defendant that the medical community had not accepted the immune dysfunction

theory as valid. The defendant’s experts also testified

that, according to the immune dysfunction theory, the

plaintiff was constantly being exposed to immunotoxic

substances and that it was impossible to say that a particular exposure was “more probable than not” to be the

cause of a given injury (12).
Appendix A-Income Replacement for Disabled Individuals .75

Outcome: Aerojet received a jury verdict in its favor.

The ease was not appealed, and the parties reached a

settlement (8).

CASE: Stites v. Sudstrand, 660 F. Supp. 1516 (W.D.

Mich. 1987).

Claim: Plaintiffs (community residents) claimed increased risk of cancer and emotional distress, partially

supported by evidence of immune system injury, due to

improper disposal of TCE, which was claimed to have

entered drinking water.

Evidence: The plaintiffs’ expert testified that the plaintiffs suffered damage to their immune systems and dysfunctions of a major enzyme system, and to his belief that

those two problems resulted in a “greatly increased susceptibility to a number of future illnesses, particularly

cancer." Defendants countered with an affidavit from 9

experts in immunology, stating that they could not show

to a reasonable certainty that the plaintiffs would develop

cancer.

Outcome: The court issued a summary judgment for

the defendants on the claim for increased risk of cancer,

finding that none of the plaintiff’s experts were able to

quantify enhanced cancer risk. The court also ruled,

however, that claims for damages for fear of cancer could

go to the jury. The case was eventually settled for an

undisclosed amount (6).

CASE: Lowe v. Norfolk& Western Railway Company,

463 N.E. 2d, 792.

Claim: Forty-seven plaintiffs (railroad employees) alleged various physical ailments, including immunological

damage, arising from exposure to dioxin contained in a

chemical, or thochlorophenol, which was spilled while

being transported by the defendant.

Evidence: The plaintiffs’ expert testified that tests

performed on blood samples to evaluate the body’s immune system indicated that each plaintiff showed some

abnormality of the immune system.

Outcome: The jury returned a verdict in favor of the

plaintiffs totaling $57,965,000. The appeals court

reversed the verdict on the basis of errors in trial procedure and remanded the case for anew trial. The case was

then settled for an undisclosed amount (15).

Congressional Interest in Toxic Tort

Congress has occasionally considered enacting legislation directed specifically to compensating victims of

non-work-related toxic exposures. The Toxic Tort Act of

1979 would have created an independent agency within

the EPA to compensate victims of pollution related injuries regardless of fault (in addition to creating a

Federal cause of action for victims of toxic substances)

(24). During the 98th Congress, legislation was considered in the House of Representatives that would have

provided compensation for injury, illness, or death

resulting from exposure to hazardous substances (23).

Some Members of Congress have argued that such legislation was an implicit promise of the Superfund legislation, which requires environmental cleanup, but no bills

have been enacted and none was considered in the 101st

Congress, though general product liability reform legislation was proposed and debated.

DIFFICULTIES COMMON TO PROVING

WORKERS’ COMPENSATION OR TOXIC

TORT CLAIMS

Workers’ compensation was intended to be a no-fault

system of compensation — if employment causes an illness or injury, the worker should recover. Tort is a system

largely based on fault, where it generally must be proved

that the defendant breached a duty owed to the plaintiff.

Only employees can collect workers’ compensation; tort

is available to everyone except employees covered by a

workers’ compensation system. Despite these significant

dissimilarities, claimants under either system share the

common burden of proving causation. It is not sufficient

for claimants to show that they have suffered an injury,

they must show that the workplace or defendant caused

the injury in order to collect compensation or damages.

This section discusses some of the difficulties entailed in

proving that exposure to an immunotoxicant caused a

particular disorder.

Scientific Uncertainty

A commonly made claim of immunotoxicity, which is

sometimes referred to as “chemically induced immune

dysregulation, " is that exposure to a chemical or substance impairs the body’s immune system, thereby

rendering an individual hypersensitive to chemicals

and/or more susceptible to many ailments, including

cancer. Many scientists doubt whether state-of-the-art
76. Identifying and Controlling Immunotoxic Substances

immunotoxicology can actually establish immune system

dysfunction as a result of chemical exposure. For instance, there is no agreed upon definition of “normal”

immunological parameters. As discussed in chapter 3,

scientists do not know how great a quantity of any particular cell type is required for proper immune function.

Cell counts can vary greatly among individuals that appear to have functional immune systems.

It is also the case that various environmental and host

factors, such as exposure to other toxic and nontoxic

chemicals, tobacco, alcohol, drugs, or radiation, cooking

habits, bacteria, viruses, nutritional imbalances, obesity,

and existing medical conditions, may provide alternative

explanations for plaintiffs’ conditions. The illnesses from

which immunotoxicity plaintiffs allegedly suffer generally do not have chemical-specific pathologies and occur

in the general population. It is, therefore, difficult to

isolate the specific cause of such alleged findings and

illnesses in light of the panoply of environmental and host

factors, and to prove causation with the degree of certainty required bylaw (3,14).

Warring Experts

The plaintiff must rely on scientific and medical experts to establish that he or she has suffered some type

of physical damage and that the toxic substance is capable of

causing that damage. Experts may also be required to

prove that the defendant caused the plaintiff to be exposed to the toxic substance and to attest to the extent of

the plaintiff’s damages. These expert witnesses must convey their highly specialized knowledge to the trier of fact

(the judge or jury) who generally has little scientific

training.

Most often experts who present evidence of immunotoxicity

for the plaintiff are clinical ecologists. These medical practitioners are at odds with much of the established medical

and scientific community. The American Academy of Allergy

and Immunology has published position statements refuting the theory that any valid scientific evidence supports the

theory that exposure to chemicals or pollutants in the environment adversely affects the function of T cells and

rejecting the medical effectiveness of treatments prescribed

by clinical ecologists (1,2). This disagreement among experts adds to the difficulty of trying immunotoxicity

claims since judges and juries have difficulty sorting out

the scientific evidence.

Continuing Debate Over Animal Testing

Very few substances have been tested to determine

whether they are immunotoxic. Where testing has been

done, it has generally been done on animals. Human

evidence is available from clinical trials or case reports

concerning immunosuppressive therapeutics.Very few

epidemiologic studies have been conducted on immunotoxicants, and the results have been inconclusive.

Recent court cases, however, have found plaintiffs' experts’

opinions regarding immunotoxicity based on animal data

unsupported by epidemiologic data to be inadequate to

sustain the burden of proof (7,10). This absence of data

presents a serious dilemma for plaintiffs.

Further scientific developments in the field of immunotoxicology should eliminate much of the scientific

uncertainty and, presumably, end many of the disagreements between clinical ecologists and the rest of the

medical and scientific community. The necessity of

animal testing is an ongoing debate in U.S. society, and

resolution lies well outside the field of immunotoxicology

(20).

APPENDIX A REFERENCES

1.

2.

3.

4.

5.

6 .

American Academy of Allergy and Immunolog,

“Position Statements: Clinial Ecology,” Journal ofA2-

lew and Clinical Invnunology 78:269, August 1986.

American Academy of Allergy and Immunolo~,

“PositionStatements: Controversial Techniqu~’’Joumal

ofAllew and Clinical Imnwnolo~ 67:333, 1981.

Comfel~ R. S., and Schlossman, S.F., “Immunologic

IAorato~ Tests: A Critique of the Alcolac Decision;’

Toxics Law Reporter, Sept. 6,1989, pp. 381-390.

Comaghie, C.A., “Evidena in Disability Claims Under

the Social Security Act,” Federal Bar News & Report

37(8):464-467, 1990 .

Gilreath, S., Attorney, Knoxville, TN, personal communication, November 1990.

Gleicher, E., Attorney, Detroit, MI, personal communication, July 1990.
Appendix A-Income Replacement for Disabled Individuals .77

7.

8.

9.

10.

11.

12

13.

14.

15.

16.

17.

18.

In re Paoti Railroad Yard PCB Litigation, 3 TXLR

843, No. 8&2229, Slip Op. (E.D. PA NOV. 29, 1988).

Kanner, A., Attorney, Philadelphi~ PA personal

communicatio~ November 1990.

Locke, L., “Adapting Workers’ Compensation to the

Special Problems of Occupational Disease~’ % Harvard Environmental Law Review, vol. 9, No. ~ 1985,

pp. 249-282.

Lych V. Merrell-NW Laboratmiq 830 FM 1190

(lstcir. 1987).

Mallino, D.L.,”Workers’ Compensation and Prevention of Occupational Disease,” Annals of the New

YorkAcademyofSctinces, 1987.

Maskin, A., “Overview and Update of Emerging

Damage Theories in Toxic Tort Litigation,” paper

presented July 14-16, 1988, Snowmass, CO, ALIABA Course of Study.

ProsserandKeeton, Presser and Keeton on Torts,5th

ed. (St. Pad MN: West Publishing Co., 1984).

Rothma~ R.A., and Maskin, A., “Defending Immunotoxicity Cla@” TtiLuwRepmtq Mar. ~1989,

pp. 1219-lZ3L

Schoenbeck,S.M., Attorney, St. Lo@ MO,personal

communicatio~ December 1990.

Shor, G.M., “Workers’ Compensation: Subsidies for

Occupational Disease,” Journal of Public Health

Pohky, December 1980, pp. 328-340.

Stemple, G., Attorney, Century City, CA personal

communicatio~ October 1990.

Thompso~ R., “Reforming Workers’ Compensatio~” Eal”torialResearch Repo~, Apr. 13,1990.

19.

20.

21.

22.

23.

24.

25.

U.S. Congres~ Office of Technology Assessment,

Genedc Monitmkg and Screening it the W*lhcC

OTA-BA-455 (Washingto~ DC: U.S. Government

Printing Office, September 1990).

U.S. Congress Office of Technology Assessmen~

Alternatives to Anima[ Use in Research Testing and

Educatio~ OTA-BA-273 (Washingto~ DC: U.S.

Government Printing Office, February 1986).

U.S. House of Representatives, Hearings before the

Subcommittee on Labor Standards of the Committee on Education and Labor, 97th Cong., 1st sess.,

Oct.6,1981,0nOmupational “kmebnpensdonand

SociaJ %curity.

U.S. House of Representatives Hearings before the

Subcommittee on Labor Standards of the Committee on Education and Labor, 98th Cong., 1st sess., on

H.R. 3175, the Occupational Disease Compensation

Act of 1983, June 13,14,27 and July 27,1983.

U.S. House of Representatives, Hearings before the

Subcommittee on Commeree, Transportation and

Tourism of the Committee on Energy and Commerce, 98th Cong., 1st sess., on H.R. 2582, the Hazardous Substance Victims’ Compensation Act, June

29,1983 (Serial No. 98-45).

U.S. Senate, Hearings before the Committee on

Labor and Human Resourees, %th Cong., 1st sess.,

on S. 420, the National Workers’ Compensation

Standards Act of 1979, Mar. 28 and Apr. 2-3,1979.

Welch L., Attorney, Kansas City, MO, personal

communication, June 1990.
Appendix B

Reviewers and Contributors

In addition to the workshop participant% OTA acknowledges the following individuals who reviewed drafts or

otherwise contributed to this study:

Joseph F. Albright

Chief, Basic Immunology Branch

Division of Allergy, Immunology,

and Transplantation

National Institute of Allergy and Infectious Disease

Bethesda, MD

Nicholas A. Ashford

Associate Professor of Technology and Policy

Center for Technology, Policy, and

Industrial Development

Massachusetts Institute of Technology

Cambridge, MA

Robert Axelrad

Director

Indoor Air Division

Office of Air and Radiation

U.S. Environmental Protection Agency

Washington, DC

Thomas Burke

Johns Hopkins School of Hygiene

and Public Health

Baltimore, MD

Gary R. Burleson

Pulmonary Immunology

Health Effects Research Laboratory

U.S. Environmental Protection Agency

Research Triangle Park, NC

Dorothy A. Canter

Science Advisor

Office of Solid Waste and

Emergency Response

U.S. Environmental Protection Agency

Washington, DC

Richard Cornfeld

Coburn, Croft, and Putzell

St. Louis, MO

Mark Cullen

Yale-New Haven Occupational Medicine Program

School of Medicine

Yale University

New Haven, CT

John J. Domanski

Lehn & Fink Products Group

Sterling Drug, Inc.

Montvale, NJ

Richard N. Hill

Senior Science Advisor

Office of Pesticides and Toxic Substances

U.S. Environmental Protection Agency

Washington, DC

Dennis M. Hinton

Research Chemist

General & Molecular Toxicology Branch

Center for Food Safety and Nutrition

U.S. Food and Drug Administration

Washington, DC

Meryl H. Karol

IEHS Department

University of Pittsburgh

Pittsburgh, PA

Mary Lamielle

National Center for Environmental Health Strategies

Voorhees, NJ

Sheryl Lard

Division of Anti-Viral Drug Products

U.S. Food and Drug Administration

Rockville, MD

Marie Ann Leyko

Staff Scientist

Cytokine/immunotoxicOlog Laboratory

Hazleton Laboratories America, Inc.

Vienna, VA

78
Appendix B-Reviewers and Contributors . 79

Robert W. Luebke

immunotoxicolofzy Section

U.S. Environmental Protection Agency

Research Triangle Park, NC

Anne McCay

Medical College of Virginia

Richmond, VA

Frances A. Mielach

Reviewing Pharmacologist

Division of Antiviral Drug Products

U.S. Food and Drug Administration

Washington, DC

Claudia Miller

Department of Pediatrics

University of Texas Health Science Center

San Antonio, TX

Albert E. Munson

Department of Pharmacology and Toxicology

Medical College of Virginia

Richmond VA

Charles Noble

Research Laboratories

Merck Sharp and Dohme

West Point, PA

Helen North-Root

Dial Corporation

Scottsdale, AZ

Tara O'Toole

Oceans and Environment Program

Office of TechnologyAssessment

Washington, DC

David P. Rail

Director, National Institute

of Environmental and Health Sciences

Research Triangle Park, NC

Anthony Roisman

Cohen, Milstein, Hausfeld, and Toll

Washington, DC

Noel R. Rose

Department of Immunology and

Infectious Diseases

Johns Hopkins University

Baltimore, MD

William G. Rosenberg

Assistant Administrator for

Air and Radiation

U.S. Environmental Protection Agency

Washington, DC

J. Harold Saylar

Procter & Gamble Company

Cincinatti, OH

Mark Schaefer

Senior Staff Associate

Carnegie Commission on Science,

Technology, and Government

Washington, DC

Paul A. Schulte

Chief, Screening & Notification Div. of Surveillance,

Hazard Evaluations and Field Studies

National Institute for Occupational Safety and Health

Cincinatti, OH

John C. Selner

Denver, CO

Roy D. Sjoblad

Health Effects Division

Office of Pesticide Programs

U.S. Environmental Protection Agency

Washington, DC

Ralph Smialowicz

immunotoxicology Section

U.S. Environmental Protection Agency

Research Triangle Park, NC

Bob Sonawane

Office of Research and Development

U.S. Environmental Protection Agency

Washington, DC
80 ● Identifying and Controlling Immunotoxic Substances

Robert S. Speirs

Brooks, CA

Robert Stewart

S.C. Johnson& Son, Inc.

Racine, WI

Peter T. Thomas

Manager

Microbiology/Immunology

IIT Research Institute

Chicago, IL

R.S. Tomar

G Project ENTOX

University of California

Riverside, CA

Mark J. Utell

Department of Medicine

University of Rochester Medical Center

Rochester, NY

Kimber L. White, Jr.

Department of Biostatistics

Medical College of Virginia

Richmond, VA

LuJuana Wilcher

Assistant Administrator for Water

U.S. Environmental Protection Agency

Washington, DC

Grace Ziem

Baltimore, MD

NOTE: OTAisgrateful forthevaluable assistance and thoughtful critiques provided bythereviewers and contributors. Theviewsexpressed

in this background paper, however, are the sole responsibility of the Office of Technolo~ Assessment.
Appendix C

Glossary of Terms and Acronyms

Glossary of Terms

Acquired immunity Disease resistance acquired after

birth and characterized by antigen-specific promises. See

humoral IMMUNITY and CELL-MEDIATED IMMUNITY; Compare NONSPECIFIC IMMUNITY.

Adaptive immunity: See ACQUIRED IMMUNITY.

Agranulocytosis: Absence of granulocytes in the

blood.

Allergen: A substance known to be an agent contributing to hypersensitivity.

Allergy: Immunologic hypersensitivity. See HYPERSENSITIVITY.

Anaphylaxis: Acute reaction that follows rapid introduction of an antigen into an individual having preexisting

IgE antibodies. Systemic anaphylaxis develops within

seconds and is characterized by constriction of the larynx and

bronchi and falling blood pressure. Local anaphylactic

reactions are acute inflammatory reactions caused by

local contact with antigen. See IMMEDIATE HYPERSENSITIVITY.

Antibody: A protein produced by B cells in response

to stimulation by an antigen and that reacts specifically

with that antigen. Antibodies are immunoglobulins.

Antigen: A substance that brings about an immune

response when introduced into the body. Antigens are

usually high molecular weight compounds, such as proteins.

However, low molecular weight compounds (e.g., drugs or

industrial chemicals) can bind to serum proteins and

become antigenic.

Asbestosis: Fibrosis of the lungs resulting from inhalation of asbestos fibers.

Asthma: A usually chronic condition characterized

by episodes of labored breathing.

Atopic: Having a tendency toward immediate hypersensitivity reactions due to IgE antibodies. Approximately

10 percent of the population manifest one or more forms

of atopy. See IMMEDIATE HYPERSENSITIVITY;

ANTIBODY.

Autoantibody: An antibody against a self antigen. See

ANTIBODY.

Autoimmunity A condition characterized by cellmediated or humoral immunologic response to antigens

of one’s own body. This occasional departure from the

usual recognition of self and nonself contributes to a

variety of diseases.

B cell: A lymphocyte that produces antibodies. See

LYMPHOCYTE; ANTIBODY.

Bronchoalveolar lavage fluid: The fluid obtained

from the lungs by lavage. Lavage is a technique in which

an organ is flushed with water in order to analyze

material in the drainage fluid (in this case, cells from the

bronchioles and alveoli).

Bronchopulmonary aspergillosis: Infection of the

bronchi and lungs by the species Aspergillus, characterized by inflammatory lesions.

Bronchus: One of the large conducting air passages

of the lung.

Byssinosis: An occupational respiratory disease associated with inhalation of cotton, flax, or hemp dust. It

is characterized initially by chest tightness, shortness of

breath, and cough but may lead to permanent lung

damage.

Carcinogen: A substance that causes cancer.

Cell-Mediated immunity: Immunological reactions

initiated and mediated by T cells. See T CELL. Compare

humoral IMMUNITY.

Challenge: Administration of an antigen to assess the

state of immunity. In immunotoxicological testing, an

experimental animal is challenged with an infectious

agent or tumor cells to determine whether exposure to a

chemical decreased the animal’s ability to fight infection or

cancer. See ANTIGEN.

Complement: A series of reactions involving approximately 20 proteins that circulate in the blood in an

inactive form. When the first complement substance is triggered – usually by an antibody locked to an antigen– it sets

in motion a ripple effect. As each component is activated, it

acts upon the next in a precise sequence of carefully regulated

steps. This phenomenon, known as the complement cascade,

causes release of the chemicals that produce the redness,

warmth, and swelling of the inflammatory response. It can

also bring rapid death to bacteria and other cells by puncturing their cell membranes. See ANTIBODY; ANTIGEN.

Contact sensitization: To stimulate an immune

response upon initial skin contact with an antigen with

the consequence of preparing the body for a stronger

response upon reexposure to the antigen.

Cytokine: A substance produced by cells, including

cells, that transmits messages between cells to control

and modulate immune response.

Cytotoxic: Lethal to cells.

81
82 ● Identifying and Controlling Immunotoxic Substances

Delayed-type hypersensitivity: An inflammatory

reaction that occurs 24 to 48 hours after challenge with

antigen and is a result of cell-mediated immunity. See

HYPERSENSITIVITY.

Dermatitis: An inflammatory skin condition.

Dose-response: The quantitative relationship between exposure to a substance, usually expressed as a

dose, and the extent of toxic injury or disease.

Edema: Swelling.

Endpoint: The disease, condition, or adverse effect

resulting from exposure to a toxic substance (e.g., immunosuppression, infection, cancer, death).

Epidemiology: The scientific study of the distribution

and occurrence of human diseases and health conditions and their determinants.

Erythema: Redness.

Hematology: The science of blood and its nature,

function, and diseases.

Histocompatibility: The extent to which individuals

or their tissues are immunologically similar.

Histology: The study of the minute structure, composition, and function of body tissues.

Host resistance: The ability of an organism to mount

a successful immune response against disease-causing

antigens.

humoral immunity: Immunity associated with antibodies that circulate in the blood. See ANTIBODY.

Compare CELL-MEDIATED IMMUNITY.

Hypersensitivity: A state of heightened reactivity to

a previously encountered antigen.

Immediate hypersensitivity: Immune response

mediated by antibodies, characterized by hives, wheezing, and/or abrupt changes in blood pressure, and occurring with a few minutes or hours after exposure to an

antigen.

Immune system: A specialized group of body cells,

cell products, tissues, and organs that respond to foreign

organisms and substances in the body.

Immunize: To deliberately introduce an antigenic

substance (vaccination, or active immunization) or antibodies (passive immunization) into an individual, with

the aim of producing immunity to a disease. Immunotoxicologists sometimes refer to the process of

exposing an animal to an antigen in order to test the

animal’s ability to mount, at some later point, an immune

reaction to the antigen as immunization.

Immunocompetence: The capacity to respond immunologically to an antigen.

Immunoglobulin. Protein that has antibody activity

or that is antigenically related to an antibody. They are

grouped into five categories based on structural differences: IgG, IgM, IgA, IgD, IgE. See ANTIBODY.

Immunology. The science concerned with the

phenomena that allow an animal to respond to a subsequent exposure to a foreign substance in a way that is

distinct from the way it responds to the initial exposure

to that same substance.

Immunologic: Pertaining to immunology.

Immunosuppression: Suppression of immune response.

immunotoxic. Having the potential to adversely affect immune response or damage components of the

immune system.

immunotoxicant: A substance that elicits an adverse

immune response or damages the immune system.

immunotoxicity: An adverse or inappropriate

change in the structure or function of the immune system after exposure to a foreign substance.

Inhalant: A substance that may be taken into the

body through the respiratory system.

Innate immunity See NONSPECIFIC IMMUNITY.

In vitro: Literally, in glass; pertaining to a biological

process taking place in an artificial environment, usually

a laboratory.

In vivo: Literally, in the living; pertaining to a biological process or reaction taking place in a living organism.

Latent effect: A reaction to a toxic substance that is

not immediately evident but that appears later in life;

also referred to as a silent effect.

Leukocyte: A white cell. Major classes of leukocytes

are granulocytes, lymphocytes, and monocytes.

Lymphocyte: A specialized leukocyte involved in the

immune response. B-lymphocytes originate in the bone

marrow and when stimulated by an antigen produce

circulating antibodies; See humoral IMMUNITY.

T-lymphocytes are produced in the bone marrow and

mature in the thymus gland and engage in a type of

defense that does not depend directly on antibody attack; See CELL-MEDIATED IMMUNITY. See B

CELL; T CELL.

Lymphoid organs: The principal organs of the immune system, including bone marrow, thymus, spleen,

and lymph nodes. They produce, store, and distribute

the immune system cells.

Lymphokine. A protein that mediates interactions

among lymphocytes and is vital to proper immune func-
Appendix C-G1ossary of Terms and Acronyms ● 83

tion. Interleukins and interferon are lymphokines.

Lymphokines are cytokines.

Lyse: To break up or rupture a cell membrane.

Microphage: A type of large, amoeba-like cell, found

in the blood and lymph, which ingests dead tissue, tumor

cells, and foreign particles such as bacteria and

parasites. The microphage also plays an important role

in antigen processing and presentation.

Mitogenesis: The initiation of cell division, or mitosis.

Monocyte: Phagocytic, large leukocytes containing

one nucleus.

Myelogenous leukemia: A cancer of the blood

granulocytes that usually occurs in persons of age 30-50.

Nasal lavage fluid: The fluid obtained from the nasal

passages by lavage. See BRONCHOALVEOLAR

LAVAGE FLUID.

Natural killer cell: A type of lymphocyte that attacks

cancerous or virus-infected cells without previous exposure to the antigen. Also called NK cell.

NK cell: See NATURAL KILLER CELL.

Nonself: That which is not recognized by an individual’s

immune system as being a natural constituent of that

individual’s body.

Nonspecific immunity: Immunity that exists from

birth and that occurs without prior exposure to an antigen; also called innate immunity. Compar e

AQUIRED IMMUNITY.

Pathology: The scientific study of the cause of disease

and of the associated structural and functional changes

that are the result of disease.

Peripheral blood: Blood in the circulation remote

from the heart.

Pesticide: A generic term referring to toxic substances developed to control pests; they include insecticides,

fungicides, rodenticides, and herbicides.

Phagocytosis: Consumption of foreign particles (e.g.,

bacteria) by cells that use ameboid movement to surround the particle and then ingest it. Macrophages are

phagocytes.

Pneumoconiosis: A condition characterized by the

deposition of mineral dust in the lungs as a result of

occupational or environmental exposure.

Pneumonitis: Inflammation of the lungs.

Reference dose (IUD): A term used to characterize

risk and derived by applying safety factors to the highest

level at which a substance produces no effect. If human

exposure to a substance is below the RfD, no risk is

assumed to exist; if exposure exceeds the RfD, risk is

assumed to exist. The term maybe used interchangeably

with acceptable daily intake.

Rhinitis: Inflammation of the lining of the nose.

Right-to-know laws: State and local laws requiring

companies to inform workers and communities of the

chemical names and hazards of their products.

Self: That which is recognized by an individual’s immune system as being a natural constituent of that

individual’s body.

Silicosis: A condition of lung fibrosis which is

brought about by prolonged inhalation of silica dust.

Structure-activity relationship: The relationship between a chemical’s structure and the biochemical changes

it induces.

T cell: A lymphocyte produced in the bone marrow

that matures in the thymus and is integral to cellmediated immunity. T cells regulate the growth and

differentiation of other lymphocytes and are involved in

antibody production. See LYMPHOCYTE.

Teratogen: A substance that causes physical defects

in offspring by adversely affecting developing embryos.

Toxicity: The quality of being poisonous or the degree

to which a substance is poisonous.

White cell: A colorless cell in the blood, lymph, or

tissues that is an important component of the immune

system. See LEUKOCYTE.

ACGIH

ADAMHA

AIDS

ATSDR

AZT

CAA

CBER

CDC

CDER

CERCLA

CFSAN

CPSA

CPSC

CTL

CWA

Acronyms

–American Conference of

Governmental Industrial Hygienists

–Alcohol, Drug Abuse, and Mental

Health Administration

–Acquired Immune Deficiency Syndrome

–Agency for Toxic Substances and

Disease Registry

–Azidothymidine, now known as

zidovudine

–Clean Air Act

– Center for Biologics Evaluation and

Research (FDA)

– Centers for Disease Control

– Center for Drug Evaluation and Research (FDA)

– Comprehensive Environmental Response,

Compensation and Liability Act

– Center for Food Safety and Nutrition

(FDA)

–Consumer Product Safety Act

– Consumer Product Safety Commission

– cytotoxic T lymphocyte

– Clean Water Act
84 ● Identifyingand Controlling Immunotoxic Substances

DES

DHHS

DMN

DNA

DTH

EPA

EPCRA

FDA

FDCA

FHSA

FIFRA

FTE

HAH

HLA

HSDB

Ig

IND

LPS

MCL

MCS

MEST

MLR

MSHA

NAAQS

NCI

NCTR

NDA

NIEHS

NIH

NIOSH

–Diethylstilbestrol

–Department of Health and Human

Services

–Dimethylnitrosamine

–Deoxyribonucleic acid

–Delayed-type hypersensitivity

–Environmental Protection Agency

–Emergency Planning and Community

Right-to-Know Act

–Food and Drug Administration

–Food, Drug, and Cosmetic Act

–Federal Hazardous Substances Act

–Federal Insecticide, Fungicide, and

Rodenticide Act

–full-time equivalent

–halogenated aromatic hydrocarbon

–human leukocyte antigen

–Hazardous Substances Data Bank

– immunoglobulin

–Investigative New Drug

–lipopolysaccharide

— maximum contaminant level

— multiple chemical sensitivity

— mouse ear swelling test

— mixed leukocyte response

–Mine Safety and Health

Administration

–National Ambient Air Quality

Standards

–National Cancer Institute

–National Center for Toxicological

Research (FDA)

–New Drug Application

–National Institute of Environmental

Health Sciences

–National Institutes of Health

–National Institute for Occupational

Safety and Health

NK

NLM

NTP

OHR

OPP

OSHA

OTA

OTS

PAH

PBB

PCB

PEL

PFC

PLA

PMN

POMS

PPB

PPM

PVIZT

RCRA

RQ

RTECS

SRBC

SDWA

SSA

SSDI

SSI

STEL

TCDD

TDI

TPQ

TRI

TSCA

TWA

– natural killer

–National Library of Medicine

–National Toxicology Program

–Office of Health Research (EPA)

–Office of Pesticide Programs (EPA)

–Occupational Safety and Health

Administration

– Office of Technology Assessment

–Office of Toxic Substances (EPA)

– polycyclic aromatic hydrocarbons

–polybrominated biphenyls

–polychlorinated biphenyl

–permissible exposure limit

–plaque forming cell

–Product Licensing Application

–Premanufacture Notice

– Program Operations Manual System

– parts per billion

– parts per million

– l-phenyl-5-vinyl-2-imidazolidine-thione

–Resource Conservation and Recovery

Act

— reportable quantity

– Registry of Toxic Effects of Chemical

Substances

– sheep red blood cell

–Safe Drinking Water Act

–Social Security Administration

–Social Security Disability Income

–Supplemental Security Income

– short-term exposure limit

–2,3,7,8-tetrachlorodibenzo-p-dioxin

– toluene diisocyanate

–threshold planning quantity

–Toxic Release Inventory

–Toxic Substances Control Act

– time weighted average

Index

Acetonitrile, 51

Acquired Immune Deficiency Syndrome (AIDS), 5,13,

50

Acquired immunity, 4-5,17-18

Adaptive immunity. See Acquired immunity

Aflatoxin, 53

Agency for Toxic Substances and Disease Registry

(ATSDR)

meeting on human exposure data sponsored by, 32

information programs of, 61,63

research by, 9,49,53

Airborne pollutants

EPA studies on, 52

immunosuppression and, 7,37

Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA), research by, 8,53

Aldicarb oxime, 51

Alkylating agents, 35

Allergy

definition used in OTA background paper, 4,19,20

disability claims and, 69

genetic component of, 22

misperceptions about, 22

substances that induce, 38-39

see also Contact sensitivity; Delayed-type hypersensitivity; Hypersensitivity; Immediate-type hypersensitivity

Allyl isovalerate, 51

American Academy of Allergy and Immunology, 76

American Conference of Governmental Industrial

Hygienists (ACGIH), 54,61

Anaphylaxis. See Immediate-type hypersensitivity; Hypersensitivity; Allergy

Antibody

classes of (immunoglobulin), 14

humoral immunity and, 18-19

plaque forming cell response test, 28

production by B cells of, 4,14

role in immune responsiveness of, 4, 14-15

structure, 14

test to measure levels of, 5,29

Antigen

acquired immunity and, 17

binding to antibody of, 13-14

definition of, 4,13

humoral immunity and, 18-19

processing of, 16

self, 20

Antimetabolites, 35

Arsine, 51

Asthma, 8,22,39,69

Autoimmune disease. See Autoimmunity

Autoimmunity

as a response of the immune system, 4,20

difficulty in assessing, 20,40

disability claims and, 69

epidemiologic studies of humans for, 6,40

genetic role in, 40

Spanish Toxic Oil Syndrome and, 40

substances inducing, 40

Azathioprine, immunosuppression and, 6,35,51

Azidothymidine (AZT), 50

B cells

humoral immunity and 18-19

quantitation of as a measure of immunotoxicity, 28

role in antibody production of, 4, 14, 18-19

suppression by glucocorticosteroids on, 35

test to assess antibody production capability of, 28

test to assess mitogen response of, 29

Barth v. Firestone Tire and Rubber Co., 74

Benzene, 6,36,57

Benzidine, 51

Benzo(a)pyrene, 51

Benzo(e)pyrene, 51

Benzothonium chloride, 52

Benzyl-p-chlorophenol, 52

o-benzyl-p-chlorophenol, 51

Buehler test, 30

t-butylhydroquinone, 51

Cadmium, immunosuppression and, 7,38

Cadmium chloride, 51

87
88 ● Identifying and Controlling Immunotoxic Substances

California

legislation related to MCS, 9

workers’ compensation, 72

Captafol, 55

Carcinogens

historical interest in, 3

Cell-mediated immunity

description of, 5,19,23

immunotoxicological tests for, 5,27,29

importance to normal immune function of, 19-20

occupational dermatoses and, 38

potential adverse consequences due to, 19-20

see also Allergy; Contact sensitivity; Delayed-type

hypersensitivity

Cells, immune system, 14-17

Cellularity, as a test for immune pathology, 28

Center for Biologics Evaluation and Research

(CBER)–FDA, 53

Center for Drug Evaluation and Research (CDER) –

FDA, 53,56

Center for Environmental Health and Injury Control –

CDC, 53

Center for Food Safety and Nutrition (CFSAN) – FDA,

52-53

Centers for Disease Control (CDC), research in immunotoxicology by, 8,53

Chloral hydrate, 32

Chlordimeform, 34

4-chloro-o-phenylenediamine, 51,52

Cigarette smoke

as a confounding factor in immuntoxicity assessment,

22

immunosuppressive potential of, 7,37

Clean Air Act (CAA), 8,37,52,54,56-57

Clean Water Act (CWA), 54,56,57-58

Cobalt, 55

Cobaltous sulfate, 54

Community Right-to-Know, 8,61-62,63

Complement activation, 14

Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), 54,56,60,62

Consumer Product Safety Act (CPSA), 54,60-61

Consumer Product Safety Commission (CPSC), research or regulation by, 8,60-61

Contact sensitivity

cosmetics and regulation by FDA of substances causing, 55-56

description of, 19

EPA research in, 52

substances causing, 38

see also Cell-mediated immunity; Delayed-type hypersensitivity; Hypersensitivity

Cosmetics

hypersensitivity and, 8,21,38

regulation of, 56

Crotonaldehyde, 52

Cyclophosphomide, immunosuppression and, 6,35,51

Cyclosporin A, immunosuppression and, 6,36,56

Cytokines, 4,16

Cytotoxic T lymphocyte (CTL) assay, 29

Dayron Corporation v. Morehead, 72

Definitions. See Terminology

Delayed-type hypersensitivity (DTH)

description of, 19

EPA requirements to assess biochemical pesticides

for, 58-59

substances inducing, 38-39

test to measure, 29

see also Cell-mediated immunity; Contact sensitivity;

Hypersensitivity

Department of Agriculture, research or regulation by,

8,53

Department of Defense, research or regulation by, 8,53

Department of Health and Human Services, research

by, 8,49

Department of Labor, research or regulation by, 8

2,4-diaminotoluene, 51,52

Dichloroethane, 32

Dideoxyadenosine, 51

Diethylstilbestrol (DES), 34,51

Dimethyl vinyl chloride, 51

Dimethylbenz(a)anthracene (DMBA), 37,51

Dimethylnitrosamine (DMN), 32

Dinitrofluorobenzene, 52

Dioxin

Department of Defense study of, 53

immunosuppression and, 7,32,36-37

see also TCDD
Index ● 89

Diphenylhydantoin, 51

Disability, income replacement for immunotoxicity-related, 69-76

Draize test, 30

Drugs

autoimmunity and, 40

hypersensitivity and, 8,38,39

immunotoxic effects of illegal, 35

immunosuppression and, 6,39,41

regulation of, 55-56

see also Therapeutic drugs

Elam v. Alcolac, 73-74

Emergency Planning and Community Right-to-Know

Act (EPCRA), 61-62

Environmental Protection Agency (EPA)

community right-to-know and, 8,61-62

coordination about TRI with NLM, 62

funding of study on multiple chemical sensitivity by,

9

immunotoxicity testing of biochemical pest control

agents and, 58

regulation by, 56-60

regulation of oxidant gases based on health effects

other than immunotoxicity by, 37

research in immunotoxicology by, 8,52,63

role in NTP of, 49

tier testing and, 52,58-59

Epidemiology

difficulties in obtaining human immunotoxicity data,

5-6,31-32

studies of autoimmunity in humans, 5-6, 40

studies of hypersensitivity in humans, 5-6,31-32

studies of immunosuppression in humans, 5-6,31-32

Estradiol benzoate, 32

Ethyl carbamate, 51

Ethylene dibromide, 51

Ethylene thiourea, 52

Federal Hazardous Substances Act (FHSA), 54,60-61

Federal Insecticide, Fungicide, and Rodenticide Act

(FIFRA), 54,56,58-59

Florida, workers’ compensation, 72

Food and Drug Administration (FDA)

regulation by, 55-56

research in immunotoxicology by, 8,52-53,63

restriction of sulfites by, 8,55,63

role in NTP of, 49

view on tier testing, 31,53

Food, Drug, and Cosmetic Act (FDCA), 55

Foods, regulation of, 55

Formaldehyde, 37,39,51

Freund’s complete adjuvant test, 30

Funding

levels for irnmunotoxicological research by CDC, 53

levels for immunotoxicological research by EPA, 52

levels for immunotoxicological research by NIEHS,

53

levels for immunotox.ecological research by NIH, 53

levels for immunotoxicologicd research by NIOSH,

53

levels for immunotoxicological research by NTP, 51

Gallium arsenide, 51

Genetics

role in autoimmunity, 8,40

role in evaluating immunotoxicity of populations, 22

Ginseng, 51

Glucocorticosteroids, immunosuppression and, 35

Glutaraldehyde, 52

Grayson v. Gulf Oil Company, 71-72

Halogenated aromatic hydrocarbon (HAH)

immunosuppression and, 6,36-37

see also Polybrominated biphenyls; Polychlorinated

biphenyl; Dioxin

Hazardous Substances Data Bank (HSDB) –NLM, 62

Hematology, as a test for immune pathology, 28

Hexachlorobenzo-p-dioxin, 51

Higgens v. Aerojet-General Corp., 74-75

Histology, as a test for immune pathology, 28

Host resistance, immunotoxicological tests for, 5,30,50,

52

Human leukocyte antigen (HLA), 22

humoral immunity

description of, 5,18-19,23

immunotoxicologal tests for, 5,27,28-29

importance to normal immune function of, 18-19

potential adverse consequences due to, 19

see also Allergy; Antibody; Hypersensitivity

Hypersensitivity

definition, 4

EPA efforts in methods development for lung, 52
90 ● Identifying and Controlling Immunotoxic Substances

epidemiologic studies of humans for, 6

genetic component of, 22,23

immunotoxicity and, 19-20

immunotoxicological tests for, 5,30-31

pesticides and, 8,39

respiratory disorders and, 38-39

substances causing contact sensitivity and skin disorders, 38

substances tested by NTP for, 52

see also Allergy; Contact sensitivity; Delayed-type

hypersensitivity; Immediate-type hypersensitivity

Immediate-type hypersensitivity

allergy and, 19

potential adverse consequences due to, 19

see also Allergy; humoral immunity; Hypersensitivity

Immune suppression. See Immunosuppression

Immune system, 13

cell surface receptors of, 14, 16

cells of, 4, 14-17

organs of, 4, 16-17

reserve capacity of, 5,40

responses of, 4, 17-20

tests to analyze effects of substances on 5,27-31

Immunity. See Acquired immunity; Cell-mediated immunity; humoral immunity; Nonspecific immunity

Immunoglobulin. See Antibody

Immunosuppression

definition, 3-4

halogenated aromatic hydrocarbons and, 36-37

immunotoxicity and, 20

indoor air pollutants and, 37

lack of data on human studies, 34

metals and, 37-38

oxidant gases and, 37

pesticides and, 6,36

polycyclic aromatic hydrocarbons and, 7,37

substances tested by NTP for, 51

tests for, 5

therapeutic drugs and, 6,35-36

immunotoxicant

examples of substances that are, 6-8,35-40

OTA definition of, 4,20

populations at risk to effects of, 22-23

see also immunotoxicity

immunotoxicity

challenges in studying, 5,20-23,32-35,40-41

difficulties in proving claims for, 75-76

disability and, 69-76

epidemiologic evaluation of, 31-32

existing data on, 5,35-40

terminology used in OTA background paper, 3-4,

20-21

tests for, 27-31

tort claims and, 73-75

workers’ compensation and, 71-72

see also immunotoxicant

Indomethacin, 51

Indoor air pollutants, 21,37

Inhalants

EPA development of methods to assess, 52

hypersensitivity induced by, 8

Innate immunity. See Nonspecific immunity

Interferon-alpha, 51

Isocyanates, hypersensitivity and, 8

Isobutyraldehyde, 52

Isophorone diisocyanate, 52,55

Jewelry, hypersensitivity to, 8,38

Kyles v. Workers’ Compensation Appeals Board, 72

Lead, 7,37,57

Lithium carbonate, 51

Lowe v. Norfolk & Western Railway Company, 75

Lymphocytes. See B cells; T cells; Natural killer cells

Lymphoid organs. See Organs

Macrophages

cell-mediated immunity and, 19

humoral immunity and, 18

nonspecific immunity and, 17

role in immune responsiveness of, 4, 13, 16, 18

test to assess activity of, 29,30

test to assess functional capability of in antibody

production, 28

Maryland, study related to environmental illness and

multiple chemical sensitivity, 9

Material safety data sheets, 61,62

2-mercaptobenzothiazole, 52

Mercury, 7,38,57

Metals

immunosuppression and, 7,37

role in autoimmune processes, 8

role in hypersensitivity, 8

see also Cadmium; Lead; Mercury; Nickel; Organotins

Methyl carbamate, 51

Methyl isocyanate, 50,51
Index ● 91

Michigan, polybrominated biphenyl exposure case in,

33

Mine Safety and Health Act, 54,61

Mine Safety and Health Administration (MSHA), research or regulation by, 8,61

Mixed leukocyte response (MLR), 29

Moore v. Polish Power, Inc., 74

Mouse ear swelling test (MEST), 30-31

Multiple chemical sensitivity, 9,73

Murine local lymph node assay, 30-31

NK cells. See Natural killer cells

National Academy of Sciences

meeting on human exposure data sponsored by, 32

study of multiple chemical sensitivity by, 9

National Ambient Air Quality Standards (NAAQS), 52,

57

National Cancer Institute (NCI), 49

National Center for Toxicological Research (NCTR) –

FDA, 49

National Commission on State Workmen’s Compensation Laws, 72

National Institute for Occupational Safety and Health

(NIOSH), 49

National Institute of Allergy and Infectious Diseases, 53

National Institute of Environmental Health Sciences

(NIEHS), 49,53

National Institutes of Health (NIH), research in immunotoxicology by, 8,49,53

National Library of Medicine (NLM), 9,62-63

National Toxicology Program (NTP)

agencies comprising, 49

funding for immunotoxicological research by, 51,63

objectives of, 49

research in immunotoxicology by, 8,49-52

substances tested for hypersensitivity by, 52

substances tested for immunosuppression by, 51

testing approach developed by, 8,49-52

Natural killer cells

cell-mediated immunity and, 19

nonspecific immunity and, 17

role in immune responsiveness of, 4, 17

test to assess activity of, 29,30

New Jersey, study related to environmental illness and

multiple chemical sensitivity, 9

Nickel

hypersensitivity and, 8,38

immunosuppression and, 37-38

Nickel chloride, 38

Nickel sulfate, 51

Nitrobenzene, 51

Nitrofurazone, 51

Nitrogen dioxide,7, 37,59

n-nitrosodimethylamine, 51

m-nitrotoluene, 51

p-nitrotoluene, 51

Nitrophenylpentadien, 50,52

Nonspecific immunity

description of, 4,17

immunotoxicological tests for, 5,27,29-30,50

role of NK cells in, 17

tests for host resistance as a measure of, 30

Ochratoxin A, 51

Occupational Safety and Health Act (OSH Act), 54

Occupational Safety and Health Administration

(OSHA)

regulation by, 8,54,63

role in NTP of, 49

substances regulated as sensitizers by, 8,54-55

worker right-to-know and, 8,61,63

workers’ compensation and, 70-71

Office of Health Research (OHR) –EPA, 52

Office of Pesticide Programs (OPP) –EPA, 52,58-59

Office of Technology Assessment (OTA)

evaluation of environmental noncancer health risks

by, 3

organization of report by, 3

previous studies on regulation of toxic substances by,

49

Office of Toxic Substances (OTS) –EPA, 52

Oleic acid diethanolamine, 52

Organotins, 7,38

Organs

immunotoxicity testing of, 28

of the immune system, 4, 17

Oxidant gases, 37. See also Immunosuppression;

Nitrogen dioxide; Ozone

Oxymetholone, 51

Ozone, immunosuppression and, 7,37,57
92 ● Identifying and Controlling Immunotoxic Substances

Pathology, immunotoxicological tests for, 5,28

Penicillin, hypersensitivity and 8,39

Pentachlorophenol, 51

Pentamidine isethionate, 51

Pesticides

EPA testing guidelines for immunotoxicity of, 8,58-

59

hypersensitivity and, 8,39

immunosuppression and, 7,38

Pharmaceuticals. See Drugs

Phenothiazine, 55

Phenyl glycidyl ether, 55

l-phenyl-5-vinyl-2-imidazolidine-thione (PVIZT), 40

o-phenylphenol, 51

Phorbol myristate acetate, 51

Picric acid, 55

Plaque forming cells (PFC), test to assess, 28

Polybrominated biphenyls (PBBs)

immunosuppression and, 6,32,36

Michigan exposure case, 33

Polychlorinated biphenyl (PCB)

immunosuppression and, 6,32,36

regulation by EPA under CWA of, 58

regulation by FDA of, 55

Taiwan exposure case, 34

Polycyclic aromatic hydrocarbons (PAH), immunosuppression and, 7,37

Polydimethylsiloxane fluid, 52

Prednisolone, immunosuppression and, 6,35

Registry of Toxic Effects of Chemical Substances

(RTECS)–NLM, 62

Regulation

by OSHA of substances as sensitizers, 54-55

major Federal laws controlling toxic substances, 54-

61

of sulfites based on immunotoxic criteria, 8,55

of Yellow Dye No. 5 based on immunotoxic criteria,

55

Research

Federal agencies involved in, 8,49-54

interest in Federal interagency coordination committee, 54

need for integration of immunology and toxicology,

35

see also Funding

Resource Conservation and Recovery Act (RCRA), 56,

60

Respiratory disorders and hypersensitivity, 7-8,38-39

Ribavirin, 51

Safe Drinking Water Act (SDWA), 56,58

Selenium, immunosuppression and, 37-38

Senate Committee on Environment and Public Works,

Subcommittee on Toxic Substances, Environmental

Oversight, Research and Development

interest in noncancer health risks by, 3

request for this OTA background paper by, 3

Silicone, 50,51

Social Security Administration (SSA), 69

Social Security Disability Income (SSDI), immune system injury and, 69

South Carolina, workers’ compensation and immune

system injury, 71-72

Spain, toxic oil exposure case in, 40

Stiles v. Sudstrand, 75

Subtilisins, 55

Sulfites, role in hypersensitivity and restriction by FDA

of, 8,55,63

Supplemental Security Income (SSI), 69

Suppression of immune responsiveness. See Immunosuppression

T cells

cell-mediated immunity and, 19-20

humoral immunity and, 18-19

mixed lymphocyte response as a measure of, 29

quantitation of as a measure of immunotoxicity, 28

role in immune responsiveness, 4, 15-16, 18, 19

suppression by cyclosporin A on, 36

suppression by glucocorticosteroids on, 35

test to assess cytotoxic, 29

test to assess functional capability of antibody

production, 28

test to assess host resistance activity of, 30

test to assess mitogen response of, 29

Taiwan, polychlorinated biphenyl exposure case in, 34

Terminology, 3-4

Testing

challenges and difficulties of, 5-6,32-35

methods of, 27-31

Tests

for cell-mediated immunity, 29

for host resistance, 30

for humoral immunity, 28-29

for nonspecific immunity, 29-30

for pathology, 28
Index .93

for potential to induce hypersensitivity, 30-31

selection of, 31

see also Testing; Tier testing

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 36, 51

See also Dioxin

Tetraethyl lead, 51

Tetrahydrocannibinol, 51

Therapeutic drugs. See Drugs

4,4-thiobis (6-t-butyl-m-cresol), 51

Tier testing

EPA approach for biochemical pesticides and, 58-59

EPA efforts to develop, 52,63

FDA perspective on appropriateness of, 31

for possible immunotoxicants, 31

interest in developing for hypersensitivity assessment, 31

NTP approach to, 49-52

Toluene, 51

Toluene-2,3-diisocyanate (TDI)

hypersensitivity and, 39

regulation by OSHA as sensitizer, 39,55

Tort law

congressional interest in, 75

description of, 72-73

difficulties in proving immune system injury under,

75-76

immune system injury and, 73-75

Toxic Release Inventory (TRI) – NLM, 62

Toxic Substances Control Act (TSCA), 54,56,59-60

Toxic torts. See Tort law

Toxicology, general principles of, 7,21-23

Toxicology Data Network (TOXNET) – NLM, 62

TOXLINE-NLM, 62-63

Tributyltin oxide, 52

Triethanolamine, 52

Tris (2,3-dichloropropyl) phosphate, 51

Vanadium pentoxide, 51

Vinyl chloride, 57

4-vinyl-l-cyclohexene diepoxide, 51

White cells, 4, 15

Wisconsin, workers’ compensation and, 70

Woodrow Sterling et al. v. Velsicol Chemical Corp., 73

Worker Right-to-Know, 8,61,63

Workers’ compensation

congressional interest in, 72

description of, 69-71

difficulties in proving immune system injury under,

75-76

immune system injury and, 71-72

OSHA and, 70-71

Xylenesulfonic acid, 52

Yellow Dye No. 5,55,63

Zirconium, hypersensitivity and, 38
Other Related OTA Reports

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GPO stock #052-003-01184-1; $15.00 per copy

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NOTE: Reports are available from the U.S. Government Printing O&Ice, Superintendent of Documents,

Washington, DC 20402-9325, (202) 783-3238; and/or the National Technical Information Service, 5285

Port Royal Road, Springfield, VA 22161-0001, (703) 487-4650.