The Role of Genetic Testing in the

Prevention of Occupational Diseases

April 1983

NTIS order #PB83-233734
Library of Congress Catalog Card Number 83-600526

For sale by the Superintendent of Documents,

U.S. Government Printing Office, Washington, D.C. 20402
Foreword

This report examines a technology, genetic testing, that may be useful in reducing

occupational disease, but that also raises concerns about potential misuse. Genetic testing

encompasses two major techniques, one (screening) that may be able to identify individual

workers who are genetically at higher risk to disease; and another (monitoring) that

may serve as an early warning system that exposure to a hazardous agent in the workplace has occurred. Information from these techniques might be used in various preventive measures, but some people fear it could result in workers being unfairly excluded

from jobs.

OTA undertook the study at the request of the House Committee on Science and

Technology. The study examines the technology and its social implications. It evaluates

the evidence supporting its claimed benefits, the extent of testing, and how the results

have been used. Social issues, particularly of a legal and ethical nature, are identified

and discussed. Finally, congressional options for both promotion and control are

presented.

In preparing this report, OTA consulted with members of the project advisory panel,

with contractors and special consultants, and with numerous other experts in industry,

academia, labor, medicine, law, economics, and ethics. Drafts of the final report were

reviewed by the advisory panel chaired by Arthur Bloom and by approximately 32 other

individuals and groups representing a wide range of disciplines and perspectives. We

are grateful for their many contributions. As with all OTA reports, however, the content is the responsibility of the Office and does not constitute an

advisory panel or the Technology Assessment Board.

endorsement by the

Director

. . Ill
Advisory Panel on Occupational Genetic Testing

Arthur D. Bloom, Panel Chair

professor of Pediatrics, College of Physicians and Surgeons, Columbia University

Eula Bingham

J

Environmental Health Department

University of Cincinnati

Grant Brewen

Molecular and Applied Genetics Laboratory

Allied Chemical Corp.

Patricia Buffler

School of Public Health

University of Texas

Ira Cisin

Social Research Group

George Washington University

Burford W. Culpepper

Medical Division

E. I. du Pent de Nemours & Co.

James D. English

United Steel Workers of America

Neil Holtzman

Johns Hopkins University

Paul Kotin

Denver, Colo.

Thomas O. McGarity

School of Law

University of Texas at Austin

Rafael Moure

Oil, Chemical and Atomic Workers Union

Robert F. Murray Jr.

Division of Medical Genetics

College of Medicine

Howard University

Elena Nightingale

Institute of Medicine

National Academy of Sciences

Gilbert Omenn

Dean, School of Public Health

University of Washington

William N. Rom

Rocky Mountain Center for Occupational

and Environmental

University of Utah

Stuart Schweitzer

Director, Program in

Policy Analysis

Health

Health Planning and

UCLA School of Public Health

Robert Veatch

The Kennedy Institute of Ethics

Georgetown University

iv
OTA Project Staff—Genetic Testing Assessment

H. David Banta, Assistant Director, OTA

Health and Life Sciences Division

Gretchen Kolsrud, Biobgical Applications Program Manager

Geoffrey M. Karny, Project Director

Nanette Newell, Senior Analyst *

Ann Rose, Senior Analyst

Louise Williams, Senior Analyst

Nina Graybill, Editor

Ted Wagner, Administrative Assistant **

Fatimah Taylor, Administrative Assistant***

Lynne Alexander, Secretary

Marese Miles, Secretary†

Special Contributors

Hellen Gelband, Analyst

Michael Gough, Senior Analyst

Principal Contractors

David Brusick, Litton Bionetics, Inc.

Edward Calabrese, University of Massachusetts, Amherst

Betty Dabney, Boulder, Colorado

Marc Lappe, University of California, Berkeley

Mark A. Rothstein, West Virginia University College of Law

Cynthia A. Thomas, National Opinion Research Center

Judith L. Wagner, Technology Research Associates

OTA Publishing Staff

John C. Holmes, Publishing Officer

John Bergling Kathie S. Boss Debra M, Datcher Joe Henson

Doreen Foster Donna Young
—.-

Contents

Chapter Page

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Part I: Introduction to Genetic Testing

1. Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2. Introduction: Occupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . 23

3. Survey of the Use of Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . 35

Part II: Underlying Scientific Principles

4. Essentials of Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

5. Principles of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 7

Part 111: An Assessment of the State of the Art

6. Genetic Monitoring in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

7. Genetic Screening for Heritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Part IV: Legal, Ethical, and Economic Issues

8. Legal Issues Raised by Genetic Testing in the Workplace . . . . . . . . . . . . . . . 111

9. Application of Ethical Principles to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

10. Prospects and Problems for the Economic Evaluation of Genetic Testing . . . . . . . . . . 151

Part V: Congressional Issues and Options

11. Issues and Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Appendixes

A. Survey Design and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17.5

B. Report From the National Opinion Research Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179

C. Survey Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

D. Background Frequencies for Chromosome Aberrations . . . . . . . . . . . . . . . . . . . . . . . . 227

E. Background Frequencies for Sister Chromatid Exchanges. . . . . . . . . . . . . . . . . . . . . . . . . 231

F. Screening Tests (Available in Hospitals or Medical Centers) for Heritable Traits . . . . . . . . 233

G. Other Contractors and Contributors and Acknowledgments . . . . . . . . . . . . . . . . . . . . , . . 235

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... , . . . . . . . . . . 239

vii
Glossary

Acetylation.–The introduction of one or more acetyl

groups into an organic compound.

Allele.--One of several alternate forms of a gene.

Amino acid.—Any one of a class of organic chemical

compounds characterized by the presence of an

amino group (NHZ) and a carboxyl group (COOH) attached to either side of a central carbon atom. They

are the primary building blocks of proteins; 20 major types are found.

Anemia.—A condition characterized by a decreased

oxygen-carrying capacity of the red blood cells because of reduced number of cells, too little hemoglobin, or malfunctioning hemoglobin.

Assay.—Any technique that measures a biological

response.

Biologically significant.-An exposure or dose that

can cause detectable damage or disease.

Carcinogen/carcinogenesis.-An agent that induces cancer.

Carrier.—An individual apparently normal, but possessing a single copy of a recessive gene obscured

by a dominant allele; a heterozygote.

Centromere.--A specialized region of a chromosome

that holds the two chromatics together and that is

involved in directing chromosome movements during cellular reproduction.

Chromatid.--One of the two daughter strands of a

duplicated chromosome that is still joined by a single

centromere.

Chromosomal aberration.-–An abnormality of

chromosome structure or number.

Chromosomes.—The structures in the cell nucleus

that store and transmit genetic information.

Clastogen.--Chromosome-damaging agent.

Codominant.—Alleles are codominant if each is expressed independent of the presence of the other;

the effects of expression are additive.

Cyanosis.—Slightly bluish, grayish, slatelike, or dark

purple discoloration of the skin due to the presence

of abnormal amounts of reduced hemoglobin in the

blood.

Cytogenetics.–The study of the relationship of the

microscopic appearance of the chromosomes and

their behavior to the genotype and phenotype of the

individual.

Deletion.—A chromosomal aberration involving the

loss of a portion of a chromosome.

Deoxyribonucleic acid (DNA) .—The genetic

material of all cells.

Dominant.–An allele that exerts its phenotypic effect when present either in homozygous or hetero -

zygous form.

Des&response. -An increasing biological response

with increasing dose of a chemical or ionizing radiation.

Dosimeter.—Device or methodology for measuring

the dose of a chemical or ionizing radiation to a

biological system.

Duplication.—A chromosomal aberration in which

a portion of a chromosome is present more than

once; may involve whole genes, parts of genes, or

series of genes.

Endpoint.—The particular biological response being

measured,

Erythrocyte.--Mature hemoglobin-rich red blood

cell involved in oxygen transport.

Gene.—A unit of heredity. At present, genes are usually equated with units of function, that is, the sequence of DNA required to code for one polypeptide chain or one RNA molecule.

Genetic monitoring.—The periodic testing of

workers to assess damage to their DNA or chromosomes from exposure to hazardous substances or

agents.

Genetic predisposition. -Susceptibility to illness

on the basis of one’s inherited genetic constitution

and triggered by an environmental stress.

Genetic screening.—A one-time test to determine

the presence of particular genetic traits in individuals. For this report, the term is limited to the

screening of workers for genetic traits that might

cause them to be at increased risk for occupational

disease.

Genetic tests. -Those tests that determine a person’s

genetic makeup or that identify changes (damage)

in the genetic material of certain cells for the purpose of identifying people who may be at risk of

disease when exposed to hazardous substances.

Genotoxic.—Damaging to the genetic material.

Genotype.-The genetic constitution of an organism

(to be distinguished from its physical appearance or

phenotype).

Germ cell—The male and female reproductive cells;

egg and sperm.

Hemoglobin. -Protein carrier of oxygen found in

red blood cells. Composed of two pairs of polypeptide chains and an iron-containing heme group.

Hemolytic.--Pertinent to the breaking down of red

blood cells.

Heterozygous--Having different alleles at a genetic

locus.

Homozygous.–Having indistinguishable alleles at a

particular locus on both chromosomes.

Human leukocyte antigens (HLAs).—A set of imix
munologic proteins found on the surface of all cells;

each person’s set is thought to be as unique as fingerprints.

Hypoxia.—Result of lack of an adequate amount of

oxygen in inspired air such as occurs at high

altitudes; reduced oxygen content.

Initiation.—The first step in the development of

cancer.

Inversion.-A chromosome rearrangement in which

a central segment produced by two breaks is inverted prior to repair of the breaks.

In vitro. -Pertaining to experiments done in a cellfree system. The term is sometimes used to include

the growth of cells from multicellular organisms

under cell culture conditions.

In vivo.—Pertaining to experiments done in a system

such that the organism remains intact, either at the

level of the cell (for bacteria) or at the level of the

whole organism (for animals).

Ionizing radiation. —High energy electromagnetic

radiation, associated with gamma and X-rays, which

is capable of changing the electronic structure of

atoms.

Karyotype.-A chart made from a photograph of the

chromosomes in which the homologous pairs are

matched and arranged in numerical order from the

longest to the shortest pair.

Leukocyte.–White blood cell.

Locus (pl—loci).—The position of a gene on a chromosome.

Lymphocyte.-One of the major groups of white

blood cells.

Messenger RNA (mRNA).—Type of RNA that carries the transcribed genetic code from the DNA to

the protein-synthesizing enzymes to direct protein

synthesis.

Mutagen/mutagenesis.--Any substance that damages the genetic material.

Nucleotide base.—Structural unit of nucleic acids.

Nucleus.—A relatively large spherical body inside a

cell that contains the chromosomes in their uncoiled, threadlike state.

Oxidation. -Chemical reaction where there is a loss

of electrons.

Phenotype.—Appearance or observable nature of an

individual as determined by his or her genotype and

the influence of the environment. Individuals that

appear alike may be genetically different.

ppm.-–parts per million.

Predictive value.—The likelihood that a person with

a positive test result has the disease or that a person with a negative result does not have the disease.

Also refers to the likelihood that the index or marker (chromosome damage) predicts the occurrence

of a disease.

Promotiom--The second step in the development of

cancer.

Protein--A linear array of amino acids joined by peptide bonds. In their biologically active states, proteins are folded into specific three-dimensional

structures and function as catalysts in metabolism

and to some extent as structural elements of cells

and tissues.

Recessive.–An allele which exerts its phenotypic effect only when present in homozygous form, otherwise being masked by the dominant allele.

Reduction--Chemically, the acceptance of electrons;

used as the opposite of oxidaticm.

Relative risk—The ratio of the incidence of disease

among exposed persons divided by the same rate

among nonexposed persons.

Reliability.—The ability of the same specimen to give

the same result repeatedly when measured by different laboratories or by different individuals in the

same laboratory on several occasions.

Sensitivity.–The ability of a test to identify correctly

those who have a disease.

Serum.—The liquid portion of the blood that carries

the blood cells.

Somatic cell--All cells of the body except the germ

cells.

Specificity.--The ability of a test to identify correctly

those who do not have the trait or disease which

is being tested.

Teratogen/teratogenesis. -An agent that interferes with embryonic development.

Trait.—A distinguishing feature; a characteristic or

property of an individual.

Transcription.—In gene function, the complementary copying of the genetic code from DNA to messenger RNA.

Translation.—In gene function, decoding the messenger RNA into an amino acid sequence in the production of a protein.

Translocation.—A chromosomal aberration in

which a portion of one chromosome is attached to

another chromosome; often a reciprocal exchange

of segments between two chromosomes.

Validity.–The extent to which a test will correctly

classify true susceptible and true nonsusceptible individuals; sensitivity and specificity are components

of validity.

x
Part I

Introduction to Genetic Testing

Chapter I—Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Chapter 2—Introduction: Occupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . 23

Chapter 3—Survey of the Use of Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . . . 35
Chapter I

Executive Summary
Contents

Page

Occupational Illness and Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

The Problem of Occupational Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Health Hazards in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

The Use of Genetic Testing for the Prevention of Occupational Disease . . . . . . . . . . . . 7

Theoretical Foundations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Detection of Increased Risk in Individuals or Groups . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Potential Benefits and Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Survey of the Use of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

The State of the Art . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Genetic Testing and the Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Ethics of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Economic Evaluation of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Congressional Issues and Policy Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Issue: What Actions Could Congress Take With Respect to Genetic Testing

in the Workplace? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Issue: How Could Congress Regulate Genetic Testing in the Workplace? . . . . . . . . . . . 16

Issue: How Could Congress Foster the Development and Use of This Technology? . . . 18
Chapter 1

Executive Summary

Occupational illness and genetic testing

The problem of occupational illness

Occupational illness cost the U.S. economy over

850,000 workdays in 1981. * Diseases and other

medical conditions associated with the workplace

range from minor skin rashes to cancer. Some

experts estimate that exposures to hazardous substances at work may play a role in 5 percent of

all cancers. one substance-asbestos-is at the

center of litigation over claimed illness that could

result in insurance payments in the tens of billions

of dollars over the next three or four decades.

A large asbestos company has had more than

16,500 lawsuits filed against it and, as a result,

has filed for reorganization under the Bankruptcy

Act. Clearly, occupational illness has a serious and

far-reaching impact not only on society as a whole

but also on individuals who face impaired health

and shortened lifespans.

What steps are being taken to mitigate this

problem? Scientific and industrial response has

varied: environmental and biological monitoring,

engineering controls, personal protection devices,

and modified work practices are among the techniques used today.

And on the horizon is an emerging technology

–genetic testing–that may prove useful in reducing occupational disease, especially disease arising from exposure to two main workplace hazards: chemicals and ionizing radiation. That new

technology—its potential applications and its limitations, its current state of development, and its

legal, ethical, and social implications—is the subject of this report.

Genetic testing, as used in the workplace, encompasses two types of techniques. Genetic

screening involves examining individuals for certain inherited genetic traits. Genetic monitoring

involves examining individuals periodically for en-

*’I hr nllnlt)f’r of lost w (Irk{id}s ]s t)iisf’(1 (m a sun fw t)y the BLIJ’f’iILI

. .

01 I .at)OI” stat ist 1[’s \$hl(’h ‘i(’k Il(l\$’lf’(lgf’h t hilt 11)(’ t’igu [’(’ LIJN](’I’St:it(’S

thr dn)ount of ()([l]~):iti{)ll:il illness t)w<iusf’ the sun f~> dof~s not a(l(’-

(ludt(’l\ rf~tlfwt (hroni( (1 ib[ww~s aII(l 1 hoso” w ith h )ng kitfw~ [)(lrlods

vironmentally uced changes in the genetic material of certain cells in their bodies. The assumption underlying both types of procedures is that

the traits or changes may predispose the individuals to occupational diseases. (Changes in the

germ cells--egg and sperm-could result in birth

defects in offspring but such reproductive effects

are not part of this study.)

Although this technology is still in its infancy,

it has the potential to play a role in the preven -

tion of occupational diseases. It is technologically

and economically impossible to lower the level of

exposure to hazardous agents to zero. However,

if individuals or groups who were predisposed

to specific types of occupational illness could be

identified, other preventive measures could be

specifically directed at those persons. This is the

promise of genetic testing. At the same time, however, the technology has potential drawbacks and

problems. For example, the ability of the techniques to identify people who are predisposed to

occupational illness has not been demonstrated.

In addition, some people are concerned that its

use could result in workers being unfairly excluded from jobs or in attention being directed

away from efforts to reduce workplace hazards.

While it may be too soon to be able to answer

many of the questions raised by genetic testing,

it is not too soon for society to begin to consider

them. The technology is developing, and some major companies have used it to a limited degree,

Many more companies have expressed an interest

in using it in the future. Moreover, genetic testing

is one of a number of technologies that purport

to identify people, both in and out of the

workplace, who face an increased risk for disease.

Policy decisions made on issues raised by genetic

testing are likely to be relevant to the issues raised

by those other technologies. Thus, the Committee on Science and Technology of the House of

Representatives requested an assessment of genetic testing in the workplace.

5
6 . The Role of Genetic Testing in the Prevention of Occupational Disease

Health hazards in the workplace

While there are many different kinds of hazard

ous substances or physical agents in the workplace, this report focuses on chemicals and ionizing radiation. It is for these two categories of

hazards that genetic testing has been used and

that some data exist for evaluating the scientific

validity of such tests.

Virtually all chemicals are hazardous, if a person is exposed to a sufficient degree. Chemicals

may be irritating, toxic, mutagenic, teratogenic,

and/or carcinogenic. Moreover, the hazard of

working with chemicals is compounded by the

likelihood of multiple exposures to one or more

chemicals over time. Exposure to more than one

chemical may result in a synergistic effect—

damage greater than the additive damage of the

individual exposures,

The exact number of hazardous chemicals

found in the American workplace is unknown.

An Environmental Protection Agency (EPA) inventory lists more than 55,000 different chemicals

in commerce, most of which are hazardous at sufficiently high exposure. Chemicals are found not

only in companies that produce them but

throughout the manufacturing sector, The National Institute for Occupational Safety and Health

estimated that 8.9 million workers in the manufacturing sector were exposed to hazardous chemicals in 1980.

Photo credit: Off/cc of Technology Assessment

Chemical manufacturing plants sucn as the one shown

produce hazardous chemicals to which

workers may be exposed

Ionizing radiation is energy in the form of

waves or particles that produce certain charged

particles in passing through matter. X-rays are a

well-known example of ionizing radiation. This

radiation can harm exposed individuals or their

unborn children, For the exposed individual, the

principal risk is that he or she may develop cancer. For unborn children, the principal risks are

childhood leukemia and birth defects.

Occupational exposures to ionizing radiation

(above natural background levels) occur in many

fields, such as the health professions, nuclear fuel

mining and production, industrial testing, and 1aboratory research. Estimates of the number of exposed workers have varied from 750,000 by the

Committee on the Biological Effects of Ionizing

Radiation to 1.1 million by EPA.

Photo credit; Department of Energy

Protective clothing worn by employees in nuclear power

generating facilities to avoid radiation exposure
Ch. l—Executive Summary ● 7

The use of genetic testing for the

prevention of occupational disease

The problem of occupational diseases resulting

from exposure to chemicals or ionizing radiation

can be addressed in many ways. These include

lowering exposure levels through engineering

controls, physical and biological monitoring of exposure levels, medical screening and monitoring

of workers, and individual protective devices.

Genetic testing falls within the category of medical

screening and monitoring.

THEORETICAL FOUNDATIONS

Genetically determined individuality is a fact of

life. People differ not only in such obvious physical characteristics as height, facial features, and

skin color, but also in ways that can be determined only in a laboratory, such as by blood type

or types of proteins found in blood serum. Variations in some characteristics or traits result from

the interaction of many genes; variations in other

traits result from variations in a single gene that

controls that trait. The probability of any two people (except identical twins) being exactly alike is

astronomically small.

Genetic variability is also a factor in the differing reactions of people to environmental stresses,

which include disease-causing agents such as bacteria, viruses, and chemicals. For example, some

people have a deficiency in an enzyme called glu -

cose-6-phosphate dehydrogenase (G-6-PD). The

production of this enzyme is controlled by a single gene, and the deficiency is caused by a variant form of the gene. The deficiency usually is

harmless. However, if these people take certain

drugs for malaria or eat fava beans, they may suffer from acute anemia, due to the destruction of

their red blood cells. Thus, G-6-PD deficient individuals are at a higher risk of illness than other

people when exposed to those environmental

stresses. Some scientists have postulated that people with G-6-PD deficiency may also be at increased risk of disease in workplaces where they

are exposed to chemicals that are similar to the

antimalarial drugs.

Many factors besides genetic makeup can cause

an individual to be predisposed to illness from environmental stresses. Some of these are age, sex,

preexisting illnesses, nutritional status, personal

habits (such as smoking), and prior exposure to

the environmental factors.

prior exposure is particularly important for the

purposes of this report. If the environmental factor is a chemical, it may be in the body at leveIs

at which even slight additional amounts could

cause illness. In fact, the prior exposure may already have begun the disease process even

though the disease may not yet have manifested

itself in overt symptoms.

These considerations lead to the concept in occupational medicine of unequal risk. People who

differ according to age, sex, medical history, nutritional status, lifestyle, genetic makeup, or prior

exposure to hazardous agents might differ in their

risk for future illness when exposed to hazardous

agents in the workplace. Some may be at increased risk; in other words, they might have a

higher probability than others for developing a

condition, illness, or other medically abnormal status. Theoretically, it should be possible to identify such people if the risk factors could be reliably identified and if the factors could be demonstrated scientifically to be correlated with an

increased risk of disease. In some cases, however,

depending on the disease mechanisms involved

and the state of scientific knowledge, it might be

possible only to identify groups at an increased

risk of disease. In other words, the group as a

whole might have a higher risk compared to other

groups, but it would be impossible to predict

which individuals in the increased risk group

might develop the disease. Genetic testing is a collection of emerging techniques that may eventually permit the identification of individuals or

groups at increased risk to certain occupational

diseases.

DETECTION OF INCREASED RISK IN

INDIVIDUALS OR GROUPS

The term genetic testing applies to several techniques used to examine workers for particular

inherited genetic traits or environmentally induced changes in the genetic material of certain

cells on the assumption that the traits or changes

may predispose them to illness. It has been used

by some manufacturing companies and utilities

for medical evaluation and by others for research.
8 ● The Role of Genetic Testing in the Prevention of Occupational Disease

There are two inherently different kinds of testing, genetic monitoring and genetic screening,

whose results can be used in the workplace for

different purposes.

Genetic monitoring involves periodically examining a group of workers by collecting blood or

other body fluids to assess whether genetic damage has occurred in certain cells. This damage

may indicate exposure to a hazardous agent, such

as a carcinogenic chemical or ionizing radiation.

It may also indicate the possibility that the exposed group will be at an increased risk of developing disease, most likely cancer. The procedure focuses on the risk for the exposed group

as a whole because there is no evidence to suggest that it could be used to identify which individuals in the group are at increased risk. If the

scientific validity of genetic monitoring were fully

established, it would have potential as an early

warning system, by indicating that exposures to

known or suspected carcinogens are too high or

that a previously unsuspected chemical should be

viewed as a potential carcinogen,

In contrast, genetic screening, when used in the

workplace, is a one-time testing procedure to determine if a person has particular genetic traits,

regardless of whether the person has been exposed to a hazardous substance. The traits are

identified through laboratory tests on body fluids,

usually blood. Some scientists have hypothesized

that these genetic traits might predispose an individual to adverse health effects in the presence

of particular chemicals. While normally not harmful, the traits theoretically may make the individual more susceptible to blood-damaging chemicals, pulmonary irritants, oxygen deprivation, or

other physical or chemical stresses in the workplace.

In sum, genetic screening has the potential to

determine individual susceptibility to certain hazardous agents, It may be that, in time, genetic

monitoring also will be able to determine individual susceptibility; however, currently it appears

only to have potential for assessing a chemical’s

effect on an exposed population as a whole, Because of this distinction, screening could be used

to exclude genetically susceptible individuals from

jobs where they would be exposed to hazardous

substances, whereas monitoring would most likely indicate a need to lower exposure levels for a

group exposed to a previously unknown hazard.

POTENTIAL BENEFITS AND RISKS

Although genetic testing is still in its infancy,

its advocates believe that it might be able to play

an important role in the prevention of occupational disease. It is technologically and economically impossible to attain a no-risk workplace by

lowering the level of exposure to hazardous substances to zero, However, if individuals or groups

who were predisposed to occupational illness because of past exposure to hazardous substances

or particular genetic makeup could be identified,

preventive measures could be taken by the company or the workers themselves. In addition to

the obvious and significant benefits from preventing serious illnesses, there could be indirect benefits, such as a reduction in the costs associated

with occupational illness for employers, employees, and society. These costs include medical, insurance, and legal expenses; time lost from work;

and disability or unemployment payments.

The use of this technology, however, raises several questions. Can the techniques truly predict

an association between genetic makeup or genetic

damage and disease? How much of the variation

in risk can be attributed to such predisposing

genetic factors and how much to variation in environmental exposure? Since many of the genetic

traits sought in screening happen to be distributed

unevenly among some races and ethnic groups,

could the use of the tests result in discrimination

on the basis of race or national origin? How will

the availability of the tests affect the employer’s

responsibility for maintaining a safe workplace?

How might these procedures affect efforts to reduce the level of hazardous substances in the

workplace? If the tests are predictive, to what

degree should society protect high-risk individuals

or groups, at what cost, and who should bear that

cost?
Ch. l—Executive Summary ● 9

Findings

Because genetic testing is an emerging technology, there is insufficient evidence to assess many

of its potential benefits, risks, and impacts. However, this report does examine the degree to

which it has been used, the current stage of its

development, expected future developments, and

various legal, ethical, economic, and policy issues

that it raises. This examination provides the basis

for a discussion of the broader social issues and

the options for possible congressional action.

Survey of the use of genetic testing

There have been conflicting accounts about the

extent of testing and the use of the results. None

of the accounts examined by OTA was based on

a rigorous, scientifically valid survey. Therefore,

in order to reduce the confusion and speculation

and to provide necessary data for policy analysis,

OTA surveyed major U.S. industrial companies,

utilities, and unions about their use of this technology.

The survey was conducted for OTA from February 25 to June 8, 1982, by the National opinion

Research Center (NORC), a nonprofit survrey research corporation affiliated with the University

of Chicago. NORC sent confidential questionnaires

to the chief executive officers of the 500 largest

industrial companies and 50 largest private utilities in the United States and to the presidents of

11 major unions representing the largest number

of employees in these companies. Of the 366 (65.2

percent) organizations responding, 6 (1.6 percent)

were currently using one or more tests, 17 (4.6

percent) used-some of the tests in the past 12

years, 4 (1.1 percent) anticipated using the tests

in the next 5 years, and 55 (15 percent) stated they

would possibly use the tests in the next 5 years.

Of the 17 organizations that have tested in the

past 12 years, 5 are currently testing. None of the

four responding unions reported any testing.

For each type of test, companies were asked

about the circumstances under which the tests

were done (that is, routinely, for research, or for

other reasons) and how employees were selected.

Respondents generally tested routinely or for

other unspecified reasons. Testing for sickle cell

trait was most often based on ethnicity; for other

types of tests, employees were selected on the

basis of job category. No organization reported

basing a genetic test on an employee’s sex.

The 18 respondents who are testing or have

tested took various actions based on the results.

The most common action reported—by eight organizations —was informing an employee of a potential problem. Five organizations transferred

employees. Two companies suggested the employee seek another job, and one changed or discontinued a product.

In evaluating the results of the survey, several

caveats must be considered. The most important

of these are:

Since the questionnaire instructed respondents to include any instances of testing, pos -

itive responses can include isolated cases as

well as long-term testing programs.

The questionnaire was not structured to provide information on the numbers of workers

tested.

Results of this study are more representative

of the larger companies in this survey than

other groups, since more large companies responded than did small ones.

Since approximately one-third of the population did not respond and the number of organizations testing is very small, any generalizing of these results to the study population

as a whole is not warranted.

The state of the art

This assessment took a two-stage approach to

analyzing the scientific data available on genetic

testing. First, the laboratory tests themselves were

evaluated to determine their reliability and validity, Then the available studies were evaluated to

determine if there is a correlation between the

genetic damage or trait in question and an increased risk for disease. None of the genetic

tests evaluated by OTA meets established

scientific criteria for routine use in an occupational setting. However, there is
10 ● The Role of Genetic Testing in the prevention of Occupational Disease

enough suggestive evidence to merit further research.

GENETIC MONITORING

The concept of monitoring workplace populations for genetic damage from chemicals or ionizing radiation is well grounded on a theoretical and

experimental base. Ionizing radiation and a wide

range of chemicals cause damage to the genetic

material in experimental animals and, in some

cases, humans. This damage may result in mutations, which are changes in the genetic information. The consequences of increasing the mutation rate of a population are not well understood,

but mutations have been implicated in several diseases, most notably cancer.

There are two major types of genetic monitoring methods-the established cytogenetic methods

which detect major structural changes in chromosomes and the newer noncytogenetic methods,

which detect damage to the DNA (deoxyribonucleic acid). The noncytogenetic methods, for

the most part, are still in experimental stages, but

eventually could lead to faster and less expensive

monitoring methods.

The detection of chromosome damage using

cytogenetic techniques is a fairly complex procedure. It requires skilled laboratory technicians

and is often labor intensive. But if laboratory variables are kept constant, chromosome damage can

be determined reliably.

There are two stages involved in the assessment

of genetic monitoring. The first determines

whether the agent actually causes the genetic

damage in a manner such that increasing dosages

of the agent gives increasing amounts of damage

(dose-response). The second stage of the analysis

asks whether the observed genetic damage actually will predict an increased risk for disease, If

good scientific evidence is available to support

both stages of the analysis (this is, that the hazardous agent causes genetic damage, and that this

damage predicts an increased risk for disease),

then the assumption can be made that the agent

causes disease. OTA found that there are some

studies where a dose-response relationship has

been established, but there are few studies showing a correlation between genetic damage and an

increased risk for disease.

A large number of studies on workplace populations, using cytogenetic techniques, have been

done, but there are several factors which make

the interpretation of these studies difficult. In

very few cases has the level of exposure of the

workers to the hazard been documented, making the establishment of a dose-response relationship impossible. Also, it is fairly well established

that other factors such as age, smoking and drinking habits, nutritional status, and the presence of

disease can cause differences in the level of

chromosomal damage. Because most studies have

not taken these factors into account, there is a

large variability in both exposed and unexposed

populations. When exposed populations are

studied, rarely is there found more than a twofold

increase in damage over the average of the unexposed population. Thus, given the variability of

the unexposed population, interpretations of

these studies are difficult. Finally, it is not known

whether chromosomal changes in blood cells reflect the presence of chromosomal damage in internal organs.

Studies done on populations exposed to ionizing radiation, including atomic bomb survivors

in Japan, are less equivocal than those for chemical exposure, mainly because radiation exposure

levels are more easily documented. The evidence

does show an increase in chromosomal damage

with increasing dose of radiation. This damage,

though, has not been correlated with an increased

risk for disease with one exception. Extensive

studies on the bomb survivors have shown clear

dose-related increases in both chromosomal abnormalities and various cancers for these populations as a whole. Yet there seems to be no correlation between the frequency of chromosomal abnormalities for a given individual and his or her

risk for cancer.

Currently, genetic monitoring has the potential

for use as a biological indicator of exposure to

workplace chemicals or ionizing radiation and

could aid in the identification of hazardous agents,

The correlation of induced genetic damage with

risk for disease has been shown statistically only

for the Japanese population exposed to ionizing

radiation from the atomic bombs, For people exposed to hazards in the workplace, more information is needed to elucidate other environmen-
Ch. I—Executive Summary ● 11

tal and genetic factors which may contribute to

increased risk for disease.

GENETIC SCREENING

Differential susceptibility to chemicals has been

predicted, in part, from differential reactions to

drugs, which have been extensively documented.

Explicitly defining this genetic differential

susceptibility is not yet possible given the current

state of knowledge; however, some data do exist

on a few genetic traits, implicating them in susceptibility differences to certain chemicals. The list

probably represents only a small percentage of

the genetic traits involved in responses to chemicals. This report examines the following traits:

glucose-6-phosphate dehydrogenase (G-6P-D) deficiency, sickle cell trait, alpha and beta thalassemia

trait, NADH dehydrogenase deficiency, serum

alpha1

-antitrypsin (SAT) deficiency, aryl hydrocarbon hydroxylase (AHH) inducibility, slow v. fast

acetylation, human leukocyte antigens (HLA), carbon oxidation, diseases of DNA repair, and several

other less well-characterized genetic traits.

OTA found that most tests for identifying these

traits are accurate and reliable, but only when

applied to subgroups already suspected of having the trait at a relatively high prevalence. Because the predictive value of these tests is low

when used in the general population, studies

using these tests could be seriously flawed. In fact,

the predictive value of the test, which is based

not only on accuracy but also on the prevalence

of the trait in the population, will only be high

when the prevalence of the trait is high,

There is some suggestive evidence, from adverse drug reactions and illnesses resulting from

exposures to chemicals, that associations may exist between certain traits and risk for disease from

particular occupational exposures. This report reviewed occupational studies on several genetic

traits and found that the data were not extensive

enough to draw any conclusions on the correlation between given genetic traits and risk for disease. On the other hand, the data are suggestive

of these correlations, and research seems indicated for attempting to determine these relationships.

Genetic testing and the law

Genetic testing raises legal questions related to

workplace safety and employee rights. Although

the law generally has not dealt with genetic testing, many existing legal principles are directly applicable to the issues raised by this technology.

Moreover, employers and unions could negotiate

mutually agreeable solutions to the problems

raised by genetic testing. Unions, however, have

no legal duty to bargain over such issues or to

take special steps to protect workers who might

be at increased risk.

The employer has the legal responsibility for

workplace safety. Failure to meet the responsibility can result in costly judgments or civil or criminal penalties against the employer. This responsibility would not require the employer to use genetic testing, even if it were highly predictive of

future illness. If the employer chose to use a highly predictive test, it would probably be negligent

if it ignored the results and placed employees in

a high-risk rather a than low-risk environment.

However, recovery of damages by such an employee who developed the predicted illness would

probably be barred by the “exclusive remedy”

provision of workers’ compensation laws and possibly by the doctrine of assumption of the risk,

if the employee had been informed of the risk.

If the risk had been concealed from the employee,

recovery probably would not be barred under

workers’ compensation laws, and the employer

would face the possibility of punitive damages.

Under the Occupational Safety and Health Act

of 1970 (OSH Act), the Secretary of Labor is empowered to promulgate standards that protect all

employees from toxic substances to the extent

that the standards are directed toward a significant risk to health and to the extent that they are

technologically and economically feasible. These

standards can, among other things, set maximum

exposure levels, require personal protection gear,

and require various medical procedures. The feasibility requirement may leave some percentage

of exposed workers at risk, depending on the

circumstances of the particular hazardous

substance and industry. Of those workers at risk,
12 ● The Role of Genetic Testing in the Prevention of Occupational Disease

some may be genetically susceptible and others

may be at increased risk because of genetic

damage. An open question is whether the courts

would allow a standard designed to protect a very

small number of susceptible individuals or would

invalidate it on the grounds that it failed to address a significant risk because of the small

number of workers involved.

The OSH Act and regulations thereunder neither prohibit nor require genetic testing. However, the Secretary of Labor has broad authority to regulate employer medical procedures as

long as the regulation is related to worker health

and meets the feasibility and significant risk requirements. Therefore, the Secretary could require genetic testing in its various forms, if the

techniques were shown to be reliable and reasonably predictive of future illness. The Secretary

also could regulate the use of genetic testing, but

only to the extent that the regulation was related

to employee health. The act grants no authority

over rights or conditions of employment per se

and no authority to protect applicants for employment from discrimination.

State and Federal laws place few restrictions

on how medical exams or testing procedures may

be conducted in the workplace and what the employer does with the resulting information other

than the requirements that the procedure not be

negligently performed and that the employee be

informed of potentially serious health risks. Submission to medical exams, which include various

tests, can be a valid condition of employment. As

a result, employees or applicants would have no

right to refuse to participate without jeopardizing their job. Moreover, participation in research

can be a valid condition of employment. How

much the employee needs to be told about the

research is unclear, except in two cases. If the

research were federally funded, subjects must

understand the risks and other aspects of the

study and consent to them, A few States require

research to be reviewed by special boards in

order to protect the interests of human subjects,

and these boards may require informed consent.

With respect to the data generated by genetic

testing, there are few requirements regarding

confidentiality except in the State of California.

But employees have a right of access to medical

records under Occupational Safety and Health Administration (OSHA) regulations and unions have

a similar right under a recent decision by the National Labor Relations Board. This access could

help prevent abuse of genetic testing. However,

those who face the greatest risk of being denied

employment because of their genetic makeup—

job applicants—would not have access to the test

results.

For those applicants or employees who were

subject to some adverse job action because of

their genetic makeup, Federal and State antidiscrimination statutes may offer some relief.

However, they do not deal specifically with genetic screening except for a few State statutes that

prohibit employment discrimination on the basis

of certain genetic traits, usually sickle cell trait.

Title VII of the Civil Rights Act of 1964 prohibits

discrimination in employment based on race, color, religion, sex, or national origin, In addition to

intentionally discriminatory actions, neutral employment practices that have a disparate impact

on a protected group may violate title VII. Some

types of genetic screening, such as for sickle cell

trait, would have a disparate impact; therefore,

an adversely affected genetically susceptible employee in one of those classes would have a prima

facie case of discrimination. Then, the employer

would have the burden of justifying the screening program by demonstrating its relation to legitimate job requirements or business needs. It is

presently unclear whether using genetic testing

to screen out employees who might become ill in

order to avoid the cost of engineering controls

is a business necessity. Nor is it clear whether the

employee’s capacity to perform the job without

a risk of future illness is a legitimate job requirement. However, it is clear that any job selection

method must be predictive of the characteristic

for which it allegedly selects. Since the ability of

genetic screening to identify workers at increased

risk for disease has not been demonstrated, a program that had a disparate impact on the employment opportunities of the classes protected by

title VII probably would violate that act.

The Rehabilitation Act of 1973 prohibits employment discrimination against otherwise qualified handicapped people by employers who are
Ch. l—Executive Summary ● 1 3

Government contractors or recipients of Federal

assistance. Virtually all of the States have similar

statutes, and the State laws usually offer broader

protection to handicapped people. These statutes

offer a greater potential than title VII for aiding

the employment opportunities of genetically susceptible individuals; however, for those laws to

be applicable, two currently unresolved legal

questions must be settled in favor of the employees. The first is whether or not a particular genetic makeup is a handicap. If not, these employees

would have no rights under these laws. If it is a

handicap, the next question is whether employment may be denied to handicapped individuals

on the basis of a reasonable probability of future

illness. If the courts were to rule that future risk

of illness was not a legitimate area of inquiry for

employers, the Rehabilitation Act and similar statutes would prohibit adverse job actions on the

basis of genetic makeup. If risk of illness were

recognized as a legitimate concern, the employer

wouId have the burden of showing the genetic

screening techniques were reasonably predictive

of illness. Even if the employer demonstrated this,

however, it might have to accommodate the “genetically handicapped” employee anyway. But

such accommodation probably would not require

the installation of expensive engineering controls

to lower exposure. *

Ethics of genetic testing

Because genetic testing is relatively new and has

not been widely used, there is little direct experience on which to make judgments regarding its

use, Nor are there direct legal precedents. Under

these circumstances, it is appropriate for policymakers and others involved in decisions concerning this technology to look to ethical principles

for guidance.

Ethics may be defined as the study of moral

principles governing human action. These principles, or general prescriptive judgments, create

moral duties that guide action in particular circumstances. Sometimes, however, the principles

conflict in their application and provide no clear

guidance. Then, difficult choices must be made.

“()’1’.1 is conducting a study on the use of engineering controls

to enhanre worker safety and health.

Such is the case with genetic testing in the workplace.

Genetic screening and monitoring are not inherently unethical. The tests are morally justified

to the extent they enhance worker health in a

manner consistent with established ethical principles. Whether or not they are consistent with

these principles will depend on how the tests are

done and how the information is used.

Ethical principles regarding the duties of company medical personnel toward workers are often

conflicting or not well established. Therefore,

they offer little specific guidance about the manner in which tests should be conducted with the

exception of procedures done for purposes of

medical research. In cases of research on humans,

ethical principles are well established and provide

for the rigorous protection of individual rights

and interests.

Ethical principles constrain how the results of

genetic testing may be used. In the absence of a

significant correlation between genetic endpoints

(traits or evidence of damage from exposure) and

disease, it would be unethical for the employer

to act adversely to the employee’s interests, such

as by denying him or her a job.

In the hypothetical case of a strong correlation

between genetic endpoints and disease, the morally correct course of action is significantly less

clear. For screening, the employer might justify

excluding susceptible workers from certain jobs

on the grounds of benefiting the employees. on

the other hand, employees might claim that they

have the right to decide whether to assume the

risk. Whether or not genetically susceptible people are entitled to protection from discrimination

or compensation for harm depends on which of

several theories of justice is chosen. For monitoring, the most ethically feasible course of action

for an employer would be to inform the workers

of adverse findings and to reduce worker exposure, Failure to do so would be inflicting harm,

and it is unlikely that the group would consent

to assuming this risk.

Economic evaluation of genetic testing

Genetic testing in the workplace has potential

benefits and costs to workers, employers, and so-
14 . The Role of Genetic Testing in the Prevention of occupational Disease

ciety as a whole. The magnitude and distribution

among the sectors of society of these benefits and

costs will help determine the desirability of this

approach to improving occupational health. Two

techniques of economic evaluation-cost-benefit

and cost-effectiveness analysis—are methods for

collecting, organizing, and presenting evidence

about the benefits and costs of alternative courses

of action so that choices can be better informed.

They are systematic approaches to examining the

tradeoffs among the different kinds of consequences–for example, dollar outlays today v. improved levels of health 5 years hence—stemming

from a decision.

The usefulness of economic evaluation rests on

its ability to improve decisions. Even when economic analysis is severely limited by uncertainties about the magnitude, direction, or value of

certain consequences, as with genetic testing, it

can still be a useful exercise. The identification

of key areas of uncertainty, for example, can be

used to set priorities for further research, Thus,

economic evaluation can be used to dissect and

examine alternative strategies in order to understand their underlying assumptions and uncertainties.

In the case of genetic testing, rigorous economic

analysis of the costs and benefits is not possible

because of the lack of knowledge about the association between test results and risk of disease,

the numbers of people to whom testing could be

applied, and the amount of occupational disease

that could be prevented, If additional information

became available, economic analysis could provide a rough sense of the benefits, burdens, and

tradeoffs associated with genetic testing programs.

Congressional issues and policy options

ISSUE: What actions could Congress take

with respect to genetic testing in

the workplace?

OPTIONS:

A. Maintain the status quo,

Congress could choose not to take any action

to stimulate, constrain, or regulate genetic testing.

This would allow private parties to continue research into the merits of the technology. Constraints on its use would develop through court

rulings in lawsuits between these parties or by

negotiations between companies and unions. Interested congressional committees could continue

their practice of holding oversight hearings to

raise the issues for public discussion.

The primary argument supporting this option

would be the view that congressional action

would be premature. The technology is not being widely used, and it is primarily in the research

phase of its development. In addition, there are

existing constraints on its potential misuse. These

include the possibility of lawsuits and adverse

publicity. Finally, much of the important information necessary for legislation is unavailable because it is unknown. For genetic screening techniques, this information includes the number of

workers who might be genetically predisposed

to disease, the extent to which they might face

adverse employment actions, the availability of

other employment opportunities, and the cost of

safeguarding these workers. For genetic monitoring techniques, this information includes their

predictive value, the extent to which they might

be used, and the costs associated with either using

or not using them.

The arguments against this option relate to how

society controls an emerging technology. Many

policy decisions will need to be made with respect

to genetic testing, and arguably Congress is a better forum for doing so than the courts or private

parties. Congress can gather all information and

viewpoints and then balance the conflicting interests. In addition, while the courts often play

a major regulatory role for any technology, they

are limited in their ability to encourage the development of a technology in a positive manner.

However, Congress can do so by providing funds

for research or other incentives.
——-.—

Ch. I—Executive Summary 1 5

B. Stimulate the technology’s development and

use.

Congress could stimulate the technology by providing money for research on the techniques, for

epidemiological studies to determine associations

between genetic endpoints and disease, and for

basic research on the cause of occupational disease in general, If genetic testing could be developed to the point where the tests are predictive

of an individual’s or group’s increased risk of occupational illness, their use could result in a number of direct and indirect benefits. The principal

direct benefit would be a lower incidence of occupational disease among workers. They and

their families would be spared some of the pain,

cost, and emotional trauma that accompany illness. In addition, employers would save some of

their direct and indirect costs of occupational disease-employee time lost from work, insurance

premiums, legal fees, and monetary damages assessed in lawsuits. Society would benefit through

the greater health and productivity of its work

force. A major indirect benefit of developing this

technology might be a greater understanding of

the causes of occupational disease and disease in

general.

The principal argument against this option is

the concern about the potential misuse of the

technology and about potential adverse impacts.

Some of these concerns relate to unfair employment discrimination and attention being directed

away from other ways to address occupational

diseases. These concerns might be dispelled by

regulation to direct the technology’s development

in socially desirable ways. In fact, if the tests were

highly predictive of future illness, OSHA could require their use and constrain how they were

used, so long as those constraints were shown

to enhance worker health and were not directed

merely toward prohibiting unfair employment

practices.

Another drawback to this option is the fact that

there is no definitive information on the amount

of occupational disease that could be prevented

by genetic testing, even if the tests were reliable

predictors of disease. Similarly, there is no information on what it would cost to develop the tests

to the point of clinical usefulness.

C. Prohibit the use of genetic testing in the

workplace.

The principal reason for prohibiting genetic

testing in the workplace would be concern over

its potential misuse, particularly at its current

stage of development where its ability to predict

future disease has not been demonstrated. This

potential for misuse probably would be greater

for genetic screening than genetic monitoring because the former is targeted toward identifying

individuals at increased risk while the latter

focuses on groups at increased risk. However,

concern exists that employers might use either

type of test to exclude individuals from jobs. Existing law may offer protection in some circumstances, but there are many questions to be resolved. The collective bargaining process could

be used by unions to negotiate protection for

workers, but the primary focus of bargaining has

been economic matters. While health matters

have also been important, little, if any, negotiating

has occurred with respect to genetic screening.

In addition, most of the work force is not unionized. Moreover, these remedies are not helpful

if a susceptible person does not know why he or

she was denied a job. Finally, while ethical principles provide guidance for the proper use of this

technology, it is difficult to know if they are being

followed.

The principal drawback to this option is that

it is a drastic solution to the problem of potential

misuse. Genetic testing does not appear to be

widely used. Law, ethics, and public opinion provide incentives against its misuse. Moreover, banning its use would prevent research that might

determine its usefulness in preventing occupational disease or provide basic knowledge about

occupational disease.

Another argument in favor of this option would

be the claim that an employee’s risk of future illness is not an appropriate factor for job selection,

even if screening or monitoring were highly predictive, Employees have no control over their genetic makeup and generally have no control over

previous exposures to harmful agents, In addition, their increased risk would not affect their

current ability to do the job.
16 ● The Role of Genetic Testing in the Prevention of Occupational Disease

There are at least two counterarguments to the

assertion that risk of illness should not be a job

selection factor. First, society accepts the proposition that immutable characteristics can be proper criteria for employment selection. Intelligence

is at least an implicit selection criterion for many

professional jobs and physical attributes are exceedingly important for jobs ranging from professional basketball to neurosurgery. Second, this

viewpoint places the autonomy interests of the

individual above the interests of society in lowering the costs of occupational illness even when

it may not be feasible to take other steps, such

as lowering exposure,

D. Regulate the technology.

This option represents a judgment that any

risks presented by the technology can be controlled and that the claimed benefits will be of

value to society. The option would permit research to continue, yet constrain the manner in

which genetic testing is used, One type of constraint would be limitations on what job actions

employers could take on the basis of test results.

Another type of constraint would be a requirement that the tests meet minimum standards of

scientific validity before employment decisions

were made on the basis of the results. Such a statute need not specify detailed standards; it could

adopt a standard such as “reasonably predictive

of future illness” and allow the appropriate agency to provide details.

This option has the advantage of addressing the

potential risks of genetic testing immediately and

in a comprehensive manner rather than waiting

for the law to develop on a case-by-case basis

through the courts. Congress may be uniquely

able to study the problem fully, balance competing interests, and provide comprehensive yet targeted solutions.

A possible drawback of this option is that the

problem may not yet be “ripe” for congressional

action. On the basis of available evidence, genetic

testing in the workplace does not appear to be

widespread. Moreover, there is no available evidence about: 1) the number of workers who potentially could be screened or monitored if the

tests were sufficiently predictive, 2) the number

who might be excluded from jobs, 3) the ease with

which excluded workers could find comparable

jobs, and 4) the costs of various regulatory

alternatives.

E. Encourage the development of voluntary

guidelines on the acceptable use of genetic

testing.

Congress could request the National Academy

of Sciences or a similar body to establish a special

commission of representatives from industry,

labor, academia, and other sectors of society to

draft voluntary guidelines for the use of the tests,

This would allow the parties most involved to

make the difficult value judgments in balancing

competing interests and would avoid direct governmental regulation.

ISSUE: How could Congress regulate genetic testing in the workplace?

OPTIONS:

A, Constrain employment actions that may be

taken on the basis of genetic testing.

Congress could address many of the concerns

raised by genetic testing by regulating how employers may use the results of the tests, even if

they were highly predictive. The following represent some possible elements of such an approach:

1) prohibit job exclusion on the basis of genetic

makeup or genetic damage, 2) prohibit job transfers because of genetic makeup or genetic damage

unless the transfer were to a comparable job at

comparable pay and benefits, 3) require strict confidentiality of medical information, and 4) require

that employees be told the results of testing and

be given counseling.

This option clearly would protect the interests

of workers, preventing potentially serious consequences to individuals who have no control

over the reason for the discrimination. In addition, no difficult judgment would have to be made

as to how predictive the tests should be before

they are permitted.

There are at least two major disadvantages to

this option. First, it may be too broad, If not carefully drafted, a statute could reach genetic diseases (not traits) that do affect an employee’s current ability to perform the job safely and effective-
Ch. I—Executive Summary 17

ly. It is generally accepted that inability to perform a job, even for medical reasons, is a valid

criterion for job selection. Second, if workers with

certain traits were in fact predisposed to occupational illnesses and chose to ignore that information, the additional direct and indirect costs of

their illnesses eventually would be borne by society. This would be the case even if employers were

required to install additional engineering controls,

since the costs of those controls would be passed

on to society. On the other hand, if excluded

workers were unable to find comparable jobs, society would bear the costs of lost productivity and

possibly additional unemployment payments. The

answer to the question of who should bear the

costs associated with genetically predisposed or

damaged individuals will depend not only on economic analyses but on prevailing political views

of distributive justice.

B. Prohibit employment decisions on the basis of

genetic testing unless the employer can demonstrate that the results are reasonably (or substantially) predictive of future illnesses.

This option places the burden on an employer

to justify the claimed correlation between test

results and risk of illness. The specific criteria for

meeting a necessarily general statutory standard

could be provided by agency regulation and case

law.

There are several advantages to this option, especially when compared to option A. First, it focuses on the immediate concern of job denial on

the basis of poorly predictive tests, thus protecting employees’ interests. Second, it protects employers’ interests in lowering their costs from

occupational diseases by allowing the exclusion

of certain workers when there is a rational, scientific basis for doing so. Third, it would allow research on the techniques to continue.

The principal drawback of this option is that

it could be a de facto determination without a full

public debate that future risk of illness is a proper job selection criterion. On the other hand, there

is a substantial lack of the type of information desirable for deciding this fundamental issue at this

time.

C. Amend the Rehabilitation Act of 1973 to state

that genetic makeup is a handicap and clarify

whether individuals who are genetically predisposed to illness are considered to be “otherwise qualified” within the meaning of that act.

A major advantage of this option would be

working with an existing statute rather than devising an entirely new one. Sections 503 and 504

of the Rehabilitation Act deal with problems that

conceptually are very similar to those posed by

genetic screening. If applied to genetic screening,

the act would require at a minimum that the tests

be reasonably predictive of future illness.

On the other hand, this option would force legislative activity into an existing statutory framework that may not be completely suited to genetic

screening. The Rehabilitation Act was designed

to bring millions of handicapped people into the

mainstream of American life. Genetic screening

has not created a problem anywhere near the

magnitude of that addressed by the Rehabilitation Act. Moreover, section 503 requires employers to take affirmative action to employ the handicapped. Congress may not wish to require affirmative action to employ people who are genetically predisposed to occupational illness, if that predisposition can, in fact, be demonstrated.

D. Require that research on employees be done

according to existing Federal regulations designed to protect human subjects of research.

The Department of Health and Human Services

has promulgated regulations governing federally funded biomedical and behavioral research on

humans. The regulations contain a number of

provisions designed to protect the interests of the

research subjects. Requiring private companies

to follow these regulations in research involving

genetic testing or any other kind of research done

in the workplace would mitigate the potential for

abuse.

E. Require full disclosure to employees and their

representatives of the nature and purpose of

all medical procedures performed on employees.

Under current law, employees and unions have

access to employee medical records, but employers are not required to disclose the nature

and purpose of medical procedures and how the

results are used. Required disclosure of this in-
18 . The Role of Genetic Testing in the Prevention of Occupational Disease

formation to the employee at the time the procedure was being performed would be a strong incentive to employers for self-regulation. If workers and their medical advisors had full knowledge

of a company’s medical procedures, they could

take steps to prevent abuses, through negotiation

or legal action. Publicity alone could prevent the

worst abuses. This would also protect the autonomy interests of workers by allowing them to be

part of a decisionmaking process that affects their

health and economic interests. Some of the arguments against this option would be that it might

be burdensome and costly for employers and that

it would intrude too much on the professional

judgment of the occupational medical specialist.

ISSUE: How could Congress foster the development and use of this technology?

OPTIONS:

A. Fund research for the development of tests

with high reliability and validity.

Genetic variability and differential susceptibility

to toxic chemicals are well-established concepts

in the scientific literature. Currently there are

many genetic screening tests which could be done

in a workplace setting to detect potentially susceptible individuals. For the most part, these tests are

accurate, reliable, and valid for identifying the

genetic traits in question when applied to subgroups already suspected of having the trait at

a relatively high prevalence; a notable exception

is the test for aryl hydrocarbon hydroxylase

(AHH) inducibility. Research on developing tests

for those traits which are more prevalent in the

population should receive higher priority because

they are more likely to have a high predictive value. The only test covered in this report which falls

into this category is AHH inducibility.

With respect to genetic monitoring, the notion

that exposure to toxic chemicals and ionizing

radiation can cause genetic damage in humans

is less well established scientifically than the concept of differential susceptibility. However, there

is an overwhelming amount of evidence that this

is true in experimental mammals. Moreover, the

impact of genetic damage on one’s risk for disease,

especially cancer, or on future generations is not

known, yet the current thinking of the scientific

community is that increased amounts of genetic

damage is generally deleterious.

Alternatives are needed to the time-consuming

cytogenetic tests currently in use. If genetic

monitoring is to be done on a large scale, the availability of automated tests becomes important. The

development of various noncytogenetic methods

could be useful in this respect. Those that show

promise currently include tests for detection of:

mutagens in urine, alkylated hemoglobin, HGPRT

mutation in lymphocytes, hemoglobin mutations,

chemically damaged DNA bases, and LDH-X variants in sperm. For both cytogenetic and noncytogenetic tests, a better understanding of the factors that contribute to genetic damage in the absence of occupational exposure is needed (that is,

a “normal” or baseline response) in order for the

tests on exposed populations to be meaningful.

The government agencies which could be involved in these studies include the Environmental Protection Agency (EPA), the National Institute

for Occupational Safety and Health (NIOSH), and

the National Institute for Environmental Health

and Safety (NIEHS).

B. Fund epidemiologic studies in occupational settings directed by NIOSH or NIEHS.

Data are most lacking concerning the correlation of genetic traits or genetic damage to an increased risk for disease. Epidemiologic studies in

an occupational setting can address this problem.

If these studies were to be undertaken, they must

use good epidemiological practices and document

exposures. Studies should only be undertaken if

they are likely to yield statistically reliable data.

For instance, genetic monitoring studies would

require exposure levels high enough to yield a

clear-cut statistical response between exposed and

nonexposed groups without having to use excessively large numbers of people. Especially important would be to establish a dose-response relationship. Genetic screening studies would have

to focus on genetic traits which have a significant

prevalence in the population (greater than 1 percent).
Ch. l—Executive Summary 19

Epidemiologic studies are very costly and difficult to control, especially if they run over long

time periods. Some genetic screening studies

could be done in a short time (1 to 3 years) once

a population with the trait was selected because,

presumably, the symptoms of disease resulting

from exposure would manifest themselves soon

after exposure. These traits include the red blood

cell traits. Most of the other traits reviewed here

are potentially correlated with diseases which

have a long latent period, such as emphysema and

cancer. To correctly assess the exposure information with the disease endpoint, much longer

epidemiologic studies (10 to 30 years) are necessary.

For genetic screening, higher priority should

be given to studies on traits which have a high

prevalence in the population. These include SAT

deficiency, AHH inducibility, carbon oxidation

ability, and the association of particular human

leukocyte antigens with risk for disease.

Epidemiologic studies using genetic monitoring

techniques would have to be long term in order

to determine the association between genetic

damage and cancer. The chemicals chosen for

study would have to be selected carefully. Many

of the agents discussed in this report are known

already to cause cancer in humans (for example,

ionizing radiation, benzene, vinyl chloride), and

occupational exposure to these is very low and

possibly not detectable by the genetic techniques

now in use.

C. Establish a federal!y funded data bank, directed

by NIOHS, EPA, or NIEHS, to be used in the

stud&v of the causes of differential susceptibility to occupational disease.

Because the study of the effects of harmful

agents includes many scientific disciplines, it

would be useful to have the relevant data collected in an accessible location. This computerized

data bank could include not only genetic factors

affecting toxicity, but developmental, aging, nutritional, and lifestyle factors as well. The data bank

would include epidemiologic studies that have

been or are being done in occupational settings,

either governmentally or privately funded (somewhat in the same manner as EPA’s Gene-Tox Program). Those working in the field of genetic toxicology could draw on the information in the bank

in order to design studies and to prevent duplication of effort. The toxicology data would be of

considerable value to various regulatory agencies

in their standard setting.
Chapter 2

Introduction: Occupational

Illness and Genetic Testing
Contents

The Problem of Occupational Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Health Hazards in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Hazardous Chemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Ionizing Radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Control of Occupational Health Hazards.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Theoretical Foundations: Biological Diversity and Differential Susceptibility . . . . . . . . .

Detection of Individuals or Groups at Increased Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Potential Benefits and Risks of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Organization and Scope of Report . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure

Figure No.

l.Components of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23

24

24

25

25

27

27

27

29

29

30

Page

28
chapter 2

Introduction: Occupational

Illness and Genetic Testing

The problem of occupational illness

Occupational illness is a major problem in this

country. In a 1981 private sector work force of

approximately 75.6 million people, there were an

estimated 126,000 cases of work-related acute illness, which resulted in more than 850,000 lost

workdays, according to the Bureau of Labor Statistics (2). * Moreover, an estimated 5 percent of

all cancers are believed to be associated with exposure to harmful substances in the workplace

(17). * * Litigation over illness claimed to have

resulted from one substance alone—asbestos—

could result in insurance payments as high as $38

billion over the next 35 years, and one major

manufacturer of asbestos, faced with more than

16,500 lawsuits, has filed for reorganization under

the Bankruptcy Act (21,22).

The health risks posed by the workplace environment vary with the industry and the type of

job but are often associated with exposures to

harmful substances or agents. These substances

or agents include minerals, chemicals, and ionizing radiation. This report focuses on an emerging technology, genetic testing, that may be useful

in reducing occupational illness arising from such

exposure, especially to chemicals and ionizing

radiation.

*The accorac~ of these figures is subject to much debate among

the experts ‘1’he ~ureau of I,abor Statistics itself acknowledges that

the figurm understate the amount of occupational illness because

they do not adequately rcfle(t chronic diseases and diseases with

long latenr} peri[xis because of problems with detection and recognition (2) ‘1’hry are US(YI hwe simply to prolide the reader with a

gwreral notion of the magnitude of the problem.

● “F:stimating the amount of cancer associated with occupational

exposures is extremely difficult, and experts often disagree. In the

past, estimtites haie ranged from S to 38 percent In 1981, OTA

suggested that almost all estimates of work-related cancer fit into

a range of 10 ( ~ 5) percent of all cancer (141. Data presented at

an international conference on quantification of occupational cancer

suggest that the (ITA rstirnate ma}’ ha~e been too high (17). Five

percent now appears to be the fig;lre acceptable to most experts,

although some experts still argue for estimates greater than 20 per

cfmt I 17,19).

Genetic testing, as used in the workplace, encompasses two types of techniques. Genetic

screening involves examining individuals for certain inherited genetic traits (9). Genetic monitoring involves examining individuals periodically for

environmentally induced changes in their genetic

material. The assumption underlying both types

of procedures is that the traits or changes may

predispose individuals to illness. Although this

technology is still in its infancy, genetic testing

potentially could play an important role in the prevention of occupational diseases. It is technologically and economically impossible to attain a norisk workplace by lowering the level of exposure

to hazardous substances to zero. However, if individuals or groups predisposed to occupational

diseases could be identified, other preventive

measures could be specifically directed at those

persons. This is the promise of genetic testing.

At the same time, however, the technology has

potential drawbacks and problems. For example,

it could result in workers being unfairly excluded

from jobs or in attention being directed away

from efforts to “clean up” the workplace.

Because genetic testing is still in its infancy,

many of its potential impacts—both positive and

negative—at present cannot be precisely defined.

Nonetheless, it is not too soon for society to begin

to consider how genetic testing may affect us. In

industry, genetic testing has been little used to

date, but an Office of Technology Assessment

(OTA) survey has found several companies interested in using it in the future. Thus, this report,

requested by the Committee on Science and Technology of the U.S. House of Representatives as an

assessment of genetic testing, can provide a foundation for future debate as this technology continues to develop.

23
24 . The Role of Genetic Testing in the Prevention of Occupational Disease

Health hazards in the workplace

Of the many different kinds of hazardous substances or physical agents in the workplace,

chemicals and ionizing radiation are the two

categories of hazards for which genetic testing

has been used and for which some data exist for

evaluating the scientific validity of that testing.

Hazardous chemicals

Many, but not all, chemicals are hazardous.

Chemicals may be irritating, toxic, mutagenic,

teratogenic, and/or carcinogenic. They may enter

the body through the skin, the lungs, and the gastrointestinal tract. Contact with skin can produce

irritation and dermatitis. Breathing chemicals can

cause irritation or damage to the upper respiratory tract and the lungs. Contact with some chemicals through virtually any route may cause cancer.* Exposure to more than one chemical may

result in a synergistic effect--diamage greater than

the combined damage of the individual exposures.

The degree of risk posed by a hazardous substance depends on the degree to which a person

is exposed to it, and risks can be reduced by

reducing exposures,

There are more than 55)

000 different chemicals

in commerce (14). The percentage of these that

are hazardous at current exposure levels is unknown. Chemicals are found not only in companies that produce them but throughout the manufacturing sector. The National Occupational

Hazard Survey (NOHS), conducted by the National

Institute of Occupational Safety and Health,

estimated that approximately 8.5 million workers

were exposed to chemical hazards in the manufacturing sector during the years 1972 to 1974

(11). Because the manufacturing labor force grew

at a 0.7 percent annual rate during the years 1973

to 1979, the number of exposed workers in manufacturing in 1980 may have totaled 8.9 million

(11). According to the Occupational Safety and

Health Administration, exposure to chemicals is

the most important occupational health problem

because of the number of workers involved (13).

● The National Institute of Occupational Safety and Health has published a list of approximately 2,400 suspected carcinogens (14).

Photo credit: Occupational Safety and Health Administration

Exposure to chemicals in work-related environments over

long periods of time can be hazardous to health

For the individual, the hazard of working with

chemicals is compounded by the likelihood of

multiple exposures. A worker may be exposed to

numerous chemicals at any one time or over a

long period of employment. Rubber workers, for

example, are exposed to an estimated 3)

000 chemicals (18). The NOHS data indicate that more than

280 million chemical exposures* occurred in the

manufacturing sector during 1972 to 1974 (18).

By 1980, based on growth projections in the number of workers and in the number of chemicals, * *

chemical exposures among workers in manufacturing were estimated to be 361 million. * * *

● NOHS defined “exposure” as “employees’ iidud or potential, direct

or indirect, contact with any chemical and biological agent, or physical and safety condition” (1 1).

* *Data indicate that new chemical substances are generated at

the rate of about 8 percent annually and 5 percent of existing

chemicals are discontinued, resulting in an assumed annual growth

rate of 3 percent (3,12).

● * ● 47 Fed, Reg. 12092, 12108 (1982).
.

Ch. 2—introduction: Occupational illness ● 2 5

Photo credit’ Occupational Safety and Health Administration

Special clothing protects worker’s skin and respiratory

tract from exposure to toxic chemicals

Ionizing radiation

Ionizing radiation is energy in the form of

waves or particles that produces certain charged

particles known as ions in passing through matter. It may harm exposed individuals or their unborn children. For the exposed individual, the

principal risk is that he or she may develop

cancer. Radiation-induced cancers include leukemia and most of the commonly occurring solid

cancers. Other possible adverse effects of ionizing radiation include eye cataracts, nonmalignant

skin damage, blood disorders, and impaired fertility. Unborn children can be harmed in two

ways. The first is through radiation-induced adverse changes in the genetic material from their

parents, which can be passed on to future generations. The second is by direct in utero exposures

which can result in birth defects, growth retardation, or cancer (4).

Occupational exposures to ionizing radiation occur in many fields. In the health professions, for

example, exposures result from the use of medical

and dental X-rays and radiopharmaceuticals. In

industry, exposures result from the use of X-rays

and gamma rays for flaw detection and other testing of materials. In the production and use of nuclear energy, exposures occur for miners, fuel

processors, material handlers, and others. Radium

workers and research laboratory workers often

are exposed to ionizing radiation.

Estimates vary on the number of workers potentially exposed to ionizing radiation. The Environmental Protection Agency estimated that 1.1

million workers were potentially exposed in 1975

(4). * The Committee on the Biological Effects of

Ionizing Radiation estimated that approximately

7 50)

000 workers each year were potentially exposed, based on exposure data for different

groups in different years between 1969 and 1977

(8),

Control of occupational health hazards

To prevent occupational disease, health hazards

must be recognized, evaluated, and controlled.

● workem exws~ in mining operations were not included in these

estimates; there is little information on exposure of such workers

with the exception of underground uranium miners.
26 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Environmental and biological monitoring, engineering controls, personal protective measures,

and modified work practices are the techniques

used to accomplish this goal (1). Genetic testing

is just one of many techniques that fall into these

general categories, It could complement but probably not replace any of the existing techniques.

Recognition and evaluation of hazardous substances or agents involves identification of potential hazards in the workplace and determination

of the degree of exposure. The two major complementary ways to do this are through environmental and biological monitoring (1), Environmental monitoring uses various sampling instruments

or personal monitoring devices to identify hazardous substances in the environment and to

determine their concentration (l). Biological

monitoring uses biochemical and other tests on

body fluids, tissues, expired air, or human wastes

to estimate the amount of a hazardous substance

actually absorbed by a particular worker as well

as its health effects (7). Some genetic testing

techniques are a type of biological monitoring,

Control of hazardous substances and their effects may be accomplished by engineering techniques designed to lower or eliminate exposure

or by measures designed to protect individual

workers (I). Engineering controls include the substitution of a less harmful material for a hazardous one, the alteration of a process to lower the

Photo credit: Occupational Safety and Health Admlnistration

Environmental monitoring

degree of exposure, the isolation or enclosure of

a process to lower the degree of exposure, the

use of exhaust systems, and ventilation with clean

air (l). Measures targeted to individuals include

personal protection devices such as respirators

or special clothing and workplace practices such

as job placement in a suitable environment, job

rotation to minimize exposure, and job denial (1).

The use of personal protective measures requires the identification of individuals or groups

who can benefit from them. Such identification

is the goal of medical surveillance, a preventive

activity using preemployment or periodic medical

examinations both to identify individuals or

groups that may be predisposed to some occupational illnesses and to monitor the health experience of workers exposed to presumably safe levels of potentially hazardous substances (7).

Genetic testing has potential for use in medical

surveillance.

Photo credit.’ Occupational Safety and Health Adminlstration

Personal protection mask is utilized to safeguard workers

in many occupations where hazardous

substances are present
Ch. Z—Introduction: Occupational Illness and Genetic Testing ● 2 7

Genetic testing

Theoretical foundations: biological

diversity and differential

susceptibility

Genetically determined individuality is a fact of

life. People differ not only in such obvious

physical characteristics as height, facial features,

and skin color, but also in ways that can only be

determined in a laboratory, such as blood type

and types of proteins found in blood plasma. Variations in some characteristics or traits result from

the interaction of many genes; variations among

other traits result from variations in a single gene

that controls that trait. On the basis of a mere

two dozen traits that have been extensively studied, some scientists have calculated that the probability of any two people (except identical twins)

being exactly alike is roughly 1 in 4 billion (15). *

Genetic variability is also a factor in the different reactions of people to environmental factors, including disease-causing agents such as bacteria, viruses, and chemicals. There is evidence

that some people are at a higher risk than others

of contracting diseases-cancer and heart disease,

for example—not only because of environmental

factors such as diet or smoking, but because of

their genetic makeup (5,6). In fact, there are a few

cases where a person’s genetic makeup has been

proven to predispose him or her to certain illnesses in the presence of some environmental factor. One situation involves a deficiency in the enzyme glucose-6-phosphate dehydrogenase (G-6-PD).

The production of this enzyme is controlled by

a single gene; some people have a variant form

of that gene that results in a deficiency in the enzyme. The deficiency generally causes them no

harm. However, if they take certain antimalarial

drugs or eat a type of bean known as the fava

bean, they may suffer from acute anemia (16).

Thus, G-6-PD deficient individuals are at a higher

risk of illness than other people when exposed

to those environmental stresses.

‘Another approach to the question of human variability is to look

at the number of nucleotides in the human ,genome, which is about

log. on this basis, the chances of two people being exactly alike

is 1 in 1 ()’~ (109 X 1()’).

Many factors besides genetic makeup can cause

an individual to be predisposed to illness triggered

by environmental factors. Among these are age,

sex, nutritional status, lifestyle, and prior exposure to the environmental factors.

Prior exposure is particularly important for the

purposes of this report. If the environmental factor is a chemical, it may be in the body at levels

where only slight additional amounts could cause

illness. In fact, the prior exposure may already

have begun the disease process even though the

disease itself may not appear for many years.

These considerations lead to the concept in occupational medicine of unequal risk. Individuals

or groups that may be predisposed to illness have

been called, among other terms, “hypersusceptible,” ‘(high -risk,” and “sensitive.” These terms often

have been used interchangeably but also have

been defined by different experts in different

ways.

This report uses the terms “increased risk, ” “genetically predisposed)” and “susceptible. ” When

applied to individuals or groups, the terms “increased risk” or “susceptible” refer to a higher

probability than average of developing a condition, illness, or other abnormal status. In the context of genetic testing, this increased risk may

result from either inherited genetic traits or previous exposure to environmental insult. The term

‘(genetically predisposed” refers to the situation

where one or more of an individual’s inherited

genetic traits may cause him or her to be at an

increased risk of illness when exposed to some

environmental stresses.

Detection of individuals or groups

at increased risk

Genetic testing, as used in this report, applies

to several techniques used to examine workers

for particular inherited genetic traits or environmentally induced changes in their genetic material

on the assumption that the traits or changes may

predispose them to illness. It has been used by

some manufacturing companies and utilities in

both medical practice and research. There are
28 ● The Role of Genetic Testing in the Prevention of Occupational Disease

two inherently different kinds of testing, genetic

monitoring and genetic screening (fig, 1).

Genetic monitoring is done to assess whether

or not genetic damage has occurred in certain

cells of an individual as a result of exposure to

hazardous chemicals or ionizing radiation. Monitoring can also be done over a period of time to

look for responses to variations in exposure. Thus,

it can be used to measure genetic changes in certain cells from before exposure through various

levels of exposure. Monitoring can be done in one

of two ways. Cytogenetic techniques look for

damage to the gross structure of chromosomes,

the cellular structures that contain the genetic

material, deoxyribonucleic acid (DNA). Noncytogenetic techniques look for damage to the actual

molecular structure of DNA. For the most part,

these latter techniques are still in a developmental stage.

Genetic monitoring involves examining blood

and other body fluids for evidence of genetic

damage to cells from chemicals or ionizing radiation. This damage may indicate exposure to a hazardous agent and the possibility that the group

so exposed will be at an increased risk of developing diseases, particularly cancer. Thus, this procedure has potential as an early warning system,

by indicating that exposures to known or suspected carcinogens are too high or that a previously unsuspected chemical should be viewed as

a potential carcinogen.

SOURCE: Office of Technology Assessment

In contrast, genetic screening is a one-time testing process to determine the presence of particular genetic traits, regardless of whether the person has been exposed to a hazardous substance

(9). Some genetic traits appear to predispose an

individual to adverse health effects in the presence of a particular chemical. while normally not

harmful, the traits may make the individual susceptible to hemolytic chemicals, pulmonary irritants, oxygen deprivation, or other physical or

chemical stresses in the workplace. For example,

two scientists proposed in 1963 that workers in

the chemical industry be tested for G-6-PD deficiency on the grounds that 37 chemicals or families of chemicals may cause such employees to

develop anemia (20). Most screening tests require

that blood be drawn for laboratory tests.

In sum, screening is used to determine individual susceptibility, whereas monitoring may be

able to assess a chemical’s effect on an exposed

population in order to determine if that population is at increased risk. Because of this distinction, one use of screening could be to exclude

genetically susceptible individuals from jobs

where they would be exposed to hazardous substances, whereas monitoring would most likely

indicate a need to lower exposure levels for a

group identified to be at increased risk.

Genetic monitoring must be subjected to two

principal technical questions: Are the techniques

used to assess genetic damage reliable and valid?

Is there an association between positive test results and an increased risk of disease? Similarly,

the reliability and validity of screening tests are

important technical questions, but the key question here is whether or not there is an association between the genetically determined trait and

any increased susceptibility of that individual to

harm from particular chemicals.

When used as described here, screening and

monitoring are forms of medical practice. They

can also be used in medical research. It is important to distinguish between medical practice and

medical research because different legal and ethical principles can govern each, depending on the

situation. The term “practice” generally refers to

medical interventions that are designed solely to

enhance the well-being of an individual and that

have a reasonable expectation of success, The
Ch. 2—introduction: Occupational Illness and Genetic Testing ● 2 9

purpose of medical practice is to provide diagno- in the form of theories, principles, and statements

sis, preventive treatment, or therapy to individ- of relationships (10). Medical research is often

uals. Research, on the other hand, refers to an done to determine the value of new techniques

activity designed to test a hypothesis so that con- for medical practice. It generally does not enhance

elusions may be drawn. Its purpose is to contrib- the well-being of the individual, and, in fact, may

ute to a general body of knowledge, expressed have some risks associated with it.

Potential benefits and risks of genetic testing

Advocates of genetic testing believe it might be

able to play an important role in the prevention

of occupational disease. By identifying workers

who may be at increased risk of disease because

of past or potential exposure to hazardous substances, additional preventive measures could be

taken by the company or the workers themselves.

In addition to the obvious and significant benefits

of preventing serious illness, there could be indirect benefits, such as a reduction in the costs

associated with occupational disease for employers, employees, and society. These costs include

medical, insurance, and legal expenses; time lost

from work; and disability or unemployment payments,

The use of this emerging technology, however,

raises several questions. Are the techniques suf -

Organization and scope of

This report attempts to assess the potential

risks, benefits, and effects of genetic testing. Part

I discusses the extent of testing on the basis of

a survey of major companies and unions conducted by OTA. Part H explains the underlying

scientific principles. Part III assesses the current

state of the technology and expected future developments. It addresses the question of whether

the technology in fact could play a role in reducing occupational disease. Part IV analyzes the

legal, ethical, and economic issues raised by this

technology. It considers whether genetic testing

is compatible with law or established ethical principles and how the costs and benefits of the technology could be assessed. Part V integrates the

findings of the previous parts into a discussion

ficiently developed so as to predict reliably an

association between either genetic damage or a

person’s genetic makeup and disease? Since many

of the genetic traits sought in screening are found

disproportionately among some races and ethnic

groups, could the use of the tests result in discrimination on the basis of race, sex, or national

origin? How will the availability of the tests affect the employer’s responsibility for maintaining a safe workplace? How might these procedures affect efforts to reduce the level of hazardous substances in the workplace? If the tests are

shown to be effective, to what degree should society protect high-risk individuals or groups, at

what cost, and who should bear that cost?

report

of issues and policy options for possible congressional action.

The report does not consider certain aspects

of genetic testing. Hazards to offspring are not

addressed; the report considers only the risk to

the workers themselves. The report also does not

assess many of the claimed risks of the widespread use of this technology. Because genetic

testing is an emerging technology, little evidence

exists concerning its potential impacts. Finally, it

was not within the scope of this study to assess

whether occupational exposures to hazardous

substances are at “safe” levels and whether other

technologies might be more appropriate for preventing occupational diseases.
30 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Chapter 2 references

1. Anton, Thomas J., Occupational Safety and Health

hfanagement (New York: McGraw Hill, 1979), pp.

143-156.

2. Bureau of Labor Statistics, Department of Labor,

Occupational Injuries and Illnesses in the United

States Qv Indust[v, 1981, Bulletin 2164, January

1983.

3, Environmental Protection Agency, Economic

Ana[vsis of Proposed Hazard Warning Regulations,

prepared for the Office of Pesticides and Toxic

Substances, Office of Regulatory Analysis under

contract No. 68-01-5924, September 1980.

4. Environmental Protection Agency, Proposed Federal Radiation Protection Guidance for Occupational Exposure: Background Report, Office of Radiation Programs, Criteria and Standards Division,

Report No. EPA-520 4-81-003, Jan. 16, 1981.

5. Harsanyi, Z., and Hutton, R., Genetic Prophecy:

Beovond the Double HeZix, (New York: Rawson,

Wade Publishers, Inc., 1981).

6. Institute of Medicine, Genetic Influences on

Responses to the Environment (Washington, D. C.:

National Academy Press, 1981).

7. Monroe, Carl B, ‘(The Role of Biological Monitoring in Medical and Environmental Surveillance, ”

in Chemical Hazards in the Workplace: Measurement and Control, Gangadhar Choudhary (cd.)

(Washington, D. C.: American Chemical Society,

1981), p. 223.

8. National Academy of Sciences, Committee on the

Biological Effects of Ionizing Radiation, The Effects

on Populations of Exposures to Low Levels of Ioniz -

in,g Radiation, table III-23 (Washington, D. C.: 1980).

9. National Academy of Sciences, Genetic Screening:

Programs, Principles, and Research (Washington,

D. C.: 1975).

10. National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research,

The Belmont Report: Ethical Principles and

Guidelines for the Protection of Human Subjects

of Research (Washington, D. C.: 1978) DHEW publication No. (OS) 78-0012, p. 2.

11. National Institute for Occupational Safety and

Health, Centers for Disease Control, “Proposed

Hazard Communication Standard, ” 47 Fed. Reg.

12092, 12108 (1982), citing, U.S. Department of

Health, Education, and Welfare, Public Health

Service, National Occupational Hazard Survey,

DHEW (NIOSH) publication No. 78-114, 1977, p.

792.

12. Occupational Safety and Health Adminstration, Of -

fice of Regulatory Analysis, Draft Regulatory Impact Analysis and Regulatordy Flexibility Analysis

of the Hazard Communication Proposal, March

1982, p. 11-21, citing Kearney, A. T., Inc.

13. Occupational Safety and Health Administration,

Field Operations Manual, pp. xiii - 2.

14. Office of Technology Assessment, U.S. Congress.

Assessment of Technologies for Determining

Cancer Risks From the Environment, OTA-H-138,

June 1981.

15. Omenn, G., “Predictive Identification of Hypersusceptible Individuals, ” Journal of Occupational

Medicine, 24:369, May 1982.

16. Omenn, G., and Motulsky, A., “Eco-Genetics: Genetic Variation in Susceptibility to Environmental

Agents, ” in Genetic issues in Public Health and

Medicine, B. Cohen (cd.) (Springfield, Ill.: Charles

C. Thomas, 1978).

17. Pete, R., and Schneiderman, M., Banbuqv Report

9: Quantification of Occupational Cancer (New

York: Cold Spring Harbor Laboratory, 1981).

18. Ruttenberg, R., and Hudgins, R., Occupational Safetuy and Health in the Chemicaf Industry (New York:

Council on Economic Priorities, 1981), p. 25.

19. Schwartz, J., and Epstein, S., “Problems in Assessing Risk From Occupational and Environmental Exposures to Carcinogens,” in Quantification of Occupational Cancer, 1981, pp. 559-576.

20. Stokinger, H,, and Mountain, J., “Test of Hypersusceptibility to Hemolytic Chemicals, ” Arch. Environ. Health, vol. 6, 1963, p. 57.

21. Wall Street Journal, “Asbestos Lawsuits Spur War

Among Insurers, With Billions at Stake, ” June 14,

1982, p. 1.

22. Washington Post, “Conglomerate Facing Asbestos

Lawsuits Files for Bankruptcy, ” Aug. 27, 1982, p.

A-1,
Chapter 3

Survey of the Use of Genetic

Testing in the workplace
Contents

Page

Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Overall Rates obtesting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Types of Testing: Genetic Screening and Cytogenetic Monitoring . . . . . . . . . . . . . . . . . . 34

Actions Taken as a Result of Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Generalizability of the Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Comments on Survey. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Caveats .. .. .. .. ... ... ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Conclusions . . . . . . . . . . . . . . . . . . . . . . .. .. .. .. ... ... ......O .. .. .. . . $ . . . . . . . . . . . . 39

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

List of Tables

Table No.

l.Frequency of Response to Survey by 6/8/82 By Type of Response . . . . . . . . . . . . . . . .

2.2x 2 Contingency Table for Organizations Engaged in Genetic Testing . . . . . . . . . . .

3. Distribution of Organizations By Type, Indicating Current, Past, and/or Future Use

of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Frequency of Current, Past, and/or Future Use of Genetic Testing, By Type. . . . . . .

5. Distribution of Companies by Classification, Indicating Current, Past, and/or

Future Use of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6.Genetic Testing Ever Conducted By Purpose and Type of Test . . . . . . . . . . . . . . . . . .

7.Genetic Testing Ever Conducted By Criteria and Type of Test. . . . . . . . . . . . . . . . . . .

8.Genetic Testing Ever Conducted By Reasons for and Type of Testing . . . . . . . . . . . .

9. Genetic Testing Ever Conducted By Criteria for Test Selection and Type obtesting

10.Distribution of Type obtesting By Status of Tester. . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Actions Taken by Respondents That Have Ever Used Genetic Testing . . . . . . . . . . . .

Page

34

34

35

35

35

36

36

36

37

37

38
—

Chapter 3

Survey of the Use of Genetic

Testing in the workplace

There have been conflicting accounts of the extent of genetic testing and the use of its results.

In testimony given before Congress in the fall of

1981, the corporate medical director of a large

chemical company stated that except for sickle

cell trait tests, his company “ . . . is not conducting genetic screening of its employees, and I am

not aware of any other company which is” (2).

However, a series of articles in the New York

Times in February 1980 alleged a widespread corporate practice of such testing on American

workers (3). Furthermore, a May 1981 survey of

east coast industrial physicians indicated that

preemployment, preplacement, and periodic testPurpose

The survey was

●

ing for sickle cell anemia, hemoglobin disease, and

glucose 6-phosphate dehydrogenase (G-6-PD) deficiency was being conducted in some large east

coast companies (l).

None of these or other accounts examined by

OTA has been based on a rigorous, scientifically

valid assessment of the use of genetic testing.

Therefore, in an attempt to dispel the confusion

and speculation and to provide necessary data for

policy analysis, OTA surveyed major U.S. industrial companies, utilities, and unions about their

use of this technology.

designed to determine: ● which tests were used and under what

circumstances:

the frequency of past, present, and an- ●

ticipated genetic screening and cytogenetic ●

monitoring * in the workplace and whether

they had been conducted on a routine,

how the results of the tests were used; and

the criteria against which tests have been

measured to determine acceptability for use.

special, or research basis; The survey did not attempt to establish the

number of workers involved in these tests: that

“The questionnaire used the term biochemical genetic testing to

refer to genetir screening and the term cytogymetic testing to refer

to cytngfmetir monitoring

Study design

The survey was conducted for OTA from

February 25 to June 8, 1982, by the National Opinion Research Center (NORC), a nonprofit survey

research corporation affiliated with the University of Chicago. NORC sent confidential questionnaires to the chief executive officers of the 500

largest U.S. industrial companies, * the chief executive officers of the 50 largest private utility

information would have required a much more

extensive effort.

companies, * * and the presidents of the 11 major unions that represent the largest numbers of

employees in those companies.** * For further information on the study design and other aspects

of survey methodology, see appendix A, The

NORC report to OTA on the survey is in appendix B.

● *Identified by Fortune hfagazim? List C; Forrune, ~rol. 10S, No.

9, Nla}’ 4, 1981.

* Identified by Fortune 500 listing of [ 1.S, mmpaoi[?s engaged in * * ‘Identifiecl in

manl]fa(’t l]ring(nlilling: I’orfunr, \’ol. 103, No, 9, Nla} 4, 1981 . Association (19791

Dirt? rtory of National Llnions and F,mployees

h~r the Cl S. Department of Lahor.

33
34 . The Role of Genetic Testing in the Prevention of Occupational Disease

Table 1 .—Frequency of Response to Survey by 6/8/82

By Type of Response (based on 561 organizations) By the June 8, 1982, cutoff date, 366 organizations had answered the questionnaire, a 65.2 per- Type of response Number Percent

cent response rate, and 26 organizations had spe- Participated . . . . . . . . . . . . . . . . . . . 366 65.2%

cifically declined to do so, a 4.6 percent refusal Refused to participate: . . . . . . . . . 4.60/o

Policy not to reply to surveys .

rate. Those who declined generally gave either (:;

Not interested, no time. . . . . . . (3)

no reason for refusal or the reason of corporate Object to methodology . . . . . . . (1)

policy not to respond to surveys. (See table 1.) Phone refusal—no reason . . . . (12)

Unknown . . . . . . . . . . . . . . . . . . . . . 169 30.1%

Total . . . . . . . . . . . . . . . . . . . . . . . 561

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982,

Results

Overall rates of testing

Of the 366 organizations responding, 6 (1,6 percent) were currently conducting genetic testing, *

17 (4.6 percent) used some of the tests in the past

12 years, 4 (1,1 percent) anticipated using the tests

in the next 5 years, and 55 (15 percent) stated they

would possibly use the tests in the next 5 years.

Most of these organizations are in manufacturing/mining (particularly chemicals) or are utility

companies. Of those organizations that have

tested in the past 12 years, five are currently

doing so, (See table 2.) Because the questionnaire

instructed respondents to include any instance

of testing, positive responses can include isolated

instances of testing as well as long-term testing

programs. Among the six companies currently

testing, two are in the chemical industry, two are

utilities, and two are in the electronics industry.

Half of those that tested in the past are chemical

companies. Of the four organizations that anticipate the use of genetic testing, two are conducting testing at present, one has done so in the past,

and one has never had such a program. None of

the four responding unions reported any testing.

These results are set forth in more detail in tables

3, 4, and 5.

Types of testing: genetic screening and

cytogenetic monitoring

Organizations that reported some genetic

screening were asked whether they had ever

tested employees for genetic traits associated

● Genetic screening and/or cytogenetic monitoring

Table 2.—2 x 2 Contingency Table for

Organizations Engaged in Genetic Testing

(past testers by current testers)

Past testers

Yes No Total

Current Yes 5 1 6

testers No 12 348 360

Total 17 349 366

SOURCE: National Oplnlon Research Center, survey conducted for OTA, 1982.

with: (A) any red blood cell and serum disorders,

(B) liver detoxification systems, (C) immune system

markers, or (D) heterozygous chromosomal instabilities. For each of the four broad categories A

through D, the questionnaire listed several examples. Of those who have ever tested, 14 of the organizations had tested in category A, 3 in category

B, 5 in category C, and none in category D. Organizations that have used red blood cell and serum

disorder tests, category A, often used more than

one type of test. The most frequently used test

in this category was that for sickle cell trait, for

which 10 organizations have tested. The G-6-PD

and serum alpha-1 antitrypsin deficiency tests

were the second most frequently used. (See table

6 for a summary of the frequency of individual

genetic screening tests.)

For each test, companies were asked about the

circumstances under which the tests were done

(that is, routinely, for research, or for other reasons) and the type of employee tested. Respondents generally said they tested routinely or for

unspecified reasons. (See table 6.) Employees most

often were selected on the basis of ethnicity and

race for sickle cell trait testing and on the basis
Ch. 3—Survey of the Use of Genetic Testing in the Workplace ● 35

Table 3.—Distribution of Organizations By Type, Indicating Current, Past, and/or Future Use of

Genetic Testing (based on 366 responses)

Testing

Current Past Future

Organization type (number of respondents) Yes No/NAa Yes No/NAa Yes/Poss. No/NAa

Manufacturing/mining companies (322). . . . . . . . . 4 318 16 306 49 273

Private utility companies (31) . . . . . . . . . . . . . . . . . 2 29 1 30 9 22

Unions (5) . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . 0 5 0 5 0 5

Unknown (8) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 8 0 8 1 7

Total (366). , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 360 17 349 59 307

(1.6%) (4.6%) (16.1 0

/0)

aA combination response Further breakdown is fmposslble stnce the category (current, past, future) is a summary of responses to two questions dealtng with genetic

screen i n g and cytogenet!c mon Itori ng In the case of No/NA, most responses were No, for Yes/Poss , most responses were possibly. See table 4 for further breakdown

SOURCE National Opinion Research Center, survey conducted for OTA, 1982

Table 4.—Frequency of Current, Past, and/or Future Use of Genetic Testing, By Type (based on 366 responses)

Testing

Current Past Future

Type of test Yes No N/A Yes No N/A Yes Poss. No N/A

Genetic screening . . . . . . . . . . 5 350 11 12 342 12 1 53 292 20

Cytogenetic monitoring . . . . . . 2 354 10 6 348 12 3 49 294 20

SOURCE National Oplnlon Research Center, survey conducted for OTA, 1982

Table 5.— Distribution of Companies by Classification,a Indicating Current, Past,

and/or Future Use of Genetic Testing (based on 366 responses)

Genetic testing

Current Past Future

Main industrial classification

(number of respondents) Yes No/NAb Yes No/NAb Yes/Poss. No/NAb

Chemical (37) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 35 8 29 11 26

Utilities (33) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 31 1 32 10 23

Petroleum (18) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 18 0 18 4 14

Pharmaceuticals (9) . . . . . . . . . . . . . . . . . . . . . . . . . 0 9 0 9 3 6

Rubbers/plastics (4) . . . . . . . . . . . . . . . . . . . . . . . . . 0 4 0 4 3 1

Metals (16) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 16 0 16 2 14

Others (249) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2C

247 8 241 26 223

Total (366) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 349 307

(1 .6%) (4.&o) (16.1%)

~Main industrial classification based on the first listed response of respondent to question concerning the major Industrial classification of their company

A combination response. Further breakdown Impossible since the category (current, past, future) is a summary of two questions” 1) genetic screening, 2) cytogenetlc

monitoring. In the case of No/NA, most responses were No; for Yes/Poss. most responses were possibly. See table 4 for further breakdown

cBoth of t~ese companies report electronics as their main industrial classification

SOURCE National Optn!on Research Center, survey conducted for OTA, 1982.

of job category for other types of tests. No organization reported basing a genetic screening test

on an employee’s sex. (See table 7.)

Of the organizations that reported cytogenetic

monitoring, four had tested for chromosomal

aberrations and two for sister chromatid exchanges (SCE). None reported having tested for

mutations by assaying either deoxyribonucleic

acid (DNA) or enzymes. Most frequently, no

reason was given for chromosomal aberration

testing. The two companies that did SCE testing

said it was for research purposes. (See table 6.)

Job category was the only employee-related

characteristic used to determine who would be

tested. (See table 7.)
36 ● The Role of Genetic Testing in the prevention of Occupation/ Disease

Table 6.—Genetic Testing Evera Conducted By Purpose and Type of Test (based on 18 responses)

Genetic screening Cytogenetic monitoring

Unspecified Unspecified

red blood immune Sister

Methemoglobin cell/serum Unspecified system Chromosomal chromatid

Purpose Sickle cell G-6-PD SAT reductase disorder liver detox markers aberrations exchanges

Routine ., . 5 3 1 0 1 1 4 1 0

Research , . 1 0 2 1 2 1 0 1 2

Other ... , . 6 2 2 1 2 1 3 3 0

Total

number of

respondents

utilizing

test b . . . . 10 4 4 1 3 3 5 4 2

aln the past 12 years. bSince categories above are not mutually exclusive, total can be Iesslmore than sum of categories.

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

Table 7.—Genetic Testing Evera Conducted By Criteria and Type of Test (based on 18 responses)

Genetic screening Cytogenetic monitoring

Unspecified Unspecified -

red blood immune Sister

Methemoglobin cell/serum Unspecified system Chromosomal chromatid

Criteria Sickle cell G-6-PD SAT reductase disorder liver detox markers aberrations exchanges

Job category 1 2 2 0 2 1 2 1

Ethnicity/race 7 0 0 0 0 0 : o 0

Sex . . . . . . . . 0 0 0 0 0 0 0 0 0

Total

number of

respondents

utilizing

test b . . . . . 10 4 4 1 3 2 4 4 2

~ln the past 12 years.

Since categories above are not mutually exclusive, total can be less/more than sum of categories,

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982,

Recipients were asked about the factors considered in the decision to implement testing and

the criteria employed in selecting specific tests.

Data from epidemiological studies, data from animal studies, and other reasons such as employee

protection were the highest ranked factors involved in decisions to implement genetic testing

for both genetic screening and cytogenetic monitoring. (See table 8.) The predictive value of a test,

its specificity, scientific consensus, and other factors such as research findings were the factors

cited most frequently as criteria for selecting a

specific genetic test. These responses were similar

for both genetic screening and cytogenetic monitoring. (See table 9.)

The types of testing carried out by current

testers were compared with those of past testers.

For genetic screening, current testers are using

Table 8.—Genetic Testing Evera Conducted

By Reasons for and Type of Testing

(based on 18 responses)

Type of testing

Reasons for deciding to Genetic Cytogenetic

implement testing screening monitoring

Data epidemiologic studies 6 2

Data animal studies . . . . . . 4 2

Legal consequences of not

testing . . . . . . . . . . . . . . . . 3 0

Union employee initiative . 3 0

Cost-benefit analysis . . . . . 2 0

Other b . . . . . . . . . . . . . . . . . . 4 3

~ln the past 12 years.

Includes reasons related to protecting employees, research findings.

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

a slightly greater variety of tests (tests for red

blood cell and serum disorders, liver detoxification systems, and immune system markers) than
Ch. 3—Survey of the Use of Genetic Testing in the Workplace ● 3 7

Table 9.–Genetic Testing Evera Conducted By

Criteria for Test Selection and Type of Testing

(based on 18 responses)

Type of testing

Genetic Cytogenetic

Criteriab

screening monitoring

Predictive value of testc 

. . . 5 1

Specificity of testd . . . . . . . 5 1

Scientific concensus . . . . . 4 2

Sensitivity of teste . . . . . . . 3 0

Cost of test . . . . . . . . . . . . . 2 0

Other f . . . . . . . . . . . . . . . . . . 4 3

~ln the past 12 years.

A respondent may have based its selection for a test on one or more of the

above criteria

cpredictive value of test the l~kellhood that the disease status of the ind~vidual

wi I I be correctly Identified by the test; i e., a disease-free individual will have

negative test result, a diseased indiwdual will have positive test result

‘Specificity of test: ability of test to correctly identify individuals without disease

:Sensltlwty of test” ability of test to correctly identify individuals with disease

Includes research findings (general).

SOURCE National Opinion Research Center, survey conducted for OTA, 1982

past testers and at a slightly higher proportion

of usage. of the six current testers, five are testing

for red blood cell and serum disorders, three for

liver detoxification systems, and two for immune

systems markers. Eight of twelve past testers had

tested for red blood cell and serum disorders,

none had tested for liver detoxification systems,

and two had tested for immune system markers.

In fact, however, because of the small numbers

involved, the only notable difference between current and past testers may be the current use of

tests for liver detoxification systems. In any event,

testing for red blood cell and serum disorders

continues to be the most frequently used test. (See

table 10. )

A different pattern of use emerges for cytogenetic monitoring, Of the six current testers, one

is testing for chromosomal aberrations and one

is testing for sister chromatid exchanges, For the

12 past testers, 3 tested for chromosomal aberrations and 1 tested for sister chromatid exchanges.

This may reflect the change in the state of the

art concerning the science of sister chromatid exchanges. (See table 10.) In any event, the number

of tests remain small and caution is advised in

interpreting these data.

Actions taken as a result of testing

Responses concerning the way in which the results of genetic screening or cytogenetic monitoring were used varied greatly, ranging from actions involving an employee to changing or discontinuing a product. Of the 18 companies that reported taking some action, 8 reported that they

had informed an employee of a potential problem. Five respondents reported transferring the

“at-risk” employee. Two suggested that the employee seek another job as a result of testing. One

discontinued or changed a product, The complete

list of actions taken appears in table 11.

Generalizability of the survey

Can the results of this survey be generalized

to the population of Fortune 500 companies, large

utility companies, and major unions? An answer

to this involves two additional questions: Are the

responses equally distributed among the groups

Table 10.—Distribution of Type of Testing By Status of Tester (based on 18 responses)

Status of tester

Current N-6 Past N-12

Percent Percent

Type of testing Yes No/NA using Yes No/NA using Total

Genetic screening:

Red blood cell and serum disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Liver detoxification systems ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Immune system markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Heterozygous chromosomal instabilities . . . . . . . . . . . . . . . . . . . . . . . 0

Cytogenetic monitoring:

Chromosomal aberrations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Sister chromatid exchange. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Mutations by assaying DNA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Mutations by assaying enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0

Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

1 830/o 8

3 50 ”/0 o

4 33% 2

6 0% o

5 17 ”/0 3

5 17“/0

6 0% :

6 0% o

5 17 ”/0 o

4 670/o 18

12 O

O

/o 18

10 1OO/o 18

12 0% 18

9 250/o 18

11 80/0 18

12 O

O

/o 18

12 0% 18

12 O

O

/o 18

SOURCE National Opinion Research Center, survey conducted for OTA, 1982
38 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Table 11 .—Actions Taken by Respondents That Have

Ever a Used Genetic Testing (based on 18 responses)

Number of

Type of actionb

companies

Informed employee of a potential problem 8

Transferred employee . . . . . . . . . . . . . . . . . . 5

Personal protection device . . . . . . . . . . . . . . 3

Other action . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Suggested employee seek other job . . . . . 2

Installed engineering control . . . . . . . . . . . . 2

Implemented research program . . . . . . . . . . 1

Discontinued/changed product . . . . . . . . . . 1

~ln the past 12 years.

A respondent may have taken more than one action

SOURCE: National Opinion Research Center, survey conducted for OTA, 1982.

represented in the survey? Are characteristics of

the respondents different from the nonrespond -

ents? These two questions are discussed in turn.

By the close of the survey, a discrepancy in response rate among the groups represented in the

survey became apparent. The large corporations

had the highest response rates: 68 percent for

utilities and 61.5 percent for the top 200 companies in the Fortune 500 listing; the unions and

small corporations had the lowest response rates:

36.4 percent for unions and 44 percent among

the bottom 300 companies in the Fortune 500 listing. (See app. A.) The variation in response pattern was most probably due to the followup efforts that focused on the top 100 companies of

the Fortune 500 listing and organizations in selected industrial classifications such as utilities.

Thus, the results of this survey may be more applicable to the larger manufacturing/mining and

utility companies than to smaller manufacturing/mining companies and unions.

Analysis of selected characteristics of respondents compared with nonrespondents is limited to

the Fortune 500 companies. Respondents and

nonrespondents were compared on the following characteristics: geographic location, size of

organization, and type of industry. Rates of

response and nonresponse did not differ greatly

geographically. (See app. A.)

For size of company, however, the rate of nonresponses did differ widely from the rate of responses. For example, 53 percent of the nonrespondents were in the smallest companies, compared with 32 percent of the respondents. Again,

because larger companies were used in followup

efforts, the response rates may reflect these efforts. (See app. A.)

Rate of nonresponse did not vary greatly from

rate of response with respect to industry classification. Eleven industries had a slightly higher

rate of response than predicted. Of these industries, five (chemicals, petroleum refining, rubber

and plastic products, metal manufacturing, and

pharmaceuticals) were the key industries selected

for followup activities and the rates from the remaining six (glass/concrete, electronics, measuring equipment, motor vehicles, aerospace, and office equipment) may be explained by such factors

as the effect of followup based on size of company or chance. (See app, A.)

Thus, the results of the survey may be more

representative of the larger manufacturing/mining corporations and private utility companies as

identified in Fortune magazine listings; however,

the respondents do not appear to differ greatly

from the nonrespondents in geographic location

or type of company.

Comments on survey

Respondents were encouraged to write explanatory notes or other comments on the questionnaires and on the post cards. Thirty-one respondents did so. (See app. C for complete text of comments,) Three current testers sent in comments.

Two of these respondents said testing was being

done for reasons of health evaluation—preplace -

ment and/or routine monitoring; one respondent

said that such testing should not be interpreted

to mean a large-scale testing program or a problem exists.

Comments were received from two companies

that had tested in the past, Both respondents referred to testing for sickle cell trait, one at the

request of the State health department, and the

other at the request of the employer for employees of child-bearing age as part of the company’s

preventive medical program.

Seven organizations that anticipate future testing but that have not conducted any testing to

date provided comments. The comments ranged
Ch. 3—Survey of the Use of Genetic Testing in the Workplace 39

from addressing animal research to questionnaire

improvement to any future testing being dependent on ‘(practical utility. ”

Comments received from 19 organizations that

have never tested or that do not plan to test in

the future focused on three major points. The

first was the genetic testing was not relevant to

the products or processes to which their workers

were exposed. The second was that these tests

were not sufficiently developed for use. The third

point was that the organization was satisfied with

its current conventional industrial hygiene practice and standard medical surveillance of its

workers.

Caveats

In evaluating the results of the survey, several

caveats must be considered. First, since the

questionnaire instructed respondents to include

any instances of testing, positive responses can

include isolated cases as well as long-term testing

programs. Second, the questionnaire was not

structured to provide information on the number

of workers tested. Positive responses indicate only

the existence of testing, not its extent. Third, since

approximately one-third of the population did not

respond and the number of organizations testing

is very small, any generalizing of these results to

the study population as a whole is not warranted.

Fourth, the level of effort employed in completing

each questionnaire is unknown. For example,

holding companies which have autonomously operating subsidiaries may or may not have included

the activities of those subsidiaries in their responses. Fifth, a limitation of an anonymous questionnaire is that respondents cannot be contacted

about missing information or unclear responses.

Approximately 3 percent of the respondents failed

to answer every item in the core questions. Eight

returned questionnaires did not provide enough

information to allow the respondents to be classified as a Fortune 500 company or as a utility.

Sixth, the use of post cards for followup has pitfalls: respondents may return post cards but not

questionnaires or vice versa; NORC received 293

post cards and 366 questionnaires. This may have

resulted in duplication of information or minimized the effect of followup.

Conclusions

The survey of major U.S. industrial companies,

utilities, and unions has shown that genetic testing

currently is being used by a few companies, that

its use has declined in the past 12 years, but that

it may be used by many more companies in the

future. The responses cannot be generalized to

the survey population or to all U.S. companies and

labor unions. However, it is clear that 17 organizations have used genetic testing in the past 12

years, 5 of the 17 and 1 other currently are doing so, and 59 organizations have expressed an

interest in using these tests. None of these organizations is a union. The extent of testing by these

organizations is unknown.

Further, of the 18 companies that have ever

conducted genetic testing in the past 12 years,

more companies have conducted genetic screening (17 companies) than cytogenetic monitoring

(8 companies). Tests for sickle cell trait were the

most frequently used type of genetic screening

and tests for chromosomal aberrations were the

most frequently used type of cytogenetic monitoring. Research was the least frequently mentioned

purpose for testing. Respondents generally tested

routinely or for other unspecified reasons. The

type of employee chosen for testing was based

most often on ethnicity and race for sickle cell

trait testing, and job category for other types of

tests. Sex was never stated as a criterion used in

determining the test of choice. Actions taken on

the results of the tests ranged from informing the

employee of a potential problem (eight companies)

to discontinuing or changing the product (one

company).

Data from epidemiological and animal studies

were the most frequently cited factors in the decision to implement testing of those companies that

tested. A cost-benefit analysis was the least impor-

,2,_”, q ,, — ~ J — . .
40 . The Role of Genetic Testing in the Prevention of Occupational Disease

tant factor. The predictive value and specificity while research findings were most important in

of a test were the most important criteria in the the selection of the specific cytogenetic monitorselection of the specific genetic screening test, ing test.

Chapter 3 references

1. Compton, A., “Company Practices in Protecting Pent de Nemours & Co., testimony before SubcomMinority Workers, ” paper presented at The Na- mittee on Investigations and Oversight of the

tional Conference on Occupational Health and House Committee on Science and Technology, Oct.

Issues Affecting Minority Workers, sponsored by 14 and 15, 1981.

the National Institute of Occupational Safety and 3. Severe, R., ‘(Screening of Blacks by DuPont

Health, July 6-8, 1981. Sharpens Debate on Gene Tests)” The New York

2. Karrh, B. W., Corporate Medical Director, E. I. du Times, Feb. 4, 1980.
Part II

Underlying Scientific Principles

Chapter 4—Essentials of Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Chapter 5—Principles of Genetic Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Chapter 4

Essentials of Genetics
Contents

Page

Chromosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. .. ... ... ... ....$ . . . . . . . . . . . . . . 45

DNA) Genes) and Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Genetic Variability in Humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Mutation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Single Gene Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Mutations, Chromosomes, and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Body Fluids Used in Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

List of Figures

Figure No. Page

2.A Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

3.Normal Human Male Karyotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

4. Sister Chromatic Exchanges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

5.The Structure of DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

6.Mechanism of Gene Expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Chapter 4

Essentials of Genetics

The role of genes in disease is still not fully

understood. Many diseases--cancer and heart disease, for example—appear to have some genetic

influence. These genetic variations may be inherited or may arise from environmental sources.

In other cases, it is hypothesized that a person

with inherited types of gene variations may suffer harmful effects when exposed to hazardous

substances.

The occupational studies assessed in Part 111 of

this report rely on genetic analyses. An understanding of genetics—the basic structure and

function of genes and their connection with disease—will enable the reader to comprehend more

readily the report’s interpretation of those studies.

This chapter, therefore, attempts to provide an

introduction to the complex subject of genetics.

Chromosomes

In higher organisms, the nucleus of each cell

contains the genetic material DNA (deoxyribonucleic acid), which directs all the functions of

the cell such as metabolism and growth. The DNA

in its normal state in the nucleus is joined with

proteins to form a set of complicated structures

called chromosomes. Each human cell contains

46 chromosomes, half derived from the mother

and half from the father. These 23 pairs of chromosomes mean that all genetic material is represented twice in each cell. One of the twenty-three

pairs is a pair of sex chromosomes. Females have

two X chromosomes and males have one X and

one Y. When the cell is in a resting stage, all the

chromosomes are tangled and difficult to distinguish; just prior to cell division, however, the

chromosomes condense and replicate to appear

in a light microscope as dual structures, each

chromosome consisting of two identical chromatics (fig. 2). These two sister chromatics are held

together by a central constriction, the centromere. At cell division, the sister chromatics are

pulled apart at the centromere, and one chromatid goes to each of the two daughter cells, thus

ensuring a full complement of DNA in each cell.

Each of the 23 pairs of chromosomes is a unique

size and shape, permitting the chromosomes to

be distinguished from one another, In addition,

various staining treatments have been developed

that reveal, for each chromosome, a characteristic

Figure 2.—A Chromosome

Sister

chromatids

Chromat

\

SOURCE: Office of Technology Assessment

sequence of “bands” composed of alternately dark

and light staining regions. From the combination

of size, shape, and banding patterns, the 46 chromosomes from a single cell can be arranged into

a systematic picture called a karyotype (fig. 3).

Chromosomal abnormalities, which alter the

45
46 . The Role of Genetic Testing in the Prevention of Occupational Disease

Figure 3.—Normal Human Male Karyotype

1 2 3 4 5

A B

6 7 8 9 10 11 12

14

c

D

19 20

F

SOURCE” Cytogenetics Laboratory, The Johns Hopkins University

banding patterns or size or shape, can be detected

using this technique.

The study of cytogenetics compares the appearance of the chromosomes in the karyotypes to

identifiable traits in the individual. Several chromosomal abnormalities have been identified, and

they fall into two classes: a change in the number

of chromosomes and a change in the chromosome

structure. Changes in the number of chromosomes occur during germ cell (egg or sperm) formation and are detected in the offspring. For example, Down’s syndrome is a result of an extra

chromosome 21 in all cells. Although it is possible for the number of chromosomes to change

in somatic cells (all cells other than germ cells)

by a mistake made during cell division, these cells

are usually nonviable; thus, this type of change

will not be discussed further.

E

G X Y

Chromosomal aberrations, or changes in chromosome structure, can occur spontaneously or

can be caused by chemicals or ionizing radiation.

They are important because, whatever their origin, they can be replicated and passed on to succeeding generations of somatic cells. How chemicals or ionizing radiation causes these aberrations

is not well understood.

Everyone has some chromosomal aberrations

in his or her somatic cells. In lymphocytes (white

blood cells) grown under laboratory conditions,

roughly 2 out of every 100 cells contain at least

one structurally abnormal chromosome. Similar

levels of aberrations have been seen in preparations of bone marrow cells and fibroblasts (connective tissue cells) and presumably are present

to some extent in every kind of somatic cell (see

app. D). These “background” or “spontaneous”
Ch. 4—Essentials of Genetics . 47

chromosomal aberrations are thought to be the

consequence either of failure to repair rare

replication errors or of postreplication chromatid

exchanges, which may be a normal part of the

cell cycle. However, an increase in the number

of aberrations may imply the existence of certain

rare chromosomal instability diseases (discussed

below) or exposure to clastogens (chromosomedamaging agents) in the environment. In the latter case, such an increase may serve as a method

for monitoring exposure to harmful agents.

Another type of chromosomal change is a sister

chromatid exchange (SCE). SCEs are exchanges

of apparently equivalent sections of the sister

chromatics of the same chromosome (fig. 4). This

phenomenon, which can be seen only under special laboratory conditions, occurs at a much

higher frequency than do chromosomal aberrations, with most reported background frequencies being in the range of 5 to 15 SCEs per cell

(see app. E). * The biological or genetic significance

of SCEs is unknown. While the presence of SCEs

in a cell is not necessarily indicative of damage

to that cell, some empirical evidence suggests a

relationship between SCEs and agents which

damage DNA (7). The detection of SCEs thus is

seen as another way to monitor damage to chromosomes. A major exception is that SCEs are not

usually induced by ionizing radiation (3).

● ’I’hese higher background frequencies are thought to be due to

the laboratory procedures necessary for ~’isualization of S(’ES.

Figure 4.—Sister Chromatid Exchanges
48 ● The Role of Genetic Testing in the Prevention of Occupational Disease

DNA, genes, and proteins

The genetic information contained within the

familiar DNA double helix (fig. 5) is completely

defined by the linear order of four chemical compounds known as nucleotide bases, adenine (A),

guanine (G), cytosine (C), and thymine (T). These

bases, attached to the double strands of the helix,

interact in a specific fashion to form the rungs

of the DNA ladder: A’s can pair only with T’s, and

G’s only with C’s. Therefore, the two sides of the

ladder are not identical but are “complementary.”

The chemical nature of the complementary base

pairing is vital to the function of DNA. The pairing is specific, which ensures that the genetic information will be maintained, but not very strong,

so that sections of the helix can “unzip” to expose

the bases, thus making the genetic information

available for use,

An ordered sequence of a few thousand nucleotide bases is the unit of heredity known as the

gene. A gene has regulatory signals at either end

specifying its beginning and end. The signals

themselves are a series of nucleotide bases, usually on the order of 10 to 100 bases long. For the

most part, one gene contains the information for

the synthesis of one protein. Thus, the four bases,

A, G, T, and C, depending on their order, contain the information for the synthesis of proteins.

The genetic code is the same for all organisms,

The difference between organisms, therefore, is

not the inherent chemical nature of the genetic

material, but the different sequences of nucleotide bases.

The DNA present in every cell of every living

organism has the capacity to direct the functions

of that cell. Gene expression is the way in which

the genetic directions in any particular cell are

decoded and processed into the final functioning

product, usually a protein (fig. 6). In the first step,

Figure 5.—The Structure of DNA

r Base pairs

A schematic diagram of the DNA double helix. A three-dimensional representation of the DNA double helix.

The DNA molecule is a double helix composed of two chains. The sugar-phosphate backbones twist around the outside, with the paired bases on the inside serving to hold the chains together.

SOURCE” Office of Technology Assessment
. .

Ch. 4—Essentials of Genetics ● 4 9

Figure 6. —Mechanism of Gene Expression

Transcription

mRNA released and

transported out of

nucleus

Protein

called transcription, the DNA double helix is locally unzipped, in the region of the gene of interest,

and the intermediate product, messenger RNA

(mRNA), a single-stranded, linear sequence of

nucleotide bases chemically very similar to DNA,

is synthesized. The transcription process dictates

the synthesis of mRNA that is complementary to

the section of unzipped DNA. The second step is

translation. The mRNA, after release from the

DNA, becomes associated with the protein-synthesizing machinery of the cell, and the sequence of

nucleotide bases in the mRNA is decoded and

translated into a protein. The protein goes on to

perform its particular function, and when the

protein is no longer needed, the protein and the

mRNA coding for that protein are degraded. This

mechanism allows a cell to “fine tune” the quantity of its proteins while keeping its DNA in a very

stable and intact form.

Proteins actually perform the necessary functions of the cell. By far the most diverse group

are the enzymes, or the proteins that catalyze all

biological reactions. Another group, the structural

proteins, are found, for instance, in cell membranes. Other proteins, such as hormones, have

regulatory functions; still others have highly

specialized functions—for example, hemoglobin

carries oxygen from the lungs to the rest of the

tissues.

SOURCE Office of Technology Assessment.

Genetic variability in humans

Because all humans need to perform the same are called alleles. It is the variation in these alleles

life-supporting tasks, they all have genes that code that forms the basis for diversity within species.

for the same types of proteins. But for any given

protein, there may be many variants, some “nor- Variants have been discovered for many human

real” and some deleterious. This means that the genes. For example, of the 319 possible detectable

genes that code for these variants are also slight- variants of beta-globin, 104 had been observed

ly different. These forms of the same basic gene by 1976. More than 80 different variants of glu-
50 The Role of Genetic Testing in the Prevention of Occupational Disease

cose-6-phosphate-dehydrogenase (G-6-PD) have

been identified, and some of these differ in their

metabolic and clinical effects.

Although most variants are rare, a few occur

with frequencies of at least 2 percent. The products of such variable alleles include beta-S globin

(which produces a sickling of red blood cells), the

A- G-6-PD allele, blood groups, and histocompatibility substances. One study estimated that for the

“average” gene coding for an enzyme, approximately 6 percent of individuals will be easily

detected as carrying a variant gene. Other variants, which are not so readily detectable, probably

occur more frequently. Thus, it may be that for

a given gene, 20 percent of the population might

possess two variant alleles. If this is true, the prospects for detecting individuals with susceptibilityconferring genotypes by mass screening seem

high.

At first glance, it would appear unlikely that

genes conferring susceptibility to chemical or

physical agents in the workplace could gain high

frequency; they should have been selected

against. This is not necessarily the case.

The frequency of an allele will decrease over

the course of generations if the individuals who

possess it have, as a result, lower reproductive

fitness (that is, die before having children or have

children who die before reproductive age). However, those who possess alleles whose only harmful effect results from workplace exposures may

be well into the reproductive phase of their lives

before their first exposure. If, in addition, a latent period occurs between exposure and harmful effect, as is the case for most cancers, those

individuals may have completed their reproduction before the disease appears, Thus, the allele

would not reduce reproductive fitness. Such

alleles could attain high frequency by random

genetic drift or by an advantage that they confer to the reproductively active members of the

population or that they conferred in an earlier

evolutionary setting. For example, the hemoglobin

alleles (such as sickle cell) gained in frequency

because of the protection they conferred against

malaria.

On the other hand, in situations where the harmful effect of an allele only occasionally manifests

itself during the reproductive phase, some individuals with that allele would have their reproductive years shortened, Therefore, the average

reproductive fitness of those possessing the allele

would be slightly less than those lacking it. Over

many generations, even a small decrease in reproductive fitness would diminish the frequency of the allele and, in the absence of other effects, result in its eventual disappearance. Thus,

there may not be very many alleles present today

with high frequency whose harmful effects are

usually manifested later in life.

Harmful reactions to newly invented chemicals

also may occur frequently simply because most

individuals lack genetically determined mechanisms for detoxifying them or repairing the

damage they cause. It remains to be determined

whether biological detoxification methods have

already evolved for many chemicals that cause

disability today. If they have not, only rare individuals may be able to cope with those chemicals.

Thus, the susceptibility-conferring alleles then

would be the predominant types.

Even when a genetically determined detoxification mechanism has evolved, it might protect

against an acute effect of the chemical (and consequently confer a reproductive advantage), but

the mechanism itself might cause a change in the

chemical that increases the chance of a latent

harmful effect. If the latency period exceeds the

reproductive period, this long-term effect would

not have a selective disadvantage.
Ch. 4—Essentials of Genetics ● 5 1

Mutation

A mutation is a heritable change in the sequence

of nucleotide bases. * A mutation can be an insertion or deletion of a base or a base change. A base

change is usually caused by a mispairing reaction

during DNA replication which effectively changes

one base pair to the other one. For instance, if

a modified A mispairs with a C, the C will correctly pair with a G during replication and will

have effectively converted an A-T base pair to a

G-C base pair in one of the daughter cells.

Mutations normally occur at a low rate and, indeed, are the raw material for the evolutionary

process. They can occur in spaces between genes

and thus be neutral, or they can occur within

genes. Occasionally an intragene mutation will

cause the gene to encode a protein that is better

adapted to its function, but most mutations within

genes are deleterious (l). Mutations within genes

are well documented in humans. In fact, at least

‘Some of the (hromosomal ahf’rrations discussed a!)o\e are actually mutations, t)ut for simplicity, thr Llse of “mutation’ in this

report mill refer to nucle{)tidr hase changes ~ihereas “chromosomal

aberration” will refer [o ~ros~ structural rhangm iisihle in the light

microscope

Single gene traits

A genetic trait is any detectable condition that

is known to be inherited. The easiest case to study

genetically is a trait specified by a single gene. Examples include sickle cell anemia and Tay-Sachs

disease. Suppose a hypothetical single gene trait

B determines the normal condition and the rarely occurring allele b results in an observable deficiency. Because there are pairs of each chromosome, a normal individual will be either BB (both

1,000 human diseases are known to be genetic

in origin (5), and many more are thought to have

a significant genetic contribution.

Induced mutations can be caused by genotoxic (gene-damaging) chemicals or ionizing radiation.

Mispairing of nucleotide bases during DNA replication can be caused by chemical modification

of bases or by the incorporation of compounds

that look like bases. Some compounds insert themselves between base pairs, distort the helix, and

thus cause additions or deletions of nucleotide

bases during DNA replication. Radiation is

thought to cause mutations by damaging the

structure of the nucleotide base or the backbone

of the DNA helix.

DNA damage that can lead to mutations can

often be repaired. A mismatched base pair or

chemically modified base will distort the double

helix and alert cellular repair mechanisms. The

damaged section of the DNA strand can be excised and new DNA synthesized using the other

strand as a template. It is important for DNA to

be repaired prior to replication because mismatched bases become fixed during replication.

chromosomes of the pair have the B allele) or Bb

(one chromosome has the B allele and the other

has the b allele). An afflicted individual will be

bb (both chromosomes of the pair have the b

allele). When both chromosomes carry the same

allele, the trait is homozygous (that is, BB or bb);

when the two chromosomes carry different alleles, as in the Bb individual, the trait is

heterozygous. In a heterozygous trait where only
52 The Role of Genetic Testing in the Prevention of Occupation/ Disease

one allele appears to be contributing to the observable condition (in this case, B), that allele is

said to be dominant. The allele (b) that is masked

by the dominant allele is recessive. Only when

both chromosomes of a pair carry the recessive

allele will the deficiency be detected. A heterozygote for the trait is called a carrier.

The actual genetic constitution of a trait (or an

individual) is the genotype, In the case of BB and

bb individuals, the genotype is reflected in the observed trait, or phenotype. In general, a specific

phenotype associated with the heterozygous genotype is not observed. In this simple case, because

B is dominant, the phenotype of the heterozygote

is the same as the homozygote (BB). In addition,

the phenotype reflects the interaction of the genotype with the environment,

Occasionally, a heterozygous trait is expressed

at an intermediate level, that is, neither allele is

fully dominant or recessive. In these cases the alleles are said to be codominant, and the observed

phenotypes reflect both homozygous and heterozygous genotypes.

The deficient phenotype (from genotype bb)

may be expressed by various symptoms, but it

is the result of a single protein deficiency. The

result may be due, for example, to a nonfunctional

structural protein, the lack of a protein or hormone, or a deficient metabolic enzyme. Moreover,

there are many traits whose phenotypic expression is the result of several gene products working together. An example of a polygenic trait is

a person’s height,

Mutations} chromosomes, and cancer

Both mutations and chromosomal aberrations

are thought to play a role in the set of diseases

known as cancer. Many (about 90 percent) of the

chemicals known to cause cancer (carcinogens)

in animals are also known to cause mutations in

in vitro tests (6). In fact, chemicals being tested

for their potential carcinogenic effects are first

screened for their ability to cause mutations. One

theory of carcinogenesis postulates that one or

more mutations causes a cell to reproduce out

of control and, subsequently, form a tumor.

Strongly supporting a mutational origin of many

cancers is the fact that they arise from a single

somatic cell; that is, the cancer genotype, once

present, is stable and passed on to daughter cells

during tumor growth.

Most cancer cells have abnormal karyotypes;

there are frequently changes in chromosome

number, and more recently, it has been shown

that there are an unusually high number of chromosomal aberrations. It is not known whether

these abnormalities are a cause or an effect of

the malignant state, but several inherited diseases, * in which there is an increased aberration

*Bloom’s syndrome, ataxia telangiectasia, Fanconi’s anemia, and

xeroderma pigmentosum.

frequency, are associated with an increased risk

for developing cancer (9). These single gene

recessive diseases are thought to be due to deficiencies in DNA repair processes, and the chromosomes of afflicted individuals are much more

susceptible to breakage caused by radiation and

chemicals. Clearly, these chromosomal instabilities

precede any malignancy, because these individuals also have many aberrant cells that are not

malignant. Still, some types of cancer (for example, myelocytic leukemia) correlate with specific

chromosomal abnormalities.

One hypothesis holds that mutations and/or

chromosomal aberrations are precancerous

events, but, as yet, there is very little definitive

scientific evidence to support this. A recent report

has shown that the gene presumably responsible

for one type of human bladder cancer differs

from its normal counterpart by a single base

mutation (10).

A conspicuous feature of carcinogenesis is the

generally long period of time that elapses between

the initial exposure to the carcinogen and the

appearance of the disease. Why this time course

is so long is unknown, but based on extensive

animal experimentation, carcinogenesis can be

separated into two distinct steps, initiation and
--—.

Ch. 4—Essentials of Genetics ● 5 3

promotion. Evidence has accumulated to suggest

that initiation may be nothing more than mutagenesis, the most powerful initiators being the

most potent mutagens. However, initiation alone

apparently is not enough to produce the disease;

promotion is also necessary. * The nature of promotion is still obscure. Various agents or physical

insults (for example, wounding) can act as promoters, often a long time after initiation. The

feature all promoters have in common is that they

provoke increased cell multiplication of initiated

cells; generally, they do not affect noninitiated

cells. How rapid cell proliferation in the presence

of a mutation could lead to a malignant state is

unknown. At any rate, both genetic and environmental factors can influence whether one develops cancer, but the elucidation of these factors

has not yet been achieved (6).

If cancer indeed has one or more genetic components, individuals who have the “wrong” combinations of genes may be genetically more susceptible to cancer. Several gene products that

could be involved in determining one’s inherited

predisposition to cancer are genes for DNA repair,

immune function, and carcinogen metabolism.

Certain complex pathways of DNA repair are

beginning to be understood in higher animals. If

damaged DNA is repaired in such a way that the

nucleotide base is the same as the old, no permanent change has taken place. On the other hand,

if mistakes are made during DNA repair due to

deficiencies in the repair enzymes, the new base

sequence will be different from the original one,

and, by definition, a mutation will now exist.

Hence, this deficient repair may play an intimate

role in the mechanism of formation of some kinds

● Som[? agents, known as “complete carcinogens ,“ ran act as hth

initiators and promoters.

of mutations, Individuals who have deficient pathways of DNA repair might then be more susceptible to cancer.

Immune deficiencies, or the inability to fight disease, also might predispose one to cancer. If initiation is the result of a somatic cell mutation, then

potential cancer cells would continually be

formed in our bodies at a low frequency. An efficient immune system would recognize these cancer cells as “foreign” and kill them. Hence, reduced immune function may increase the risk for

cancer. Indeed, many chemical carcinogens are

also immunosuppressants, and this has been speculated to be part of their carcinogenic mechanism.

Organ transplant patients who receive massive

doses of immunosuppressants are at increased

risk for developing cancer later (8).

Finally, genetic differences in the ability to metabolize chemical agents to carcinogens may be

involved in determining an individual’s predisposition to cancer. Many chemicals alone are not

harmful, but in mammals a metabolic activation

by complex enzymatic systems can occur to form

an active carcinogenic compound. However, there

are also enzyme systems that deactivate potential carcinogens by forming compounds that are

safely eliminated from the body.

Hence, a person who is deficient in DNA repair

or cellular immune function or who has higher

levels of the activation enzymes or lower levels

of the deactivation enzymes may be more susceptible to chemically induced cancer than someone

who is competent in DNA repair or immune function or who does not activate specific chemicals

to carcinogens very well or who efficiently

eliminates potential carcinogens by deactivation.

Because each of these critical functions may show

a wide spectrum of activity, cancer susceptibility may be quite variable as well (2,4).

Body fluids used in genetic testing

The detection of genetic traits or abnormalities eral sources of body fluids are available, but usualin humans presents special problems because ly blood, urine, and feces have been used in

tests for these factors must be noninvasive, that genetic tests. Because they are waste material and

is, they must use easily obtainable material. Sev - do not participate in the normal functions of the
54 ● The Role of Genetic Testing in the Prevention of Occupational Disease

body, urine and feces have limited application in

genetic testing. Their current use is as sources

of material for the detection of mutagens. The

assumption is that the presence of mutagens in

waste material indicates that those mutagens also

were present in body tissues.

Only blood serves as an easily obtainable source

of body fluid and cells for genetic tests, and, again,

an assumption is made that blood reflects events

happening in the other parts of the body. An argument against this assumption is the fact that

chemicals act in tissue-specific manners. On the

other hand, in experimental situations with animals, it has been found that blood cells do reflect

exposure levels. In addition, because blood is so

easy to obtain, much of the research on genetic

mutations in humans has been done on blood proteins.

Blood can be divided into two components: cells

and serum, the fluid in which they float. Serum

can be assayed for three types of compounds: proteins normally found in serum such as clotting

factors, protein degraders, and antibodies; proChapter 4 references

1.

2.

3.

4.

5.

6.

teins from liver cells, some of which are important in carcinogen metabolism; and mutagens.

The two types of blood cells, red and white, can

be used to detect genetic traits or abnormalities.

Red blood cells, or erythrocytes, have both enzymatic functions and an oxygen-carrying function, handled by the protein complex called hemoglobin. Because the red cells are so easily obtained, a great deal is known about both the normal and genetic variants of erythrocyte proteins,

In addition, hemoglobin is probably the easiest

protein in the body to isolate in large quantities.

For these reasons, tests to identify genetic or

chemical variants of hemoglobin have been used

to detect the presence of mutagens and are included in this assessment.

White blood cells, or leukocytes, are a heterogeneous set of cells involved primarily in the immune functions. A subset of these cells, the lymphocytes, are the cells most often used to detect

mutagenic activity. It is the lymphocytes that are

assayed for chromosomal aberrations and SCEs.

Many other biochemical tests to detect mutagenesis also use lymphocytes.

Crow, J. F., “How We]] Can We Assess Genetic

Risk? Not Very,” Lauriston S. Taylor Lectures in

Radiation Protection and Measurement, Lecture

No. 5. (Washington, D, C.: National Council on Radi- 7<

ation Protection and Measurements, 1981).

Harris, C. C., et al., “Individual Differences in

Cancer Susceptibility, ” Ann. Int. Med. 92:809-825,

1980. 8.

Latt, S. A., et al., “Sister Chromatid Exchanges: A

Report of the Gene-Tox Program)” Mutat. Res. 87: 9.

17-62, 1981.

Marks, P. A., “Genetically Determined SusceptibiliTechnologies for Determining Cancer Risks From

the Environment (Washington, D.C.: U.S. Government Printing Office, OTA-H-138, June 1981).

Perry, P., and Evans, H. J., “Cytological Detection

of Mutagen-Carcinogen Exposure by Sister Chromatid Exchange, ” Nature (London) 258:121-125,

1975.

Siskind, G. W. (cd.), Immune Repression and

Cancer (New York: Grune & Stratton, 1975).

Swift, M., et al., “Reassessment of Cancer Predisposition of Fanconi Anemia Heterozygotes, ” JNCZ

65:863-867, 1980.

ty to Cancer,” g~ood 58:415-419, 1981. 10. Taparowsky, E., et al., “Activation of the T24 Blad -

McKusick, V., ‘

( Mendelian Inheritance in Man” der Carcinoma Transforming Gene is Linked to

(Baltimore: Johns Hopkins University Press, 6th a Single Amino Acid Change, ” Nature (London)

cd., 1982). 300:762-765, 1982.

Office of Technology Assessment, US. Congress,
Chapter 5

Principles of Genetic Testing
Contents

Page ,

Validity) Reliability, and Predictive Value.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Relative Risk. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

OTA’s Assessment of Occupational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

List of Tables

Table Page

12. Calculation of Predictive Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

13. Influence of Genotype Frequency on the predictive Value of Screening Tests.. . . . . 59

14. Influence of Genotype Frequency and Relative Risks on the Proportion of Workers

at Risk for Harmful Reactions Who Will Have Positive Screening Test Results . . . . . 60

Figure

Figure Page

7. Example of a Hypothetical G-6-PD Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Chapter 5

Principles of Genetic Testing

Genetic testing of employee populations is a

basic method for identifying individuals or groups

with particular inherited traits or evidence of genetic damage in certain cells who may be at increased risk for disease. It is the application of

tests to a group of apparently well persons in

order to identify those who have a high probability of developing a disease so that prevention or

early treatment is possible. Genetic testing involves laboratory examination of body fluids such

as blood to determine the presence of inherited

traits or changes in chromosomes or deoxyribonucleic acid (DNA). It includes both genetic

screening and genetic monitoring. Each uses

specific laboratory tests but the goals of each are

slightly different.

A genetic screening test is a one-time procedure

used in occupational settings to identify individuals with certain inherited traits. Some scientists

have hypothesized that these traits may cause the

individual to be at increased risk for certain occupational diseases when exposed to hazardous

chemicals (1). Because these inherited traits do

not change, a single test for them is sufficient.

Genetic monitoring periodically examines induced genetic damage in certain cells of workers.

Some scientists believe that certain types of

genetic damage may indicate exposure to hazardous agents and may be associated with an increased risk for certain diseases, in particular

cancer, The laboratory tests search for endpoints

different from those used in genetic screening,

and the procedures are applied initially to determine a baseline of genetic damage prior to exposure and then periodically to determine

changes in that damage. Changes in certain genetic characteristics of the population may indicate that the population is at an increased risk

for disease.

Before a rational decision can be made on the

value of any genetic screening or monitoring program in the workplace, two questions must be

answered. The first is: “Does the test being employed reliably identify either the genetic trait or

type of damage in question?” The answer to this

question requires an assessment of the particular

laboratory techniques used to identify genetic

traits or genetic damage from exposure to hazards. Only after achieving a positive answer to

this question can the following question be asked:

“Does this particular trait or damage cause the

individual or population to be at increased risk

for disease?” The answer to this question involves

assessing the conclusions of epidemiologic studies regarding the association between these genetic factors and disease. Available scientific evidence indicates that the first question can be answered in some cases; the answer to the second

one awaits significantly more research. In ascertaining whether the test identifies either a genetic

trait or damage, the tests must be subjected to

scientifically recognized analytical criteria: validity, reliability, predictive value, and relative risk

(6).

Validity, reliability, and predictive value

The validity of genetic testing—i.e., the proba- ance) and biological (i.e., the influence of other

bility that a test will correctly classify true sus- genetic as well as environmental factors).

ceptible (“positive”) and true nonsusceptible (“negative”) individuals—should be evaluated before the From the distribution of the test results in those

test is placed into routine use. Few tests are 100 for whom the presence or absence of a genetic

percent valid. The reasons are both methodology - endpoint (trait or genetic damage) has been concal (i.e., the inherent variability in test perform- firmed, the validity of the test at different cutoff

57
58 ● The Role of Genetic Testing in the Prevention of Occupational Disease

points can be determined (fig. 7). Two separate,

independent characteristics are subsumed under

validity; each depends on the cutoff point that is

selected. These are:

●

●

sensitivity, or true positive ratio—the frequency with which the test will be positive

when the genotype in question is present;

and

specificity, or true negative ratio—the frequency with which the test will be negative

when the genotype in question is absent. An

ideal test would be 100 percent sensitive and

100 percent specific. In actual practice this

does not occur.

Sensitivity and specificity are usually inversely

related. That is, one usually achieves high sensitivity at the expense of low specificity and vice

versa. This can be demonstrated by examining

a hypothetical situation to determine the cutoff

point for a screening test (fig. 7).

The selection of the actual cutoff point depends

on the objective of the screening or monitoring

test. If the objective is to identify all individuals

with the abnormal genotype or genetic damage,

cutpoint A would be selected. As the figure shows,

such a cutpoint will pick up all true positives, but

it will also result in many false positives. If no

followup test is planned in the routine operation

of a screening program, this cutoff point would

mislabel many people as affected who are not.

With cutoff point B, no individuals would be falsely labeled as affected, but some affected individuals would be falsely labeled as unaffected. Methods of determining the cutpoint that minimize

costs of mislabeling or that maximize the information to be gained from the screening tests are

available (5,7),

In addition to validity, reliability under conditions of routine use must also be demonstrated.

That is, tests of the same specimen must repeatedly give the same result whether performed by several different laboratories or by the same laboratory on several occasions.

predictive value is related to sensitivity, specificity, and the prevalence of the trait or genetic

damage in the population. When the prevalence

of a particular trait or genetic damage is low in

the population, even a highly specific test will give

a relatively large number of false positives because many persons being tested will not have

the endpoint. The likelihood that an individual

with a positive test has the disease, and vice versa

for a negative test result, is the predictive value

of the test. The importance of prevalence for the

predictive value of a test can be seen in the following example. Table 12 presents hypothetical data

Figure 7.—Example of a Hypothetical G-6-PD Distribution

SOURCE: Office of Technology Assessment
Ch. 5—Principles of Genetic Testing ● 5 9

Table 12.—Calculation of Predictive Valuea

Number with Number with

positive test negative test Total

Genotype present . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990 1,000

Genotype absent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990 98,010 99,000

Totals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1,980 98,020 100,000

Predictive value of a positive test result = 990 =0.5 0

1,980

98,010 = 0.9999 Predictive value of a negative test result = —

98,020

sensitivity, specificity = O 99.

SOURCE: N A Holtzman, “Principles of Screening Applied to Testing for Genetic Susceptibilities to Harm From Workplace Exposure,” prepared for OTA, September 1982

for calculating the predictive value of a positive

test result for a genotype frequency of 1 percent

(1,000/100,000) (2). Even where the sensitivity and

specificity are arbitrarily set high, 0.99, the positive predictive value is only 50 percent. This

means that the test correctly measures the result

only half the time; in the case of genetic screening, half of the workers with positive test results

would, in fact, not have the predisposing genotype. Followup testing would have to be a part

of a screening or monitoring program in order

to detect the false positives or false negatives.

Table 13 shows the influence of selected frequencies when a cutpoint for the screening test

is used that yields both a specificity and a sensitivity of 0.99. The predictive value of the positive

test will vary between O and 0.92 percent as the

frequency of the genotype varies between 1 and

10,000 per 100)000 (0.001 to 10 percent) people

screened. The chance that a person with a negative test result does not have the genotype is also

shown. Note that all the predictive values for a

negative test result in the table are very close to

1.0. A genotype frequency (prevalence) of approximately 50 percent (not shown) is needed before

the predictive value of a negative test rises to 0.99

(3,6).

Table 13.—lnfluence of Genotype Frequency on the Predictive Value of Screening Testsa

Frequency of the genotype (per 100,000)

1 10 100 1,000 10,000

Predictive value of a positive test result . . . . . . . . . . . . . . . . . . 0 0.01 0.09 0.50 0.92

Predictive value of a negative test result . . . . . . . . . . . . . . . . . . 1 1 1 1 1

%ensitivlty, specif~clty =0 99.

SOURCE: N. A. Holtzman, “Principles of Screening Applied to Testing for Genetic Susceptibilities to Harm From Workplace Exposures,” prepared for OTA, September 1982,

Relative risk

The proportion of workers likely to contract

a disease depends not only on the previously mentioned variables (reliability, validity, frequency of

the genotype), but on the relative risk for the

disease imposed by the genetic trait or damage.

Information for calculating relative risk* can be

● Relati\re risk is the ratio of the incidence of disease among exposed persons divided by the same rate among nonexposed persons.

collected in two ways. In the prospective approach, all individuals comprising the population

exposed to the agent would be tested for the genotype and followed for a set period of time to

determine the incidence of harmful effects in

those with the specific genotype and in those

without it. Alternatively, a retrospective study

could be used to compare the frequency of the

genotype among workers who developed the
60 The Role of Genetic Testing in the Prevention of Occupational Disease

harmful reaction to the frequency in workers

who did not. (Note: The latter approach would

yield a risk ratio which is a close approximation

to the relative risk measure.)

Table 14 shows the influence of relative risk

and genotype frequency on the proportion of

workers at risk for harm from exposure discovered by a test whose sensitivity and specificity are set equal to 0.99 (3). For example, with a

genotype frequency of 1,000/100,000(1 percent),

those with the genotype must be 100 times more

likely to suffer adverse reactions before the

screening test will discover half of those who will

suffer harm. In addition, in this table and the two

preceding tables, sensitivity and specificity levels

Table 14.-lnfluence of Genotype Frequency and

Relative Riska on the Proportion of Workers at Risk

for Harmful Reactions Who Will Have Positive

Screening Test Resultsb

Frequency of Relative risk

genotype (per 100,000) 5 10 50 100

Proportion of at-risk workers

discovered by screening

1 0.01 0.01 0.01 0.01

10” : : : : : : : : : : : : : : : : 0.01 0.01 0.01 0.02

100 . . . . . . . . . . . . . . . 0.01 0.02 0.06 0.10

1,000 . . . . . . . . . . . . . . 0.06 0.10 0.34 0.50

10,000 . . . . . . . . . . . . . 0.36 0,53 0.64 0.91

‘Relative risk = incidence of adverse reaction in

those with the susceptible genotype

incidence of adverse reaction In

those without the susceptible genotype

bSensitivlty, specificity set at = 0.99

SOURCE: N, A. Holtzman, “Principles of Screening Applied to Testing for Genetic

Susceptibilities to Harm From Workplace Exposures,” prepared for

OTA, September 1982.

have been set at 0.99 in order to elucidate the

other components. In actual studies sensitivity

and specificity are never as high. Thus, the ability to detect predisposing factors is further compromised.

From this discussion, it is clear that attention

must be paid to validity, reliability, predictive

value, and relative risk or screening and monitoring in the workplace may turn out to be costly

and of little benefit. The less frequent the genetic

endpoint being tested, the less likely that the person with a positive test result will truly have that

trait or damage. Unless testing of high validity is

restricted to conditions in which the frequency

of the trait or damage is high, a significant number of false positives and false negatives can be

expected. False positives increase the social, economic, and psychological costs of screening; false

negatives reduce the health benefits, When the

frequency of the endpoint is high, however, lowering exposure for the entire work force may be

the most effective way of reducing disability. If

a genetic screening program were instituted, a

population that would ensure a relatively high frequency (greater than 1 percent) of the trait of interest should be chosen, One way to increase the

frequency in a population is to select a subgroup

that is expected to have a higher frequency of the

trait than the general population. A monitoring

program should be instituted only when bacterial

and animal tests have proven that the chemical

in question is mutagenic or carcinogenic. Moreover, worksite sampling should establish that the

hazardous agent is present in areas where workers would be significantly exposed.

OTA’s assessment of occupational studies

The correlation of a test endpoint (for example, chromosomal damage) with the later occurrence of disease is difficult to ascertain because

the possibility remains that adverse consequences

from exposure will not occur in all of those with

the predisposing condition; other genetic or environmental factors (for example, smoking) may

be necessary for the development of the disease

or may contribute differently in different individuals. Because an illness may have multiple

causes, it may also occur in workers without the

predisposing condition. Thus, genetic tests may

identify only a proportion of the workers who

will develop adverse reactions,

Part III of this report contains OTA’s assessment

of relevant monitoring and screening studies conducted on human populations. The following cri-
Ch. 5—Principles of Genetic Testing . 61

teria were applied to determine whether the ●

studies were based on sound methodological approaches (4):

• Is the observed association consistent? That

●

is, has the same association been observed

in similar studies?

●

● Is the association specific? Was there a mix

of exposure levels or grouping of individuals

such that the precise nature of the effect of

exposure is difficult to ascertain?

● Is the strength of the association strong? Is

it strong enough to indicate a causal relationship between exposure and disease?

Is there a dose-response relationship? Does

it appear that higher exposure levels are associated with higher prevalence of the

disease?

Is there a biological mechanism to explain the

association?

Was the study designed so that the assumptions of statistical methodology were met?

Has the sample been properly drawn?

Chapter 5 references ___

1. Buffler, P., manuscript of Presentation to the American Council of Governmental and Industrial Hygienists Conference on the Sensitive Worker, Tucson,

Ariz., November 1981.

2. Galen, R. S., and Gambino, S. R., Beuvond Abrrnalituv 5

(New York: John Wiley, 1975).

3. Holtzman, N. A., “Principles of Screening Applied 6.

Chromatid Exchange,” Mutat. Iles. 99:373-382, 1982,

Elsevier Press, International Commission for protection Against Environmental Mutagens and Carcinogens, ICPEMC Working Paper 5/2.

McNeil, B. J., et al., iVetv Eng). J. Med. 293:211-215,

1975.

National Academy of Sciences (NAS), Genetic Screento Testing for Genetic Susceptibilities to Harm From kg: Programs, Principles and Research, Committee

Workplace Exposure, ” prepared for OTA, Septem- for the Study of Inborn Errors of Metabolism (Washber 1982. ington, D. C.: NAS, 1975).

4. Hook, E. B., “Epidemiologic and Design Aspects of 7. Weinstein, M, C., and Feinberg, H. t’., Clinical DeStudies of Somatic Chromosome Breakage and Sister cision Ana@sis (Philadelphia: W. B. Saunders, 1980).
Part III

An Assessment of the

State of the Art

Chapter 6-Genetic Monitoring in the Workplace . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Chapter 7-Genetic Screening for Heritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
.—— — .——

Chapter 6

Genetic Monitoring

in the workplace
Contents

Cytogenetic Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Associations Between Chromosomal Aberrations and Disease . . . . . . . . . . . . . . . . . . . . .

Correlation Between Chromosomal Aberrations, SCEs, and Carcinogenicity . . . . . . . . .

Chromosomal Studies on Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Studies on Unexposed Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Studies on Atomic Bomb Survivors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Ionizing Radiation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Benzene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ... .....

Occupational Studies on Epichlorohydrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Ethylene Oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Lead, Cadmium, and Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Occupational Studies on Vinyl Chloride Monomer . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Priorities for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Noncytogenetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Survey of Monitoring Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Mutagens in Body Fluids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Somatic Cell Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Germ Cell Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Priorities for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

List of Tables

Table No.

15. Summary of Noncytogenetic Monitoring Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . .

16. A Summary of Noncytogenetic Methods Used in Human Monitoring . . . . . . . . . . . . .

Page

67

68

67

69

70

70

71

71

72

72

72

72

73

74

74

75

75

75

77

79

79

80

80

Page

76

80
Chapter 6

Genetic Monitoring in the workplace

Although humans have been exposed to chemicals and radiation for thousands of generations,

the numbers and amounts of these potentially

hazardous agents in the environment have increased dramatically since the industrial revolution. Moreover, certain occupational groups are

exposed to these substances over many years at

much higher concentrations than is the general

population.

While the contribution of toxic chemicals and

ionizing radiation to the human genetic burden

has not been directly shown, some of these agents

do cause mutations and chromosomal damage in

laboratory animals. Geneticists are concerned that

exposures to new mutagenic agents could increase the number of gene mutations in the

human population and hence the incidence of disease. Because of the increasing chances for exposure to harmful agents, it is desirable to develop

tests that identify the mutagenic and clastogenic

(chromosome-damaging) potential of chemicals

and ionizing radiation. When hazards are identified, prevention programs can he considered

that will reduce exposures to the hazards. In addition, genetic tests may be useful to monitor

human populations for exposure.

Ideally, an occupational monitoring technique

would provide early, reliable, and quantitative information regarding “biologically significant”

exposure * to hazardous agents. Once a biological-

““1’he ciefinitlon of’ hiolr~gl(alljsignifi(’ant ” exposure is a difficult

011(1, and there IS hj no means a concurrence of opinionamong

healttl (art’ pr[)f[~ssionals It normallj ref(~rs to an [~xposure Imel

that can (’aust> detwtdhle dtirnage or- dis(>ase

ly significant level of exposure has been established, intervention measures to eliminate or significantly reduce worker exposure and prevent

untoward biological effects could be implemented.

Genetic monitoring in the workplace involves

the periodic testing of employees to assess damage

to their deoxyribonucleic acid (DNA) or chromosomes from exposure to hazardous agents. Currently, genetic monitoring techniques are most

useful for identifying or monitoring exposure to

a chemical that causes genetic damage. The objective of these techniques ultimately is to predict

risk of disease due to genetic damage.

There are two types of techniques covered in

this assessment. The first type, cytogenetic techniques, looks for gross changes in chromosomal

structure. These techniques, including tests for

chromosomal aberrations and sister chromatid

exchange (SCE), represent the currently used

methods for monitoring for genetic damage.

Other monitoring techniques that also look for

damage to the genetic material have been proposed for human populations. These newer noncytogenetic techniques may offer advantages in

sensitivity, cost, and performance time over the

cytogenetic methods, often because of automation, but most of them have had little actual application in human monitoring programs at the

present time. This chapter reviews the occupational studies done to date, first examining the

use of cytogenetic monitoring and then noncytogenetic monitoring.

Cytogenetic monitoring

The empirical association between chromo- SCEs may be used as possible biological dosisomal damage and mutagenic/carcinogenic agents meters (measures of exposure) for human exestablished from animal studies implies that posure to these agents. There are three natural

chemically induced chromosomal aberrations and extensions of this dosimeter hypothesis. One is

67
68 . The Role of Genetic Testing in the Prevention of Occupational Disease

the idea that studies using cytogenetic endpoints*

may be used to identify human carcinogens or

mutagens. * * The second is that these studies

might identify populations at risk for cancer and

other diseases as a result of exposure to these

clastogens. Last, the studies may identify individuals in those populations who, because of a defect

in DNA repair mechanisms, may be particularly

predisposed to chromosomal damage. In the

workplace, the goals of such studies would be to

determine acceptably safe levels for occupational

exposure to chemicals and radiation (that is, those

levels associated with minimal, or acceptable, risk

of disease) for the average population and to insulate susceptible individuals from the chemical.

This section examines the appropriateness of

chromosomal endpoints to detect occupational exposures to chemicals and radiation. This critical

review of the literature seeks to determine

whether chromosomal endpoints can be used as

a measure of occupational exposures and whether

the results of cytogenetic monitoring are a predictor of risk for disease for either groups or individuals. The discussion is limited to studies that

are pertinent to adult somatic effects resulting

from occupational exposures.

Associations between chromosomal

aberrations and disease

Many diseases are thought to involve somatic

cell genetic defects. Interference with immune

function, manifested as autoimmune disease, allergy, or increased susceptibility to infectious

agents, may involve somatic cell genetic changes.

Hence, induced chromosomal aberrations may

prove to be related to these clinical states. However, there are no studies, either in animals or

in man, that address the possible association between induced chromosomal aberrations or SCEs

and immune function,

. —

‘The term endpoint refers to the biological response to exposure

being monitored. In this section, two endpoints are discussed, chromosomal aberrations and SCEs.

● *Studies would not be done primarily to investigate this issue,

but results identifying human carcinogens or mutagens could derive

from cytogenetic studies investigating risk for disease. The identification of mutagens and carcinogens is done with animals and

extrapolated to humans; cytogenetic studies would either verify the

animal data or refute the extrapolation.

Photo credit: National Institutes of Health

Cytogenetics involves the examination of chromosomes

under a microscope

other diseases of the blood/lymph system, such

as aplastic anemia and multiple myeloma, also

may be the result of somatic cell genetic changes.

Because cytogenetic monitoring usually utilizes

blood lymphocytes as the chromosomal source,

cytogenetics may prove useful in predicting

whether individuals exposed to high levels of

clastogens may be candidates for these blood cell

diseases, but this association is only speculative.

Cancer is the disease most commonly hypothesized to be associated with induced chromosomal

aberrations, undoubtedly because of the large

animal literature linking carcinogens with chromosomal aberrations. Additionally, many types

of human cancer cells contain specific chromosomal aberrations (31,34,63,76,93,99,141). Chromosomal aberrations have been found for both

lymphoproliferative disorders, such as leukemia,
Ch. 6—Genetic Monitoring in the Workplace ● 6 9

and solid tumors. The strength of the association

between the specific aberration and the presence

of cancer varies from one cancer to another. At

one extreme, the Philadelphia chromosome (a

translocation from the long arm of chromosome

#22 most often to the long arm terminus of chromosome #9) correlates highly with chronic myelogenous leukemia, with 85 to 95 percent of patients having this marker chromosome in their

affected cells. On the other hand, in the case of

a pair of identical twins, each carrying the specific

deletion associated with Wilms tumor, only one

of the twins developed the disease (76). Thus, even

when specific chromosomal markers are involved,

other nongenetic factors can play a role in the

development of cancer.

Correlation between chromosomal

aberrations, SCEs, and carcinogenicity

The extensive literature on animal studies that

use chromosomal endpoints has recently been appraised and reviewed by the U.S. Environmental

Protection Agency’s (EPA) Gene-Tox Program

committees (80, 113). The Gene-Tox committee for

mammalian in vivo and in vitro cytogenetic assays

(chromosomal aberrations) reviewed 177 papers

published through October 1978 using several

somatic cell systems (113). For one or another of

these systems, 150 chemicals were reviewed.

According to the Gene-Tox findings for chromosomal aberrations and SCEs, the data base for

chemicals that have been adequately studied in

animal or in in vitro systems is quite limited, and

the number of the chemicals for which carcinogenicity is known is even more limited. In addition, the carcinogenicity data were generated in

separate studies from the chromosomal data and

are not directly comparable. But within these

restrictions, it would appear that the induction

of chromosomal aberrations and SCEs by chemical agents are reasonable indicators of carcinogenicity, with the former possibly being the

better predictor. However, for both endpoints,

examples exist of chemicals that cause chromosomal damage but not cancer, and vice versa. In

order to relate genotoxicity more closely to

humans, the Gene-Tox review recommended human cells as being suitable for in vitro studies.

The review is still is progress, and EPA has yet

to issue any recommendations on the predictive

value of any of the techniques.

A recent review by Gebhart (57) summarizes

the world’s literature concerning the agreement

between chromosomal aberrations and SCEs.

Gebhart found a 30 percent disagreement between these two endpoints where the same chemical had been evaluated for aberrations and SCEs

both in vitro and in vivo. This indicates that the

fundamental way in which a particular chemical

interacts with the DNA to produce SCEs may be

different from the mechanism that produces

chromosomal aberrations.

Chromosomal studies on groups

This section provides a comprehensive review

of occupational studies using chromosomal endpoints. Many of the studies fall short of ideal. For

instance, confounding factors, such as cigarette

smoking, were not always determined, and some

studies examined populations too small to produce reliable results. In general, more recent

studies are better designed and executed. However, rather than discard the evidence of the older

studies, the strengths and weaknesses of all the

studies are reviewed, and overall conclusions are

drawn.

The review covers studies addressing the normal range of values for chromosomal endpoints,

studies on the chromosomal endpoints and health

status of atomic bomb survivors exposed to ionizing radiation, and occupational studies on the

chromosomal endpoints of workers exposed to

ionizing radiation and specific chemicals.

For the occupational studies, the following questions were asked:

●

●

●

Was there substantial evidence of an increase

in the endpoint that could be associated with

exposure to a specific agent? was there a

dose response? Were chronic as well as acute

exposures monitored?

Was there evidence to link any of these endpoints with increased risk for disease?

Are these tests sufficiently sensitive to permit detection of effects at current occupational exposures?
70 . The Role of Genetic Testing in the Prevention of Occupation/ Disease

• For each of the agents discussed in detail, is

there evidence that cytogenetic endpoints can

detect susceptible individuals?

STUDIES ON UNEXPOSED POPULATIONS

Several large studies have examined the range

of chromosomal aberration and SCE frequencies

and the variables affecting them in unexposed

populations (13,15,28,29,35,59,71,79,86,88,90,

95,100). Seasonal variations, age, sex, smoking,

and alcohol effects have been reported, although

not consistently for every study. From these studies, it is apparent that background frequencies

for chromosomal aberrations and SCEs may fluctuate greatly. The background frequencies reported in several studies are shown in appendix

D for chromosomal aberrations and in appendix

E for SCEs. Comparison of findings from studies

with varied laboratory methodology is difficult

but useful to the extent that it conveys a sense

of possible variability for these endpoints.

The range of reported frequencies per cell for

individual aberrations found was:

● chromatid breaks: 0.11 to 6.72 percent,

. chromosome breaks: 0.1 to 3.0 percent,

● exchange aberrations: O to 0.34 percent,

● cells containing any aberration: 0.2 to 8.5 percent, and

● SCEs: 5.8 to 16.2 per cell.

These wide variations suggest that the range

of “normal” values for chromosomal endpoints

may be dependent on the particular laboratory

methodology. Certainly the fortyfold differences

seen for background values of chromosomal aberrations are much greater than those reported in

individual studies between occupationally exposed and unexposed groups.

STUDIES ON ATOMIC BOMB SURVIVORS

Since the end of World War II, the Japanese

survivors of the atomic bombs and their offspring

have been extensively monitored by the Atomic

Bomb Casualty Commission, recently redesignated the Radiation Effects Research Foundation,

for residual and latent biological effects, These

studies have been a joint effort between eminent

Japanese and American scientists and are ongoing (102). Refinements are still being made in

dosimetry estimates and epidemiology.

This Japanese population has been observed to

have an increased risk for many types of cancer

(14). Leukemias were the first evident cancers,

with incidence peaking 7 to 8 years after exposure, The incidence of all leukemias for this

population has subsided with time, but it is not

clear if the risk for leukemias has declined to

background values.

With the decline of leukemias, the onset of

other types of cancer has become apparent. To

date there is a clearly increased risk for cancers

of the thyroid, female breast, and lung. Excess

stomach and salivary gland cancers are suspected

but not yet confirmed. In contrast to the leukemias, the time of onset for breast cancer in exposed populations has not been earlier than

would be predicted on the basis of studies in

unexposed populations. Rather, breast cancer has

appeared at a higher, dose-related frequency at

the age when it usually occurs. All of these

cancers have shown a dose dependence for radiation, but the shape of the dose-response curves

differs with different cancers. These differences

in patterns of cancer incidence are consistent

with the widely held opinion that the mechanisms

of radiation-induced cancers are complex and

perhaps different from one cancer to another.

In conjunction with these morbidity and mortality studies, extensive cytogenetic investigations

on these survivors have revealed a dose-dependent increase in chromosomal aberrations (14).

These cytogenetic studies have been possible

because some of the chromosomal abnormalities

induced by ionizing radiation are very long lived.

The frequencies of these aberrations seen in the

atomic bomb survivors are very high compared

to the aberration frequencies found in occupational exposures, even in individuals receiving

small doses (less than 1 rad * ). The reason for this

is unknown.

The ongoing epidemiological studies on these

same individuals provide an unparalleled opportunity to examine directly the relationship be-

*A ~a~ is a measure of absorbed dose of ionizing radiation,
Ch. 6—Genetic Monitoring in the Workplace . 71

tween chromosomal aberrations and cancer. In

an extensive study reported by King, et al. (75),

where chromosomal aberrations, malignancy, and

other clinical findings were tracked for individuals in the Hiroshima population, the tentative

conclusion was that such correlations do not exist.

with populations or groups, however, the studies on the Japanese clearly demonstrate a relationship between estimated radiation dose and certain cancers and between radiation dose and

chromosomal aberrations. But for individuals, elevated frequencies of chromosomal aberrations

are not reliable predictors for risk of cancer or

other somatic cell diseases. Thus, even these ex -

tensive studies do not provide evidence that radiation-induced chromosomal aberrations mean that

individuals with these aberrations will necessarily

develop cancer.

Several points should be borne in mind in relating these studies to the ionizing radiation

studies discussed below. First, the Japanese

studies reported quite high frequencies for rare

aberrations, even in groups receiving less than

1 rad. Second, because of the manner in which

the studies were designed, little or no cytogenetic information is available on the group receiving exposures between 1 and 100 rads. This group

is probably the most comparable, in terms of

equivalent genotoxic dose, to groups receiving occupational exposures to radiation. Thus, because

of the different types of chromosomal aberrations

involved and, because of probably larger radiation doses in the exposed Japanese populations,

it is difficult to relate the significance of these findings to occupational studies. Finally, the Japanese

studies deal with the effects of a single, large,

acute dose of radiation. In the majority of occupational situations, the effects of chronic lower

doses of radiation may not be so easily detected.

OCCUPATIONAL STUDIES ON ION1ZING RADIATION

If chromosomal aberrations induced by radiation are indicative of some health risks, albeit for

a group, then occupational cytogenetic studies on

workers exposed to chronic lower doses of radiation may be of some value in setting acceptable

standards for occupational exposure to radiation.

Several occupational studies have been done on

uranium miners, workers in a plutonium processing facility, and nuclear powerplant workers

(17,20,21,22,23,46,89,98). Every study reviewed

has shown that increases in chromosomal aberrations are associated with occupational exposures to ionizing radiation. If these aberrations

are as stable as those in the Japanese, they would

not necessarily indicate recent exposures under

current occupational exposure standards, but

rather accumulated exposure over several years. .

From these studies, it is not clear if the chromosomal aberration endpoint is sensitive enough

to detect chronic exposures within the current

occupational exposure standard of 5 reins* per

year. occupational groups would have to be

studied at low-level chronic exposures to determine if individuals exposed to the current occupational standard have increased frequencies of

aberrations.

OCCUPATIONAL STUDIES ON ARSENIC

Arsenic is a ubiquitous element that can occur

in several chemical forms, some of which have

commercial uses as fungicides, insecticides, and

herbicides. It also has been used for medicinal

purposes, for instance, in the treatment of ailments ranging from asthma to psoriasis and syphilis. When arsenic is eaten or inhaled, about 50

percent of the dose is absorbed. Of the absorbed

dose, roughly half is excreted within 2 days. The

remainder is eliminated more slowly, and a fraction can accumulate in the body, where it is

distributed in many different tissues (85). Arsenic

is classified as a human carcinogen (72). Several

types of cancers have been associated with occupational exposure to arsenic in smelters, in the

chemical industry, and in gold mining (103).

Both chromosomal aberrations and SCEs have

been reported to be elevated in individuals exposed to arsenic, with SCEs possibly being the

more sensitive indicator (26,97,1 10). Chromosomal effects of arsenic exposure are long lived

and possibly reflect cumulative exposure. It is not

clear if chromosomal endpoints can detect lowlevel chronic exposure to arsenic, because the exposures in the studies reviewed here were relatively high. The one study on arsenic in an oc-

‘~ rem is a raci multiplied b> a number that takrs into account

I}lf’ potential darnage<’ausing abilit} of a particular t~pe of ionizing

radiation in a biological sl’stem.

,)— , .; – 27

- r,
72 . The Role of Genetic Testing in the Prevention of Occupational Disease

cupational setting (97) is not sufficient to permit

a decision on the suitability of cytogenetic endpoints for measuring exposure.

OCCUPATIONAL STUDIES ON BENZENE

Benzene is a constituent of fossil fuels and also

is a major industrial and laboratory chemical. As

a result, a substantial number of people are

chronically exposed to benzene at work, and

many more receive transient exposures outside

the workplace, for instance, while pumping gasoline. As with arsenic, benzene is classified as a

human carcinogen (72), with an excess of leukemias, particularly erythroleukemia, associated

with high exposures (73,134), Benzene is also a

potent blood cell poison, with manifestations including pancytopenia (reduction of all blood elements) and aplastic anemia, The current occupational exposure standard for benzene in the

United States is 10 parts per million (ppm), a timeweighted average for 8 hours.

Benzene is one of the most widely studied chemicals in occupational cytogenetics. Several studies

consistently have shown that exposure to high

doses of benzene (greater than 40 ppm) is associated with chromosomal aberrations, even

though frequencies are low in comparison with

radiation-induced effects (52,53,54)111)112,131)

132,136). The aberrations appear to be stable for

years and most likely reflect cumulative rather

than recent exposure. Whether exposure to benzene within the current occupational standard of

10 ppm induces chromosomal aberrations has yet

to be determined.

OCCUPATIONAL STUDIES ON EPICHLOROHYDRIN

Epichlorohydrin is a highly reactive major industrial chemical that has been extensively

studied for genotoxic activity (126). It is mutagenic

in microorganisms, causes chromosomal aberrations in mouse bone marrow, and induces chromosomal aberrations in human lymphocytes in

vitro (126). Epichlorohydrin causes nasal tumors

in rats by the inhalation route at levels higher

than 10 ppm (N. Nelson, unpublished study). One

study has indicated a slight, but not statistically

significant, excess in respiratory cancers among

workers exposed to this chemical (45), and IARC

(72) found that it “could not be classified as

to . . . carcinogenicity for humans.”

The only adequate cytogenetic study on epichlorohydrin (127) showed that occupational exposure to the chemical may be associated with

low frequencies of chromosomal aberrations. No

studies have been done linking chromosomal

aberrations with risk for disease in a population

exposed to epichlorohydrin.

OCCUPATIONAL STUDIES OF ETHYLENE OXIDE

Ethylene oxide is an extremely reactive chemical whose commercial uses are primarily as a

sterilizer of medical products and as a chemical

intermediate. Ethylene oxide has been shown to

cause leukemias in rats by the inhalation route

at doses higher than 33 ppm (58). It can induce

chromosomal aberrations in vitro and mutations

in tester micro-organisms (46). Because of ethylene oxide’s volatility, there is a high potential for

occupational exposure in situations where it is not

properly contained. The current Occupational

Safety and Health Administration’s (OSHA) occupational exposure standard is so ppm, timeweighted average. Two reports (.57,68) suggest an

increase in leukemia among workers exposed to

this chemical.

Three published studies associate present levels

of ethylene oxide found in the workplace with

chromosomal aberrations and possibly SCEs

(56, 109, 130). However, frequencies for these endpoints were low. Two additional studies on ethylene oxide (S. Galloway and A. Carrano, personal

communication) are now being conducted. Preliminary reports on a study being conducted at

three Johnson & Johnson plants indicate a consistent dose-response for both chromosomal aberration and SCE endpoints. Statistically significant

increases in cytogenetic aberrations were seen

even in a plant where exposures range from 1

to 10 ppm. No effects were found at less than 1

ppm (32, 101).

OCCUPATIONAL STUDIES ON LEAD,

CADMIUM, AND ZINC

Lead, cadmium, and zinc tend to occur together

in mineral deposits in nature and, therefore, in

occupational exposures. High exposures to lead

or cadmium can produce both acute symptoms
— —. —

Ch. 6—Genetic Monitoring in the Workplace . 73

of poisoning and chronic effects. Lead poisoning

involves nerve degeneration, interference with

some metabolic processes, and, in its severest

form, mental retardation. Lead acetate is carcinogenic in rats, but has been negative for chromosomal aberrations and SCEs in vitro (80,113).

Cadmium has been shown to cause birth defects

and cancer in rodents, and there is some evidence

for human carcinogenicity (72). Occupational exposure to cadmium has been associated at least

tentatively with lung and prostate cancers (36).

Both cadmium and lead tend to accumulate in the

body with chronic exposure, a point which may

be important in interpreting the occupational

studies on these agents because damage may reflect a cumulative exposure.

Zinc, unlike lead and cadmium, is necessary for

the function of some of the enzymes involved in

DNA replication and repair, and it is possible that

Photo credit Occupation/ Safety and Healfh Administration

Cytogenetic monitoring has been explored as a possible

technique for monitoring worker exposure to lead

cadmium and lead, when present in high

amounts, can replace zinc in these enzymes. If

this happened, the enzymatic activity would be

greatly reduced.

Many conflicting findings exist in the literature

addressing occupational exposure to lead, cadmium, and zinc (16)25,37,38,39 )50,51)69)89, 104,

105,120, 132). Increased frequencies of chromosomal aberrations and correlations with blood

lead values have been reported often enough to

provide some credibility to the correlations, but

many good studies have failed to find such relationships. Perhaps one reason for such discrepancies is the diversity of occupational exposures

studied. Different work situations could have entailed quite different kinds of exposures with

respect to the specific compounds in the work

environment and possibly to different primary

routes of exposure. The relationship between the

three elements and chromosomal aberrations

clearly is complex and awaits further elucidation.

OCCUPATIONAL STUDIES ON VINYL

CHLORIDE MONOMER

Vinyl chloride monomer is a major industrial

chemical used to make polyvinyl chloride plastics.

It is mutagenic for tester micro-organisms and

causes chromosomal aberrations in rats treated

with 1,500 ppm by the inhalation route, a very

high level (7). Vinyl chloride is a human carcinogen (72) and has been implicated in several

types of cancer (103).

Elevation of chromosomal aberrations to relatively high levels by occupational exposure to

viny I chloride is consistent and well documented

(5,8,41,49,55,62,74,77,1 14,1 18,129). The chromosomal aberration endpoint seems to be more sensitive than the SCE endpoint to vinyl chloride exposure. In contrast to the aberrations seen with

benzene, arsenic, and ionizing radiation, the aberrations associated with vinyl chloride exposure

are short lived, disappearing over days or weeks.

The mechanism for this difference is unknown.

Chromosomal aberrations, in this case, could be

used to document recent exposure but not necessarily cumulative exposure. Elevations in chromosomal aberration frequencies have not been

detected when documented exposures have been

less than 5 ppm. (The OSHA standard states that
74 ● The Role of Genetic Testing in the Prevention of Occupational Disease

the vinyl chloride level shall not exceed 1 ppm

during any 15-minute period). Thus, chromosomal aberrations and SCEs do not seem to be

sensitive enough to detect chronic low-level exposures to vinyl chloride for the number of cells

usually scored (200 or fewer) per individual.

Conclusions

Elevated chromosomal endpoints are associated

with occupational exposures to ionizing radiation

and may be associated with exposure to some

chemicals (arsenic, benzene, and vinyl chloride),

particularly where long- lived aberrations (arsenic

and benzene) are involved. The nature and longevity of the aberrations vary from one agent to

another. For some chemicals such as benzene, the

aberrations may persist for years. In these instances, the aberrations would indicate a cumulative exposure. For others, such as vinyl chloride

monomer, the aberrations disappear quickly after

reduction of exposure, and the cytogenetic tests

could monitor exposure only over short time periods. It is not known whether cytogenetic monitoring will detect chronic low-level exposure. Hence,

the appropriateness of chromosomal endpoints

for occupational monitoring needs to be determined on a case-by-case basis for each chemical.

In addition, a monitoring program should only

be instituted when bacterial and animal tests have

proved that the chemical in question is mutagenic

or carcinogenic,

No occupational studies directly relate positive

findings for any chromosomal endpoint with increased risk for any disease. Therefore, the

clinical significance of a positive occupational

cytogenetic study is unknown; nor is it known

whether cytogenetic monitoring can be used to

determine “safe” levels of exposure.

Retrospective cytogenetic studies done in conjunction with morbidity and mortality studies on

populations of survivors of the atomic bomb attacks in Japan have found both high frequencies

of stable chromosomal aberrations, particularly

complex aberrations, and increased risk of cancer. On the other hand, there is no known correlation between an individual’s chromosomal

aberrations and his or her risk for cancer.

Cytogenetic monitoring, or any other test based

on a single endpoint, may never be sufficient to

predict health risks for an individual (with the

possible exception of the Philadelphia chromos ome )) because the causes of cancer and other

chronic diseases are complex and multifactorial,

with some genetic and some environmental components. As more is understood about the molecular basis of each disease, an appropriate battery

of tests may be designed with a variety of endpoints, each reflecting some aspect of the potential causes, Given the present information, any

single endpoint, such as chromosomal aberrations

or SCEs, may have some predictive value for a

group, Even findings about groups with increased

chromosomal damage require epidemiological

studies on the populations to determine if increased risk for disease accompany the damage.

More research is needed to identify any relationships between chromosomal aberrations,

SCEs, and disease in populations. At the present

time, genetic monitoring may be most useful for

detecting exposure to harmful agents. The most

pressing questions yet to be answered concerning the use of monitoring in the workplace are:

What is the biological significance of small elevations of aberrations or SCEs? Is there consistency between a given frequency of aberrations or

SCEs induced by different agents and risk for disease?

Priorities for future research

Additional occupational cytogenetics studies are

needed, combined with epidemiological investigations, to define further the meaning of induced

chromosomal aberrations and SCEs, There is also

a need to develop faster and easier tests for occupational genetic monitoring. Discussions with

scientists involved in this work led to the following

●

●

suggestions for future research:

There is a need to standardize the laboratory

conditions for cytogenetic tests.

The best method of categorizing chromosomal damage for analysis has not been determined. Perhaps more comprehensive and

critical analysis of results already available

could contribute to the understanding of
.

Ch. 6—Genetic Monitoring in the Workplace ● 7 5

both the effects of confounding variables and

the biological mechanisms involved in the induction of chromosomal aberrations and

SCEs. It maybe worthwhile to single out the

percentage of cells with large numbers of

SCEs and to display the chromosomal aberrations of each category for each individual

in a study, including a distinction between

the percentage of cells with aberrations and

the percentage of aberrations per ceil.

• New cgytogenetic tests that are less labor intensive and that possibly could be automated

are essential if cytogenetic testing is to be conducted on a large scale. Manual scoring, such

as is done now, is so labor intensive and timeconsuming that most cytogenetics laboratories in the United States are now working at

capacity. Test scorers require several years

of training to reach the point of consistent

scoring. The use of a fluorescent-activated

cell sorter has been studied as a possible

means of automating chromosomal analysis,

but this technique has intrinsic insensitivities

and has not successfully been used to detect

low frequencies of aberrations in human

chromosomes (107,140).

●

●

●

Noncytogenetic monitoring –

Further research needs to be done on in vitro

sensitivity of human lymphocytes to chemicals encountered in the workplace. This approach could eventually have some value in

predicting human clastogens as well as individual sensitivities to clastogens.

The variables influencing baseline (normal)

frequencies of chromosome] aberrations and

SCEs need to he elucidated.

There apparently has not been a prospective

study done that looks for the association between chromosomal aberrations and risk for

somatic disease in the same individual. There

is a critical need for such studies, where individuals with no previous occupational radiation or chemical exposure are tracked, with

concurrent comparisons. The National Institute for occupational Safety and Health has

developed protocols for studies on radiationexposed workers, but has yet to begin them.

Any study addressing biological effects of

current occupational exposure standards for

radiation or chemicals should examine some

individuals whose entire occupational history

has been under the current standards.

Because of the need for inexpensive and rapid

tests to monitor human exposure to mutagens,

many tests originally developed to screen chemicals for mutagenic activity have been modified

to identify human exposure to mutagens. * All of

these tests, either directly or indirectly, identify

the presence of mutagens or DNA damage resulting from the presence of mutagens. Most of these

developments are recent and, for the most part,

have not been used for routine human monitoring.

——

“The extensive literature on animal studies using noncytogenet -

ic endpoints for mutagenicity}’ or carcinogenecity has recently been

reviewed and evaluated by EPA’s Gene-Tox program (61). klost of

the papers have yet to be published, but two reviews ha\’e been

published on specific mutation analysis in Chinese hamster cells

( 1970). Both of these papers state that the correlation between

mutagenicity in this t~’pe of assa}’ and animal carcinogenicit~r is high

Survey of monitoring methods

Virtually none of the tests described in table 15

has as yet been established as a reliable technique

for monitoring human populations. The only test

applied to population monitoring on more than

a single trial basis has been the analysis of urine

for mutagens. A few of the remaining tests have

been used in human pilot studies, but these

studies were for baseline analysis and not actual

monitoring,

MUTAGENS IN BODY FLUIDS

The assumption is made that the presence of

mutagens in body fluids represents a genetic

hazard. Mutagenic activity in these fluids can be

shown by using the rapid screening tests developed for bacterial or in vitro cell culture systems.
76 . The Role of Genetic Testing in the Prevention of Occupational Disease

Table 15.—Summary of Noncytogenetic Monitoring Techniques

Test type Description

Mutagens in body fluids:

1. Urine

2. Feces

3. Blood

Somatic cell damage:

1. Binding of mutagens to hemoglobin

2. Specific mutation analysis in lymphocytes

3. Unscheduled DNA synthesis in lymphocytes

4. Hemoglobin gene mutations

5. Chemically damaged DNA bases

6. Lymphocyte transformation

Germ cell (sperm) damage:

1. YFF test

2. LDH-X variants

Body fluids used as test materials in bacterial or

in vitro cell culture mutagenicity assays.

Alkylation of the hemoglobin protein

Technique that measures gene mutatation

Technique that measures DNA damage

Immunological technique that measures gene

mutation

Technique that measures DNA damage

Technique that probably measures gene mutation

Detection of abnormal number of chromosomes

Immunological technique that measures gene

mutation

SOURCE Office of Technology Assessment

Since blood and urine are routinely collected in

medical examinations, these types of tests could

be integrated into a medical monitoring program.

A number of studies have been performed with

body fluids, primarily urine, from humans presumably exposed to mutagens in their occupation

or exposed to mutagens in the course of medical

treatments (82,83,123,124). Lifestyle factors such

as cigarette smoking also have been studied (2,

133,139). It is anticipated that urine analysis increasingly will be used for human epidemiological

studies, both because it successfully identifies

mutagens and because this test probably can be

automated. Less commonly used tests of fecal

sources and blood are not expected to be useful

in general screening because of inherent technical

problems.

Analysis of urine for the presence of mutagens.–The use of urine collected from humans

as a test material is readily applicable to human

monitoring situations for the following reasons

(18):

● Studies have demonstrated that mutagenic

activity can be detected in the urine of individuals exposed to various therapeutic drugs

and industrial chemicals and of individuals

with specific lifestyles or occupational experiences.

●

●

●

●

Collection of urine samples is easy and can

be obtained from both males and females on

a regular schedule.

Both mutagenic and chemical analysis can be

performed simultaneously from a single collection of urine.

Urine samples can be tested for the presence

of mutagens not only in bacterial cells but

also in mammalian cells.

The costs and performance time associated

with this approach are amenable to largescale sampling studies.

There are also drawbacks to the use of this test

in occupational settings. For example, only recent

exposures can be measured. Moreover, the presence of mutagens in urine has not been translated

into a known risk to the individual. Presence of

mutagens in the urine can be considered evidence

of exposure to a mutagenic chemical or to a chemical that forms mutagenic metabolizes which are

eventually excreted. However, excretion of mutagens may be a protective process. In fact, the

absence of mutagens in the urine could be interpreted as evidence that the mutagens are bound

to cellular molecules (thus potentially causing

damage) and are not available for urinary excretion. Consequently, knowledge of the metabolic

fate of the suspected mutagens is critical to the

proper interpretation of this monitoring technique. Moreover, there may be many confound-
Ch 6—Genetic Monitoring in the Workplace 77

Analysis of blood serum for the presence of

mutagens.—There are only two reports on blood

serum analysis for mutagenicity (40,82). Because

of the difficulty of obtaining large quantities of

serum, it is doubtful that serum analysis will contribute to the array of human monitoring techniques unless the detection tests could be made

more sensitive.

Photo credit: National Institutes of Health

Noncytogenetic monitoring involves the use of

biochemical tests

ing variables in urine analysis. For instance, the

urine of cigarette smokers has been shown to contain mutagens (139).

Analysis of feces fez” the presence of mutagens.–Because cancer of the colon is a major

cause of cancer mortality in Western countries,

the incidence of the disease has been associated

with diet (12,96, 103). Examination of human feces

for mutagens is gaining some attention following

a report (24) that showed that feces from individuals on typical Western diets contain high levels

of mutagens. Consequently, analysis of human

fecal samples might represent a monitoring approach for examining the relationship of dietary

factors to specific types of cancer. Because of

technical difficulties, such as concentration of the

feces, the use of this procedure in occupational

settings currently is limited.

SOMATIC CELL DAMAGE

Binding of mutagens to hemoglobin. —Th e

possibilities for using hemoglobin from red blood

cells as a biological dosimeter have been explored

by Ehrenberg and coworkers in a series of experiments on mice using alkylating agents (43,

106,121). The assay is designed to measure alkylated amino acids in hemoglobin from exposed individuals. This phenomenon is not a genetic alteration, but protein alkylation strongly implies concurrent alkylation of DNA, a presumed first step

in the production of mutations. The assay seems .

to work well for several alkylating agents. It can

be used as a dosimeter, that is, it gives a positive

dose-response curve, and it is a measure of accumulated damage over a period of a few months.

This latter point is important because many other

tests have to be done within a day or two of

exposure.

The accumulation of alkylated groups in hemoglobin and the relatively large amounts of hemoglobin that can be isolated from one blood sample and analyzed, together with the availability

of sensitive chemical and analytical techniques,

make it feasible to determine small quantities of

alkylated amino acids formed as a consequence

of exposure to mutagens in the environment. For

the most part, however, the procedures have

been used only for mice injected with known

mutagens. In the single report on the practical

application of these procedures to human monitoring, Ehrenburg (42) showed that hemoglobin

molecules were alkylated in workers exposed to

ethylene oxide,

Before these techniques can be used in routine

monitoring, more extensive validation studies are

needed to standardize protocols, evaluate reproducibility, and determine intrinsic individual
78 . The Role of Genetic Testing in the Prevention of Occupational Disease

variability. Once these factors are established, the

procedure might have wide applications for specific chemical classes.

Specific mutation analysis in lymphocytes. —The

production of the enzyme hypoxanthine-guanine

phosphoribosyltransferase (HGPRT) in humans is

controlled by the hpt gene located on the X-chromosome (65). Cultured cells in which hpt has

mutated are easily detected because of their

resistance to normally poisonous guanine analogs,

such as 6-thioguanine (TG). Thus, cells lacking

HGRPT can be selected and grown by exposing

them to one of these analogs in the culture medium. The frequency of TG-resistant (presumed

mutant) cells in the peripheral blood lymphocytes

of normal persons is very low (128), but the frequency increases among cancer patients being

treated with known mutagens (4,128). Although

the technique has been hampered by high background levels, recent modifications appear to

have resolved some of these problems (3).

Although no studies have been undertaken, it

is speculated that the detection of TG-resistant

cells that arise in vivo could play a role in occupational monitoring. This technique could provide

a sensitive assay for the induction of genetic mutations in human somatic cells. An increase in the

percentage of TG-resistant cells in individuals exposed to toxic agents in the workplace might indicate exposure to a mutagen.

Unscheduled DNA synthesis in lymphocytes. —

The damage to DNA by chemicals or radiation is

often repaired by cellular mechanisms that remove the damaged area and replace it with new

nucleotides (33,116), A test that measures this

DNA repair, referred to as unscheduled DNA synthesis (UDS), has been suggested as a good indicator of exposure of chromosomes to mutagenic

agents since the amount of DNA repair induced

should be proportional to the amount of DNA

damaged. In fact, reported data with human lymphocytes suggest that UDS is associated with

mutation and chromosomal aberrations (108).

This assay also can be used to identify agents

that inhibit DNA repair. Chemicals capable of inducing DNA damage while simultaneously inhibiting DNA repair may be especially hazardous.

Results of a preliminary study of workers exposed

to ethylene oxide show increases in both chromosomal aberrations and suppression of DNA repair synthesis (109).

There have been few UDS studies on lymphocytes in vivo. Limited studies of normal human

lymphocytes (108) and lymphocytes from exposed

humans (109) indicate that sex, age, and blood

pressure may affect both background and chemically induced levels of UDS.

At present it appears that this assay can best

be used to study the nature of tissue specificity

of chemical DNA damage. For instance, compounds that cause stomach cancer may induce

UDS in stomach tissue but not in liver tissue. On

the other hand, it may not be a very good assay

for mutagenesis because it is a measure of DNA

repair, not damage, and repair may not correlate

with genotoxicity.

Hemoglobin gene mutations. —Hemoglobin proteins can be altered by single gene mutations, and

specific antibodies prepared against altered hemoglobin proteins can be used to detect these rare

variants. Normal individuals generate the rare

variants at a rate of about one variant per 10 million red blood cells. If the specific antibodies are

linked to a fluorescent molecule, an automated,

fluorescent-activated cell sorter can detect these

rare cells with high sensitivity and specificity (92),

Presumably, individuals exposed to mutagens

would have an increased rate of production of

the variants. This method could provide an excellent tool for evaluating human populations since

it can be conducted objectively, quantitatively,

and economically. Some preliminary pilot studies,

using blood samples from individuals on cancer

chemotherapy drugs or radiation therapy, found

that the frequencies of abnormal hemoglobin

were within the normal range but statistically

higher than the frequencies for the corresponding controls (Omenn, personal communication).

Detection of chemically damaged DNA bases. —

The detection of chemically damaged DNA bases

is a direct measure of binding of a chemical to

DNA. This binding can interfere with accurate

DNA base pairing, thus causing mutations during DNA replication. Several detection methods

have been described recently (1)64,66)138). All

these methods are extremely sensitive and some,
Ch. 6—Genetic Monitoring in the Workplace ● 7 9

depending on the chemical, can detect as few as

one event per cell. This level is in the range

necessary for a test to be predictive for chronic

low-level exposure.

There are limitations to the study of chemically damaged bases. It is a measure of an early event

and a base change may not result in a mutation.

For instance, the mutated bases could be repaired

prior to cellular DNA synthesis and be of no consequence at all. It also is not known how persistent the damaged bases are. For instance, in monitoring a population, it is necessary to know when

to collect samples and then whether the damaged

bases found are a result of recent or prior exposure.

The detection of damaged DNA bases has

moved beyond the laboratory. A prospective epidemiological study was begun recently on coke

oven workers; the researchers are using specific

antibodies to detect benzo(a)pyrene bound to

DNA bases (137).

Lymphocyte transformation assay. —Several

reports (30)60) 117) suggest that mammalian cells

exposed to mutagenic chemicals in vitro exhibit

an enhanced susceptibility to transformation, a

condition that has many similarities to tumor cells.

It is possible that a modification of this transformation assay could be used to monitor exposure

to harmful chemicals. The lymphocytes from exposed individuals are grown in culture under conditions that select for transformation. Presumably, increased exposure will -yield more transformed cells.

GERM CELL DAMAGE

Studies on germ cells have focused exclusively

on sperm. The advantage of monitoring sperm,

aside from the ease of obtaining viable cells, is

that studies using sperm have tested about 10

times the number of chemicals that have been

tested using any other cell type. Whether toxicological studies of sperm will reflect the genetic status of somatic cells is unknown, but, assuming that they will, two assays show promise in

an occupational setting.

YFF’ test. —The YFF test purports to identify an

extra Y chromosome. Sperm with increased fluorescence under a microscope in the presence

of quiniline dye are scored as having more than

one Y chromosome. They are abnormal and presumably arise due to abnormal chromosome segregation during cell division. Yet it has not been

shown conclusively that the increased fluorescence is not due to a change in the fluorescence

pattern of the other chromosomes. Thus, this

change may be an important indicator of exposure to chemicals, but cannot be taken as a result

of abnormal segregation. This sperm assay, because of its relative experimental ease, might be

most useful in determining priorities for longer

term studies of chemical agents.

LDH-X variants. —The principle on which this

assay is based is the same as that of the test for

mutant hemoglobin. Lactate dehydrogenase-X

(LDH-X) is a protein found on the tail of sperm

and is detectable by specific antibodies (27). Experiments with rats and mice have shown that

LDH-X mutants are detectable with different antibodies (10,11). Presumably, LDH-X variants could

be detected with a battery of different monospecific antibodies. One experiment with mice

showed a linear relationship between increased

dose of mutagen and increased mutant LDH-X

molecules (9).

The presence of LDH-X mutants presumably

will reveal whether an individual is sensitive to

an environmental mutagen in an analogous fashion to the hemoglobin gene mutation assay. As

in that assay, the method could be automated by

using fluorescent-labeled antibodies and a

fluorescent-activated cell sorter. The human LDHX mutants need much better characterization,

however, before this assay will find applicability

in a routine monitoring situation (H. Mailing, personal communication).

Conclusions

At present, there is not enough research experience using humans for most noncytogenetic

techniques to determine accurately their usefulness in workplace monitoring situations. The

detection of mutagens in urine is the only assay

that has been used with human subjects often

enough to show that spurious results will not be

generated. The other techniques will require considerably more development to be considered of
80 . The Role of Genetic Testing in the Prevention of Occupational Disease

value as monitoring techniques. The most obvious accurately low levels of the abnormality being

deficiency in these tests is the lack of the avail- assayed, the likely prospects for automation, and

ability of the normal baseline response. Without low cost. Six of the tests discussed in this section

a good estimate of the range of responses in unex - potentially have these necessary characteristics,

posed humans, the data from test populations will and their development could lead to better workbe difficult to interpret. Table 16 summarizes all place monitoring. These tests include the detecof the human studies that used noncytogenetic tion of:

methods. ●

●

Priorities for future research ●

Several of the noncytogenetic techniques may ●

have potential for use in human monitoring. The ●

characteristics necessary for a good workplace ●

monitoring technique include the ability to detect

mutagens in urine,

alkylated hemoglobin,

a specific mutation (HGPRT) in lymphocytes,

hemoglobin mutations,

chemically damaged DNA bases, and

LDH-X variants in sperm.

Table 16.—A Summary of Noncytogenetic Methods Used

in Human Monitoring

Technique Population monitored Reference

1. Mutagens in body fluids

A. Urine

B. Blood

C. Fecal

2. Somatic cell damage

A. Hemoglobin alkylation

B. Specific mutations in

lymphocytes

C. Unscheduled DNA

synthesis

D. Hemoglobin gene

mutations

E. Chemically damaged

Rubber industry workers

Coke plant workers (smokers v.

nonsmokers)

Nurses administering cytostatic drugs

Chemical workers in ink and solvent plants

Patients receiving cancer therapeutic drugs

Patients receiving drugs

Cigarette smokers v. nonsmokers

Persons dosed with an

antiparasitic drug which has mutagenic

and carcinogenic activity

Comparison of humans with different diets

and geographical origin

Workers exposed to ethylene oxide

Cancer patients treated with chemotherapeutic drugs

Factory workers exposed to ethylene oxide

Cancer patients treated with chemotherapeutic drugs

Coke oven workers exposed to benzo(a)pyrene

Falck, et al. (47)

Moeller and Dybing (94)

Falck, et al. (48)

Mazzoll (91)

Siebert and Simon (123,124)

Legator, et al. (82,83,84)

Speck, et al. (125)

Wang, et al. (135)

Roxe, et al. (1 19)

Legator, et al. (81)

Yamasaki and Ames (139)

Legator, et al. (82)

Dobias (40)

Ehrich, et al. (44)

Reddy, et al. (115)

Kunhleln, et al, (78)

Ehrenberg (42)

Strauss and Albertini (128)

Albertini and Allen (4)

Pero, et al. (109)

Mendelssohn, et al. (92)

Weinstein and Perera (137)

DNA bases

SOURCE: Off Ice of Technology Assessment.

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Chapter 7

Genetic Screening for

Heritable Traits
Contents

Red Blood Cell Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Glucose-6-Phosphate Dehydrogenase Deficiency and Hemolytic Anemia . . . . . . . . . . . . 90

Sickle-Cell Trait and Sickle-Cell Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

The Thalassemias and Erythroblastic Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

NADH Dehydrogenase Deficiency and Methemoglobinemia. . .. .. .. .. ... ... ......O 9 2

Traits Correlated With Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Serum Alpha1 Antitrypsin Deficiency and Susceptibility to Emphysema . . . . . . . . . . . . 93

Aryl Hydrocarbon Hydroxylase Inducibility and Susceptibility to Lung Cancer . . . . . . 94

Other Characterized Genetic Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

Acetylation and Susceptibility to Arylamine-Induced Bladder Cancer . . . . . . . . . . . . . . . 95

HLA and Disease Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Carbon Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Diseases of DNA Repair. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

Less Well-Characterized Genetic Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Immunoglobuhn A Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Paraoxanase Polymorphism . . . . . . . . . . . . . . . . . . . . . .. ., . .., ... ... ...,. . . . . . . . . 97

Pseudocholinesterase Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Erythrocyte Catalase Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Dermatological Susceptibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

Priorities for Future Research .......,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Red Blood Cell Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100

Differential Metabolism of Industrial/Pharmacological Compounds . . . . . . . . . . . . . . . . . 100

SAT Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101

Figure

Figure No. Page

8.Distribution of Red Cell Phosphatase Activities in the English Population . . . . . . . . . . 99
Genetic Screening

Chapter 7

for Heritable Traits

Individuals differ widely in their susceptibility

to environmentally induced diseases. Differential

susceptibility is known to be affected by developmental and aging processes, genetic characteristics, nutritional status, and the presence of

preexisting diseases (11,12). This chapter assesses

the way in which genetic factors contribute to

the occurrence of differential susceptibility to toxic substances.

Clearly, genetic factors do not act in isolation

from physiological processes. Genetic influences

may be exaggerated or diminished by one’s age,

diet, or overall health status. For example, while

people with an erythrocyte glucose-6-phosphate

dehydrogenase (G-6-PD) deficiency may be at increased risk to a variety of drugs, it is also likely

that their nutritional status may be able to mitigate or enhance their susceptibility (23). Many disease processes are affected by multiple factors,

any one of which may not explain the variation

in responses within a population.

It has long been suspected that biological factors affect the occurrence of occupational diseases. In fact, during World War 1, it was speculated that TNT-induced adverse effects were intensified by inadequate diets (9,10). In 1938, J.B.S.

Haldane (42) suggested a possible role for genetic

constitution in the occurrence of bronchitis

among potters and even raised the possibility of

eliminating the genetically predisposed person

from potential unhealthy work environments.

This assessment of the evidence that selected

genetic conditions affect the occurrence of occupational disease focuses on those few single gene

traits where substantial data are available. For

each genetic trait, the following questions were

asked:

What is its prevalence in the population?

Is it compatible with a normal lifestyle?

With what diseases does the trait correlate?

In what industrial settings might the traits

cause a person to be at increased risk?

Is there an increased risk for homozygous

or heterozygous individuals, or both?

What do epidemiological studies show, and

are they well designed?

What is the cost, ease, and predictive value

of the available tests for detection of the trait?

(See app. F.)

This chapter also briefly discusses those traits for

which there is limited evidence suggesting an association with occupational disease. The traits

discussed here represent only a fraction of a percent of all human traits. The discussion does not

intend to imply that these traits are necessarily

responsible for most of the occupational diseases

that could result from genetic predisposition. In

fact, the traits discussed here most likely comprise

very few of the potential predisposing traits when

increased susceptibility to chemicals or ionizing

radiation is the issue.

Many data on differential susceptibility to chemicals come not from industrial settings but from

documented responses to prescription drugs.

These studies are relevant in that the detoxification or activation pathways for drugs may operate

on a wide variety of other chemicals. where relevant, drug studies have been included in the analysis because it is possible that an extrapolation

from a clinical to an industrial setting can be

made.

Red blood cell traits

Because human red blood cells (erythrocytes) all traits. Erythrocytes contain hemoglobin, the

are so accessible, the genetic traits expressed in protein responsible for carrying oxygen to tissues

these cells are among the best characterized of and carbon dioxide away from them. Any reduc89
✙✐ ● The Role of Genetic Testing in the prevention of Occupational Disease

tion in this ability, caused by either nonfunctional

hemoglobin or fewer erythrocytes, results in the

clinical manifestation of anemia.

The prevalence of hereditary blood conditions

varies greatly among different ethnic groups, with

their highest occurrence being in tropical climates. It appears that several of these traits have

been evolutionarily selected over time because

they provide a partial resistance to malaria. Since

most of these traits in their heterozygous form

are compatible with a normal lifestyle, they give

a selective advantage to people in areas where malaria is common. However, such heterozygous individuals may exhibit a greater sensitivity to toxic chemicals in an industrial setting.

G1ucose-6-phosphate dehydrogenase

deficiency and hemolytic anemia

G-6-PD deficiency is a sex-linked genetic condition, the G-6-PD gene being located on the X chromosome. * The gene’s normal function is important for maintenance of erythrocyte membrane

integrity. Under hemolytic (destruction of red

blood cell membrane) stress conditions (as in the

presence of oxidizing agents including some antimalarial drugs), the erythocyte membranes of

G-6-PD deficient individuals break down and those

persons develop anemia. Otherwise, these individuals are healthy.

For industry, the first suggestions that G-6-PD

deficiency may be involved in worker susceptibility to chemically induced anemia occurred during the early 1960’s (8)52,127). In addition, in 1963,

Stokinger and Mountain (117) proposed a list of

37 industrial chemicals known to cause hemolysis

to which those with a G-6-PD deficiency may be

at enhanced risk. They further suggested that

screening tests to identify G-6-PD deficient individuals be conducted as part of preemployment

medical examinations in order to identify those

individuals before job placement. Later, Stokinger

and Mountain (116) reported that more than 15

industries, research centers, or health-oriented

groups either were using the G-6-PD test or had

*The deficiency is found mostly in men because of their single

copy of the gene. Women can he heterozygous carriers and not

f?xhibit the dt?ficit?ncbv. ttromen homozygous for the deficiency ar(?

known, but rare.

inquired into its use. More specifically, they noted

that industries most interested in the test were

manufacturers of dyes and dye-stuff intermediates, metals (especially lead), and drugs,

In addition to medical and industrial oxidizing

agents as potential causes of hemolytic anemia in

G-6-PD deficient individuals, interest recently has

focused on the effects of copper and ozone on

G-6-PD deficient erythrocytes. Because erythrocytes of the Dorset sheep are G-6-PD deficient and

also are quite susceptible to copper-induced hemolysis, it was speculated that G-6-PD deficient

humans likewise may display an enhanced susceptibility to copper. Subsequent studies have supported this hypothesis (9,13). An hypothesis that

G-6-PD deficient individuals may be at enhanced

risk to ozone toxicity has recently been supported

by in vitro experiments showing that G-6-PD deficient erythrocytes are more susceptible to oxidant

damage than normal erythrocytes (14).

Numerous surveys of G-6-PI] deficiency, employing different methods of identification, have

been conducted among various groups of people

in different geographical locations (4). The frequency of this trait is very high among U.S. black

males (13 to 16 percent). other population frequencies of this trait are: Caucasians: American,

0.1 percent, British 0,1 percent, Greek, 2 to 32

percent, Scandinavians, 1 to 8 percent, East Indians, 0.3 percent, Mediterranean Jews, 11 percent, European Jews, 1 percent; Mongolian: Chinese, 2 to 5 percent, Filipinos, 12 to 13 percent.

There are many genetic variants of the G-6-PD

allele. of particular importance here is the

Mediterranean variant in which G-6-PD activity

ranges from 1 to 8 percent of normal, compared

to the A – variant of American blacks which

maintains 15 to 25 percent of normal G-6-PD activity, The greater severity of the enzyme deficiency is of clinical concern because individuals

with the Mediterranean variant are likely to be

considerably more susceptible to oxidizing agents

and infectious agents (for example, hepatitis) and

experience more serious hemolytic crises (4).

Many substances commonly used in industry

are known to cause hemolytic changes, and it has

been speculated that they present an increased

risk to G-6-PD deficient individuals. A few of these

substances have been evaluated in vitro and
Ch. 7—Genetic Screening for Heritable Traits ● 9 1

found to display a greater stress on G-6-PD deficient cells. However, the only specific industrial

substances for which proof exists that G-6-PD deficient individuals are at greater hemolytic risk than

normal individuals are certain aromatic amino

and nitro compounds (for example, naphthalene,

TNT, and naladixic acid) (4,80). No quantitative

risk assessments of the hemolytic actions of these

substances on those individuals have been published. that is emerging is a growing body of in

vitro evidence strongly implicating the enhanced

susceptibility of G-6- PD deficient erythrocytes to

a wide variety of industrial and environmental

oxidants. Such in vitro exposures have not been

related to actual exposures.

Sickle-ceIl trait and sickle cell anemia

These genetic conditions result from the presence of an abnormal hemoglobin molecule, hemoglobin S (HbS) in the erythrocytes of affected

individuals, HbS differs from the normal hemoglobin A (HbA) only by the substitution of an

amino acid at a single location in the hemoglobin

protein beta-chain. * The decreased solubility of

HbS under conditions of low oxygen may result

in the formation of a gel within red blood cells,

distorting them and causing the cells to look like

sickles under the light microscope. An individual

with sickle-cell anemia is homozygous for HbS

while one with sickle-cell trait is heterozygous for

HbS. The homozygous person has 100 percent

HbS while the heterozygous person has from 20

to 40 percent HbS; the latter will experience sickling only when blood oxygen is greatly reduced

(22, 1 1.5).

While those with sickle-cell anemia are known

to have a reduced lifespan, the health hazards of

sickle-cell trait are considered minimal or nonexistent under most circumstances (91 ). Some situations have been thought to cause sickling problems in those with sickle cell trait. For instance,

four deaths were attributed to sickle cell trait in

Army recruits in basic training at a high altitude

(55). The Air Force until recently had a policy that

excluded blacks with sickle cell trait from the Air

Force Academy and flight training (124). However,

● I hc hf’moglohin IIl(JlWLIlfI is c(JmposfI(i of tour protf’ill chciins,

two ident](al beta C}M ins and t~~o i(lcnt i(’al alpha chains.

it has been determined that not enough data are

available to support that policy. The overwhelming majority of people with sickle cell trait in the

United States apparently never have any problems associated with this genetic condition.

The gene for HbS is found at high frequency

in equatorial Africa, parts of India, countries of

the Middle East, and areas around the Mediterranean. Sickle cell trait is found in about 8 percent of U.S. blacks. The frequency of sickle-cell

anemia is about 0.2 to 0.5 percent among American blacks. However, because this disease most

likely would have revealed itself in overt illness

prior to adulthood, preemployment physical

testing would not be used to discover the condition (22).

According to a survey of major industries (see

ch. 3), the majority of genetic screening done in

the workplace has been for sickle cell trait. The

purpose of this testing is not known.

The thalassemias and erythroblastic

anemia

Thalassemia is an erythroblastic anemia, a deficiency in the production of red blood cells, occurring early in life and varying in severitv from . .

mild to fatal. The severe form, found in the homozygous state, is called thalassemia major; the

milder condition, found in the heterozygous state,

is called thalassemia minor. The classic Mediterranean form of thalessemia, the beta form, is

thought to be caused by a deficiency in beta-chain

production of hemoglobin A. A different form of

thalessemia, alpha thalessemia, involves a disruption in alpha-chain synthesis. The homozygous

state for the alpha condition is fatal, leading to

intrauterine death (76).

Of particular concern to this report is the health

status of both alpha and beta thalessemic heterozygous individuals because of the milder manifestations of the disease and their considerably

greater prevalence in the population compared

to homozygous people. The frequency of alpha

thalassemia heterozygous individuals among

American blacks is thought to range between 2

and 7 percent (85,126). In more limited surveys,

those of Greek ancestry were reported to have

a 2 percent incidence of heterozygous alpha thal-
92 . The Role of Genetic Testing in the Prevention of Occupational Disease

assemia (98). Beta thalassemia heterozygous individuals comprise about 4 to 5 percent of ItalianAmericans (93) and Greek-Americans (98). The

health status of heterozygous individuals is difficult to generalize since there appears to be extremely broad differential expression of the clinical features of the disease. However, what does

seem predictable is that symptoms of the disease,

however mild, may be exacerbated when additional stress is encountered, for example, in the

presence of bronchopneumonia or during pregnancy. In a thalassemia heterozygous individual,

auxiliary mechanisms of blood production already

have been called into action and, under stress,

may no longer be able to handle the expanded

activity needed to maintain normal hemoglobin

levels (76).

Since persons heterozygous for the thalassemic

trait have a compromised adaptive capacity to

maintain blood production, it has been suggested

that they may be at increased risk from hazardous chemicals. The research to date, mostly in

Europe, has involved a limited clinical assessment

of occupational exposures to benzene and lead

on persons heterozygous for beta thalassemia

(33,37,40,99,106,107). In light of the limited

number of individuals studied and the lack of environmental monitoring, it is not possible to conclude that susceptibility to benzene and lead toxicity is enhanced in persons with thalassemia trait.

However, the clinical studies suggest the need for

epidemiologic investigations to test this hypothesis.

NADH dehydrogenase deficiency and

methemoglobinemia

The transportation of oxygen to tissues is contingent on the capability of hemoglobin to bind

oxygen reversibly, a process that relies on the iron

atom in the protein. The binding of oxygen by

hemoglobin involves the oxidation of the iron

atom. When the oxygen is released, the iron atom

typically returns to its reduced state. occasionally

it stays oxidized, thereby leaving the hemoglobin

in an oxidized state called methemoglobin. Normally, only about 1 percent of total hemoglobin

is present in this state because the capacity of the

red blood cell to reduce this state is several hundred times greater than the spontaneous rate of

oxidation. Methemoglobin levels accumulate

when the rate of oxidation of the iron atom exceeds the reducing capacity; a change in the protein chain stabilizes methemoglobin, making it

resistant to reduction; or there is a marked deficiency in the reducing ability of the red blood cell.

The most important metabolic pathway for the

reduction of methemoglobin involves an enzyme

called NADH dehydrogenase, which accounts for

about 60 percent of the normal reduction rate

(110).

Methemoglobinemia in humans initially was reported in homozygous people who were exposed

to certain drugs capable of increasing the rate of

oxidation of the iron atom of hemoglobin, but persistently high levels of methemoglobin have been

clinically diagnosed with no known exposure to

chemicals that oxidize hemoglobin (62). Subsequent research on such individuals has frequently

revealed an NADH dehydrogenase deficiency as

the cause of the high methemoglobin levels (110).

A very high occurrence of hereditary NADH dehydrogenase deficiency has been reported among

Alaskan Eskimos and Indians (112), Navajo Indians

(2), and Puerto Ricans (47,111). Heterozygous carriers of this enzyme deficiency display about 50

percent of the normal enzyme activity, with the

frequency of such carriers in the U.S. population

thought to be about 1 percent (94,125).

Methemoglobinemia acquired from industrial

exposures to various chemicals, especially

aromatic nitro and amino compounds, ranges

from mild to severe. With 10 to 30 percent methemoglobin, only cyanosis (bluish skin) is observed.

At 35 to 40 percent, headaches and shortness of

breath on exertion are reported. At 60 percent,

lethargy occurs, and above 70 percent, deaths

have been reported. Biological monitoring for exposures to cyanogenic aromatic: chemicals at Du

Pent’s Chamber Works facility by measurement

of methemoglobin levels and recording of cyanosis was carried out beginning in the 1940’s (80).

During the 10-year period following 1956, 187

episodes of cyanosis were detected, occurring in

143 employees. (These workers would be an appropriate group for clinical testings of NADH

dehydrogenase activity.) The company regularly

used results of the biological monitoring of work

crews to pinpoint areas requiring tighter control
Ch. 7—Genetic Screening for Heritable Traits ● 9 3

of exposures (80). In possibly analogous cases of

cyanosis in Vietnam where American military

personnel were given malaria prophylaxis, Cohen,

et al. (19) did show that the affected men were

partially deficient heterozygotes for NADH dehydrogenase.

It has been shown repeatedly that persons

homozygous or heterozygous for NADH dehydrogenase deficiency display an increased risk of

cyanosis following exposure to drugs that form

methemoglobin. However, there have been no

reports of industrial exposures indicating that

those with NADH dehydrogenase deficiency are

at increased risk to methemoglobin-forming

agents, probably because industrial screening for

such a condition has not been conducted.

Traits correlated with lung disease 4

Serum alpha, antitrypsin deficiency

and susceptibility to emphysema

Homozygous serum alpha, antitrypsin (SAT) deficiency is an important biological factor predisposing the occurrence of emphysema (26,66)71,

78,103,105). In fact, it is recognized that nearly

80 percent of those with this genetic condition

develop the disease. Since only 1 individual in

4,000 to 8,000 displays the homozygous trait,

there has been little concern about the screening for such individuals. On the other hand, heterozygous carriers who display an intermediate

SAT deficiency (about 50 percent of normal values) may be at increased risk of developing emphysema, especially if they smoke tobacco or

work in dusty environments. Heterozygous individuals comprise about 3 percent of the U.S. population, or about 7 million persons.

Initial studies of SAT deficiency and its role in

the occurrence of emphysema focused on the risk

to the homozygous genotype. However, subsequent reports began to mention that the heterozygous carrier also displayed a significantly

enhanced risk of developing emphysema, although at a much lower frequency than the

homozygous individual (67,79). In general, much

of the data supporting the notion that the heterozygote is at enhanced risk came from studies in

the United States, Germany, and Scandinavia.

These studies covered about 1,400 patients with

emphysema, 6.2 percent of whom were heterozygous for SAT deficiency (3,66)88,89)114)121).

That percentage is highly significant when compared with the expected prevalence of about 3

percent for this group. Other research methodologies also have supported these observations

(27,70).

Despite a consistent trend in most research findings showing enhanced susceptibility of the heterozygous individuals to obstructive lung damage,

several reports have not supported that hypothesis (16,20,72,84,90). For the most part, these

dissenting reports have found no difference in

pulmonary function between SAT heterozygous

persons and controls matched for age and sex,

and little, if any, increased risk of emphysema

when smoking was brought into the analysis, Because about 90 percent of individuals with the

heterozygous genotype will not develop symptomatic disease, some researchers feel those studies

have not given the hypothesis of enhanced heterozygote risk an adequate evaluation.

Environmental factors play a dominant role in

the etiology of emphysema. For example, studies

have indicated that cigarette smoke has been

found to significantly lower SAT activity in rats

after three puffs (51), while investigations with

normal individuals likewise have found that

chronic smokers displayed a nearly twofold decrease in functional activity of SAT as compared

to nonsmokers (30). Other experimental studies

have suggested that cadmium (17,18) and ambient

ozone at levels approaching the current OSHA

standard of 0.1 ppm (time-weighted average over

an 8-hour day) may be contributing factors in the

development of emphysema because of their ability to inhibit SAT activity (54).
94 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Emphysema is a multicausal disease (58,87) and

the heterozygous state, by itself, is not a major

predisposing factor in its development. It is possible, however, that in combination with other predisposing factors, some of which have been identified (1,31,69,77), the heterozygous individual

could be at an increased risk. It is necessary to

evaluate the relative contribution of these variables in the development of emphysema. If the

associations prove to be valid and are amenable

to widespread screening, such screening most

likely would involve an assessment of several

factors.

Aryl hydrocarbon hydroxylase

inducibility and susceptibility to

lung cancer

The differential ability to induce the enzyme

aryl hydrocarbon hydroxylase (AHH) has been

correlated with lung cancer. This enzyme, found

in most mammalian tissues, is known to catalyze

the first step in the metabolism of polycyclic

aromatic hydrocarbons (PAHs), many of which

are found in cigarette smoke and the industrial

workplace. Being an inducible enzyme (one whose

activity can be increased in the presence of certain compounds), AHH displays increased activity following administration of a number of agents

such as PAHs, various drugs, steroids, and insecticides (21). AHH is thought to play a key role in

the modification of PAHs into biologically active

compounds by metabolizing them to epoxides

which can bind to DNA and other macromolecules (39). Epoxide binding appears to be an initial cause of malignant transformation in cells.

Consequently, PAH metabolism via AHH can result in activation to more highly mutagenic and

carcinogenic intermediates.

There is considerable variation in the extent to

which AHH can be induced in cultured leukocytes

from different individuals. The induction has been

reported to be under genetic control (59), with

the normal Caucasian population divided into

three distinct groups with low, intermediate, and

high degrees of inducibility, all of which are compatible with a normal lifestyle (60), This variation

was hypothesized to result from a single gene

with the three groups representing the homozygous low and high alleles and the intermediate

heterozygote. The phenotypic frequencies were

calculated to be 53 percent for low inducers, 37

percent for heterozygotes, and 10 percent for

high inducers.

Since the inducibility of AHH was found to be

under genetic control and exhibited wide variation in the population, Kellermann, et al. (60),

sought to evaluate whether AHH inducibility

could help to explain differential susceptibility to

lung cancer presumably caused by PAHs which

may have been activated to carcinogenic compounds. The lung cancer patients studied displayed a marked shift from the normal phenotypic frequencies in that only 4 percent were low

inducers, 66 percent were moderate, and 30 percent were high, The authors concluded that the

risk of lung cancer for the groups with intermediate and high inducibility was 16 and 36

times greater, respectively, than that of the low

inducibility group.

A variety of research teams have sought to replicate and extend these findings because of their

public health implications. Four studies have supported the initial findings (41,53,102,123). For the

most part, these studies have shown that persons

with lung and laryngeal cancer displayed significantly greater lymphocyte AHH inducibility than

controls. With some exceptions these studies were

better designed than the original Kellermann, et

al. (60), report, but they did not investigate the

genetics, Not all reports, however, even support

the association between AHH inducibility and

susceptibility to lung cancer (95,96).

A methodological issue that may lead to difficulties in reproducing the work of others is the

seasonal variation in AHH levels; this variation implies that measurements of AHH activity cannot

be collected in a population over prolonged periods of time. Also, the lymphocyte AHH inducibility

assay is difficult to standardize (65). A significant

improvement in the cell culture procedure or another way of measuring the genetic trait is essential before large-scale population studies can be

undertaken.

A genetic basis affecting susceptibility to environmentally induced lung cancer has been documented overwhelmingly in animal studies (92)
. .

Ch. 7—Genetic Screening for Heritable Traits . 95

and supported by human epidemiologic investigations (122). However, the identification of a precise and reliable marker or predictor of risk to

lung cancer—such as AHH inducibility—is currently unresolved,

The theory of Kellerman and associates that susceptibility to PAH-induced lung cancer is in part

a function of the ability to induce AHH remains

to be unequivocally established, but is still of

public health interest. To date, the total number

of cancer patients studied in the testing of this

hypothesis is less than 1,000. Given that in 1981

the number of deaths from lung cancer in the

United States alone was estimated to be more than

105,000, there is a need to evaluate this hypothesis

once a valid and reliable test has been developed.

Other characterized genetic traits )

Acetylation and susceptibility to

arylamine-induced bladder cancer

Acetylation in the liver is a common pathway

for the metabolism of a variety of compounds.

Humans display genetic variation with respect to

acetylation, the population consisting of fast and

slow acetylators. The responsible liver enzyme,

N-acetyltransferase, is coded for by a single gene.

The slow acetylator phenotype is a recessive trait

with an approximate 1:1 distribution of slow:fast

phenotypes among North American Caucasians

and blacks, while among the Japanese there are

nine fast acetylators to one slow one (44). Numerous reports in the literature indicate that the ability to acetylate is associated with increased susceptibility to a number of acetylatable nitrogen compounds. For example, when acetylated metabolites have proved to be more toxic than the parent

compound, the fast acetylator is the individual at

increased risk (5,86). On the other hand, individuals with the slow acetylator phenotype have

been found to be at considerably increased risk

to the development of neurological symptoms associated with the antitubercular drug isoniazid

(48), the antidepressant phenelzine (28), the antihigh-blood-pressure agent hydralazine (100), sulfa

drugs, and the anti-leprosy drug, dapsone, presumably because of lack of ability to detoxify

these substances by N-acetylation.

Humans are able to deactivate arylamines by

acetylation, thus inactivating a class of potent

bladder carcinogens. Persons who are fast acetylators have about 9 to 10 times more acetylase

activity than the “slow” individuals (38).

Lower, et al, (81), hypothesized that humans

with the slow acetylator phenotype would be at

increased risk to develop arylamine-induced bladder cancer. Their preliminary epidemiologic study

supports this hypothesis. The authors reported

that a population of urban urinary bladder cancer

patients exhibited a small excess of individuals

with the slow acetylation phenotype as compared

to a control group. Lower, et al. (81), did not investigate the most ideal population to test this

theory, since the selection of patients did not involve persons occupationally exposed to aryla -

mines. Furthermore, the study had important

methodological limitations in that potential confounding variables such as smoking and occupation were not controlled.

Since 50 percent of the North American Caucasian and black populations are slow acetylators,

the sheer number of those at potential increased

risk is striking. Currently, the theory is well

founded in cancer research with a variety of

animal models (81). However, additional epidemiologic studies of populations with bladder cancer

are needed to follow up the preliminary evidence

that the degree of risk for such cancer depends

on one’s ability to acetylate arylamines. A Japanese study is being organized to test this hypothesis

(82). The Japanese are particularly suited for this

study because of the low prevalence of the slow

acetylator phenotype in that population and the

availability of a group of former workers exposed

to high levels of arylamines in past decades

(Omenn, personal communication).
96 ● The Role of Genetic Testing in the Prevention of Occupational Disease

HLA and disease associations

Just as each individual has his or her own

unique fingerprints, it is now known that each

individual also has a biochemical fingerprint

determined by the presence of specific proteins

on the surface of cell membranes. This array of

cellular surface proteins has been best studied

with leukocytes and is called the human leukocyte

antigen (HLA) system (83). Several Striking associations between many human diseases and various

HLAs have been revealed (6,24,109,118). For instance, the antigen B27 has been associated with

ankylosing spondylitis (a disease that causes spinal

immobility) and the antigen B8 with thyroid disease.

These antigens are coded by a set of very closely

positioned genes. Since each person inherits a

total of 10 HLA genes, the number of possible antigen combinations is in the hundreds of millions

(46).

Despite some striking statistical association of

certain diseases with specific HLAs, any mechanistic relationship is yet to be uncovered, thereby

precluding at present the possibility of knowing

whether the relationship is causal or only associational. Nevertheless, the recognition of the statistical relationships of HLAs with a wide range

of human diseases suggests that inherent genetic

factors are affecting the occurrence of the diseases within the population.

At present, there is not enough information to

suggest the use of HLA typing in an occupational

setting, but this simple test may in the future be

used to indicate classes of chemicals to which a

person is likely to be susceptible.

Carbon oxidation

Numerous drugs and environmental pollutants

are metabolized in part via oxidation. The metabolic significance of this process is profound

because oxidation may result in a metabolize

either more or less toxic (or carcinogenic) than

the parent compound. Interspecies differences in

the ability to oxidize various compounds have

resulted in differences in toxic and carcinogenic

responses. For example, the inability of guinea

pigs to oxidize aromatic amines is thought to explain their lack of susceptibility to developing

cancer from these compounds.

Among humans, individual variations exist with

respect to the metabolism of certain drugs. The

magnitude of these differences may be considerable. For instance, a 20,000-fold” variation in the

metabolism of debrisoquine has been reported

(49). Such differences help to explain the wide variation in the optimal dose requirement of debrisoquine (20 to 400 mg/day) to control blood pressure

in hypertensive patients, a phenomenon of considerable clinical significance.

Experimental studies have revealed that the

ability to oxidize drugs such as debrisoquine is

controlled by a single gene, with the low activity

being recessive. Limited experimental evidence

suggests that the frequency of the low activity

gene in the population varies markedly according

to the ethnic group (Caucasian-British, 5 percent;

Egyptian, 1.5 percent; Nigerian, 15 percent; and

Ghanaian, 12 percent). A report studying

Nigerians has suggested that low activity oxidizers

may have a decreased frequency of bladder cancer from aflatoxin, a compound known to require

activation to become a carcinogen (50). Heterozygous individuals, who display an intermediate oxidation capability, are predicted to represent about

50 percent of the population if homozygous recessive individuals make up 6 percent of the population (49).

The occupational and environmental health implications of these findings are notable. For example, many known mutagens and/or carcinogens require an initial activation step via an oxidative process. The extent to which humans differ in their ability to activate potential toxic or

carcinogenic compounds may contribute significantly to explaining the variation in population

responses to such agents. In addition, the number

of potentially affected people is enormous.

Diseases of DNA repair

There is a group of heritable traits* in which

a DNA repair defect has been proved or strongly implicated. Moreover, an increased frequen-

● Xeroderma pigrnentosum (XP), ataxia telangiectasia (AT), Fanconi’s

anemia, and Bloom’s syndrome.
Ch. 7—Genetic Screening for Heritable Traits ● 9 7

cy of chromosomal abnormalities is found in the

lymphocytes of these individuals (with the exception of xeroderma pigmentosum). Affected individuals also are at increased risk for certain

cancers, further linking chromosomal abnormalities with cancer (7)36)61)73, 108)113). The diseases, all results of homozygous recessive traits,

cause overt illness and are not compatible with

a normal lifestyle. On the other hand, it is possible that the heterozygous conditions which show

no clinical manifestations could lead to increased

susceptibility to toxic chemicals or ionizing radiation in an occupational setting.

Individuals heterozygous for these traits have

normal frequencies for chromosomal aberrations

and SCEs (15,32,68). Evidence suggests that these

individuals are deficient in particular aspects of

DNA repair and consequently may be at higher

risk than the general population to DNA-damaging

chemicals or radiation. It has been estimated*

● IIsing the Har>cl~-\\’c~inl]erg equation

from the frequency of the homozygotes in the

population that the heterozygote frequency may

be at least 1 percent. Nonetheless, good tests for

identifying those individuals do not exist. The high

estimated frequency suggests that many individuals may be at increased risk from occupational

exposures.

The four major heritable recessive syndromes

of DNA repair also are associated with an increased risk for cancer in homozygous and possibly heterozygous individuals (97,119), The results

for heterozygous individuals are not well documented because so few of them have been studied. The types of cancer for which one is at increased risk vary among syndromes and are not

specific for any one trait. This suggests that many

types of cancer may be caused by, or related to,

specific defects in DNA repair. Because many industrial chemicals are known to damage DNA, it

is possible that individuals heterozygous for these

traits may be at increased risk for disease from

exposure to certain chemicals.

Less well-characterized genetic traits

Other human genetic variants also may put individuals at potential risk to environmental

disease. For the most part, these are highly

speculative and are of research interest only.

Superoxide dismutase

This enzyme is known to play a critical role in

the cell’s defense against oxidizing stress. Recently, it has been discovered that genetic variants of

superoxide dismutase exist within the human population. The prevalence of the variant allele in the

U.S. population is unknown, but, based on a British study in which the heterozygote for the variant was 6.2:1,000 (43), the projected prevalence

in the United States may approach 1.2 million. The

extent to which this variant alters risk to any oxidizing agents remains to be determined.

Immunoglobulin A deficiency

This genetic condition is known to occur in

about 1 in every 400 to 800 persons and is thought

to increase the risk of respiratory tract infections

(63,64). The extent to which persons with this condition are at increased risk to respiratory irritant

gases such as ozone, nitrogen dioxide, and sulfur

dioxide remains to be assessed.

Paraoxanase polymorphism

Human blood serum has been found to contain

an enzyme, paraoxanase, that hydrolyzes the

compound paraoxon, which is the oxidized metabolize of the insecticide parathion. Paraoxanase,

coded for by a single gene, displays considerable

interindividual variability while its activity remains constant within a given subject (35,101).

Approximately 50 percent of the population is

thought to be homozygous for the low activity

allele, exhibiting one-third to one-sixth the activity

of those homozygous for the high activity form

(34). An individual with low paraoxanase activity

would be expected to be at increased risk to parathion toxicity, although there is no substantiation of this hypothesis.
98 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Pseudocholinesterase variants

There are two types of cholinesterase: acetylcholinesterases (ACHase) and pseudocholinesterase (pACHase), ACHase inactivates acetylcholine

(ACH) produced at the neuromuscular junction

during neurotransmission. pACHase is found in

many tissues as well as blood plasma. While its

function is unknown, it has been suggested that

it may hydrolyze certain cholinesters which inhibit ACHase (74). While most people have identical pACHase, a number of pACHase variants exist. Most individuals with variant forms typically

show no symptoms, but some may exhibit an extreme sensitivity to the muscle relaxant, suxamethonium, because they cannot hydrolyze such

substrates as efficiently as those with normal

pACHase (25).

Research involving screening of large numbers

of humans has revealed that the presence of

atypical or variant types of pACHase is under

genetic control (56,57). Gene frequencies have

been determined for some of the variant genotypes. The most common “atypical” homozygous

variant (the dicubaine variant) occurs with a frequency of 1 in 2,800 Canadians of European ancestry (56) and has been found to be extremely

sensitive to the insecticide R02-0683 (74). This is

of particular significance in light of the widespread use of this insecticide. Moreover, 3 to 4

percent of the Canadian population tested were

found to be heterozygote carriers of intermediate

sensitivity (56). Additionally, of the 10 recognized

genotypes of pACHase, 4 are known to display

a marked sensitivity to suxamethonium, Their

combined frequency in individuals of European

ancestry is 1 in 1)250 (120),

In terms of public health, the data indicate that

individuals have differential sensitivity to the activity of various neuromuscular-acting drugs and

insecticidelike chemicals. Differences in sensitivity

are directly related to the occurrence of pACHase

variants and their diminished ability to inactivate

the drug or insecticide analog. Individuals with

such pACHase variants should be considered potentially at high risk to anticholinesterase insecticides (75). It should be emphasized that not all

drugs and insecticidelike compounds act with

greater sensitivity in atypical pACHase variants.

Erythrocyte catalase deficiency

Genetic variants of the red blood cell enzyme,

catalase, exist in humans. This has resulted in the

grouping of humans into three classifications

based on catalase activity levels: normal, hypocatalasemic (50 percent of normal), and

acatalasemic (1 to 2 percent of normal). Since red

cell catalase facilitates the detoxification of exogenous and endogenous hydrogen peroxide (29),

it has been hypothesized that those with a catalase

deficiency may beat risk for hydrogen-peroxideproducing agents such as ozone or radiation (12).

Since there are an estimated 5 million hypocatalasemics in the United States, it would be important to assess any differential susceptibility this

group may exhibit toward such stressor agents.

Dermatological susceptibility

Dermatitis is the single largest cause of occupational disability (104). Susceptibility to irritants is

known to vary widely among individuals, and

both primary irritant and allergic contact dermatitis are probably dependent on genetic factors.

Yet, with the possible exception of some HLA correlations, these genetic factors have yet to be identified. Therefore, it is not now possible to genetically screen individuals for their susceptibility to

industrial chemicals. On the other hand, a dermatological problem is easily noted and the offending chemical can be isolated.

Conclusions

The identification of genetic factors that may appears that genetic differences may in part

contribute to the occurrence of job-related disease explain a variability of responses to chemicals in

is a science truly in its infancy. Nevertheless, it the workplace. What percentage of the total
——. .

Ch. 7—Genetic Screening for Heritable Traits ● 9 9

variability may be explained by genetic factors

is uncertain. The biological foundations of the

concept of genetic screening to identify predispositions to occupational disease are sound. In addition, most of the well-studied traits are reliably

identified by easy and inexpensive tests. It should

be recognized that other biological variables such

as age, nutritional status, preexisting diseases, and

lifestyle also affect the body’s susceptibility to a

variety of environmental insults. The study of factors affecting susceptibility to occupational

diseases, therefore, should not stop with a quantification of genetic influences, as important as

they may be, but also should incorporate the

other biological variables.

Most variants discovered thus far are rare, with

frequencies of less than 1 per 1,000. The benefit/

cost ratio of screening for those who possess rare

alleles that predispose to disease could well be

negative. Screening for variants that occur in at

least 1 percent of the population is more likely

to be cost beneficial. The following reservations

apply to screening for evidence of prevalent variants as well as rare alleles:

● Screening tests might not be capable of distinguishing with high specificity and sensitivity one variant from another or from the predominant allele (if one exists). When more

than one allele exists, the number of possible different enzymes in the population, each

of which may have a mean activity different

from the others, exceeds the number of alleles, The distribution of the activities of these

different enzymes may overlap. For example,

three alleles of the gene for red blood cell acid

phosphatase have been found in the English

population. The distribution of phosphatase

activity in the population, which follows a

fairly smooth unimodal distribution (45) (see

fig. 8), is accounted for by the overlapping

distribution of the activities of five of the six

different enzymes that would be expected

from three alleles. In screening for acid phosphatase activity, many classification errors

would be made regardless of the cutpoint.

Figure 8.—Distribution of Red Cell Phosphatase Activities

In the English Population

r

100 140 180 220 280

Red cell acId phosphatase activity

SOURCE: H. Harris, The Pr/nc/p/es of Human B/octrerrrica/ Genet/cs (Amsterdam:

●

●

●

North-Holland Publishing Co., 1977).

Where continuous, unimodal variation in enzyme activity in a population is observed, the

chance of disease in response to an environmental agent also might vary continuously,

correlating approximately with the amount

of enzyme activity. Thus, even if it were possible to distinguish those who possess one allele from those who possess another, it might

not be appropriate to dichotomize the population into two categories of those at high

risk of disease and those at low risk,

The chance that a person with a specific allele

will develop disease on exposure may depend

on the presence of other factors, some genetic and some environmental, For instance,

the slow acetylator phenotype may explain

only a small percentage of the bladder cancer

variance within the population.

Despite the high degree of genetic diversity,

and possibly even of differences in enzyme

activity conferred by different alleles at a

locus, allelic differences may not be associated with differences in susceptibility. Different alleles may coexist precisely because they

do not differ in the biological fitness they confer. Their respective frequency may depend

on random genetic drift from one generation

to the next.
100 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Priorities for future research

Well-designed, prospective epidemiologic studies are needed to assess the correlation between

specific genetic traits and predisposition to illness.

A major weakness in several important existing

studies (59,60,81) is that both clinicians and laboratory research scientists have attempted to conduct epidemiological research studies without the

apparent assistance of persons specifically trained

in epidemiological research methodology. Unless

the epidemiologist is involved in the initial design

of the study as well as in subsequent analysis procedures, there is a serious likelihood that expensive and time-consuming research will yield far

less valuable and defensible data.

During epidemiological studies, researchers

could acquire HLA profiles when appropriate.

This would begin to provide a greatly expanded

data base which would be useful in understanding the associations of HLA markers with environmentally related diseases.

Red blood cell traits

Given that these traits are prevalent in the

population and that many potential hemolytic and

oxidizing chemicals are employed in a wide variety of industries, there is a clear need to assess

whether individuals with traits potentially predisposing susceptibility to these chemicals are indeed

at risk. Two approaches to this assessment could

be undertaken,

Research could be initiated on the development

of a predictive animal model that would simulate

the response of human red blood cell deficiencies. This would allow for the rapid evaluation

of large numbers of potential hemolytic compounds singly or in combination under precise

exposure conditions, It would also assist in providing direction for epidemiologic research studies.

An animal model recently has been developed in

which guinea pigs are transfused with human red

blood cells, thus overcoming interspecies differences. Using this model, chemical exposures can

be done and the responses of the red blood cells

monitored. Human red blood cells have been

shown to survive in the animals for 2 to 4 days,

allowing some good, preliminarily experiments to

be done.

The second approach involves epidemiological

research studies in appropriate industries where

hemolytic and oxidizing agents (and benzene and

lead) are used and where exposures approach

Federal limits. Such research should attempt to

differentiate the susceptibility of the A – and

Mediterranean variants for G-6-PD deficiency.

The studies also should assess any possible synergistic interaction between medications and hemolytic industrial chemicals.

Differential metabolism of industrial/

pharmacological compounds

Further documentation of the extent to which

humans differ both qualitatively and quantitatively in metabolizing foreign compounds is needed.

More specifically, further work on genetic variants of carbon oxidation and AHH could be conducted. The research should involve not only a

genetic component but nutritional and aging considerations as well. Results from such studies

should contribute markedly to the present understanding of idiosyncratic drug reactions as well

as the occurrence of differential susceptibility to

environmental toxins. These studies may involve

a wide variety of chemical agents including drugs

or industrial or commercial products.

In addition, methods for measuring AHH inducibility which are reproducible in different

laboratories need to be developed.

Epidemiologic investigations are needed to

assess the risk of individuals with the slow

acetylator phenotype for developing arylamineinduced bladder cancer. Since the slow acetylator

represents about .50 percent of the population,

the population at risk is extremely large. As in

the case of the other complex disease processes,

arylamine-induced bladder cancer is affected by

a variety of factors in addition to acetylator

phenotype. Some confounding metabolic variables

may include the capacity to N-hydroxylate the

arylamine and the capacity to deacetylate an ace-
— —

Ch. 7—Genetic Screening for Heritable Traits ● 101

tylated compound. Moreover, factors such as age

and sex need to be recognized.

It has been hypothesized that slow acetylators

are at greater risk of developing arylamineinduced bladder cancer than fast acetylators.

However, the extent to which people differ in

their ability to deacetylate previously acetylated

arylamines can markedly affect the outcome of

studies designed to test the original hypothesis.

Deactylation capability varies widely among

species and affects susceptibility to carcinogens.

The extent to which humans differ in this regard

is not known,

SAT deficiency

Research could be conducted on the relative

contributions of SAT levels and other factors

thought to help cause development of emphysema. Data are needed to validate recent studies

that suggest that ozone exposure at ambient summertime levels and cigarette smoking may result

in a marked reduction in SAT levels.

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Pulmonary Disease, ” Amer. Rev. Resp. Djs. 114:

1077-1083, 1976.

Stokinger, H. E, and Scheel, L. D., “Hypersusceptibility and Genetic Problems in Occupational Medicine—A Consensus Report, ” J. Occup. Med.

15:564-573, 1973.

Stokinger, H. E., and Mountain, J. T., “Progress

in Detecting the Worker Hypersusceptible to Industrial Chemicals, ” J. Occup. Med. 9:537-543,

1967.

Stokinger, H. E., and Mountain, J. T., “Tests for

Hypersusceptibility to Hemolytic Chemicals,”

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Part IV

Legal, Ethical, and

Economic Issues

Chapter 8—Legal Issues Raised by Genetic Testing in the Workplace . . . . . . . . . . . . . . . . . . . . 111

Chapter 9—Application of Ethical Principles to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . 141

Chapter 10—Prospects and Problems for the Economic Evaluation of Genetic Testing . . . . . . 151
Chapter 8

Legal Issues Raised by

Genetic Testing in the

workplace
Contents

Page

Basic Rights and Duties Governing Employment and Medical Practices ... , ,., . . . . . . . 112

Employer Rights and Duties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112

New Rights and Duties Created by Workers’ Compensation Laws . . . . . . . . . . . . . . . . . 112

Exceptions to the “Exclusive Remedy’’ Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Dual Capacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Willful and Intentional Torts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Products Liability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

Rights and Duties in Company Medical Practices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

The Doctor-Employee Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

The Doctor-Employer Relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115

Duty to Conduct Medical or Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Employees Right to Refuse an Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Testing Solely for Research Purposes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Disclosure of Health Risks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Employee Access to Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Confidentiality of Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Statutory Regulation of Company Medical and Employment Practices . . . . . . . . . . . . . . . 118

Occupational Safety and Health Act . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

Genetic Testing and the General Duty Clause . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Employee Variability in Standards Setting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

Genetic Monitoring and OSHA Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

OSHA Regulation of Employer Medical Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

Medical Removal Protection and Rate Retention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Access to Exposure and Medical Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Title VII of the Civil Rights Act of 1964 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123

Disparate Impact of Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Business Necessity and Job Relatedness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

Employee Refusal To Submit to Medical Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

The Rehabilitation Act and State Fair Employment Laws . . . . . . . . . . . . . . . . . . . . . . . . . 126

Medical Examinations and Screening Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

Is Genetic Susceptibility or Chromosomal Abnormality a Handicap? . . . . . . . . . . . . . . 127

Job Relatedness of Screening and Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128

Reasonable Accommodation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130

Collective Bargaining Agreements and Employment Practices . . . . . . . . . . . . . . . . . . . . . . . 131

Protected Activities of Employees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Employee Access to Safety and Health Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131

Provisions in Collective Bargaining Agreements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Union’s Duty of Fair Representation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132

Contract Enforcement and Arbitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... ...... 133

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Chapter 8

Legal Issues Raised by

Genetic Testing in the workplace

Genetic testing raises many legal issues for

which there are few clear answers. The most fundamental question is whether the technology is

compatible with existing laws and the established legal rights of employees. This question embodies a number of issues within the broad spectrum of employee-employer relations, ranging

from the nature of the doctor-employee relationship through the proper use of the test results

to the employer's responsibility to prevent occupational illness. These questions may be specified

as follows:

Who has the legal responsibility for achieving and maintaining a safe workplace?

—What does “safe” mean?

—How is safety to be achieved?

To what extent does the law protect the interests of individuals or groups who may be

at increased risk of occupational illness?

When, if ever, does an employer have a duty to use certain medical procedures, including genetic testing?

What are the legal constraints on occupational medical testing procedures, whether

used routinely or for research?

—What information must be given to the

employee?

—What use can be made of the results?

What are the employer’s rights to use employee selection methods that it deems appropriate?

Under what circumstances could the Occupational Safety and Health Administration

(OSHA) require medical tests in general and

genetic testing in particular?

To what extent can employers and employees

or their unions negotiate their own answers

to these questions?

No Federal statute specifically covers or even

refers to genetic testing in the workplace. No

Federal court cases have dealt with the subject.

Consequently, there are no direct legal precedents

to guide decisionmaking. However, there are

many established legal principles governing the

rights and duties of employers, employees, company medical personnel, and unions. These can

be applied to the issues raised by this new technology,

There are three major ways that legal rights and

duties governing emlployer-employee relations are

created. The first is by judicial decision, which

produces a body of legal principles known as the

common law. The second is by legislative decree.

Federal and State statutes can expand, modify,

or overturn common law rights and duties or create new ones. The first major example of this in

employer-employee relations was the enactment

of workers’ compensation laws by all of the States

in the first part of this century. other applicable

statutes include the National Labor Relations Act

(NLRA), the Occupational Safety and Health Act

of 1970 (OSH Act), the Civil Rights Act of 1964,

and the Rehabilitation Act of 1973. The third way

is by contractual arrangements between employ-

.

ers and unions. These are known as collective

bargaining agreements and are authorized by the

NLRA. Rights and duties with respect to company

employment and medical practices may be cre-

.

ated, modified, or enhanced by collective bargaining agreements so long as they are not incompatible with existing law.

These sources of law provide a useful framework for addressing the legal issues raised by genetic testing in the workplace.

111
112 . The Role of Genetic Testing in the Prevention of Occupational Disease

Basic rights and duties governing employment

and medical practices _ —————. .

The common law provided the initial source of

legal principles governing relationships among

employers, employees, and company physicians.

Workers’ compensation laws substantially modified the relationship between employer and employee, but the common law continues to be relevant, especially in the doctor-employee relationship and in litigation concerning occupational illness, such as the asbestos cases.

Employer rights and duties

Under common law, an employer had virtually unfettered control in selecting its employees.

The employer could hire or refuse to hire for any

reason or no reason at all. This right included the

right to refuse to hire an individual because of

the employer’s opinion that the prospective employee was physically incapable of performing the

job. Once hired, the employee could be fired “at

will” by the employer for any reason or no reason at all, including the employer’s belief that the

employee could no longer perform the job because of his physical condition. This has been

modified by State and Federal antidiscrimination

statutes.

Under common law, employers had five main

duties for the protection of employees. These

were to: 1) provide a safe place to work, 2) provide safe tools and equipment for the work,

3) warn of dangers about which the employee

might reasonably be expected not to know, 4) provide a sufficient number of suitable coworkers

to ensure the safety of each worker, and 5) promulgate and enforce rules that would make the

work safe. These duties are still recognized by

the law in the 50 States and the District of Columbia.

An employee who suffered from an injury or

illness related to his employment had a right to

sue the employer for damages. Because these suits

were based on common law negligence, * employers usually were able to escape liability by invoking the common law defenses of contributory negligence, assumption of risk, and the fellow servant rule (53). That is, if the injury or illness was

caused in any part by the negligence of the injured worker or any coworker, or if the employee

expressly or impliedly assumed the risk of working in a hazardous job, there was no recovery.

The concept of assumption of the risk may be

relevant in some cases involving genetic testing.

New rights and duties created by

workers’ compensation laws

Beginning in 1910 with New York, the States

took steps to relieve the hardship of industrial accidents on individual workers and their families

by passing workers’ compensation laws. Today

each State has such a statute. The major objectives of these laws are to: 1) provide sure, prompt,

and reasonable income and medical benefits to

work-accident victims, or income benefits to their

dependents, regardless of fault; 2) provide a single

remedy and reduce court delays, costs, and workloads arising out of personal injury litigation;

3) eliminate payment of fees to lawyers and witnesses, as well as the expense of time-consuming

trials and appeals; 4) encourage maximum employer interest in safety and rehabilitation

through an appropriate experience-rating mechanism; and 5) promote study of the causes of accidents in order to prevent future accidents (66).

Workers’ compensation is a form of ‘(strict

liability” whereby the employer is charged with

the injuries arising out of its business without

“Negligence is conduct (an act or omission) that involves an unreasonable risk of harm to another person. For the injured party

to be compensated, he must prove in court that: 1) the defendant’s

conduct was negligent, 2) the defendant’s actions in fact caused the

injury, and 3) the injury was not one for which compensation should

be denied or limited for reasons of overriding public policy,
Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace 113

regard to fault. Common law damage actions* are

precluded, but so too are common law defenses.

The employee is assured of medical expenses and

income maintenance; employers are protected

against potentially large personal injury judgments, including those for “pain and suffering. ”

In addition, employers are assured of relatively

fixed production costs that can be passed along

to the consumers, since the employer carries insurance to pay workers’ compensation claims.

Resort to this system is, with some exceptions,

the “exclusive remedy” available to injured

workers.

Virtually all private sector employees are

covered by State workers’ compensation laws and

government employees are protected by similar

laws. Where the statute does not apply, injured

employees retain their common law rights and

remedies.

Each State law sets its own eligibility requirements, benefit levels, and administrative mechanisms for claims processing. The resulting wide

range in eligibility and benefit levels is one of the

most frequent criticisms of workers’ compensation.

One of the most troubling aspects of worker’s

compensation law is in dealing with occupational

disease. Claimants must prove that the disease

from which they suffer is work related and not

one of the “ordinary diseases of life” (41)62). This

is extremely difficult to do for many occupational

diseases, which have long latent periods and

whose causes are poorly understood. Consequently, occupational disease cases are six times more

likely to be contested than accident or other cases

(32), and relatively few claimants prevail (7).

Exceptions to the “exclusive

remedy” rule

There are a number of exceptions to the general

statement that workers’ compensation is the only

remedy available to an employee suffering from

work-related injury or illness. Two of the exceptions are most relevant here.

● The term “action” is synon~mous with suit or lausuit.

DUAL CAPACITY

In a minority of jurisdictions, an employer may

become liable to its own employee if the employee’s injury or illness resulted from the breach of

a duty arising outside the scope of an employeremployee relationship. In these situations the

employer is said to be acting in a “dual capacity. ”

The most important of these for genetic testing

is when an employer provides medical services,

whereby it incurs the risk of medical malpractice claims.

One category of these claims involves the failure

of the company physician to detect or to inform

an employee of illness. For example, in Bednarski v. General Motors Corp., * a wrongful death

action * * was permitted to be brought based on

the company’s failure to diagnose or to inform

the plaintiff’s decedent that he had lung cancer,

even after performing a series of physical examinations and X-rays. Many of these failure to

diagnose or inform cases are based on non-workrelated illnesses that were allegedly detectable

during preemployment examinations (8,9,73).

An employer might also be found liable for

negligently failing to discover an employee’s propensity to contract a work-related illness, thereby

permitting the employee to be exposed to conditions that bring about the disease (14,56). If such

a case were brought, however, the plaintiff would

be required to prove that a reasonably prudent

company doctor exercising ordinary skill and

judgment would have detected the employee’s

likelihood of contracting an occupational disease.

It is unlikely, at least at the present time, that an

employer would be liable where the employee’s

medical condition could only be detected through

sophisticated biochemical or cytogenetic procedures and the employer did not use these procedures. On the other hand, the negligent misuse of these procedures by the employer might

provide the basis for liability.

Two other points related to dual capacity medical malpractice are relevant. First, even where

the examining physician is not negligent, the

*88 Nlich. App. 482, 276 N.\\’ .2d 624 ( 1979). Arrord, Hooter 1,

It’illiams, 203 AX] 861 (hid. 1 964) (silicosis).

* *A t$’rongful death action is a suit claiming that the defendant

conduct \\rongfull}’ caused someone’s death and that the plaintiff,

usua[!v the survi~ring spouse or children, was harmed as a r[~su]t.
114 . The Role of Genetic Testing in the Prevention of Occupation/ Disease

employer may be liable if established company

medical practices are inadequate (36). Second, in

some jurisdictions the company physician may be

sued individually for negligence and is not protected by the employer’s immunity under workers’ compensation laws (30,31).

WILLFUL AND INTENTIONAL TORTS*

In almost all jurisdictions, an exception to the

exclusive remedy rule is recognized if the

employee can prove that the employer specifically

intended to harm him (4)35,59). This is a fairly

high hurdle for a plaintiff employee to clear, In

Mandolidas v. Elkins Industries, Inc.,** however,

the West Virginia Supreme Court of Appeals

greatly expanded the rule and held that an employer is liable for employee injuries resulting

from the employer’s willful, wanton, or reckless

misconduct: “[W]hen death or injury results from

willful, wanton or reckless misconduct, such

death or injury is no longer accidental in any

meaningful sense of the word, and must be taken

as having been inflicted with deliberate intention

for the purposes of the workmen’s compensation

act. ” A recent Ohio case also adopted this viewpoint (11).

The Mandolidas case could arguably support an

action against an employer by an employee if the

following conditions were met: 1) the employer

was using genetic screening tests, 2) the tests were

highly predictive, 3) the tests identified the employee as susceptible, 4) the employer placed an

employee into a high risk instead of a low risk

environment, and 5) the employer contracted the

disease for which he was identified as being at

risk.

A more substantial body of law exists to allow

recovery for injury or illness caused by the fraud

or deceit of the employer. The cases usually involve concealment of an existing illness. For example, where employers have fraudulently concealed from employees the fact that they were

suffering from lung cancer (37) or silicosis (21),

the employees were permitted to bring damage

actions for injuries caused by the aggravation of

their initial condition. There is also some limited

“~ tort is a ci~fil wrong, other than breach of contract, for which

a court will award damages or other relief.

● *246 S. E,2Ci 907 (M’. \’a. 1978).

case law to the effect that fraudulent concealment

of information about hazardous working conditions would permit an injured employee to recover damages (34). These cases on fraudulent concealment might support an action where the concealment involved the results of genetic monitoring, if the results validly predicted that employees

were at an increased risk of developing cancer

and the plaintiff developed cancer.

Products liability

The “exclusive remedy” provisions of workers’

compensation laws apply only to actions brought

by injured employees against their employer.

Some jurisdictions permit suits against other companies, for example, the manufacturer of a product used by the employee on the job. This products liability litigation—where the employee

alleges that an injury or illness was caused by a

product manufactured by the defendant and supplied to the employee’s employer—is rapidly expanding. Perhaps the best known type of case,

and certainly the most prevalent number of these

cases, involves asbestos.

Asbestos and other products liability suits often

are based on the allegation that the manufacturers failed to warn all those who might handle

the product of its hazardous nature. In the leading

case of Borel v. Fibreboard Paper Products

Corp., * the Fifth Circuit Court of Appeals accepted such a claim by ruling that the defendant

manufacturer of insulation material that contained asbestos had a duty to warn all users of

its asbestos products, including insulation workers who did not make the product but simply installed it, of the foreseeable dangers associated

with handling asbestos.

Products liability conceivably could become an

issue for genetic testing. For example, if a company manufactured a chemical that was a suspected carcinogen, it might feel compelled to use

cytogenetic monitoring to help it determine the

potential hazards associated with the chemical,

not only to protect its employees but also to be

able to warn its customers’ employees. Failure to

take such steps might provide grounds for lawsuits similar to those for asbestos.

*493 F.2d 1076 (5th Cir. 1973), cert. denied 419 U.S. 869 (1974),
Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 115

Rights and duties in company

medical practices

THE DOCTOR-EMPLOYEE RELATIONSHIP

The nature of the doctor-employee relationship

is clouded by the dilemma of the conflicting duties

of the occupational physician. On one hand, the

doctor is an employee of the company and thus

has the duty to further the company’s interests.

on the other, when the doctor examines or treats

employees, this interaction looks very much like

the standard doctor-patient relationship.

The tension between the doctor’s conflicting

duties may be seen in the following example. Suppose a person’s annual checkup by his personal

physician reveals a condition that would make

him susceptible to disease in a certain work environment. The doctor has the duty to inform the

patient of the risk, and the patient can choose to

act on that information as he sees fit. If, however,

the examination was a preemployment one conducted by the company physician, the doctor’s

primary duty would be to inform the employer,

with the likely result that the person would not

be hired or would be placed in a job different

from the one for which he was originally

considered.

It is important to determine whether a physician-patient relationship exists between an

employee and an employer-provided doctor. If

there is no such relationship, the doctor owes no

duty to the employee except to use ordinary care

not to injure the employee during the course of

the examination. If there is a physician-patient

relationship, the physician must render medical

care with the skill and learning commonly possessed by members of the profession. The physician also would have the following legal duties:

1) to discover the presence of disease, 2) to inform the patient of the results of the examination and of any tests performed, 3) to advise the

employee of risks associated with continued exposures, and 4) to preserve the confidentiality of

communications and records.

The traditional view is that there is no physician-patient relationship between an actual or

prospective employee and an employer-provided

doctor (2, 39, 58). Courts that adhere to the .

dichotomy between employer-provided and traditional patient-obtained medical care look to

whether the physician is treating or merely examining the individual or for whose benefit the

physician is performing the service. If the physician is merely examining the individual or performing services for the benefit of the employer,

no physician-patient relationship will be found.

There are indications that this is changing, and

the current state of the law is less certain (49).

The distinction between treating and examining

seems simplistic and artificial. {occupational physicians examine and treat; the benefit of their services goes to both employer and employee. Therefore, to determine if there is a physician-patient

relationship, other factors also need to be considered, including whether there is an ongoing

medical relationship between the parties or merely a single examination, what the reasonable expectations of the physician and patient are as to

the nature of the examination, whether any diagnosis or treatment is contemplated by the examination, and the nature of the employee’s consent

to the examination. In fact, the employee’s expectations as to the nature of the exam may create

a duty on the part of the employer’s physician

to inform potential employees of any serious

health problems that the doctor discovers or

should have discovered with the exercise of reasonable care. This duty would arise not out of a

physician-patient relationship per se, but out of

the natural reliance by the potential employee on

the physician to inform him of any uncovered

health problems. Acting on this reliance, the applicant may forego additional examinations to his

detriment.

THE DOCTOR-EMPLOYER RELATIONSHIP

Unlike the doctor-employee relationship, the

relationship between the employer and the doctor is more clear-cut. Generally, the doctor is

viewed as representing the employer, and, under .

the legal doctrine known as respondeat superior,

actions of the doctor are attributed to the employer. Thus, if the doctor is found to be liable

for malpractice or other improper actions with

respect to an employee, the employer generally .

will be held liable too.
116 ● The Role of Genetic Testing in the Prevention of Occupational Disease

DUTY TO CONDUCT MEDICAL OR GENETIC TESTING

Employers are under no general legal duty to

conduct preemployment or periodic medical examinations, except where required by OSHA

standards covering specific health hazards or pursuant to a provision in a collective bargaining

agreement. Nevertheless, approximately 48 percent of all employees in urban workplaces are required to take a preplacement physical examination and nearly 34 percent of all such employees

are provided with periodic medical examinations

(45).

Under these circumstances, is there a duty to

conduct genetic testing during the course of these

examinations? The physician has a duty to use

reasonable care and customary medical procedures. Since this technology does not meet

established scientific criteria for routine use, the

physician does not have a duty to use the tests,

However, if sufficiently high correlations between

genetic endpoints and disease are eventually demonstrated and the tests become a commonly used

medical procedure, the occupational physician

may have a duty to use them when conducting

medical examinations.

EMPLOYEE’S RIGHT TO REFUSE AN EXAM

With the increasing use of occupational medical

screening, examinations, and procedures comes

the growing likelihood that an applicant or

employee would refuse to take such an exam on

religious, ethical, medical, privacy, or other

grounds. Thus, the question arises whether an

applicant or employee has a right to refuse medical tests and still retain his job. Unless the test

procedure violates a specific statute, regulation,

or collective bargaining agreement, there is no

constitutional or common law right to refuse (28).

TESTING SOLELY FOR RESEARCH PURPOSES

An employer may want to conduct genetic tests

solely for research purposes, where no job actions

are taken with respect to employees. In this situation, absent a specific provision in a collective

bargaining agreement, it would appear that the

employee has no right to refuse to take part in

the testing and still retain his job. Research on

methods to determine the health effects of workplace exposures can be a valid condition of employment.

There are constraints on how the research may

be conducted. If an employer had received Federal funds for the research or were conducting

the research with a university that had received

Federal funds for the project, the researchers are

required by the National Research Act* to establish an Institutional Review Board (IRB) in order

to protect the rights of the human subjects. The

Department of Health and Human Services (DHHS)

has promulgated regulations which, among other

things, specify the criteria for IRB membership

and approval of the research. * * One of the most

important of the criteria for approval is that informed consent to the research must be given by

each subject. While the regulations specify at least

eight elements of informed consent, these elements basically condense to the following requirements: 1) all of the important information, such

as the procedures, the risks, and the possible

benefits, must be disclosed to the employee in

terms he or she can understand; 2) the employee

must understand that information; 3) the employee must be mentally competent to consent;

4) the consent must be voluntary; and 5) a statement must be provided describing the extent to

which confidentiality of records identifying the

subject will be maintained. A further discussion

of these regulations is not warranted because

most occupational medical research is not likely

to be federally funded.

Research to establish the validity of genetic

testing most likely will be governed by State law.

A few States have enacted statutes covering

human experimentation. * * * However, State tort

law (common law) probably will be the source of

applicable law. Tort law generally provides few

limitations on such experimentation other than the

requirements of informed consent and avoidance

of negligence (27). Unlike the elements of informed consent in the DHHS regulations, however, the State-law-developed doctrine of informed consent does not deal with the issue of

*42 [’.s,[:. $2891-3(2) ( 1976).

* ● 45 C.F. R. $46 [1981).

● * *See, fbr eximple, N.Y, Pub. Iiealth La\v 6 $244(J-2446 (NlcKinnt?y 1977); Wis. Stat. Ann. ~.5 1.61 (W’est Supp. 1981).
.

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 117

confidentiality of medical records. Furthermore,

in the workplace, the requirements for informed

consent are likely to be minimal. Since participation in research can be a valid condition of employment, employees probably would not have

to be told much, if anything, about the research,

unless it involved a significant risk. Since genetic

testing involves low-risk procedures, employees

probably would not have to be informed of the

tests. Of course, the employee would have to consent to the medical examination in which blood

was drawn.

Despite the generally limited legal restrictions

on medical research under State law, an employer

still might hesitate before embarking on a research program involving genetic testing. An

employer may fear that a plaintiff in a lawsuit

claiming work-related illness could get access to

the results via discovery * procedures and use

them to build a better case against the employer,

even if the employer believed the results did not

establish the validity of the tests.

DISCLOSURE OF HEALTH RISKS

Although a rule** under the OSH Act requires

that employees (but not applicants) be given access to their medical records, employers and occupational physicians do not have an affirmative

duty under this rule or the common law to disclose the results of medical exams to employees

or applicants. However, as noted previously, withholding medical information can give rise to civil

liability, where an illness, whether or not occupational, was detected or should have been detected.

This principle possibly could be extended to

situations where individuals were merely at risk.

Since employers have a common law duty to apprise employees of latent dangers, a company may

be liable for failure to disclose that employees are

working with a hazardous product. In addition,

a physician may be liable for failure to disclose

the health risks of the job, if the company gives

medical examinations,

“L)isrmcrj IS the right of parties in a lawsuit to ha~c acress to

Infornlatlon in the possession of their ad~ ersary rclm’ant to the suit.

“1’his right of :i[xPss is quite hrmd The theory underl}’ing discmw~’

is t }xi t thr pr rtIes should not k “ii rJIl)LJsh Pd” at t ria] h\ I in f[)rrna -

tlon that was prmiously unknow n to them and ciet rirnental to their

(’iise

● ● 29 (’ F K. $191020 ( 1981)

Disclosure of information about hazardous

substances provides the employer with the opportunity to use the defense of assumption of the

risk in lawsuits based on common law theories

of negligence. That is, if an employee who was

at increased risk of disease knowingly placed

himself in the risky environment, he could not

later sue the employer or physician for negligence

if he developed the disease (13,72).

EMPLOYEE ACCESS TO MEDICAL RECORDS

In view of their concern about possible misuse

of information from genetic screening and a likely

desire to know of risks to their health, employees

and applicants might want to have access to their

medical records. As of 1980, employees have a

right to see their medical records pursuant to

OSHA's Access to Employee Exposure and Medical

Records Standard. * Besides OSHA’s access standard, which applies only to toxic substances and

which is still being challenged in the courts, there

are few legal requirements that employers give

employees a right of access to medical records.

Five States—Connecticut, Massachusetts, Maine,

Ohio, and Wisconsin—provide for such a right,

usually as part of a broader right to review the

employee’s entire personnel record. * * Applicants

have no rights to company medical records. The

only other source of an access right is through

a collective bargaining agreement.

CONFIDENTIALITY OF MEDICAL RECORDS

One concern of employees or applicants who

have been genetically screened would be to prevent the spread of embarrassing, damaging, or

false information about themselves, particularly

to other potential employers. Thus, they would

wish to know to what degree such information

would be kept confidential.

The Code of Ethics for Physicians Providing occupational Medical Services provides that “employers are entitled to counsel about the medical

fitness of an individual in relation to work but

are not entitled to diagnoses or details of a specific

*45 E’ed, Reg. 35,212-3,5,303 (X!aj 2:3, 1 980), (’(Miif/(’(/ ‘1 t 2!1 ( ‘ F K

‘$I91O 20 (1981).

“‘[’[)nn [len Stat Ann title 31, $ 128c (\$r[Jst Supp 1981); Nlass

Ann 1,a\\s rh 149, $ 19A ( 1976), XI(>. R(J\ Stiit Ann t ilk 26, $631

(J1’est Supp. 1981); Ohio Re\ (;()(l(> $411323 (Pagf> 198(1}: tl IS Sta t

,Ann. title 1 :}, $ I 03.13 (It’est Sul)p 1981 I
118 . The Role of Genetic Testing in the Prevention of Occupational Disease

nature. ” In practice, however, management access to employee medical records is often much

more extensive (49)55,70).

There are few legal restrictions on such disclosures within the company. Often as a condition of employment, employees sign blanket

waivers authorizing the company to use medical

and personnel records as it deems necessary.

Even if a waiver is not signed, it has been asserted

that “workers have little genuine expectation of

true confidentiality as to employment medical

records” (49). In one case, the court stated that

the employment exam “was wholly for the benefit

of the Company, and the doctor owed to it alone

the duty to perform efficiently the work the Company had employed him to do. Appellant must be

charged with knowledge of this” (39). Thus, there

was an implied waiver of confidentiality by the

employee’s consenting to the examination. Finally, liability for wrongful disclosure would have

to be based on a breach of the physician’s duty

of confidentiality and, as discussed earlier, many

courts have found that there is no physicianpatient relationship where the physician is provided by the company.

With respect to disclosure of medical information to parties outside the company, there are also

few restrictions under common law. In any lawsuit alleging damage from such disclosure, the

plaintiff would have to overcome the defense that

there was no duty of confidentiality because there

was no doctor-patient relationship between the

company physician and the employee or job applicant (54).

Some State and Federal statutes provide a variety of protections from disclosure. OSHA’s access

standard gives OSHA the right to employee medical records in personally identifiable form, but

limits the disclosure of such information and provides safeguards to ensure confidentiality. The

DHHS regulations on human experimentation require, “where appropriate,” adequate provisions

to protect the privacy of subjects and to maintain the confidentiality of data. *

The most extensive regulation of medical information is California’s Confidentiality of Medical

Information Act. * * It requires employers who receive medical information to establish procedures

to ensure its confidentiality. Further, employers

cannot disclose this information to others without

the employee’s written consent.

*45 (:. F’.R. $46.11 1(a)(7).

* “(;al, (;i\’, (;ode Ann. $56 [[leering Sup]). 198.2)

Statutory regulation of company medical

and employment practices — ——. .-. —— —..

Three Federal statutes—the Occupational Safety or could be required, prohibited, or otherwise

and Health Act of 1970, the Civil Rights Act of regulated pursuant to the act.

1964, and the Rehabilitation Act of 1973—are

directly applicable to medical and employee selection practices used by employers. The OSH Act*

was enacted “to assure so far as possible every

working man and woman in the Nation safe and

healthful working conditions . . . .“* * The act provides the Government with broad regulatory authority over physical conditions in the work environment. Since genetic testing may play a role

in the prevention of occupational illness, questions

naturally arise about whether genetic testing is

Title VII of the Civil Rights Act of 1964, as

amended, * and sections 503 and 504 of of the

Rehabilitation Act of 1973** govern employment

rights. Title VII prohibits employment discrimination on the basis of race, color, religion, sex, or

national origin. The Rehabilitation Act prohibits

employment discrimination against otherwise

qualified handicapped individuals by employers

who are Government contractors or recipients

of Federal assistance. These statutes embody the

*29 (1 s (’ $$6.51-678 (1976 &? Sllpp. 111 1979)

● * $2! 2!1 [1.s (:, $651 ( lg~~),

.~~ [ I ,s (; (j~()()()(> ( 1976 Is?, supp. 11 1 !)7s1.

“ ● 2:1 (“.s (: $$701-796 ( 1976 &L. Supp. 111 1 979)
.

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 119

policy that individuals are not to be discriminated

against on the basis of immutable characteristics

and that their abilities are to be judged on an individual basis. Since one major type of genetic

testing—genetic screening—could result in employment discrimination against classes of individuals with particular inherited traits, the question

arises as to whether such discrimination is prohibited by these two acts.

This question is not answered simply by asserting that the OSH Act requires every employee,

even those who may be genetically susceptible to

illness, to have a safe working environment and

therefore federally mandated exposure levels of

hazardous substances must be low enough to protect these people. The broad policy of worker protection embodied in the act is limited by requirements that Government exposure standards be

technologically and economically feasible and that

they be imposed only after a finding of a significant risk of material health impairment. Thus,

there is a tension between the social goals of maximizing equal employment opportunity and safety

in the workplace.

This section examines how these three statutes

and State fair employment practices laws deal

with the sometimes conflicting policy goals and

various legal questions created by genetic testing.

Occupational Safety and Health Act

The OSH Act is the only comprehensive statute

addressing hazards in the workplace and therefore is the primary vehicle for hazard elimination

in that setting. Section 5(a) of the act requires

employers to furnish a place of employment free

from recognized hazards and to comply with all

standards promulgated under the act. “Recognized hazards” has been interpreted by the courts

to mean recognized by the employer or the industry and that there is a recognized way of dealing with it; that is, it is preventable (46). Section

S(b) requires each employee to comply with “all

rules, regulations, and orders issued pursuant to

this Act which are applicable to his own actions

and conduct .“ * Despite the seeming similarity of

these provisions, it is clear that “[f]inal responsibility for compliance with the requirements of

this Act remains with the employer” (60). Employees cannot assume the risk with respect to

health and safety hazards as they could under

common law. Only the employer may be issued

citations, assessed penalties, and ordered to abate

violative conditions. Employees may only petition

the Secretary of Labor to enforce the requirements of the act; the employer is required by law

to obtain the compliance of employees, even if

this entails disciplining disobedient employees.

Violations of the act or rules promulgated thereunder can result in civil or criminal penalties

against the employer. The act does not supersede

or affect rights and duties created by common

law or workers’ compensation statutes.

Employer duties under the OSH Act are specific

and nondelegable. An employer may not rely on . .

a union to provide safety training, and it may not

shift the burden of compliance to employees or .

supervisors. Under the act, employees may not

assume the risk nor consent to work in conditions

that violate the act’s requirements.

An important right of employees under the OSH

Act is the right to refuse to work under extremely

hazardous conditions where there is insufficient

time to eliminate the hazard by resort to regular

enforcement channels. This right, based on the

broad antidiscrimination provision in section

11(c), was established in an OSHA regulation, *

which was unanimously upheld by the Supreme

Court in Whirlpool Corp. v. Marshall.**

If cytogenetic tests showed an increased

number of chromosomal abnormalities in one or

more employees, could they walk off the job? The

answer is probably not. First, because of the

debatable predictive ability of these procedures,

it is unlikely that the employee or employees . . .

could demonstrate the regulation requirement

that there be a “real danger of death or serious

physical injury. ” Second, and more important,

most occupational illnesses are developed over a

period of time. Therefore, it is likely that the

employee would fail to meet the “imminence” or

“urgency” requirement of the regulation. To date,

all of the work refusal cases have involved safety hazards.

*29 (’ F K $1977 12(?))(2) ( 1:J81 )

* “445 [’ S. 1 ( 1 \J80)
120 ● The Role of Genetic Testing in the Prevention of Occupation/ Disease

Given the employer’s duty under the OSH Act

to maintain a safe workplace, is genetic testing

compatible with or contrary to that duty? To

answer this question, it is necessary to consider

several more specific questions that are focused

on the particular types and applications of genetic testing and the various requirements that can

be imposed on employers pursuant to the act.

These are addressed in the remainder of this

section.

GENETIC TESTING AND

THE GENERAL DUTY CLAUSE

The first clause of section 5(a) of the OSH Act,

which requires employers to maintain a workplace free from recognized hazards, is known as

the general duty clause, Does it require employers

to use genetic monitoring to identify hazards?

Does it require or permit the use of genetic

screening to identify potentially susceptible

workers?

The general duty clause simply imposes a requirement on employers without stating the

means by which that requirement can be met.

Thus, it would not support an argument that genetic testing is required by the OSH Act. Neither

would it support an argument that genetic testing

is prohibited by the act. Although genetic testing

could be adverse to the interests of particular

employees, it certainly would not be a “hazard. ”

These conclusions, however, leave open the question of whether OSHA can require, prohibit, or

regulate genetic testing under its power to set

safety and health standards.

EMPLOYEE VARIABILITY IN STANDARDS SETTING

Section 5(a)(2) of the OSH Act gives the Secretary of Labor broad power to require a safe

workplace by setting standards that can govern

virtually all aspects of the work environment in

any way related to safety or health. The standards

may be promulgated in one of three ways. First,

under section 6(a), the Secretary of Labor was initially authorized to adopt without rulemaking proceedings “established Federal standards” developed under other Federal acts and “national consensus standards” produced by nationally recognized, private standards-producing organizations.

This special authority, which expired in 1973, was

included in the act to ensure that workers would

be protected as soon as possible after the act’s

effective date. Second, under section 6(b), new

standards may be promulgated by following certain rulemaking procedures. Third, emergency

temporary standards may be promulgated under

section 6(c) without rulemaking procedures if certain conditions are met.

In 1971, pursuant to section 6(a), OSHA adopted

as established Federal standards 450 threshold

limit values (TLVs) developed by the American

Conference of Governmental Industrial Hygienists

(ACGIH). By definition, TLVs do not consider

employee variability, but set levels to which

“healthy” workers may be exposed without

adverse health effects. * These TLVs still form the

backbone of OSHA health standards, with only

21 additional health standards having been promulgated under section 6(b) during OSHA’s first

10 years,

Section 6(b)(5) provides that in promulgating

standards regulating toxic substances or harmful physical agents the Secretary must set standards to ensure, to the extent feasible, that ‘(no

employee” will suffer material impairment of

health or functional capacity, even if exposed for

his or her entire working life.** Based on this

seemingly absolute language and because of the

wide variability in human susceptibility to occupational disease, it might be assumed that OSHA has

the authority and in fact is required to promulgate

health standards that protect even the most susceptible worker. However, does this mean that

OSHA must adopt standards that will ensure that

a blind person can drive a truck without suffering an impairment? Does farm work in the Sun

Belt have to be made safe for a person with xeroderma pigmentosom, a genetic defect that creates

an increased risk for skin cancer?

There are two limitations on the broad language

of Section 6(b)(5), one in the section itself and the

other imposed by a recent Supreme Court decision. The first limitation is that employees can be

● iL TI,\’ represents the maximum time-weighted average concentration to which a healthy worker may be exposed for a normal

4@hour week up to 8 hours a day o~’er a working lifetime (4o to

50 years) without becoming i]] (l).

* *29 LJ.S.C. $65503)(5) (1976) (emphasis added).
——

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace 121

protected only to the ‘(extent feasible.” This

language was interpreted in a recent Supreme

Court case, American Textile Manufacturers Institute v. Donovan (“the Cotton Dust case ”).* At

issue was an OSHA standard governing employee

exposure to cotton dust. The standard contained

many different provisions, some of which the

Court struck down and some that it upheld. In

upholding the provisions setting exposure limits

to the dust, the Court ruled that the phrase “extent feasible” does not require or permit OSHA

to perform a cost-benefit analysis of the impact

of its standards but does require that the standards be technologically and economically feasible.

By “technologically feasible, ” the Court meant

capable of being done, and by “economically feasible” it meant feasible for the industry but not

necessarily for individual companies. The exposure limit provisions met these requirements.

In setting the limits, OSHA acknowledged that

12.7 percent of exposed employees would still suffer from the ill effects of exposure to cotton dust.

The second limitation on the language of section 6(b)[5) was imposed by the Supreme Court

in Industrial Union Department, AFL-CIO v.

American Petroleum Institute (“the Benzene

case”). * * The industry had challenged an OSHA

standard that had lowered the permissible exposure limit (PEL) for benzene from 10 parts per

million (ppm) to 1 ppm, a level that OSHA had determined to be feasible. The plurality opinion,

concurred in by four of the nine Justices, held

that the Secretary of Labor must determine on

the basis of substantial evidence that a standard

“is reasonably necessary or appropriate to remedy

a significant risk of material health impairment .“

The opinion stated further that the OSH Act “was

not designed to require employers to provide

absolutely risk-free workplaces)” but was only intended to require “the elimination, as far as possible, of significant risks of harm. ”

From the above discussion, it is clear that OSHA

can and must set exposure limits to toxic substances or harmful physical agents that protect

susceptible individuals, but only to the extent that

it finds that exposures above the limit present a

significant risk of material health impairment and

● 1(11 s (’t. 2478 ( 1 981).

* ● 448 [ 1.s 607 ( 1 980),

that the limit is technologically and economically feasible. * A question unresolved in the Benzene

case is whether significant risk is to be measured

with respect to each individual or on some group

basis. In other words, it is unclear whether OSHA

could promulgate a PEL designed to protect a very

small number of susceptible individuals or if it

first must find a significant number of workers

to be at risk.

GENETIC MONITORING AND OSHA STANDARDS

Some OSHA health standards regulate employee

exposure to substances identified as mutagens or

clastogens, such as vinyl chloride and arsenic.

Since genetic monitoring potentially could identify such substances, could this technique be

relied on or required by OSHA in the regulatory

process?

OSHA might use the technique to provide data

about the harmfulness of a particular substance.

If the technique could be used to indicate that a

substance was a mutagen or clastogen, data from

studies using genetic monitoring could be considered with other evidence when OSHA was setting a standard for a particular substance.

If the technique were sufficiently predictive as

a biological dosimeter or as a way to identify a

group of workers at increased risk, OSHA might

require its use as part of a standard governing

a hazardous substance. In that situation, OSHA

might rely on the D.C. Circuit Court decision in

the lead standard case, which upheld OSHA’s authority to attempt to prevent the subclinical effects of lead disease (38)67).

OSHA REGULATION OF

EMPLOYER MEDICAL PROCEDURES

Section 6(b)(7) of the OSH Act gives the Secretary of Labor authority to prescribe the type and

frequency of medical examinations or other tests

to determine the adverse health effects from exposure to toxic substances, OSHA’s 21 health

standards regulating toxic substances require a

* Arcording to Assistant Secretar\f of Labor Thorne G. ,Au(>hter,

mer~ new. standard must mu meet four requirements: 1 ) it must

hr addrmseti to a hazard prmenting a significant risk to workers;

2 J it most be denloost ratrd that the standard will reduce the risk;

31 the standard must tw t(’(llrlologi(’:ill~” and [~([)rl(~r~li(:tll)’ fe~isiblc

(In an industr~’w idr basis; and 4) the standiird must be the most

effic’irnt, or cost -efffW ii e, l~a~ to protf’ct u orhers ( 1S,61 )
122 . The Role of Genetic Testing in the Prevention of Occupational Disease

variety of medical procedures. In general, employers must conduct preplacement examinations. The physician must furnish employers with

a copy of a statement of suitability for employment in the regulated area, must conduct periodic (usually annual) examinations, and in some

instances must conduct examinations at termination of employment.

OSHA standards for 13 carcinogens require

company doctors to take a complete medical

history of exposed employees and consider genetic factors. * According to an OSHA directive,

however, this does not require genetic testing of

any employee and does not require the exclusion

of otherwise qualified employees from jobs on the

basis of genetic testing (50).

In general, OSHA has not become involved in

regulating the procedures and criteria by which

physicians make their determinations of the medical fitness of employees. One notable exception

concerns the “multiple physician review” procedure, in which employees can select their own

physician if they disagree with the findings of the

company physicians. The Fifth Circuit Court of

Appeals struck down this provision in the commercial diving standard, which required medical

examination of employees who were to be exposed to hyperbaric conditions (65). On the other

hand, the Court of Appeals for the District of Columbia Circuit upheld such a provision in the lead

standard (38)67). The distinction between the two

cases appears to be that the provision in the lead

standard was shown to be related to a safe or

healthy workplace while that in the diving standard was seen primarily as a job security provision and therefore outside the scope of the act,

Thus, OSHA probably could regulate genetic

testing to the extent the regulations were related

to enhancing workplace health.

MEDICAL REMOVAL PROTECTION

AND RATE RETENTION

In general, OSHA standards do not indicate

what measures an employer may or must take

when an employee or applicant is medically unfit for assignment or continued work in an area

where there is exposure to toxic substances. In

● 29 (:.F.R. $1910,1003- 1910,1016.

fact, the OSH Act has little applicability to job applicants. Its provisions continually refer to

employees but do not refer to applicants for

employment, and the term “employee” is not

defined in the definitions section of the act to include applicants, Thus, unless prohibited by a collective bargaining agreement or some antidiscrimination law, the employer would be free to refuse

to hire an applicant or to discharge an employee

based on the employer’s determination of medical

fitness.

OSHA’s only attempt to regulate the effects of

medical examinations on employment involves

medical removal protection (MRP) and rate retention (RR) of employees previously exposed to certain toxic substances. when a periodic medical

examination indicates that the employee is showing symptoms of the adverse effects of exposure,

the employee is removed from further exposure

—to a “safe” job if there is an opening—until it

is medically advisable for the employee to return.

If the new position is at a lower rate of pay or

if a safe job is not available, RR would require the

maintenance of wage and benefit levels during

the period of medical removal. Thus, MRP and

RR attempt to protect employee health without

reducing employee benefits, thereby shifting the

economic burden to the employer and ultimately to the consumer.

MRP and RR provisions in OSHA health standards have become increasingly stringent. For example, the vinyl chloride standard provides for

MRP, but not RR;* the asbestos standard provides

for MRP of employees for whom respirators are

ineffective, but RR is required only if there is an

available position. * * The most sweeping MRP and

RR provision is in the lead standard.*** Employees with blood-lead levels above the specified limit

must be removed until the level has returned to

an acceptable limit. Removed employees retain

their earnings rate, seniority, and benefits for up

to 18 months.

OSHA’s authority to require MRP and RR was

called into question by the Supreme Court’s decision in the Cotton Dust case. Although the Court

*29 ~.F.R. $1910,1017(k)(5) (1981),

* ● 29 C.F.R. $1910, l(lol(d)(z)(iv)k) (1981),

* ● *29 C.F,R, j 1910.1025(k) [1981).
Ch. 8–Legal Issues Raised by Genetic Testing in the Workplace ● 123

did not decide the issue of whether OSHA has the

statutory authority to promulgate any regulation

containing MRP and RR, the Court held that “the

Act in no way authorizes OSHA to repair general

unfairness to employees that is unrelated to

achievement of health and safety goals . . . .“*

Because OSHA had not made a finding when promulgating the cotton dust standard that MRP and

RR were related to achieving health, the Court

struck down that provision of the standard and

remanded it to the Secretary of Labor for further consideration.

ACCESS TO EXPOSURE

AND MEDICAL RECORDS

Section 8(c)(3) of the OSH Act directs the

Secretary of Labor to issue regulations requiring

employers “to maintain accurate records of

employee exposures to potentially toxic materials

or harmful physical agents which are required

to be monitored or measured under section 6.”

On May 23, 1980, OSHA promulgated the rule

granting employees a right of access to exposure

and medical records. * *

Under the rule, any current or former employee or an employee being assigned or transferred

to work where there will be exposure to toxic

substances or harmful physical agents has a right

of access to four kinds of exposure records: environmental monitoring results, biological monitoring results, material safety data sheets, and any

other record disclosing the identity of a toxic substance or harmful physical agent. The employee

may designate a representative to exercise his or

her rights, and labor unions have a right of access to employee exposure records without individual employee consent. OSHA also has a right

of access to exposure records. On July 13, 1982,

OSHA proposed revisions to the rule, which

would narrow its scope significantly. * * *

Access to employee medical records is more

restricted. Employees have a right of access to

their entire medical files regardless of how the

information was generated or is maintained. The

definition of employee does not include job applicants. * A limited discretion is also given physicians to deny access where there is a specific

diagnosis of a terminal illness or a psychiatric condition. Unions must obtain specific written consent before gaining access to employee medical

records. OSHA has a right of access to employee

medical records, but those records in a personally

identifiable form are subject to detailed procedures and protections.

Title VII of the Civil Rights Act of 1964

Title VII of the Civil Rights Act of 1964, as

amended, * * prohibits discrimination in the hiring, discharge, compensation, or other terms, conditions, or privileges of employment because of

an individual’s race, color, religion, sex, or national origin.

Aggrieved individuals must file a charge with

the Equal Employment Opportunity Commission

(EEOC) within 180 days of the alleged discriminatory act. After a period of up to 180 days for

investigation and conciliation by EEOC, the charging party may file an action in Federal district

court.

The term “discrimination” is not defined in title VII, but one court defined it as “a failure to

treat all persons equally where no reasonable

distinction can be found between those favored

and those not favored” (6). The Supreme Court

has recognized two main forms of employment

discrimination, “disparate treatment” and “disparate impact.” Disparate treatment occurs when

an employer simply treats some people less favorably than others because of their race, color,

religion, sex, or national origin. Proof of discriminatory motive is required. Disparate impact

involves employment practices that appear to be

neutral in their treatment of different groups but

in fact affect one group more severely and cannot be justified by the requirements of the job

or business. Proof of discriminatory motive is not

required.

The disparate impact concept was established

by the Supreme Court in Griggs v. Duke Power

Co.*** A unanimous Court struck down the ern-

“ 101 S.Ct at 2506

“ *45 Fed Reg 35,212 (1980), codified at 29 C.F.R, $1910.20 (1981).

● * *47 E’ed Reg. 30,420” ( 1982)

● 45 Fed. Reg at 35,261,

● *4z CI.S,C; , $2000e (1976 & Supp. 11 1978)

● ● “401 LI,S, 424 (19711,
124 . The Role of Genetic Testing in the Prevention of Occupational Disease

ployer’s use of certain standardized tests because

they disqualified black applicants at a substantially

higher rate than white applicants and were not

shown to measure job capability.

In Albemarle Paper Co. v. Moody, * the Court

clarified Griggs and held that a plaintiff may

establish a prima facie case of disparate impact

by showing that “the tests in question select applicants for hire or promotion in a racial pattern

significantly different from that of the pool of applicants .“ The burden is then on the employer to

show that “any given requirement [has] . . . a

manifest relationship to the employment in question. ” The plaintiff may still rebut this evidence,

however, by demonstrating that “other tests or

selection devices, without a similarly undesirable

racial effect, would also serve the employer’s

legitimate interest in efficient and trustworthy

workmanship .“

A crucial but still unresolved issue is how different the comparative test results must be in

order to support a finding that there was a disparate impact. Most Supreme Court and lower

court decisions have considered disparate impact

on an ad hoc basis. According to EEOC guidelines

on employee selection procedures, “[a] selection

rate for any racial, ethnic or sex group which is

less than four-fifths (4/5) (or eighty percent) of the

rate for the group with the highest rate will generally be regarded . . . as evidence of adverse

impact .“* * This formula is not binding on the

courts.

DISPARATE IMPACT OF GENETIC TESTING

The frequencies of genetic traits in the population often vary along racial or ethnic lines. Some

examples of these are sickle cell trait, G-6-PD deficiency, and thalassemia trait. According to one

study of G-6-PD-deficient individuals (10), the

population frequencies for the trait are as follows:

Americans (whites). . . . . . . . . . . . . . . . . 0.1 percent

Americans (black males). . . . . . . . . . . . . . 16 percent

British. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0.1 percent

Chinese. . . . . . . . . . . . . . . . . . . . . . . . . . . 2-5 percent

European Jews. . . . . . . . . . . . . . . . . . . . . . . 1 percent

Filipinos . . . . . . . . . . . . . . . . . . . . . . . . . . 12-13 percent

Greek. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1-2 percent

Indians (Asian). . . . . . . . . . . . . . . . . . . . . 0.3 percent

Mediterranean Jews. , . . . . . . . . . . . . . . . 11 percent

Scandinavians. . . . . . . . . . . . . . . . . . . . . . 1-8 percent

Comparing these percentages to each other rather

than to the population categories indicates that

the use of G-6-PD screening would have a disparate impact on various groups based on race,

sex, and national origin. For example, if 1,000

British and 1)000 Filipinos were screened, only

1 British person but 120 to 130 Filipinos would

be expected to show a G-6-PD deficiency. Similarly, it has been estimated that ‘1 out of 12 blacks

has sickle cell trait, but only 1 out of 1)000 whites

has it, a ratio of 83 to 1.

For title VII purposes, the use of G-6-PD or sickle

cell trait screening (or other procedures with a

disparate impact) would establish a prima facie

case of discrimination. This does not necessarily

mean there is a violation, but only that the burden

now is placed on the employer to justify the use

of the tests.

If future study should reveal that genetic

monitoring has a disparate impact by race, a

similar legal analysis would apply.

BUSINESS NECESSITY AND JOB RELATEDNESS

In discussing employer defenses in Griggs, the

Supreme Court indicated that “[tlhe touchstone

is business necessity. If an employment practice

which operates to exclude Negroes cannot be

shown to be related to job performance, the practice is prohibited.”* Based on Griggs, two intertwined defenses have emerged, “business necessity” and “job relatedness.” Although the Griggs

opinion used the terms in the same sentence and

did not differentiate between them, subsequent

decisions have attempted to do so. Business necessity applies when a general employment practice is used, the purpose of which is not to determine whether an applicant or employee is capable

of performing the job requirements. For example, an employer would attempt to use a business

necessity defense to justify not hiring someone

who had been convicted of a crime.

Job relatedness is somewhat narrower and goes

to whether the criteria used in determining

*422 U.S. 405 (1975).

* *29 C.F.R. $1607.4 (1981), “401 U.S. at 431.
— . . .

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace . 125

whether an applicant or employee is qualified for

employment bears a reasonable relationship to

the demands of the job. For example, height and

weight requirements and passing scores on standardized tests would be evaluated under job

relatedness.

The standards used for determining the merits

of the business necessity and job relatedness

defenses are similar. The key to business necessity

is:

. . . whether there exists an overriding legitimate

business purpose such that the practice is necessary to the safe and efficient operation of the

business. Thus the business purpose must be sufficiently compelling to override any racial impact, the challenged practice must effectively

carry out the business purpose it is alleged to

serve, and there must be available no acceptable

alternative policies or practices which would better accomplish the business purpose advanced,

or accomplish it equally well with a lesser differential racial impact (57).

Once the employer presents evidence to show

that its employment practice is grounded on business necessity, the courts balance all the relevant

factors to determine whether the need for the

practice sufficiently outweighs any disparate impact. In the case of genetic testing, whether

avoiding tort liability or costly engineering controls would be a business necessity is an open

question.

Job relatedness essentially involves an analysis

of an applicant’s qualifications and a comparison

of legitimate job requirements with the employer’s method for determining fitness. In Albemarle

Paper Co. v. Moody,* the Supreme Court cited

with approval EEOC’s Uniform Guidelines on Employee Selection Procedures and held that “discriminatory tests are impermissible unless shown,

by professionally acceptable methods, to be

‘predictive of or significantly correlated with important elements of work behavior which comprise or are relevant to the job or jobs for which

candidates are being evaluated. ’ “ However, the

EEOC guidelines have been criticized and the

Supreme Court has refused to follow portions of

them, particularly when the agency has changed

*422 Li.s, 405 (1975)

its position on an issue (40). Whether a risk of illness is a job-related characteristic is an open

question.

Any distinction between the defenses of business necessity and job relatedness becomes virtually obscured in the context of genetic screening

of workers and applicants. An employer’s justification for using screening procedures would necessarily involve elements of both defenses. If a

suit were to be filed, arguably a court could require an employer’s defense to include proof that:

1) there is a valid reason for excluding workers

who are presently capable of performing the required work but who may become physically

unable or impaired at some point in the future;

2) it is important to the business that employees

not be suffering from an occupational illness;

3) the specific screening procedure used accurately and reliably identifies the presence of the genetic trait; 4) there is a high correlation between

the trait and the individual’s susceptibility to disease at the permissible exposure level; 5) the company cannot feasibly reduce exposure through

engineering controls, personal protection devices,

or job placement; and 6) the company cannot insure itself at a reasonable cost against potential

tort liability.

EMPLOYEE REFUSAL TO SUBMIT

TO MEDICAL TESTS

Does an applicant or employee have the right

to refuse to submit to a medical test where the

employer’s use of the results would violate title

VII? From an employee standpoint, section 704(a)

of title VII offers the best chance of success. This

section provides that an employer may not retaliate against an employee or applicant who opposed

any employment practice made unlawful by title

VII or who participated in any proceeding under

the title. Most of the cases brought under this section involve alleged employer retaliation after the

employee files a charge with EEOC, Nevertheless,

there are some cases holding that other forms of

employee activity are protected when they oppose discriminatory employment actions (3,48).

No court has ever resolved the question of

whether section 704(a) protects an employee who

refuses to submit to a test that he or she believes

is discriminatory (and that cannot be justified by
126 ● The Role of Genetic Testing in the Prevention of Occupational Disease

the employer). In the one case where the issue

was raised, the case was decided on other

grounds (43). It is clear, however, that an

employee need not be correct; only a good faith

belief is required (42,51).

Based on these considerations, it is possible that

an applicant or employee validly could refuse to

submit to genetic testing and any retaliation by

the employer would violate title VII.

The Rehabilitation Act and State

fair employment laws

The Rehabilitation Act of 1973* was the first

comprehensive Federal effort to bring handicapped individuals within the mainstream of

American life. Of the several provisions of the act,

sections 503 and 504 have a direct bearing on the

employment rights of the handicapped.

Largely as a result of the Federal initiative, 41

States and the District of Columbia also have

enacted laws prohibiting discrimination in employment on the basis of handicap. Unlike the

Federal law, which applies only to Federal contractors and recipients of Federal funds, State

laws prohibiting employment discrimination

against the handicapped have a wider coverage

and usually exempt only small employers, Therefore, State law is much more important in cases

involving the handicapped than in other kinds of

discrimination cases.

Section 503 provides that any contract in excess of $2)500 entered into with any Federal

department or agency shall contain a provision

requiring that the contracting party take affirmative action to employ and promote qualified

handicapped individuals. The term “handicapped

individual” is defined as “any person who (A) has

a physical or mental impairment which substantially limits one or more of such person’s major

life activities, (B) has a record of such an impairment, or (C) is regarded as having such an impairmerit. ” Based on this broad statutory definition,

and on the definition contained in the implementing regulations, it has been estimated that as many

as 40 million to 68 million persons are covered

by the statute (47), Responsibility for enforcing

section 503 is vested in the Office of Federal Contract Compliance Programs (OFCCP) in the Department of Labor. Individuals who believe they

have been discriminated against must pursue

their remedies through OFCCP; the courts have

not permitted these individuals to sue directly,

Section 504 provides that no otherwise qualified

handicapped individual shall, solely by reason of

handicap, be excluded from the participation in,

be denied the benefits of, or be subjected to discrimination under any program or activity receiving Federal financial assistance. Unlike section

503, no minimum amount of financial assistance

is required for coverage under section 504, and

the courts have held that aggrieved individuals

can sue employers under this section. Section 504

also incorporates the same broad statutory definition of handicap as section 503.

Two key terms in the definition of handicapped

individual—’’physical or mental impairment” and

“substantially limits’’—are not defined in the

statute. However, regulations promulgated pursuant to sections 503 and 504 offer guidance. The

regulations under 503 state that a handicapped

person is ‘(substantially limited” if “he or she is

likely to experience difficulty in securing, retaining or advancing in employment because of a

handicap.”* The regulations under section 504

define ‘(physical or mental impairment” as:

. . . (A) any physiological disorder or condition,

cosmetic disfigurement, or anatomical loss affecting one or more of the following body systems: neurological; musculoskeletal; special

sense organs; respiratory, including speech

organs; cardiovascular; reproductive, digestive,

genito-urinary; heroic and lymphatic; skin; and

endocrine; or (B) any mental or psychological

disorder, such as mental retardation, organic

brain syndrome, emotional or mental illness, and

specific learning disabilities. * *

It has been estimated that 3 million firms—about

half the businesses in the country–are covered

by the act, either as Government contractors or

recipients of Federal funds (63),

*29 U.S. C. ‘$$701-796 ( 1976 & Supp, 111 1979)

*41 C.F.R. $60-741.2 (1981).

* ● 45 C,F.R, $84,3 (j)(2)(i) (1981).
Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 127

MEDICAL EXAMINATIONS AND

SCREENING TESTS

Under the guidelines and model regulations promulgated to implement section 504) an employer

receiving Federal financial assistance may not

make preemployment inquiry about whether the

applicant is handicapped or about the nature and

severity of an existing handicap unless a preemployment medical examination is required of

all applicants and the information obtained from

the examination is relevant to the applicant’s ability to perform job-related functions.

Under the section 503 regulations, a Federal

contractor may require a preemployment medical

examination of a handicapped applicant, even if

an examination is not required of the nonhandicapped. Nevertheless, if the employer’s job

qualification requirements “tend to screen out

qualified handicapped individuals, the requirements shall be related to the specific job or

jobs for which the individual is being considered

and shall be consistent with business necessity

and the safe performance of the job.”*

Despite the slight difference in language and approach between the section 503 and 504 regulations, both serve to limit the use of discriminatory

preemployment examinations and tests. Nevertheless, it still must be determined whether genetic differentiation is a handicap and whether

the screening procedures are job related.

IS GENETIC SUSCEPTIBILITY OR

CHROMOSOMAL ABNORMALITY A HANDICAP?

The definition of “handicapped individual”

basically includes persons who are, were, or are

believed to be suffering from an impairment. The

goal of genetic testing is to identify individuals

or groups who are not at present impaired, but

who may be or are likely to become impaired in

the future under special circumstances. An important threshold question is whether these individuals are handicapped and thereby protected

by the Rehabilitation Act.

In OFCCP v. E. E. Black Ltd. (17), a carpenter’s

apprentice was required to submit to a preemployment medical examination which revealed

*41 C.F.R. $60-741.6 (c)(2) ( 1980).

a lower back anomaly known as sacralization of

the transitional vertebra. This is a congenital condition found in 8 to 9 percent of the population.

Although the disabling long-term effects of the

condition are in dispute in the medical profession,

the employer conceded that the condition did not

affect the applicant’s current capability to perform the duties of a carpenter’s apprentice.

Nevertheless, relying on its medical officer’s conclusions, the company determined that the applicant’s spinal formation made him a poor risk for

later development of back problems and denied

him employment. The apprentice filed a complaint with OFCCP, charging the employer with

violating section 503.

The Labor Department found in favor of the

carpenter’s apprentice and ruled that the company’s use of preemployment medical examinations tended to disqualify handicapped applicants

despite their current capability to perform the

job. The Labor Department refused to limit the

definition of “impairment” to permanent disabilities such as blindness or deafness. Instead, impairment was held to be “any condition which

weakens, restricts or otherwise damages an individual’s health or physical or mental activity, ” resulting in “a current bar to employment of one’s

choice with a Federal contractor which the individual is currently capable of performing. ”

On judicial review, the U.S. District Court for

the District of Hawaii agreed with the Labor

Department that the Rehabilitation Act’s coverage was intended to be broad, but it held that the

interpretation in the Assistant Secretary of

Labor’s opinion in Black was overly broad (23). *

The court pointed out that under the Assistant

Secretary’s definition of “handicap”:

. . . a worker who was offered a particular job

by a company at all of its plants but one, but was

denied employment at that plant because of the

*The court granted partial summar~r judgment to the l,ahor De.

partment on two points: 1) the definition of “handicapped indi~’idual ”

contained in the act and regulations is constitutional; and 2] the apprentice ttas a “qualified handicapped indi~idua]” under the act and

regulations. On all other issues, summar~’ ~udgment was denied,

In a subsequent decision, the case u as rertmndd to the Department of Lahor for a decision on whether the emplo~’er met its

hurden for showing a husiness necessity defense and for formukltion of a standard for the determination of husim?ss necrssit~ in

this kind of case (22).
128 . The Role of Genetic Testing in the Prevention of Occupational Disease

presence of plant matter to which the employee

was allergic, would be covered by the Act. An

individual with acrophobia who was offered 10

deputy assistant accountant jobs with a particular company, but was disqualified from one job

because it was on the 37th floor, would be

covered by the Act. An individual with some type

of hearing sensitivity who was denied employment at a location with very loud noise, but was

offered positions at other locations, would be

covered by the Act (p. 1099).

According to the court, the Assistant Secretary’s

definition ignored critical language in the act that

restricts its coverage to handicapped individuals

who are “substantially limited” in pursuit of a major life activity. Thus, the court held that not every

physical condition that limited employment was

covered by the act; to be protected, an individual

must have been rejected for a position for which

he or she was qualified because of an impairment

or perceived impairment that constitutes, for the

individual, a substantial handicap to employment.

The court discussed several factors to be considered in determining whether an impairment substantially limits employability, including the number and types of jobs from which the individual

is disqualified, the location or accessibility of similar opportunities, and the individual’s own job expectations and training. With respect to the number and type of jobs from which the individual

might be disqualified, the court stated that it must

be assumed that all similar employers would use

the same preemployment examination.

Based on this definition, the court still concluded that the applicant was subject to the protections of the act. First, the applicant’s back condition was found to be an impairment or, at least,

was regarded as such by the employer. Second,

the impairment was found to constitute a substantial handicap to employment because the applicant would have been disqualified from all or substantially all apprenticeship programs in carpentry. Third, the court rejected the employer’s contention that Congress did not intend to protect

job applicants who have been denied employment

based on risk of future injury,

In the context of genetic screening, it may not

be that important whether a slight genetic differentiation is in fact a handicap so long as it is

perceived to be a handicap by the employer. Both

section 503 and section 504 include within the

definition of handicap an individual who is “regarded” as having an impairment. Further, on the

basis of the Black case, a person with a particular

genetic trait that is viewed as making him or her

susceptible to disease might be found to be handicapped by a court, One factor that the court did

not consider in Black and that is especially relevant for genetic screening is the consequences of

labeling a person with a congenital or genetic

anomaly as handicapped, especially since those

factors could be handicaps only in certain environments. The adverse psychological impacts of

such labeling could outweigh the benefits conferred by the protection of the act.

Most of the cases concerning the definition of

a handicapped individual have been tried in State

courts under analogous handicapped discrimination laws. The results have varied widely, and it

would be difficult to assess whether a given State

would be likely to consider genetic differential

in itself as a handicap. Nearly all of the reported

cases have been decided under the laws of Wisconsin, New York, Washington, and Oregon (40).

The Wisconsin and Washington cases have defined the term handicap very broadly, Other State

courts, however, have refused to read the statute

so broadly, often on the grounds that the legislatures had not intended them to be universal antidiscrimination laws (40).

In New Jersey, a 1981 amendment to the State

employment discrimination law * specifically prohibits employment discrimination based on an individual’s “atypical hereditary cellular or blood

trait. ” This is defined to include sickle cell trait,

hemoglobin C trait, thalessemia trait, Tay-Sachs

trait, or cystic fibrosis trait. Thus, New Jersey has

become the first jurisdiction expressly to proscribe discriminatory use of some types of genetic screening in the workplace. Florida, North

Carolina, and Louisiana prohibit discrimination

in employment based on sickle cell trait.

JOB RELATEDNESS OF SCREENING

AND MONITORING

Determining that an individual is covered by the

act is only the beginning step in analyzing the

legality of genetic testing, The Rehabilitation Act

● 1981 N.J. Sess. Law Serv. 535, 538 (West).
.

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 129

protects otherwise qualified handicapped individuals. It still must be decided whether the person

is otherwise qualified; if not, the employer would

not violate the act by refusing him or her

employment.

Pursuant to the regulations under the act, a

qualified handicapped person is one who can perform the essential functions of the job with

reasonable accommodation to his or her handicap. * The regulations under section 503 permit

mental or physical screens to the extent they are

job related and are consistent with business

necessity and the safe performance of the job. * *

The regulations under section 504 permit such

screens only to the extent they are job related.** *

Thus, the questions become whether genetic

screening is job related or consistent with business necessity and safety and, if so, whether genetic susceptibility can be reasonably accommodated. This section addresses the first question

and the next addresses the second.

The Labor Department’s decision in Black conceded that employers could exclude handicapped

individuals from jobs on the basis of legitimate

job requirements, but it held that only an individual’s current capability to perform could be

the subject of inquiry in preemployment medical

examinations. The district court termed this interpretation “clearly contrary to law. ” The court

posed the situation where, if a particular person

were given a job, he or she would have a 90 percent chance of suffering a heart attack within 1

month:

A job requirement that screened out such an

individual would be consistent both with business necessity and the safe performance of the

job. Yet, it could be argued that the individual

had a current capacity to perform the job, and

thus was a qualified handicapped individual. * * * *

However, the court did not formulate its own

legal standard for the circumstances under which

possible future injury can be the basis of denying employment.

*41 C.F.R. $60-741.2 (19811; 45 C. F’.R. $84.4 (k)

● *41 C.F.R. j60-741.6[c) (1981).

● ” *45 C.F.R. $84.13(a) (1981).

“•” ● F Supp. at 1104

In Black, the court based its determination on

its reading of the OFCCP regulation that permitted

screens that were consistent with business necessity and safe performance of the job. The comparable regulation under section 504, however,

refers only to job relatedness. Thus, a discrimination case based on genetic screening brought

under 504 could have a different outcome, depending on how job relatedness is defined. If a

court were to define it literally, risk of future illness would not appear to be related to job performance. However, if the court were to define

it only in a general sense –for example, the Griggs

case used it as being synonymous with business

necessity—then risk of future illness might properly bar someone from employment. Whether the

court would look only to the person’s current capability to perform the job or would accept a business necessity defense based on the need for job

safety is an unresolved question.

The basic principle that a job requirement that

screens out qualified handicapped individuals on

the basis of possible future injury may be lawful

is in agreement with cases decided under State

handicapped discrimination laws. However, it is

also clear that the burden is on the employer to

justify the denial of employment, regardless of

whether the problem is viewed as whether the

employee is otherwise qualified or whether the

employer has made out a business necessity

defense.

An employer seeking to justify using a screening procedure that adversely affects handicapped

individuals has a difficult burden of proof. As

discussed earlier, in Albemarle Paper Co. v.

Moody, * the Supreme Court cited with approval

EEOC’s Uniform Guidelines on Employee Selection Procedures * * and held that “discriminatory

tests are impermissible unless shown, by professionally acceptable methods, to be ‘predictive of

or significantly correlated with important elements of work behavior which comprise or are

relevant to the job or jobs for which candidates

are being evaluated. ’ “* * * For example, in Black

it was necessary for the employer to prove that:

an important part of the job required the lifting

1981)

*4z2 L1.s, 405 (1975).

* *29 C.F.R. Part 1607 (1980).

* * *42z [1,S, at 432, [luoting 29 C, F’,R. $ 160i’.4(~]
130 ● The Role of Genetic Testing in the Prevention of Occupational Disease

of heavy objects, individuals with back problems

would not be able to perform the job, and the Xrays of the apprentice’s back had a high predictive value in determining the likelihood that the

individual would suffer from back problems. A

similar analysis would apply to genetic screening.

The relationship between job requirements and

future risk of injury has been addressed in State

handicapped discrimination cases. In a Wisconsin case (18), the employer excluded an epileptic

welder based on evidence that 10 to 30 percent

of epileptics under medication still will have

seizures. The Wisconsin Supreme Court termed

this degree of future risk “a mere possibility” and

held that the employer’s action was illegal. The

court stated that in order to justify an exclusionary practice the employer must show that there

is a “reasonable probability” that the characteristics of the employee will result in future hazards

to the employee or coworkers. No statistical criteria have ever been established for defining “reasonable probability, ” but the employer’s burden

would appear to be quite difficult to satisfy.

Similarly, in an Oregon case (33), an applicant

for the job of heavy appliance salesperson was

rejected on the advice of the company physician

because he had suffered a subendocardial infarction 6 years earlier and had subsequently complained of sporadic angina. The Supreme Court

of Oregon upheld the Bureau of Labor’s ruling

that the disqualification was unjustified because

the employer failed to show a “high probability”

of future risk of heart attack.

In a California case (64), the employer had discharged a truck driver with a congenital, but not

disabling, back condition. The court held that a

mere possibility that the employee might endanger his health sometime in the future was inadequate justification for the employer’s action.

When there is a strong likelihood that a preexisting condition will be aggravated by exposure

in the workplace, an employer’s exclusionary

practice is likely to be upheld, Thus, in a New

York case (71), the court upheld an employer’s

refusal to hire an applicant who was suffering

from dermatitis, where the company physician

concluded that exposure to the chemical elements

in the plant would so exacerbate the dermatitis

as to render the applicant unable to perform his

duties.

Moreover, employee exclusionary practices are

much more likely to be upheld where the employee’s health risk could endanger the health or

safety of others (40). This has been especially true

in cases involving common carriers, such as buses

(68).

REASONABLE ACCOMMODATION

Even if an employer can prove that the screening procedure used is job related and highly

predictive, the employer still may not be permitted to discharge or refuse to hire the individual

if “reasonable accommodation” is possible. Although neither section 503 nor section 504 mentions a duty to accommodate, the regulations

under both sections require reasonable accommodations unless it would impose an undue hardship. According to the section 503 regulations,

“reasonable accommodation” may include making facilities accessible, job restructuring, parttime or modified work schedules, acquisition or

modification of equipment or devices, and similar

actions. It is likely, however, that reasonable accommodation to individuals with proven susceptibility to occupational health hazards would be focused on practices such as shift rotation, dividing

maximum exposure time, more frequent monitoring and medical surveillance, and the added use

of personal protection equipment. It is doubtful

that an employer will be required to reduce exposure levels beneath OSHA PELs to accommodate a susceptible handicapped employee. Most

State fair employment practice laws do not require reasonable accommodation (40).
Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace ● 131

Collective bargaining

employment practices

Protected activities of employees

The National Labor Relations Act (NLRA)*

grants employees the right to organize into unions

and to negotiate with their employer over wages,

hours, and conditions of employment. The agreements that result from these negotiations, known

as collective bargaining agreements, can create

rights and duties between the parties that go

beyond those otherwise required by law. Safety

and health matters are considered to be conditions of employment and subject to collective

bargaining (44).

Although numerous exceptions abound, safety and health concerns traditionally have not been

looked on with a sense of urgency by either employers (19) or rank-and-file employees (26).**

Moreover, in times of high unemployment and

economic recession it may be assumed that employees would give the highest priority to wages,

hours, and job security.

A union is under no duty to bargain for specific

safety and health provisions. In fact, as long as

it acts in good faith, it is not prohibited from making contracts that might have an unfavorable effect on some employees (24). The decision of

whether or how best to protect susceptible employees is a policy decision based on various factors, such as the number of employees involved,

the nature of the risk, the predictiveness of

screening procedures, and the relative strength

of the union’s bargaining position. A union might

be willing to use economic weapons or forego ecoagreements and

● 29 [1. S.(; . $ j 151-168 (1976).

“ ‘The study found that “a little more safety and health” was well

behind other job improvements, such as increased retirement

benefits, more medical insurance, more paid vacations, shorter

workweek, greater chance for promotion, and greater job security, as emplo~rment conditions for which workers woLIld be willing

to forego a 10 percent pay raise (26).

nomic gains to obtain a provision prohibiting the

employer from using genetic screening on the

assumption that some qualified applicants or

members otherwise will be excluded. On the

other hand, a union might bargain to require the

employer to use cytogenetic monitoring on the

assumption that these techniques may show dangerously high levels of exposure to certain chemicals. The union could then bargain for lower exposure levels or other methods of worker protection.

Employee access to safety

and health information

Union efforts at negotiating on safety and health

matters are often complicated by an inability to

obtain detailed information about conditions in

the workplace. Unions frequently have requested,

but have been denied access to, employee medical

records and the identities, properties, and health

hazards of various chemicals used in the workplace (49). Employers often object to the release

of this information, asserting a proprietary interest, undue burden, physician-patient privilege,

employee confidentiality, or trade secrecy.

In Minnesota Mining and Manufacturing Co. *

and two companion cases (12,20), the National Labor Relations Board (NLRB) held that unions have

a right to obtain individual employee medical

records, the generic names of all substances used

in the workplace, and other safety and health

data. In the Minnesota case, NLRB said, “Few matters can be of greater legitimate concern to individuals in the workplace, and thus to the bargaining agent representing them, than exposure to

conditions potentially threatening their health,

*261 N. L.R,B. NO. 2 [1982)
132 . The Role of Genetic Testing in the Prevention of Occupational Disease

well-being, or their very lives.” NLRB rejected the

employer’s claim of proprietary interest as irrelevant and claim of undue burden as unsubstantiated. With respect to physician-patient privilege

and confidentiality, NLRB noted that the union

did not request the names of individual employees

and that confidentiality would be safeguarded by

having physicians interpret and analyze the documents. Moreover, NLRB held that even where

supplying the union with statistical or aggregate

medical data may result in identification of some

individual employees, the important need for the

data outweighs any minimal intrusion on employee privacy. Finally, as to trade secrets, * NLRB

ordered the parties to bargain about conditions

of disclosure, but, if necessary, the board would

strike the balance between the competing claims

of the parties,

Provisions in collective

bargaining agreements

Safety and health provisions have been included

in collective bargaining agreements for many

years, but the passage of the OSH Act in 1970

served to promote greater awareness of workplace hazards and increase the importance attached to safety and health in union contracts (25).

Some commentators believe that the collective

bargaining process offers great hope in fostering

the improvement of workplace safety and health

(5). However, it should be noted that only about

20 percent of all workers belong to unions.

Numerous safety and health matters can be

negotiated, ranging from medical removal protection and rate retention to the formation of joint

labor-management safety and health committees.

According to one study (16), 82 percent of the contracts in the sample** contained occupational

safety and health clauses. The subjects most often

covered were safety equipment, first aid, medical

examinations, accident investigation, employee

obligations, hazardous work, and safety committees.

● A trade secret is a formula, pattern, device, or compilation of

information that is used in one’s business and that provides an opportunity to obtain an advantage over competitors who do not know

or use it.

● *The sample contained 400 collective bargaining agreements

from a cross-section of industries,

Medical examinations are required in 30 percent of all manufacturing and 28 percent of all

nonmanufacturing contracts. Petroleum (86 percent), mining (75 percent), transportation (72 percent), rubber (67 percent), and stone+ lay-glass (54

percent) are the industries where these provisions

are most often found. Of the collective bargaining agreements in all industries containing provisions for medical examinations, 29 percent require physical exams for newly hired workers,

34 percent require physical exams when employees are rehired or return to work from layoff or

leave, and 74 percent require physical exams periodically or at management’s request. In 40 percent of these provisions, employees may appeal

an unfavorable medical opinion (16).

As a matter of widespread practice, applicants

and new employees have limited rights under

most collective bargaining agreements. For example, the great majority of contracts allow the

employer to place new employees on probation

for periods ranging from 1 to 4 months. During

this period, the new employees cannot join the

union and they can be fired without union involvement. This practice would hamper negotiations for restrictions on preemployment genetic

screening. However, unions could legally negotiate on this point because applicants are considered employees under NLRA and thus subject

to its benefits (52). Under the act, therefore,

unions would have broad authority to negotiate

with employers on whether genetic screening

could be used and, if so, under what conditions.

Union’s duty of fair representation

Although unions have authority to negotiate on

genetic testing, are they legally required to do so?

It is well settled that a union has a duty, both in

its bargaining and its contract enforcement, to

serve the interests of all of its members without

discrimination toward any, This is known as the

duty of fair representation. A breach of this duty will not be established by simple negligence,

but requires a showing that the union acted arbitrarily, perfunctorily, or in bad faith (69).

With respect to genetic screening, two questions arise. First, does the duty of fair representation extend to employees who are found to
—

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace 133

be susceptible to occupational illness on the basis

of their genetic constitution? It is clear that, as

employees, they are entitled to fair representation. Second, does a union’s duty of fair representation extend to job applicants who are refused

employment on the basis of genetic screening?

The answer to this question is less clear. Applicants are considered “employees” under NLRA

(52), and the union would probably have a duty

to enforce an existing agreement containing a provision dealing with preemployment genetic

screening. However, it is unlikely that the union

would have a duty to negotiate a contract with

such a provision (29).

Contract enforcement and arbitration

Most collective bargaining agreements contain

an express provision for resolving contract disputes through an internal grievance procedure.

If a dispute remains unresolved, however, almost

all contracts provide that it will be submitted to

an arbitrator voluntarily selected by the parties

to the contract.

Since each arbitration decision is based on the

specific contract involved, the way arbitrators

construe medical examination provisions cannot

be generalized. Nevertheless, in cases involving

discharge or denial of reinstatement to employees with physical disabilities, dismissal will usually

be held to be inappropriate unless the evidence

indicates that the employee’s disability prevents

him or her from performing a job or exposes the

employee or other employees to a serious risk of

physical harm or injury (74). Even in cases where

continued exposure may be injurious to the worker, arbitrators have been willing to allow employees to decide whether to continue work to

as long as they are able to and create no risks to

others.

Conclusion .—. —..

Genetic testing raises legal questions related to

workplace safety and employee rights. The common law, State workers’ compensation statutes,

and the OSH Act outline the rights and duties of

employers and employees with respect to safety. Title VII of the Civil Rights Act of 1964, the

Rehabilitation Act of 1973, and State fair employment practice laws govern rights and duties with

respect to hiring, firing, and conditions of employment. Although these statutes and the court cases

interpreting them by and large have not dealt

with genetic testing, they provide legal principles

that are directly applicable to the issues raised

by this technology. The principles can provide

guidance and some answers to the questions at

hand; however, many important questions remain

unresolved. In such a situation, the collective

bargaining agreements authorized by NLRA could

provide a means for employers and unions to

negotiate mutually agreeable solutions to the

problems raised by genetic testing.

With respect to safety in general, it is clear that

the common law and the OSH Act place the responsibility for workplace safety on the employer.

Failure to meet the responsibility can result in

workers’ compensation payments, damages assessed against the employer for tort liability, or

civil or criminal penalties against the employer.

This responsibility would not require the employer to use genetic testing, even if it were highly

predictive of future illness. If the employer chose

to use a highly predictive test, it would likely be

negligent if it ignored the results of screening and

placed the employee in a high-risk rather than

a low-risk environment. However, recovery of

damages by such an employee who developed the

predicted illness would probably be barred by the

“exclusive remedy” provision of workers compensation laws and possibly by the doctrine of assumption of the risk, if the employee had been

informed of the risk. If the risk had been concealed from the employee, recovery would probably not be barred under workers’ compensation

laws, and the employer would face the possibility of punitive damages.

Under the OSH Act, the Secretary of Labor is

empowered to promulgate standards that protect
134 ● The Role of Genetic Testing in the Prevention of Occupational Disease

all employees from toxic substances to the extent

that the standards are directed toward a significant risk of material health impairment and to

the extent that they are technologically and economically feasible. These standards can, among

other things, set maximum exposure levels, require personal protection gear, and mandate various medical procedures. The feasibility requirement may leave some percentage of exposed

workers at risk, depending on the circumstances

of the particular hazardous substance and industry. Of those workers at risk, some maybe genetically susceptible and others may be at increased

risk because of genetic damage. An open question is whether the courts would allow a standard

designed to protect a very small number of susceptible individuals or would invalidate it on the

grounds that it failed to address a significant risk

because of the small number of workers involved.

The OSH Act and regulations thereunder neither prohibit nor require genetic testing. However, the Secretary of Labor has broad authority to regulate employer medical procedures as

long as the regulation is related to worker health

and meets the feasibility and significant risk requirements. Therefore, the Secretary could require genetic testing in its various forms, if the

techniques were shown to be reliable and reasonably predictive of future illness. The Secretary

also could regulate the use of genetic testing, but

only to the extent that the regulation was related

to employee health. The act grants no authority

over rights or conditions of employment per se

and no authority to protect applicants for employment from discrimination.

State and Federal law places few restrictions

on either the way medical exams or testing procedures must be conducted in the workplace or

what the employer does with the resulting information other than the requirements that the procedure not be negligently performed and that the

employee be informed of potentially serious

health risks. Participation in medical exams or

medical research can be a valid condition of employment. As a result, employees or applicants

would have no right to refuse to participate without jeopardizing their job. How much the employee needs to be told about the research is unclear, except in two cases. If the research were

federally funded, subjects must understand the

risks and other aspects of the study and consent

to them. A few States have statutes that require

Institutional Review Boards in order to protect

research subjects, and these boards may require

informed consent.

With respect to the data generated by genetic

testing, there are few requirements regarding

confidentiality except in the State of California.

But employees have a right of access to medical

records under OSHA regulations and unions have

a similar right under a recent decision by NLRB.

This access could help prevent abuse of genetic

testing. However, those who face the greatest risk

of being denied employment because of their genetic makeup—job applicants-would not have access to the test results.

For those applicants or employees who were

subject to some adverse job action because of

their genetic makeup, Federal and State antidiscrimination statutes may offer some relief,

depending on the circumstances of the case. A

few States prohibit employment discrimination

based on certain genetic traits, usually sickle cell

trait, To the extent that genetic screening has a

disparate effect on the employment opportunities

of one of the protected classes under title VII, an

adversely affected genetically susceptible employee in one of those classes would have a prima facie

case of discrimination against the employer. The

employer would then have to carry the heavy

burden of justifying the screening program on

the basis of job relatedness or business necessity.

It is presently unclear whether avoiding tort liability or the cost of engineering controls is a business

necessity or whether the employee’s capacity to

perform the job without a risk of future illness

is a job-related characteristic. However, it is clear

that any job selection method must be predictive

of the characteristic for which it allegedly selects.

Since genetic screening has not been shown to

be predictive of future occupational illness, a program that had a disparate impact on the employment opportunities of the classes protected by

title VII probably would violate that act.

The Rehabilitation Act and similar State laws

offer greater potential than title VII for aiding the

employment opportunities of genetically suscep-
— .

Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace 135

tible individuals; however, for those laws to be

applicable, two currently unresolved legal questions must be settled in favor of the employees.

The first is whether or not genetic makeup is a

handicap. If not, these employees would have no

rights under these laws. If it is a handicap, the

next question is whether a reasonable probability of future illness would be a valid job-related

requirement or something going to the necessity of the business. Some State courts have ruled

that employment may be denied to handicapped

individuals on the basis of a reasonable probability of future illness. If the courts were to rule that

future risk of illness was not a legitimate area of

inquiry for employers, the Rehabilitation Act and

similar statutes would prohibit adverse job actions

on the basis of genetic makeup. If risk of illness

were recognized as a legitimate concern, the employer would have the burden of showing that

the genetic screening techniques were reasonably

predictive of illness. Even if the employer demChapter 8 references

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11,

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Hygienists, Threshold Limit Values, 1980.

Annot., A. L. R.3d, vol. 10 (1966), p. 1071.

Armstrong v. Index Journal Co., 647 F.2d 441 (4th

Cir. 1981).

Austin v. Johns-Manville Sales Corp., 508 F. Supp.

313 (D. Maine 1981).

Bacow, L,, Bargaining for Job SafettiV and Health

(Cambridge, Nlass.: MIT Press, 1980).

Baker v. California Land Title CO., 349 F. Supp. 235,

238 (D. C., Cal. 1972).

Baron F., Handling Occupational Disease Cases, p.

3, 1981.

Beadlingv. Sirotta, 41 N.J. 555, 197 A.2d 857 (1964)

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Betesh v. United States, 400 F. Supp. 238 (D.D.C.

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Beuder, E., Hemolytic Anemia in Disorders of Red

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Blankenship i. Cincinnati hlilacron Chemicals, Inc.,

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12. Borden Chemical, 261 N. L.R.B. No. 6 (1982).

13. Borel v. Fibreboard Paper Prods. Corp., 493 F.2d

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anyway. Such accommodation probably would

not require the installation of expensive engineering controls. In addition to these unresolved questions, a limitation on the Rehabilitation Act from

the plaintiff’s perspective is that plaintiffs must

pursue their remedies under section 503 through

OFCCP rather than suing employers directly.

Virtually all of these questions could be subjects

of bargaining between employers and unions.

Thus, individual employers and unions could decide for themselves whether the employer could

use genetic testing, the circumstances under

which it could, and the use that could be made

of the results. Unions, however, would have no

legal duty to bargain over such issues or to take

special steps to protect workers who were genetically predisposed to occupational disease.

14

15

16

17

18.

19.

20.

21

22

23

1076, 1096-1100 (5th Cir. 1973), cert. denied, 419

U.S. 869 (1974) (defense available in products ]ia -

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Brown v. scullin Steel Co., 364 Mo. 225, 260 S.W.2d

513 (1953).

Bureau of National Affairs, 11 Occup. Safety &

Health Rep., No. 7, July 16, 1981, p. 131.

Bureau of National Affairs, Basic Patterns in Union

Contracts, 9th cd., 1979, pp. 107-I11.

Bureau of National Affairs, 19 Fair Empl. Prac. Cas.

1624, 25 Empl. Prac. Dec. (CCH) f 30,260, U.S. Department of Labor, 1979.

Chicago, M., St. P. & Pac. R.R. v. ILHR Dept., 62

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Cohen, “The Occupational Safety and Health Act:

A Labor Lawyer’s Overview, ” Ohio St. L. J., vol.

33, 1972, pp. 788, 789.

Colgate-Palmolive Co., 261 N. L.R.B. No. 7 (1982).

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64 C)hio App. Zd 159, 411 N.E.2d 814 (1978).

E. E. Black, Ltd. v. Donovan, 27 Empl. Prac. Dec.

(CCH) fl 32,199, Aug. 5, 1981.

E, E. Black, Ltd. v. Marshall, 497 F. Supp. 1088,

1099 (I). Hawaii 1980).
136 . The Role of Genetic Testing in the Prevention of Occupational Disease

24,

25.

26,

27.

28.

29.

30.

31.

32.

33.

34

35

36

37.

38.

39.

40

41

42

43.

44.

45.

46.

47.

Ford A40tor Co. v. Huffman, 345 U.S. 330 (1953).

Freedman, A., Industry Response to Health Risk,

1981, Pp. 46-50.

Frenkel, Priest, and Ashford, “Occupational Safety and Health: A Report on Worker Perception, ”

Monthly Lab. Rev., vol. 103, No. 9, September 1980,

pp. 11, 12.

Fried, “The Legal Context of Medical Experimentation, ” in Medical Experimentation: Personal Integrity and Social Pofzcy (New York: Elsevier NorthHolland, Inc., 1974).

Garguil v. Tompkins, 525 F. Supp. 795 (N.D. N.Y.

1981).

German, R., Labor Law-Basic Text, 1976, p. 698.

Grantham v. Denke, 359 So.2d 785, (Ala. 1978).

Halenar v. Superior Court, 109 Ariz. 27, 504 P.2d

928 (1972).

Harvard Law Review, Note, Compensating Victims

of Occupational Disease, Harv. L. Rev., vol. 93,

1980, p. 916.

In re Montgomery Ward& Co., 280 Or. 163, 570

P.2d 76 (1977).

In re Johns-Manville Asbestos Cases, 511 F. Supp.

1229 (N.D. Ill. 1981).

Jacobsen v. S.E. Distributors, Inc., 413 So.2d 995

(La. Ct. App. 1982).

James v. United States, 483 F. Supp. 581 (N.D. Cal.

1980).

Johns -Manville Prods. Corp. v. Contra Costa Super.

Court, 27 Cal. 3d 465, 612 P.2d 948, 165 Cal. Rptr.

858 (1980).

Lead Indus. Assln, Inc. v. Donovan, 101 S. Ct. 3148

(1981).

Lotspeich v. Chance Vought Aircraft, 369 S.W.2d

705 (Tex. Civ. App. 1963).

McGarity and Schroeder, “Risk-Oriented Employment Screening, ” Tex. L. Rev., vol. 59, 1981, pp.

999, 1073.

Miller v. National Cabinet Co., 8 N.Y.2d 277, 168

N.E.2d 811, 204 N. Y.S.2d 129 (1960).

Monteiro v. Poole Silver Co., 615 F.2d 4 (lst Cir.

1980).

Munoz v, International Alliance of Theatrical Stage

Employees, 563 F,2d 205 (5th Cir. 1977).

NLRB v. Gulf Power Co., 384 F.2d 822 (5th Cir.

1967).

National Occupational Hazards Survey, vol. 3, table

WIIA (Summary of NOHS Estimates), 1977, p. 30.

National Realty & Construction Co. v. Occupational

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1257 (D.C. Cir. 1973).

New York Times, “Uncertainty in the Figures,” Feb.

13, 1977, sec. 4, p. 8, CO1. 1, cited in Wolff, “Protecting the Disabled Minority: Rights and Remedies

Under Sections 503 and 504 of the Rehabilitation

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25, 30.

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1235 (3d Cir. 1978).

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50. OSHA Instruction STD 1-23.4, Aug. 22, 1980.

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654 F.2d 1130 (5th Cir. 1981), cert. denied, 102 S.

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52. Phelps Dodge Corp. v. NLRB, 313 U.S. 177 (1941).

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526-530.

54. Quaries v. Sutherland, 389 S.W.2d 249 (Ten, 1965).

55. Reinhart, “Federal Protection of Employment Rec56

57.

58

59.

60

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

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Ch. 8—Legal Issues Raised by Genetic Testing in the Workplace . 137

72, Williams v. E. 1, du Pent de Nernours & Co,, 112 74. Wolkinson, “Arbitration and the Employment

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and aggravated his ulcer).

73. Wojcik v. Aluminum Co. of Amer., 18 Misc. 2d 790,

183 N. Y.S.2d 351 (1959) (tuberculosis).
Chapter 9

Application of Ethical Principles

to Genetic Testing
—

Ethical Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. ”..

Autonomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Nonmaleficence and Beneficence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........

Justice . . . . . . . . . . . . . . . .. ... .. ..... . . . . . . . . . . . . . . . .. ... ..

Applications to Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Routine Use of Tests of Doubtful Clinical Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... .. ..

Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Medical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

High Correlation Between Genetic Endpoints and Risk of Disease . . . . . . . . . . . . . . . . .

Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . .

Genetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Special Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ... ... ..... . . . .

Chapter preferences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 9

Application of Ethical Principles

to Genetic Testing

The use of genetic testing in the workplace

touches on areas of basic concern to most people: opportunity for employment, job security,

health, self-esteem, and privacy. Genetic screening may enable workers to have greater control

over their health by providing medical information on which to base job site selection and use

of personal protection devices. It could be used

by management to better match employees to

their jobs or to reduce levels of exposure to hazardous substances. It also could be used to exclude or transfer people from jobs and conceivably could result in classes of people being stigmatized. While genetic monitoring might permit

employees or management to take preventive

health measures, it may simply create unjustified

fears of nonexistent hazards. Moreover, both

techniques result in the collection of information

of an extremely personal nature. Thus, the technology has both risks and benefits, depending on

how it is used.

Because genetic testing procedures are relatively new and have not been widely used, there is

little direct experience on which to make judgments regarding their use. Nor are there direct

legal precedents. Under those circumstances, it

is appropriate for policy makers and others involved in decisions concerning genetic testing to

look to ethical principles for guidance. These principles can assist decisionmakers in ensuring that

the technology is used justly and with the greatest

regard for human values.

Ethics is the study of moral principles governing human action. These principles, or general

prescriptive judgments, create moral duties that

guide action in particular circumstances. Sometimes, however, the principles conflict in their application and provide no clear guidance. Then difficult choices must be made. Such is the case with

genetic testing in the workplace.

This technology raises a number of questions

that can be put in a framework suitable for ethical

analysis:

1.

2.

3.

Do employers, occupational health specialists,

or society in general have any particular

obligations toward workers who may be at

increased risk for disease because of their

genetic constitution or because of exposure

to hazardous substances? If so, what are

they?

Are genetic screening and monitoring for

genetic damage compatible with ethical

principles?

Does the answer to the second question depend on the particular circumstances involved? If so, the following must be examined:

a.

b

c.

d.

e.

What moral rights and duties exist between the worker and company medical

personnel?

Must participation in genetic testing programs be voluntary, and if so, how is that

to be guaranteed?

What rights and obligations exist regarding the use of medical information?

What ethically permissible actions may

be taken on the basis of information gained

through genetic testing programs?

Do the answers to these questions depend

on whether the testing is being done for

research purposes or as part of a medical

program?

To address these questions, it is first necessary

to consider some basic ethical principles. Their

application to the various ethical questions raised

by genetic testing then will be discussed.

141
142 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Ethical principles

Four ethical principles are most relevant to an

assessment of this technology: autonomy, nonmaleficence, beneficence, and justice.

Autonomy

The principle of autonomy has two aspects. The

first relates to the ability of a person to make considered judgments and decisions that lead to acts

that foster self-reliance or independence, In this

sense, autonomy depends on being able to plan

and act deliberately, based on one’s own judgment

about the consequences of certain behaviors and

their value or utility to oneself or others. This

leads to the notion that individuals should be free

to act as they wish, regardless of how foolish their

actions may appear to be and without interference by others, so long as their actions do not

harm others or interfere with their liberty (2). The

second aspect of autonomy derives from the belief

that people should be treated as ends rather than

means, a principle known as respect for persons.

In other words, in evaluating the actions of others,

one should respect them as persons with the same

right to their judgments as one has to his or her

own (2). Thus, the principle of autonomy imposes

the dual moral obligation not to interfere with

the autonomous actions of others and to respect

their personhood and beliefs,

A corollary of the principle of autonomy is the

requirement to secure informed consent from

persons before taking actions that may put them

at risk, The rule of informed consent requires full

disclosure of all important information, comprehension of the information, the ability to choose

freely, and the mental competence to make decisions (7). Thus, the rule serves to protect individual autonomy.

Not everyone is capable of full self-determination. This capacity develops during a person’s life,

and some individuals lose it in whole or part because of illness, mental disability, or circumstances that severely restrict their liberty. For example, children, prisoners, or those who are in

institutional settings may be less capable of

autonomous actions (7).

Autonomy may be compromised in other ways.

These include situations where behavioral options

are limited, where direct or implied coercion is

used toward actions favored by others, or where

circumstances limit the ability to act knowledgeably in one’s own interest.

Workers as a group may be situated in ways

that limit their full expression of autonomy. Preordained rules of behavior, job requirements, limited resources or information, and concern over

job security can limit autonomy. Whether or not

particular limitations are justified will depend on

a determination of the validity of reasons for overriding the principles of autonomy.

Respect for persons gives rise to the obligation

to protect those with diminished autonomy (7).

The extent of protection generally would depend

on the degree to which their autonomy is diminished. Some persons require little protection

beyond ensuring that they undertake activities

voluntarily and with an awareness of possible adverse consequences; others may have to be excluded from activities that harm them.

The principle of autonomy is not absolute.

Where the prospect of severe harm is evident,

some commentators have argued that intervening in order to protect the individual is justified

(3,6). Thus, it maybe justified to intervene where

persons are otherwise competent to exercise autonomous thought and action (as is the case for

the great majority of workers), but who may be

unable to so act because of their ignorance of the

risks or their inability to understand those risks

due to their complex technological nature.

Genetic testing has the potential to be used in

a way that restricts the autonomy of prospective

employees or workers already on the job. For instance, preemployment tests that presumably

identify genetically susceptible individuals may be

used to restrict the type of job an employee is permitted to undertake or to ban the worker from

employment in the industry altogether. Similarly, testing done during employment, which detects early warning indicators of possible future

disease, might be used preemptively to remove
Ch. 9—Application of Ethical Principles to Genetic Testing ● 143

employees from a given station or set of job

duties. Each of these steps, if taken unilaterally

by an employer, could be seen as a restriction of

the autonomy or liberty of the individual worker

to elect a suitable job and/or to accept the attendant risks.

Nonmaleficence and beneficence

Nonmaleficence is the obligation not to harm

others (2). Beneficence is the obligation to help

others further their important and legitimate interests when we can do so at minimal risk to

ourselves (2). In practice, it is difficult to separate

the two principles, because avoiding harms and

producing benefits exist along a continuum. However, one philosopher, William Frankena, separated this continuum into the following duties:

1. One ought not to inflict harm.

2. One ought to prevent harm.

3. One ought to remove harm.

4. One ought to do good.

Frankena stated that each of these duties should

take precedence over the next, so that nonmaleficence is the strongest duty, and doing good is

the weakest (5). Beneficence is usually considered

to encompass the second, third, and fourth elements; it is distinguished from nonmaleficence in

that it requires positive steps to help others and

not merely restraint from harming them (2).

In a workplace setting, this priority listing could

correspond to an employer’s duty to: 1) not knowingly subject workers to conditions that are likely to cause injury or ill health, 2) take steps to prevent the likelihood of workers becoming injured

or diseased, 3) remove harmful substances, and

4) take affirmative actions to improve worker

health.

our society generally accepts the proposition,

as reflected in our legal system, that we cannot

legitimately impose an affirmative duty to do

good, but may impose negative injunctions to

avoid harm. However, in certain cases, usually

involving special relationships such as that of

employer- employee or doctor-patient, society imposes a duty to prevent or to remove harm. For

example, the policy embodied in the Occupational

Safety and Health Act of 1970 that all workplaces

be safe and healthy can be interpreted as the legal

imposition on employers of at least a duty to prevent harm and remove potentially harmful

conditions.

Arguments in favor of genetic testing rely on

the principles of beneficence. If the tests are able

to identify individuals or populations at increased

risk, the employer has the duty to prevent harm

by preventing exposure to harmful substances or

to remove the harm by reducing the level of

exposure.

Such action may conflict with the principle of

autonomy, however, where it overrides a person’s

own informed choice. An example would be

where a job was denied to a susceptible person

who was willing to accept the risk. Whether or

not such paternalistic actions are justified depends

on whether one places beneficence above autonomy. Generally, ethicists favor autonomy over

beneficence (2), a choice also widely reflected in

judicial decisions and legislation.

The concept of beneficence embodies the notion of maximizing possible benefits and minimizing possible harms (2). This leads to the requirement for a risk/benefit assessment whenever a

technology is claimed to provide benefits, such

as prevention of illness. As applied to genetic

testing, this would require at a minimum that the

claimed benefits in fact exist, In other words, the

association between one’s genetic makeup and

disease or between damage to one’s chromosomes

or DNA and disease must be scientifically demonstrated.

Justice

Justice is a broad and elusive concept. Different

moral philosophers have explained it in terms of

freedom, fairness, equality, or entitlement. Most

would agree, however, that an injustice occurs

when a benefit to which a person is entitled is

denied without good reason or when a burden

is improperly imposed. A more positive and often

quoted statement of the principle of justice is that

equals should be treated equally, and unequals

should be treated unequally (2), But what does

this tautology really mean? Who is equal and who

is unequal?
144 ● The Role of Genetic Testing in the Prevention of Occupational Disease

A somewhat more useful formulation of the

principle of justice says that individuals who are

equal in relevant respects should be treated equally, and individuals who are unequal in relevant

respects should be treated differently in proportion to the differences (2). The problem then

becomes to determine relevant differences. Most

commentators would allow distinctions based on

ability, experience, need, and merit to justify differential treatment, depending on the circumstances. In addition, the other moral principles

already discussed provide some guidance in determining whether particular differences are relevant (2).

A slightly more restricted notion of justice is

the concept of distributive justice, which refers

to the proper distribution of social benefits and

burdens among different classes of people, There

are several widely accepted formulations of just

ways to distribute benefits and burdens on the

basis of relevant differences. These are: to each

person an equal share; to each person according

to individual need; to each person according to

individual effort; to each person according to

societal contribution; and to each person according to merit. These principles may give conflicting results in particular cases (2).

Thus, it is clear that a precise statement of the

requirements of the principle of justice is best left

to a case-by-case analysis. Its application to genetic

testing will be discussed in the context of the particular ethical issues raised in the following

section.

Applications to genetic testing

Ethical principles can provide some guidance

to policymakers and others who must decide

whether or not genetic testing should be done in

the workplace and, if so, under what circumstances. This section first considers the routine

use of genetic tests for clinical purposes at their

current level of development, where there is low

correlation between the endpoints and risk of

disease. It then considers the use of genetic testing

at its current level of development for purposes

of medical research. Next, because the technology is developing, it considers the issues raised

by the clinical use of these tests, where there is

an assumed high correlation between genetic endpoints and risk of disease. Finally, two particular

problems that arise in all three of these situations

are considered: What should an employee be told

about test results? What are the obligations of the

employer and company medical personnel to

maintain confidentiality of medical data?

Routine use of tests of doubtful

clinical value

GENETIC SCREENING

The use of genetic screening to identify individuals who might be at an increased risk of

disease in a workplace environment could not be

justified by the principle of beneficence where

there was a low correlation between the genetic

endpoints and disease. There would be great

uncertainty over whether or not that individual

would be at increased risk of harm. Thus, it

would be uncertain whether the employer could

prevent harm. At the same time, there would be

some risks to the workers. First, there would be

some physical risks associated with the medical

procedures. Second, there would be risks to the

worker from the use of the information, These

include adverse job actions, loss of self-esteem,

and possible stigmatization from being labeled

“genetically inferior.” Such a label conceivably

could result in the person being barred from certain jobs in an entire industry. In addition, it

would be particularly troublesome if placed on

historically disadvantaged groups because it could

help continue that status. In view of the substantial risks and uncertain benefits, one could not

argue that poorly predictive tests could be used

to prevent harm.

If the person labeled as susceptible were fired

or excluded from a desirable job, such action

would not comport with the principle of justice,

It would be difficult to argue that genetic makeup
Ch. 9—Application of Ethical Principles to Genetic Testing ● 145

was a relevant characteristic for treating one

group of workers differently from another, when

the scientific data at best show only a weak

association between genetic makeup and susceptibility to disease.

GENETIC MONITORING

Under circumstances where there is only a

weak association between cytogenetic or noncytogenetic endpoints and disease, the use of genetic

monitoring in the course of clinical practice would

also raise ethical concerns; however, monitoring

may be somewhat less at variance with accepted

ethical principles than genetic screening. Arguably, there could be a small benefit to an entire

group of people if the tests indicated they might

be at an increased risk of disease. Moreover, the

risks would be minimal; they include the physical

risks of drawing blood and the possibility that

some anxiety about future illness would be created unnecessarily. Presumably, there would be

less of a risk of adverse job actions than for

screening because monitoring cannot identify

individuals who might be at increased risk. Assuming the workers were not subject to job discrimination or other adverse action, there would

not be problems with respect to the principle of

justice.

The strongest ethical argument against such

testing, whether screening or monitoring, would

be based on autonomy. The concept of respect

for persons requires people to be treated as ends,

not means. Using medical procedures of questionable value on people could only be justified

by the voluntary and informed consent of those

subject to the procedure.

Medical research

The use of techniques of low or uncertain clinical value for purposes of research can be ethically justified when certain conditions are met (7).

The underlying purpose would be beneficent; if

the research showed the techniques to be useful

or led to their further development, society would

benefit. Those workers participating in the research also might benefit at some future time. The

risks to them would be similar to those discussed

previously, except that there would presumably

be less of a risk of adverse job actions being taken.

However, there would still be the psychological

risk of a person gaining information about himself

that he might prefer not to know.

Under these circumstances, where participants

in medical research are not likely to benefit directly from the medical interventions, the principle

of autonomy becomes paramount. This principle

usually requires that the subjects enter into the

research voluntarily and with adequate information (7). In practice, this means that the subjects

must give informed consent to the procedures.

The elements of informed consent are disclosure of information, comprehension of information, and voluntariness (7). Competence to consent is sometimes viewed as an element of informed consent and sometimes as a precondition.

In any event, it would not be relevant here because it refers to the mental capacity to make decisions on a rational basis. Workers actually on the

job are presumably competent.

The type of information disclosed usually includes the research procedure, its purpose, the

risks and possible benefits, the fact that the subjects may ask questions, and the fact that they

may withdraw at any time. Generally, the subjects should be told what a “reasonable person”

or perhaps a “reasonable volunteer” would want

to know about the experiment (7).

Information must be presented in a way that

is understandable to potential subjects. Moreover,

the investigators are generally considered to have

an obligation to determine that the information

was understood. (7).

Voluntariness requires conditions free of coercion or undue influence (7). This maybe especially

problematical in an occupational setting where

workers may perceive their job security or potential for promotion to be affected by their willingness to participate in the research.

High correlation between genetic

endpoints and risk of disease

GENETIC SCREENING

In the hypothetical case where particular genetic traits correlated with an increased risk of

disease, genetic screening could be supported by
146 ● The Role of Genetic Testing in the Prevention of Occupational Disease

the principle of beneficence, depending on how

the results were used. Clearly, the data generated

by the tests would identify a potential harm, and

given this information, steps could be taken to

prevent the harm or to remove it. How the information is used then becomes the paramount

question.

One action that the employer could take would

be to bar genetically predisposed workers from

certain jobs, by not hiring them, by placing them

in other jobs when hired, or by transferring them.

This action might be considered beneficent because harm to the employee would be averted.

However, another action, also consistent with

beneficence, would be to lower exposures to the

point where these people would not be at increased risk, Still another action might be to

devise personal protective equipment for them.

The principle of beneficence provides little

guidance in choosing among these alternatives.

The principle of justice provides some guidance.

One way of considering the problem would be

to ask if genetic makeup is a relevant characteristic on which to treat a small part of the work

force differently. One could argue that genetic

makeup is relevant because, in our hypothetical

case, these people are more prone to illness. This

illness would result in additional costs to

themselves, the employer, and society. It maybe

unfair for society or the employer to bear these

costs for the benefit of these few individuals. On

the other hand, these people are not responsible

for their genetic makeup. Therefore, it is arguably

unfair to single them out for special treatment.

In addition, their genetic makeup may be irrelevant because it is not related to their ability to

do the job efficiently and without risk to others.

Another way to address the problem is to ask

who, if anyone, has the obligation to compensate

genetically disadvantaged workers? Three schools

of thought on distributive justice are relevant: the

libertarian school; the utilitarian school; and the

needs-based school,

The libertarian school emphasizes merit and

contribution. Under this theory, a worker or

group is entitled to get back exactly that proportion of the national wealth that he or they created

(4). If genetically disadvantaged workers were not

contributing to the national wealth, even if the

reason was because they had been denied jobs,

they would not be entitled to compensation, according to this school.

The utilitarian school emphasizes consideration

of all of the various principles of distributive

justice with the goal of maximizing public and

private benefits (2). Under this theory, one could

argue that compensation could materially help

these individuals at little cost to society, which

would bear the costs directly through government compensation plans or indirectly, when the

employer passed on the costs in the price of the

product. On the other hand, if the costs of compensation were large and the number of workers

were small or if employers were forced out of

business by having to install extremely expensive

engineering controls, one could argue against

compensation.

The needs-based school emphasizes fundamental needs; that is, something without which a person will be harmed or at least detrimentally affected. If genetically disadvantaged workers faced

at least moderate difficulty in finding any job or

a job at an adequate wage level, this theory would

require compensation.

The principle of autonomy is also important in

this hypothetical situation. Respect for persons

would probably require that genetically susceptible workers be informed of their condition. At

the same time, autonomy would appear to require

that such workers be given the right voluntarily

to assume the risk, if given adequate information

in a comprehensible way. In situations of conflict

between autonomy and beneficence, most ethicists generally favor choosing autonomy. Thus,

paternalistic behavior on the part of the employer

to exclude the employee for the latter’s benefit

but without his consent generally would be

viewed as unethical, However, society sometimes

accepts paternalistic actions when they benefit

affected groups, such as compulsory vaccination

or fluoridation of the water. If genetically susceptible workers were given alternative jobs at equivalent pay and benefits, the paternalistic behavior

of excluding them from certain jobs probably

would be ethical.
Ch 9—Application of Ethical Principles to Genetic Testing . 147

GENETIC MONITORING

If there were a high correlation between cytogenetic or noncytogenetic endpoints and risk of

disease, genetic monitoring could be justified by

the principle of beneficence. The reasons would

be essentially the same as those discussed for

screening.

The actions that an employer may take on the

results of monitoring are somewhat different,

however. Unless the monitoring tests were so predictive that high-risk individuals could be identified, a situation that would be the same as

screening, monitoring would only identify a highrisk group already on the job. The most likely

courses of action open to the employer would be

to do nothing, to lower exposure levels, or perhaps to take some intermediate action such as providing personal protection devices,

Doing nothing to alleviate a known risk would

be unethical. Since the employer actually created

the risk, inaction would amount to inflicting harm.

Moreover, autonomy would appear to require informing the workers of their increased risk, arising from being members of the group.

Lowering exposure levels or providing protection devices would be consistent with the principle of justice. No discrimination would be involved, and employees would not unfairly bear

the burden of the actions.

Special problems

Two problems deserve special attention because

they arise regardless of the predictiveness of the

various tests: What information should be given

to workers about testing procedures and the results? Who besides the employees should have access to medical data and under what circumstances?

The principle of autonomy implies a duty to

provide employees with information about their

health, even where the significance of the information might be uncertain. This duty would be

even stronger when the information was highly

predictive of a risk of disease.

Autonomy would also appear to require that

workers be fully informed of the nature of medical procedures to which they are subjected.

While the concept of informed consent would be

most crucial in a medical research situation, it is

also applicable to clinical interventions. In the latter case, even though the procedures are clearly

beneficent, their application to the worker

without his informed consent is a paternalistic

action,

Once medical data have been collected, the issue

of who has access to the data arises. As a general

rule, medical data are considered confidential on

the grounds that respect for a person’s autonomy

requires respect for his or her privacy. The

stringency of this rule, however, is a matter of

much debate, particularly in the work environment where the employer is viewed as having

some rights to that information. The Code of

Ethical Conduct for Physicians Providing Occupational Medical Services states that employers are

entitled to be informed of the medical fitness of

individuals for work but are not entitled to

diagnoses or details of a specific nature (I). One

potential consequence, however, might be that

workers determined to be genetically unfit could

be stigmatized and have difficulty finding other

employment for similar jobs.

Conclusions .

Genetic screening and monitoring are not in- omy, nonmaleficence, beneficence, and justice.

herently unethical. The tests are morally justified Whether or not they are consistent with these

to the extent they enhance worker health in a principles will depend on how the tests are done

manner consistent with the principles of auton- and how the information is used.
148 . The Role of Genetic Testing in the Prevention of Occupation/ Disease

Ethicists generally agree that autonomy requires that no medical procedure, especially those

of unestablished clinical validity, be done on a person without his informed consent. This principle

would also require that the person be told the

results and what they mean and that medical data

be held confidential.

Ethical principles constrain how the results of

genetic testing may be used. With a low correlation between genetic endpoints and disease, it

would be unethical for the employer to act adversely to the employee’s interests, such as by

denying him or her a job. In the hypothetical case

of a high correlation between genetic endpoints

Chapter 9 references

1. American Occupational Medical Association, ‘(Code

of Ethical Conduct for Physicians Providing Occupational Medical Services,” 1 of Occupational Medicine, vol. 18, August 1976.

2. Beauchamp, T., and Childress, J., Principles of Bioznedica] Etk”cs (New York: Oxford University Press,

1979).

3. Dworkin, Charles., “Paternalism,” The Monist, January 1972.

4. Feinberg, J., social Philosophy (Englewood Cliffs,

N. J.: Prentice-Hall, Inc., 1973), p. 114.

and disease, the morally correct course of action

is significantly less clear. An employer may be

justified in allowing a susceptible person to assume the risks on the basis of informed consent.

On the other hand, the most ethically feasible

course of action for an employer once genetic

monitoring identifies a group at increased risk

would be to inform the workers and to reduce

workplace exposure. Failure to do so would be

inflicting harm, and it is unlikely that the group

would consent to assuming this risk. Finally,

whether or not genetically susceptible people are

entitled to compensation depends on which theory of distributive justice is chosen.

5. Frankena, William, Ethics, 2d ed. (Englewood Cliffs,

N.J.: Prentice-Hall, Inc., 1973), p. 47.

6. Gert, B., and Culver, C., “Paternalistic Behavior,”

Philosophy and Public Affairs 6, fall 1976, pp. 45-57.

7. National Commission for the Protection of Human

Subjects of Biomedical and Behavioral Research, The

Befmont Report: Ethical Principks and Guidelines

for the Protection of Human Subjects of Research,

DHEW publication No. (OS) 78-0012 (Washington,

D. C.: U.S. Government Printing Office, 1978).
Chapter 10

Prospects and Problems for

the Economic Evaluation of

Genetic Testing
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Economic Evaluation in Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

General Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Identifying and Measuring Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Problem of Value Judgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Framework for Economic Evaluation ..., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Alternatives Compared . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Population Studied . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The Consequences Considered . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Methods for Aggregating Consequences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Study Design.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Using the Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Economic Evaluation of Genetic Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Economic Evaluation of Cytogenetic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter IO References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table

Table No.

17. Hypothetical Break-Even Number of Cases Averted by SAT Testing per

1,000 Workers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Chapter 1 0

Prospects and Problems for

the Economic Evaluation of

Genetic Testing

Introduction

Genetic testing in the workplace has potential

benefits and costs to workers, employers, and

society as a whole. The magnitude of those benefits and costs and their distribution among the

sectors of society will help determine the desirability of this approach to improving occupational

health. The techniques of economic evaluation—

cost-benefit and cost-effectiveness analyses—are

methods for collecting, organizing, and presenting evidence about the benefits and costs of alternative courses of action. They are systematic approaches to examining the tradeoffs among the

different kinds of consequences—for example,

dollar outlays today versus improved levels of

health 5 years hence—stemming from a decision.

The usefulness of economic evaluation rests on

its ability to improve decisions. Even when economic analysis is severely limited by uncertainties about the magnitude, direction, or value of

certain consequences—as is the case with genetic

testing—it can still be a useful exercise. The very

identification of key areas of uncertainty, for example, can be used to set priorities for further

research, It can also show how sensitive the results of an analysis are to changes in assumptions

concerning these uncertain elements of the decision.

This chapter considers the fundamental principles and limitations of economic evaluation and

proposes a general framework for economic evaluation. Then, the specific issues and problems

that arise in applying the framework to genetic

testing are discussed. The goal is to illustrate the

kinds of information that are currently available

to support such analysis and the present level of

knowledge about the costs and benefits of these

approaches to occupational health.

Economic evaluation in health

The analytic pillars of economic evaluation are

cost-benefit and cost-effectiveness analyses. They

share a common purpose—to help decisionmakers

understand the consequences of the choices before them. This objective is approached from different perspectives under the two techniques.

Consequently, each technique has strengths and

limitations that make it more or less acceptable

to analysis of particular problems.

General principles

In theory, a cost-benefit analysis identifies,

quantifies, and places a value on all consequences,

both positive (benefits) and negative [costs) arising from each possible alternative course of action. If all such consequences are valued in the

same unit of measure (for example, dollars), the

decisionmaker would merely have to tally these

values and compare them across all possible alternatives. The alternative with the highest level of

net benefit (or lowest net cost) would be preferred

to all others.

In practice, no cost-benefit analysis is ever completely comprehensive or accurate in measuring

consequences, and the valuation of such consequences, even when they can be measured, is

replete with conceptual and methodological difficulties. Consequently, in practice a cost-benefit

151
152 ● The Role of Genetic Testing in the Prevention of Occupational Disease

analysis is not a definitive decisionmaking tool but

rather a useful framework for arraying information (11).

Indeed, the Achilles’ heel of cost-benefit analysis

is its need to assign a monetary value to all measured consequences of each alternative. This value

is generally accepted as the sum of the values of

the consequence to each affected member of

society. But how does one assess the value that

a person places on a reduction in the probability

of early death, pain, or discomfort associated with

illness, especially when the changes may occur

at different times in the future? The question of

how to value consequences has been addressed

at length in the cost-benefit literature (11). Methods do exist (some of which are discussed below)

that are generally accepted by economists as reasonable for assigning monetary values to some

important consequences. None, however, is completely satisfactory, and the technique of costeffectiveness analysis was developed to sidestep

the valuation problem.

In cost-effectiveness analysis, the monetary

costs of an alternative are compared with one or

more measures or indexes of effectiveness, such

as “number of lives saved,””number of life-years

saved, ” or “quality-adjusted life-years saved”

(11,16). The effectiveness measure must act as a

surrogate for all of the nonmonetary consequences that are otherwise unmeasured. Only

those alternatives whose consequences are well

represented by the selected effectiveness measure

should be compared with one another. Consequently, cost-effectiveness analysis can be used

to compare only a narrow range of alternatives.

Whereas cost-benefit analysis is theoretically

powerful enough to compare widely different alternatives, such as occupational health programs

versus housing programs, cost-effectiveness analysis can be used only to compare alternatives with

the same or a very similar range of nonmonetary

consequences, such as different approaches to

reducing workers’ exposure to a particular industrial carcinogen.

Economic evaluation does not require the aggregation of all benefits and costs into a single

index. Recently, some scholars have advocated a

social accounting approach in which all of the im -

portant dimensions of benefit and cost are arrayed and, to the extent possible, their magnitude

estimated (11,17). Some dimensions would be

measured in dollars, some in physical units, and

some in constructed scales. The decisionmaker

would have a balance sheet showing the performance of each alternative on each dimension. The

advantage of this disaggregated approach is that

important but hard-to-measure consequences of

an alternative will not be ignored. However, if

many dimensions of outcome are important but

cannot be measured precisely, the enumeration

of effects can obscure rather than clarify the differences among alternatives.

Identifying and measuring

consequences

What are the consequences of alternative strategies for achieving occupational health? Such

strategies typically reduce exposure to illness- or

injury-causing hazards. This exposure reduction

presumably lowers the incidence or severity of

occupational illness. These positive health effects

are bought at the price of the occupational health

program expenditures. But the positive health effects of the program also mean reductions in the

cost of illness. The cost of illness has three components, each of which maybe altered by the program’s health effects. First, the reduction in the

incidence and severity of illness over workers’

lifetimes will mean fewer expected expenditures

for health and medical care at various points in

the future. The discounted value* of these immediate and future monetary outlays is called the

direct cost of illness.

The consequences of a strategy do not end with

these direct costs. When a worker dies or falls

ill, his or her productivity is lost or diminished.

This productive activity has a value in the market

place, and its loss is referred to as the indirect

cost of illness. Thus, a program that improves

worker health will reduce the indirect cost of ill-

*An outlay in the future cannot be compared directly with one

made today because the postponement of the expenditure allows

for the investment of those funds in alternatives and because people prefer a benefit today to one in the future. The value of the

future expenditure must therefore be discounted by a rate equal

to the return from those alternative investments.
Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing 153

ness as we]]. But the consequences of illness go

still further. Quite apart from its effect on productivity, illness brings about pain, suffering, anxiety, emotional distress, and grief in patients, their

families, friends, and others. The value of these

losses are the psychosocial costs of illness (l).

The “benefit” of an occupational health strategy

is the value of changes in these costs of illness

due to the program, The goal of cost-benefit analysis is to measure the impact of a program or

strategy on the cost of illness and to compare this

benefit with the cost of the program. If the difference between benefit and cost is positive, society would be better off if it were to implement the

strategy. If the net benefit is negative, however,

the program is not worth its cost. The assumption underlying these conclusions is that all of the

costs and benefits can be quantified.

The challenges to measurement and valuation

of the cost of illness are great, even when the

health effects of a program are known with precision. There are two different conceptual approaches to measuring the cost of illness: human

capital and willingness to pay, Illness is something

that people are clearly willing to pay to avoid, and

in theory, this willingness to pay is the value of

the health benefits resulting from a program. But

for a variety of reasons it is not easy to determine

how much people would be willing to pay to reduce, say, the probability of contracting a given

disease at some point in the future. * Consequently, most cost-benefit analyses employ the human

capital approach to valuing benefits.

The human capital approach measures only

those benefits that have a value in the market

place: the direct and indirect costs of illness.

Psychosocial costs are left to be considered in

some other way. Under this method, the value

of lost production due to illness or death is measured by the market price for workers’ labor. Occupational health strategies directed toward those

members of society with lower wages or lower

rates of participation in the work force, such as

women, minorities, and the elderly, therefore

would be valued at less than those aimed at

others.

Cost-effectiveness analysis typically does not involve the valuation of either the indirect or

psychosocial costs of illness. The effectiveness

measure (such as life-years saved) presumably

acts as a proxy for both of these. The net costs

of a program are defined as the sum of the direct

program cost and the change in the direct cost

of illness-that is, present and future medical care

costs. If this net cost is negative, the program is

cost-saving without even considering effectiveness. But if program expenditures outweigh the

discounted value of savings in direct medical care

costs, ratios of net cost to effectiveness then are

constructed for each alternative under study.

The cost-effectiveness approach also contains

built-in value judgments, For example, the “lifeyears saved” measure would treat 10 extra years

of life to a 45-year-old patient the same as 10 extra years of life to a 70 year old, There is substantial evidence from survey research that the value

of these outcomes is not the same in most people’s minds (4), but a cost-effectiveness analysis

using the life-years measure would not be able

to account for such differences.

problem of value judgments

Biases and value judgments are inherent in all

economic evaluations, no matter how comprehensive. Value judgments creep in through the framing of the question, the choice of measures of

benefit, effectiveness, and cost, the choice of data

sources, and the design of measurement instruments, A value judgment also is present in the

general neutrality of economic evaluation toward

the winners and losers of a decision, Each alternative will affect the distribution of benefits and

costs among segments of the population. These

differences generally are netted out in economic

evaluations under the assumption that if the winners could more than compensate the losers, society as a whole would be ahead, whether or not

the compensation actually takes place. * In reality, of course, such compensation rarely occurs;

consequently, economists increasingly have come

to view the analysis of distributional consequences of alternatives as a fundamental element

*For a discussion of the willingness-to-pay concept, and the difficulties of measuring it, see ref. 6. *For a discussion of the compensation test, see ref. 7.
154 . The Role of Genetic Testing in the Prevention of Occupational Disease

of economic evaluation, especially when they are

major (17).

Perhaps the most important value judgment in

any economic evaluation is the definition of alternatives, Relevant alternatives can be easily excluded from consideration simply because they

are not recognized at the time the study is designed. In genetic testing, the definition of a

strategy must include not only the testing protocol and procedures, but also the followup and enforcement activities that follow testing. Minor

Framework for economic

There are five critical elements of any economic

evaluation, be it cost effectiveness, cost benefit,

or some hybrid of the two. This section identifies

and discusses the five components.

Alternatives compared

The most important characteristic of an evaluation is the set of alternatives chosen for study,

since the usefulness of an analysis for any decision depends on the choice of relevant alternatives. There are two entirely different kinds of

relevant alternatives for genetic testing in the

workplace. The first involves strategies for research on genetic testing, including development

and refinement of the testing technology and epidemiological and clinical research on the relationship between occupational exposure and disease

in various human populations.

The second set of alternatives involves the use

of these tests to screen or monitor specific worker

populations with the purpose of following up on

the test results with strategies to reduce exposure.

These are strategies of intervention, as opposed

to research.

It is possible to structure the research question

as one for economic evaluation on the rationale

that limited research resources should be allocated to projects that can promise the highest

ratios of benefit to research cost. But the measurable benefits of research rest largely on the

benefits of the interventions subsequently made

modifications in the definition of a genetic testing

strategy, such as the inclusion or exclusion of

counseling services for employees, can have major

effects on program costs, anticipated health effects, and psychosocial consequences. Yet, available funds may limit the number of alternative

strategies that can be compared, so choices must

be made as an analysis is designed. Often, one cannot be certain that the best strategy has been included as an alternative in the study.

evaluation

possible by it. Thus, even economic evaluations

of alternative research strategies must consider

interventions. To date, the use of economic analysis as a guide for biomedical research has been

limited. This is primarily the result of the inherent

difficulty of predicting the outcomes of research

projects, their timing, and even their probability

of occurring. Consequently, the discussion in

subsequent sections will concentrate on alternative strategies for implementation of genetic

testing.

Population studied

The definition of the population to which the

alternatives apply is also an important attribute

of any analysis. A comparison of two alternatives

can have widely different results depending on

the characteristics of the population. For example, the potential importance of age as a factor

in susceptibility to exposure argues for separation of populations into age groupings. Narrowly defined populations have an advantage in that

the interpersonal variation in measured costs and

benefits is low. On the other hand, if the worker

population is defined so narrowly that few fall

into each category, the analysis may lack the statistical power to identify differences among alternatives even when they actually exist.

The population also may be defined so narrowly

that the benefits and costs associated with a strategy cannot be achieved in actual practice, Con-
—

Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing ● 155

sider, for example, the costs and benefits of genetic screening for thalassemia trait in workers.

If the study were to compare alternatives only

for workers in specific high-incidence ethnic or

racial groups, the results might be irrelevant for

the actual operation of an occupational health program, where it may not be ethical or lawful to

require the test on the basis of race or nationality. In other words, an economic analysis might

show the desirability of screening for thalassemia

trait if the procedure were limited to blacks and

Mediterraneans, whereas in reality no screening

program could be limited to that population.

The consequences considered

As discussed earlier, an economic evaluation

may be characterized by the range of consequences (costs and benefits) included in its purview. It is possible to consider only the direct costs

of a program. If, for example, a screening program can be shown to reduce net direct costs

(consisting of the sum of the cost of administering the program and the net reduction in the discounted costs of present and future health care),

consideration of other consequences, such as the

indirect and psychosocial benefits, may be unnecessary. However, a usual precondition to the accurate estimation of the net direct costs of a

strategy is the ability to estimate the impact of

the program on the health of workers and therefore on their need for medical care. Thus, even

ignoring the indirect and psychosocial costs, economic evaluation generally cannot evade the need

for some estimate of a strategy’s health effects.

Inclusion of indirect cost impacts into an economic assessment adds an additional degree of

complexity to the evaluation problem. Even when

it is possible to assess the impact of a program

on the incidence of disease, it may be difficult to

assess its impact on the person’s ability to work

at his or her level of productivity.

Methods for aggregating consequences

The consequences of any action will be distributed over time and among the members of society. These effects must be aggregated into coherent summary measures if the analysis is to be useful to decisionmakers.

The usual approach for dealing with effects occurring through time is to discount future costs

or benefits by an appropriate rate. The further

away in the future that a consequence will occur, the less importance or value it will have when

discounted, There is no generally accepted ‘(correct” rate at which future consequences should

be discounted to their present value. Discount

rates of 3, 5, and 10 percent per year are common, Even nonmonetary effectiveness measures

such as ‘(lives saved” are often discounted in

economic evaluations, though it is difficult to

determine the appropriate discount rate for these

kinds of effects. Estimates of lifetime direct and

indirect costs vary widely with the choice of discount rate (3,6).

Aggregating consequences across individuals

also is necessary. Two issues are pertinent to the

aggregation methods employed. The first is the

statistical issue of the best measure to represent

a potential distribution of impacts. Commonly accepted measures such as the mean or median may

obscure important effects occurring in a subset

of the population. The direct and indirect costs

of large changes in health status may be quite different from those of smaller changes, and measures such as the mean may not reflect these important differences.

The second issue is one of equity. Consequences

are likely to be differentially distributed among

sectors of the society, Exposed workers comprise

one affected group, the industrial employer another. Workers in other industries and the general public are other affected sectors. Analyses

can be, but rarely have been, structured to show

how the costs and benefits of a program are distributed among these groups.

Study design

All analyses ultimately rest on estimates of the

expected effect of each alternative on the consequences of interest. How these estimates are derived will determine their validity and, hence, the

validity of the economic evaluation itself. Thus,

the issues inherent in study design in general—

internal and external validity-are important in

economic evaluation as well (2).
756 The Role of Genetic Testing in the Prevention of Occupation/ Disease

Most economic evaluations contain one or more

estimates that are based on assumptions or rules

of thumb. Estimates are often necessary because

of a lack of data. When such estimates are included in the analysis, however, validity necessarily suffers. An accepted procedure for dealing with

uncertainty is to conduct a sensitivity analysis, a

study of the impact of changes in assumptions on

an evaluation, it is necessary precisely and fully

to define the alternative strategies, specify the

population to which the alternative strategies will

apply, determine the consequences to be included

and the methods of measurement, select methods

of aggregating consequences over time and across

individuals, and identify those estimates whose

validity is sufficiently suspect to warrant sensitivithe findings of the evaluation. If the results of the ty analysis. These steps will be applied in the next

analysis are insensitive across the entire reason- sections as

able range of correct values (that is, the most pre- analysis of

ferred alternative remains so regardless of as- monitoring

gumptions), then its findings can be considered

valid.

the use of economic evaluation for

genetic screening and cytogenetic

is explored,

Using the framework

The five components of economic evaluation described above define the analysis. In structuring

Economic evaluation of genetic screening

To carry out an economic evaluation of genetic

screening in the workplace, the following kinds

of information must be available:

. a detailed description of the proposed testing

strategy, including followup procedures,

● estimates of the prevalence of the genetic

trait in the worker population under study,

and

. estimates of the differential effect of worksite

exposure on the incidence and severity of disease in the target population.

Genetic screening programs consist of a family of strategies for identifying and reducing exposure of workers with particular genetic traits.

A strategy may or may not include counseling of

workers with positive test results. The costs and

benefits of any such program will depend not only

on the type of screening test but also on the followup actions associated with positive and negative test results. For example, a preemployment

screening test might result in job denial, whereas

a program for employed workers could result in

transfer or termination. Alternatively, the choice

might be left to the employee, who could remain

in the position, request a transfer, or resign. Each

of these strategies has different implications for

costs and benefits and for the distribution of these

consequences among the sectors of society.

The definition of the strategy also depends on

the configuration of the screening program itself.

Since the tests for detecting genetic conditions are

rarely perfectly sensitive or specific but involve

some false positive and false negative results, the

testing strategy may well include retesting of all

those with initial positive results, Or, when two

or more different tests, one more costly than

another, are available to detect a condition, the

testing strategy might consist of a broad screening with the less costly procedure and using the

more expensive test to retest positives. Program

costs will depend on the configuration selected,

The prevalence of genetic traits in worker populations also may vary. Some susceptible workers

may self-select themselves out of high-risk environments. Therefore, reliable data on the prevalence of a trait in given populations is not always

available.

The benefits of a genetic screening strategy presumably are manifested in the reduced incidence

of the disease associated with the genetic trait.
—. —.

Ch. 10—Prospects and Problems for the Economic Evaluation of Genetic Testing . 157

A necessary condition for such an impact is that

the person with the condition be truly at enhanced risk because of exposure to hazardous

substances found in the work environment, and

the followup action must reduce the probability

of the disease. Thus, the complicated chain of relationships between the existence of a genetic trait,

occupational exposure to a hazardous agent, and

disease onset must be known if the effects of a

strategy on worker health are to be estimated.

At present, the evidence is generally inadequate

to assess the relationship between genetic traits

and increased susceptibility to industrial exposure. Yet, even lacking data on these basic relationships, economic evaluation can provide some

insights that may assist in decisionmaking regarding the use of genetic screening.

As an example of how economic evaluation

might proceed, consider screening for heterozy -

gous serum alpha1

-antitrypsin (SAT) deficiency in

work environments containing respiratory irritants. This condition has been selected as an example because estimates of its prevalence in the

general population are available and some work

has been done to estimate the economic costs of

the illness it may provoke-emphysema. Evidence

has accumulated that people who display an intermediate deficiency of SAT are at increased risk

of developing emphysema. Assume for the purposes of this example that a correlation has been

shown between intermediate SAT deficiency and

an increased risk for respiratory disease in work

environments containing respiratory irritants.

About 3 to 4 percent of the population in the

United States is thought to have this genetic condition. Tests for SAT deficiency are relatively inexpensive. Suppose a large-scale screening program could be implemented for $20 per person.

The cost of screening 1,000 workers, then, would

be $20,000. Assume also that a worker with a positive test result is removed from an environment

containing respiratory irritants. The following

question can be asked: How many cases of emphysema would have to be prevented or delayed

by such an action to make the test program pay

for itself in direct and indirect benefits? The direct

and indirect costs of emphysema in 1979 were

estimated at $1,300 per person* (10). If this estimate is accepted as accurate, the screening program would have to prevent 15.3 cases of emphysema (in the 1,000 workers screened) in order to

pay for itself in direct and indirect cost savings.

This implies that emphysema would have to be

prevented in 37 to 50 percent of the SAT-deficient

workers detected in the screening program.

Since estimates of the average cost of a SAT

screening test and the direct and indirect costs

of emphysema are uncertain, an analysis of the

sensitivity of the break-even point to different

values of these parameters is shown in table 17.

The practical lower limit of the average cost of

a genetic screening test is about $5. * * At this unit

cost, the break-even number of cases declines to

8 to 16 percent of the SAT-deficient population.

Although there are no epidemiological studies relating different levels of exposure to respiratory

irritants in work environments with increased

risks of emphysema in SAT-deficient individuals,

*This estimate is only a rough approximation of the discounted

lifetime costs associated with a new case of emph~sema, It is an

estimate of the costs incurred in 1979 by all then-extant cases of

emphysema, These “prevalence costs” o~’erestimate the lifetime costs

of a new case because they are not discounted. Conversely, to the

extent that the incidence of emphysema has been growing, the total

costs in 1979 disproportionately represent the early and presumably

less costly stages of the illness. The extent to which these sources

of overestimation and underestimation compensate for one another

is unknown. Good data on the incidence of emph~wema in the L~nited

States do not exist; hospitalization rates have been ciecreasing since

1970, but the pre~’alence of the condition has been on the increase

(9),

* *The a~erage unit cost of a worksite hypertension screening program \\’as recently estimated at $6 (13), Since hypertension screening in~’oli~es minimal equipment and technician time, it is likely that

it represents a lower bound on other types of wrorksite screening

tests as we]],

Table 17.—Hypothetical Break-Even Number of Cases

Averted by SAT Testing per 1,000 Workers

(break-even percent of SAT-deficient workers)

Direct and indirect cost Cost per test

of emphysema $20 $5

$1,040 . . . . . . . . . . . . . . . . . . . . . 19.2

(49-64%) (12-41 %)

$1,300 . . . . . . . . . . . . . . . . . . . . . 15.3

(37-50%) (10-31%)

$1,560 . . . . . . . . . . . . . . . . . . . . . 12.8 3.2

(32-430/o) (8-10°/0)

SOURCE: Office of Technology Assessment.
158 . The Role of Genetic Testing in the Prevention of Occupation/ Disease

it is known that only 10 percent of all SAT heterozygotes will develop the disease (8) and that emphysema may be brought on by multiple causes

(5,8). Thus, the likelihood is low that a SAT deficiency screening program can be justified in

terms of its impact on direct and indirect benefits.

Moreover, additional research into the relationship between exposure and disease is unlikely to

change this conclusion, given what is already

known about the potential impact of screening

on the incidence of emphysema,

This conclusion does not suggest, however, that

the SAT screening issue should be put to rest. Psychosocial consequences have not been included

in the analysis; these can be extremely important

in a debilitating disease like emphysema. Suppose,

for example, that a program of screening and subsequent removal of susceptible individuals from

exposure is able to prevent emphysema in only

5 percent of SAT-deficient workers who would

otherwise be exposed. This implies that society

would incur a net direct and indirect cost of

$1,460 to $11,800 for each case of emphysema

prevented, depending on assumptions about

screening costs, direct and indirect illness costs,

and the frequency of SAT-deficient heterozygotes

in the population tested. Is it worth up to $10,000

to prevent the psychosocial consequences of a

case of emphysema? And how do these psychosocial costs compare to the psychosocial costs of

a positive finding on a genetic screening test? Positive test results, whether correct or incorrect,

may cause anxiety and disruption to people’s lives

(that is, psychosocial costs). This is especially true

if workers are denied jobs or lose self-esteem because they are labeled as “susceptible. ” Thus, the

$1,460 to $11,800 net direct and indirect cost per

case averted cannot be measured against only one

type of psychosocial cost.

Note also that the different categories of cost

would be borne by different actors. The costs of

screening might be incurred by the employer (and

ultimately in part by the public in higher prices)

or by the government. The direct and indirect

benefits would be shared by the individual worker and the public (through impacts on health insurance and disability programs), The psychosocial costs and benefits primarily accrue to workers themselves. Thus, the immediate monetary

costs of a screening program are borne by the

employer and the public, while the worker and

the general public stand to gain monetary benefits

in the future and workers may gain psychosocial

benefits in the future at the expense of monetary

and psychosocial costs in the near term,

It is interesting to compare the principles of

economic evaluation with a set of criteria suggested by Stokinger and Scheel for applying genetic screening to the workplace (14). These investigators listed the following conditions that

should be met for a genetic screening to be appropriate:

●

●

●

●

the condition detected by the test should have

a relatively high prevalence in the worker

population;

people with the condition should be susceptible to agents commonly occurring in industry;

the genetic condition should be compatible

with an apparently normal life until exposure

occurs; and

the test should be simple, inexpensive, and

amenable to large-scale use.

These conditions are consistent with but more

rigid than economic analysis. For example, it

might be highly cost effective to screen for a rare

condition if the testing cost is low and the health

effects of exposure reduction are very large. The

conditions of Stokinger and Scheel do not make

such tradeoffs explicit, whereas an economic evaluation does.

The prevalence of a trait can be so high that

genetic screening becomes impractical. A program consisting of genetic screening with subsequent removal of the worker from the high exposure environment must then be compared with

other strategies for reducing exposure levels of

all workers. If, for example, 70 percent of all

workers are susceptible, it may be more cost effective to take general action to reduce exposure

of all workers. How high the prevalence must become before screening is eclipsed by more general

exposure reduction strategies depends on the particular situation. For example, slow acetylation

rates have been linked to aromatic amine-induced

cancer. Approximately 12)000 workers were exposed to these chemicals in the workplace in 1974
Ch. 10—Prospects and Problems for the Economic Evaluation of Genetic Testing ● 159

(15). Yet, about 50 percent of the U.S. population

have slow rates of acetylation. Thus, it may be

more effective to reduce exposure levels to all

workers than to remove about half of the workers

from the potential labor pool. The feasibility of

either alternative would depend on the pervasiveness of exposure to the offending chemicals and

the technical barriers to reducing ambient exposure levels. Of course, much more information

would be needed before such an hypothesis could

be accepted or rejected, but the question could

be addressed through economic evaluation of the

relelvant alternatives.

Whether one sees the SAT example given above

as informative or misleading depends on expectations about the use to which the information

will he put in decisionmaking. Critics of costbenefit and cost-effectiveness analyses claim that

incomplete analyses such as that provided above

are given too much attention merely because the

results are in a quantified form. Moreover, the

unquantified effects, despite their importance,

tend to be ignored because they are bothersome.

Supporters of the approach Would claim that the

analysis clarifies the central tradeoff between net

direct and indirect costs to society and psychosocial benefits and costs to workers. Both sides

would agree, however, that economic evaluation

is severely, perhaps fatally, flawed when substantial uncertainty is present in the central estimates

of effectiveness or benefit. Sensitivity analysis can

remove some of the limitations, but when the results of the analysis are highly sensitive to estimates of cost or effectiveness, as they are in the

case of SAT testing, economic analysis is of limited

usefulness.

Economic evaluation of cytogenetic monitoring

The case for using cytogenetic studies to monitor workplace exposure to hazardous material

rests on the hypothesis that exposure to mutagenic or carcinogenic agents is related to somatic

chromosomal damage, which is in turn correlated

with an increased risk of disease. If this hypothesis is accepted, and particularly if the relationship between exposure level, degree of chromosomal damage, and risk of disease is known and

quantified, then cytogenetic tests might be used

as biological monitoring devices for workplace

hazards.

The potential uses of cytogenetic monitoring are

to identify carcinogenic agents and to identify

populations at risk due to overexposure to these

agents. Ultimately it might be possible to use the

tests to develop standards for safe levels of occupational exposure to chemicals and radiation.

It is difficult to lay out a specific strategy for

evaluation of a cytogenetic monitoring program

because of the profound lack of knowledge about

the relationships between occupational exposure,

chromosomal damage, and disease in human populations. For the sake of discussion, however, let

us suppose that the research evidence were sufficient at this time to justify the use of cytogenetic

monitoring to identify carcinogenic agents. Suppose that it has been established that there is a

high correlation between chromosomal damage

in a group and subsequent cancer rates. Then,

employers might establish programs for periodic

monitoring of workers who are routinely exposed

to industrial chemicals. The cost of such a program would be highly sensitive to features such

as the frequency of testing (that is, monthly, quarterly, yearly), the sample size in each testing

period, the methods of recordkeeping and quality control, and the actual cytogenetic procedures

employed. Cytogenetic studies are relatively expensive laboratory procedures. The estimated

cost is between $100 and $300 per test, depending on a laboratory’s volume and organization,

although testing costs may be reduced in the future with the development of automated methods.

At an average cost per test of $100, however, the

features of the monitoring program make an

enormous difference in program costs. For example, testing 500 workers once each year would

cost $50,000, whereas a quarterly testing program

of the same number of workers would cost

$200,000 annually.
160 The Role of Genetic Testing in the Prevention of Occupation/ Disease

Both the costs and benefits of a monitoring program depend on the actions taken on the basis

of its results. If significant chromosomal damage

were followed by removal of the chemical from

the workplace or some other method of exposure

reduction, the major hypothesized benefit would

be a reduction in the rate of exposure-induced

cancer. The costs of exposure reduction would

depend on the technical and economic relationships in the production process. If no action were

taken, neither benefits nor additional costs would

ensue. It is reasonable to assume that an expensive monitoring program would be undertaken

only if some benefits could be expected; therefore,

a program for exposure reduction must be assumed to be a natural sequel to cytogenetic monitoring.

To estimate the economic benefits of cytogenetic monitoring programs, it is necessary to know,

or at least to estimate, the probability that the

agents found in the monitored workplaces will

be found to produce chromosomal damage, Further, precise analysis would demand that the impact of exposure on cancer rates be estimated

with reasonable certainty. But if the latter were

known, the need for a monitoring program of the

type outlined above is questionable. Thus, the

prospects are poor for reasonably accurate a

priori estimates of the health effects, and hence

benefits, of cytogenetic monitoring.

Though it is not possible now, and may never

be, to estimate the benefits of cytogenetic moniConclusion

toring with any precision, it is useful to consider

the order of magnitude of the economic benefits

that would result from each case of cancer that

might be prevented by such a program. The direct and indirect costs per case of cancer were

estimated in 1978 at about $22)000, consisting of

$5,000 in direct and $17,000 in indirect costs*

(12). These costs vary with the age of onset and

the type of cancer, but they can be taken as a

general guide to the order of magnitude of the

monetary benefits associated with each case of

cancer prevented. In a pioneering but highly speculative study, Abt attempted to estimate the combined indirect and psychosocial costs of cancer

(1). These costs were estimated at $137,000 per

case. Thus, even though this estimate is based

largely on assumptions and rules of thumb, it illustrates the overwhelming importance of psychosocial costs in the consequences of cancer.

The stakes are clearly high on both sides of the

issue. The costs of cytogenetic monitoring are

potentially high, but the costs of cancer are also

high. At present there is insufficient evidence to

assess the value of cytogenetic monitoring because the relationships between chromosomal

damage and clinically relevant effects have not

been demonstrated. Yet, the magnitude of the

costs involved argues for increased research into

these relationships.

*These are prevalence costs. Possible sources of inaccuracy in

these estimates are discussed in an earlier footnote,

Cost-benefit and cost-effectiveness analyses are risk of disease, preclude the rigorous application

economic methodologies that can be useful in of these tools to this technology. However, these

structuring the analysis involved in decisionmak- tools can help identify the uncertainties involved

ing and in assessing the desirability of alternative and provide a rough sense of the benefits, buroutcomes. The significant uncertainties associated dens, and tradeoffs associated with genetic testwith genetic testing, particularly the limited evi- ing programs.

dence of an association between endpoints and
—

Ch. 10—Prospects and Problems for the Economic Evacuation of Genetic Testing ● 161

Chapter 10 references

1. Abt, C., “The Social Costs of Cancer, ” Social Indicators Research 2:1 75-190, 1975.

2. Campbell, D., and Stanley, J., Experimental and

Quasi-Experimental Designs for Research (New

York: Rand ILlcNally, 1963).

3. Hodgson, T., “The State of the Art of Cost of Illness

Estimates, ” draft paper (Hyattsville, Md.: National

Center for Health Statistics, 1982).

4. Kalish, R., and Reynolds, D., Death and Ethnicittiy:

A Ps}’cho-Cultural Stuc@ (Los Angeles: University

of Southern California Press, 1976).

5. Kazazian, H., “A Geneticist’s L’iew of Lung Disease)”

American Retie}v of Respiratory Disease 113:261-

266, 1976.

6. Landefeld, J. S., and Seskin, E. “The Economic Value of Life: Linking Theory to Practice, ” American

Journal of Public Health 72(6):555-565, 1982.

7. Mishan, E. J., Cost-Benefit Ana[Vsk: An Introduction (New York: F. A. Praeger Publishing Co., 1971).

8. Mittman, C., et al., “The PiMZ Phenotype, ” American Re~7iew of Respiratory Disease 113:261-266,

1978.

9. National Center for Health Statistics, Health Interview Survey, 1980.

10. National Heart, Lung, and Blood Institute, personal

communication with Dr. Hannah Peavy, 1982.

11, Office of Technology Assessment, U.S. Congress,

The Implications of Cost-E ffecti\~eness Ana@sk of

Medical Technology (Washington, D. C.: U.S. Government Printing Office, August 1980), OTA-H-126.

12. Rice, D., and Hodgson, T., “Social and Economic

Implications of Cancer in the United States, ” a

paper presented to the Expert Committee on Cancer Statistics of the World Health Organization,

June 20-26, 1978.

13. Ruchlin, H., and Alderman, M., “Cost of Worksite

Hypertension Treatment, ” U.S. Department of

Health and Human Services, Public Health Service, NIH-81-21 15, November 1980.

14. Stokinger, H., and Scheel, L., “Hypersusceptibility

and Genetic Problems in Occupational Medicine—

A Consensus Report, ” Journal of Occupational

Medicine 15:7, 1973, pp. 564-573.

15. U.S. Department of Health and Human Services,

8

16

17.

National Institute of Occupational Safety and

Health, Quarter@ Hazard Summary Report, Aug.

6, 1980.

Weinstein, M., and Stason, W. “Foundations of

Cost-Effectiveness Analysis and Medical Practices, ”

iVew England Journal of Medicine 296(13):716-21,

1977.

Weisbrod, B. A., “Benefit-Cost Analysis of a Controlled Experiment: Treating the Mentally Ill,” Journal of Human Resources 16:523-48, fall 1981.
Part V

Congressional Issues

and Options

Chapter 11—Issues and Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
—

Chapter 11

Issues and Options
Contents

Page

Issue: What Actions Could Congress Take With Respect to Genetic Testing

in the Workplace? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Issue: How Could Congress Regulate Genetic Testing in the Workplace? . . . . . . . . . . . . . 169

Issue: How Could Congress Foster the Development and Use of This Technology? . . . . 171
chapter 1 1

Issues and Options

Genetic testing is an emerging technology. It has

the long range potential to play a role in the

prevention of occupational disease, but it also has

the potential for misuse. Although only a handful of companies are using genetic testing now,

many more are interested. Current law provides

some incentive for its use and some safeguards

against its misuse. Established ethical principles

also provide some guidance for its use. However,

many questions remain unanswered. Under these

circumstances, it may be appropriate for Congress to balance the competing interests and to

make the value judgments necessary in order to

maximize the technology’s potential benefits and

minimize its risks.

This chapter provides an array of issues and

options for congressional consideration. They

may be grouped loosely around the following fundamental policy questions:

●

●

●

Should the technology be stimulated and, if

SO, how?

Should there by any constraints on the use

of the tests and, if so, what?

To what degree should society protect

workers who are at increased risk for

developing disease, at what cost, and who

should bear that cost?

The first issue is an overview of the options

related to all of these questions. The issues and

opt ions that follow focus on particular aspects.

ISSUE: What actions could Congress take

with respect to genetic testing in

the workplace?

OPTIONS:

A. Maintain the status quo.

Congress could choose not to take an-y action

to stimulate, constrain, or regulate genetic testing.

This would allow private parties to continue research into the merits of the technology. Constraints on its use would develop through court

rulings in lawsuits between these parties or by

negotiations between companies and unions. Interested congressional committees could continue

their practice of holding oversight hearings to

raise the issues for public discussion.

The primary argument supporting this option

would be the view that congressional action

would be premature. The technology is not being widely used, and it is primarily in the research

phase of its development. In addition, there are

existing constraints on its potential misuse. These

include the possibility of lawsuits and adverse

publicity. Finally, much of the important information necessary for legislation is unavailable

because it is unknown. For genetic screening

techniques, this information includes the number

of workers who might be genetically predisposed

to disease, the extent to which they might face

adverse employment actions, the availability of

other employment opportunities, and the cost of

safeguarding these workers. For genetic monitoring techniques, this information includes their

predictive value, the extent to which they might

be used, and the costs associated with either using

or not using them.

The arguments against this option relate to how

society controls an emerging technology. Many

policy decisions will need to be made with respect

to genetic testing, and arguably Congress is a better forum for doing so than the courts or private

parties. Congress can gather all information and

viewpoints and then balance the conflicting interests. In addition, while the courts often play

a major regulatory role for any technology, they

are limited in their ability to encourage the development of a technology in a positive manner.

However, Congress can do so by providing funds

for research or other incentives.

B. Stimulate the technology’s development and

use.

Congress could stimulate the technology by providing additional money for research on the techniques, for epidemiological studies to determine

associations between genetic indicators and disease, and for basic research on the cause of occupational disease in general. If genetic testing

167
168 ● The Role of Genetic Testing in the Prevention of Occupational Disease

could be developed to the point where the tests

are predictive of an individual’s or group’s increased risk for occupational illness, its use could

result in a number of direct and indirect benefits.

The principal direct benefit would be a lower incidence of occupational disease among workers.

They and their families would be spared some

of the pain, cost, and emotional trauma that accompany illness. In addition, employers would

save some of their direct and indirect costs of occupational disease-employee time lost from

work, insurance premiums, legal fees, and monetary damages assessed in lawsuits. Society would

benefit through the greater health and productivity of its work force, A major indirect benefit

of developing this technology might be a greater

understanding of the causes of occupational

disease and disease in general.

The principal argument against this option is

the concern about the potential misuse of the

technology and about potential adverse impacts.

Some of these concerns relate to unfair employment discrimination and attention being directed

away from other ways to address occupational

diseases. These concerns might be dispelled by

regulation to direct the technology’s development

in socially desirable ways, In fact, if the tests were

highly predictive of future illness, the Occupational Safety and Health Administration (OSHA)

could require their use and constrain how they

were used, so long as those constraints were

shown to enhance worker health and were not

directed toward prohibiting fair employment

practices.

Another drawback to this option is the fact that

there is no information on the amount of occupational disease that could be prevented by genetic

testing, even if the tests were reliable predictors

of disease. Similarly, there is no information on

what it would cost to get the tests to the point

of clinical usefulness.

C. Prohibit the use of genetic testing in the workplace.

The principal reason for prohibiting genetic

testing in the workplace would be concern over

its potential misuse, particularly at its current

stage of development where its ability to predict

future disease has not been demonstrated. This

potential for misuse probably would be greater

for genetic screening than for genetic monitoring because the former is targeted toward identifying individuals at increased risk while the latter focuses on groups at increased risk. However,

concern exists that employers might use either

screening or monitoring to exclude individuals

from jobs. Existing law may offer protection in

some circumstances, but there are many questions to be resolved. The collective bargaining

process could be used by unions to negotiate protection for workers, but the primary focus of bargaining has been economic matters. While health

matters have also been important, genetic engineering apparently has not been a bargaining

issue. In addition, most of the work force is not

unionized. Moreover, these remedies are not

helpful if a susceptible person does not know why

he or she was denied a job. Finally, while ethical

principles provide guidance for the proper use

of this technology, it is difficult to know if they

are being followed.

The principal drawback to this option is that

it is a drastic solution to the problem of potential

misuse, Genetic testing does not appear to be

widely used. Law, ethics, and public opinion provide incentives against its misuse. Moreover, banning its use would prevent research that might

determine its usefulness in preventing occupational disease or provide basic knowledge about

occupational disease.

Another argument in favor of this option would

be the claim that an employee’s risk of future illness is not an appropriate factor for job selection,

even if screening or monitoring were highly predictive. Employees have no control over their genetic makeup and generally have no control over

previous exposures to harmful agents. In addition, their increased risk would not affect their

current ability to do the job.

There are at least two counterarguments to the

assertion that risk of illness should not be a job

selection factor. First, society accepts the proposition that immutable characteristics can be proper criteria for employment selection. Intelligence

is at least an implicit selection criterion for many

professional jobs and physical attributes are exceedingly important for jobs ranging from pro-
.

Ch. 11—issues and Options ● 169

fessional basketball to neurosurgery. Second, this

viewpoint places the autonomy interests of the

individual above the interests of society in lowering the costs of occupational illness even when

it may not be feasible to take other steps, such

as lowering exposure.

D. Regulate the technology.

This option represents a judgment that any

risks presented by the technology can be controlled and that the claimed benefits will be of

value to society. The option would permit research to continue, yet constrain the manner in

which genetic testing is used. One type of constraint would be limitations on what job actions

employers could take on the basis of test results.

Another type of constraint would be a requirement that the tests meet minimum standards of

scientific validity before employment decisions

were made on the basis of the results. Such a statute need not specify detailed standards; it could

adopt a standard such as ‘(reasonably predictive

of future illness” and allow the appropriate agency to provide details.

This option has the advantage of addressing the

potential risks of genetic testing immediately and

in a comprehensive manner rather than waiting

for the law to develop on a case-by-case basis

through the courts. Congress may be uniquely

able to study the problem fully, balance competing interests, and provide comprehensive yet targeted solutions.

A possible drawback of this option is that the

problem may not yet be “ripe” for congressional

action. On the basis of available evidence, genetic

testing in the workplace does not appear to be

widespread. Moreover, there is no available evidence about: 1) the number of workers who potentially could be screened or monitored if the

tests were sufficiently predictive, 2) the number

who might be excluded from jobs, 3) the ease with

which excluded workers could find comparable

jobs, and 4) the costs of various regulatory alternatives. on the other hand, congressional action

now could prevent potential misuse before the

technology becomes widespread, and legislation

could create a mechanism for gathering some of

the presently unavailable data.

E. Encourage the development of voluntary guidelines on the acceptable use of genetic testing.

Congress could ask the National Academy of Sciences or a similar body to establish a special commission of representatives from industry, labor,

academia, and other sectors of society to draft

guidelines for the use of the tests. This would

allow the parties most involved to make the difficult value judgments in balancing competing interests and would avoid direct governmental regulation.

ISSUE: How could Congress regulate genetic testing in the workplace?

OPTIONS:

A. constrain employment actions that may be

taken on the basis of genetic testing.

Congress could address many of the concerns

raised by genetic testing by regulating how emloyers may use the results of the tests, even if they

were highly predictive. The following represents

some possible elements of such an approach:

1) prohibit job exclusion on the basis of genetic

makeup or genetic damage, 2) prohibit job transfers because of genetic makeup or genetic damage

unless the transfer were to a comparable job at

comparable pay and benefits, 3) require strict confidentiality of medical information, and 4) require

that employees be told the results of testing and

be given counseling.

This option would clearly protect the interests

of workers, preventing potentially serious consequences to individuals who have no control

over the reason for discrimination against them,

In addition, no difficult judgment would have to

be made as to how predictive the tests should be

before they are permitted.

There are at least two major disadvantages to

this option. First, it may be too broad. If not

carefully drafted, a statute could reach genetic

diseases (not traits) that do affect an employee’s

current ability to perform the job safely and effectively. It is generally accepted that inability to perform a job, even for medical reasons, is a valid

criterion for job selection. Second, if workers with
170 The Role of Genetic Testing in the Prevention of occupational Disease

certain traits were in fact predisposed to occupational illnesses and chose to ignore that information, the additional direct and indirect costs of

their illnesses eventually would be borne by society. This would be the case even if employers

were required to install additional engineering

controls, since the costs of those controls would

be passed on to society. On the other hand, if excluded workers were unable to find comparable

jobs, society would bear the costs of lost productivity and possibly additional unemployment payments. The answer to the question of who should

bear the costs associated with genetically predisposed or damaged individuals will depend not

only on economic analyses but on prevailing political views of distributive justice.

B. Prohibit employment decisions on the basis of

genetic testing unless the employer can demonstrate that the results are reasonably (or substantially) predictive of future illnesses.

This option places the burden on an employer

to justify the claimed correlation between test

results and risk of illness. The specific criteria for

meeting a necessarily general statutory standard

could be provided by agency regulation and case

law.

There are several advantages to this option, especially when compared to option A. First, it focuses on the immediate concern of job denial on

the basis of poorly predictive tests, thus protecting employees’ interests. Second, it protects employers’ interests in lowering their costs from occupational diseases, by excluding workers when

there is a rational, scientific basis for doing so.

Third, it would allow research on the techniques

to continue.

The principal drawback of this option is that

it could be a de facto determination without a full

public debate that future risk of illness is a proper job selection criterion. On the other hand, there

is a substantial lack of the type of information

desirable for deciding this fundamental issue at

this time.

C. Amend the Rehabilitation Act of 1973 to state

that genetic makeup is a handicap and clarify

whether individuals who are genetically predisposed to illness are considered to be “otherwise qualified” within the meaning of that act.

A major advantage of this option would be

working with an existing statute rather than

devising an entirely new one, Sections 503 and

504 of the Rehabilitation Act deal with problems

that conceptually are very similar to those posed

by genetic screening. If applied to genetic screening, the act would require at a minimum that the

tests be reasonably predictive of future illness.

On the other hand, this option would force legislative activity into an existing statutory framework that may not be completely suited to genetic

screening. The Rehabilitation Act was designed

to bring millions of handicapped people into the

mainstream of American life. Genetic screening

has not created a problem anywhere close to the

magnitude of that addressed by the Rehabilitation Act. Moreover, section 503 requires employers to take affirmative action to employ the handicapped. Congress may not wish to require affirmative action to employ people who are genetically predisposed to occupational illness, if that

predisposition can, in fact, be demonstrated.

D. Require that research on employees be done

according to existing Federal regulations designed to protect human subjects of research.

The Department of Health and Human Services

has promulgated regulations governing federally funded biomedical and behavioral research on

humans. The regulations contain provisions designed to protect the interests of the research subjects. Requiring private companies to follow these

regulations in research involving genetic testing

or any other kind of research done in the workplace would mitigate the potential for abuse.

E. Require full disclosure to employees and their

representatives of the nature and purpose of

all medical procedures performed on employees.

Under current law, employees and unions have

access to employee medical records, but employers are not required to disclose the nature and

purpose of medical procedures and how the results are used. Required disclosure of this information to the employee at the time the procedure

was being performed would be a strong incentive to employers for self- regulation. If workers

and their medical advisors had full knowledge of

a company’s medical procedures, they could take
Ch. 11—Issues and Options . 171

steps to prevent abuses, through negotiation or

legal action. Publicity alone could prevent the

worst abuses. This would also protect the autonomy interests of workers by allowing them to be

part of a decisionmaking process that affects their

health and economic interests. Some of the arguments against this option would be that it might

be burdensome and costly for employers and that

it would intrude too much on the professional

judgment of the occupational medical specialist.

ISSUE: How could Congress foster the development and use of this technology?

OPTIONS:

A. Fund research for the development of tests

with high reliability and validity.

.

Genetic variability and differential susceptibility’

to toxic chemicals are well-established concepts

in the scientific literature. Currently, there are

many genetic screening tests that could be done

in a workplace setting to detect potentially susceptible individuals. For the most part, these tests are

reliable and valid for identifying the genetic traits .

in question; a notable exception is the test for aryl

hydrocarbon hydroxylase (AHH) inducibility, Research on developing tests for those traits that

are more prevalent in the population should receive higher priority because they are more likely to hate a high predictive value. The only test

covered in this report that falls into this category

is AHH inducibility.

With respect to genetic monitoring, it is less well

established scientifically that exposure to toxic

chemicals and ionizing radiation can cause genetic

damage in humans, although there is an over -

whelming amount of evidence that this is true in

experimental mammals. Not known at all is the

impact of genetic damage on one’s risk for disease,

especially cancer, or on future generations, yet

the current thinking of the scientific community

is that increased amounts of genetic damage is

generally deleterious,

Alternatives are needed to the time-consuming

cytogenetic tests currently in use. If genetic

monitoring is to be done on a large scale, the availability of automated tests becomes important. The

development of various noncytogenetic methods

could be useful in this respect. Those that show

promise currently include tests for detection of:

mutagens in urine, alkylated hemoglobin, HGPRT

mutation in lymphocytes, hemoglobin mutations,

chemically damaged deoxyribonucleic acid bases,

and LDH-X variants in sperm. For both cytogenetic and noncytogenetic tests, a better understanding of the factors that contribute to genetic

damage in the absence of occupational exposure

is needed (that is, a “normal” or baseline response)

in order for the tests on exposed populations to

be meaningful.

The government agencies which could be involved in these studies include the Environmental Protection Agency (EPA), the National Institute

for Occupational Safety and Health (NIOSH), and

the National Institute for Environmental Health

and Safety (NIEHS).

B. Fund epidemiologic studies in occupational settings directed by NIOSH or NIEHS.

Data are most lacking concerning the correlation of genetic traits or genetic damage to an increased risk for disease. Epidemiologic studies in

an occupational setting can address this problem.

If these studies were to be undertaken, they must

use good epidemiological practices and document

exposures. Studies should only be undertaken if

they are likely to yield statistically reliable data.

For instance, genetic monitoring studies would

require exposure levels high enough to yield a

clear-cut statistical response between exposed and

nonexposed groups without having to use excessively large numbers of people. Especially important would be to establish a dose-response relationship. Genetic screening studies would have

to focus on genetic traits that have a significant

prevalence in the population (greater than 1

percent).

Epidemiologic studies are very costly and difficult to control, especially if they run over long

time periods. Some genetic screening studies

could be done in a short time ( I to 3 years) once .

a population with the trait was selected because,

presumably, the symptoms of disease resulting

from exposure would manifest themselves soon

after exposure. These traits include the red blood

cell traits. Most of the other traits reviewed here
172 . The Role of Genetic Testing in the Prevention of Occupational Disease

are potentially correlated with diseases which

have a long latent period, such as emphysema and

cancer. To assess correctly the exposure information with the disease endpoint, much longer

epidemiologic studies (10 to 30 years) are necessary.

For genetic screening, higher priority should

be given to studies on traits with a high prevalence in the population. These include SAT deficiency, AHH inducibility, carbon oxidation ability, and the association of particular human leukocyte antigens with risk for disease.

Epidemiologic studies using genetic monitoring

techniques would have to be long term in order

to determine the association between genetic

damage and cancer. The chemicals chosen for

study would have to be selected carefully. Many

of the agents discussed in this report are known

already to cause cancer in humans (for example,

ionizing radiation, benzene, vinyl chloride), and

occupational exposure to these is very low and

possibly not detectable by the genetic techniques

now in use.

C. Establish a federally funded data bank, directed

by NIOHS, EPA, or NIEHS, to be used in the

study of the causes of differential susceptibility to occupational disease.

Because the study of the effects of harmful

agents includes many scientific disciplines, it

would be useful to have the relevant data collected in an accessible location. This computerized

data bank could include not only genetic factors

affecting toxicity, but developmental, aging, nutritional, and lifestyle factors as well. The data bank

would include epidemiologic studies that have

been or are being done in occupational settings,

either governmentally or privately funded (somewhat in the same manner as EPA’s Gene- Tox Program). Those working in the field of genetic

toxicology could draw on the information in the

bank in order to design studies and to prevent

duplication of effort. The toxicology data would

be of considerable value to various regulatory

agencies in their standard setting.
Appendixes

Appendix A: Survey Design and Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

Appendix B: Report From the National Opinion Research Center . . . . . . . . . . . . 179

Appendix C: Survey Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Appendix D: Background Frequencies for Chromosomal Aberrations . . . . . . . . . 227

Appendix E: Background Frequencies for Sister Chromatic Exchanges ,...,.. 231

Appendix F: Screening Tests (Available at Hospitals or Medical Centers) for

Heritable Traits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

Appendix G: Other Contractors and Contributors . . . . . . . . . . . . . . . . . . . . . . . . . 235
Appendix A

Survey Design and Methodology

Study design

SOURCE OF DATA

The survey was conducted for OTA from February

25 to June 8, 1982, by the National Opinion Research

Center (NORC), a nonprofit survey research corporation affiliated with the University of Chicago. NORC

sent confidential questionnaires to the chief executive

officers of the 500 largest U.S. industrial companies, *

the chief executive officers of the 50 largest private

utility companies, * * and the presidents of the 11 major unions that represent the largest numbers of employees in those companies. ● * *

These recipients were selected based on discussions

with industry scientists who indicated that a company’s size rather than its major product line would

more likely be the determining factor for testing.

Moreover, hazardous substances are found throughout the industrial sector, including utilities, not just

in the chemical industry. A company’s decision to implement genetic testing most likely would he based on

the extent and sophistication of its medical program,

and sophisticated programs most probably would be

found in large companies. Further, because unions

also are interested in the health of their members, they

were thought to be a potential source for undertaking such programs. All 561 recipients were surveyed,

rather than just a sample, in order to eliminate sampling error that might result from a small number of

companies testing and to avoid other potential problems associated with sample selection.

QUESTIONNAIRE

Development. -A questionnaire addressing the purposes of the study was developed by the OTA staff

and NORC over a period of approximately 2 months,

during which it was extensively reviewed and revised.

Reviewers for technical accuracy included individuals

in science, medicine, and law, and persons affiliated

with the American Industrial Health Council, the

Chemical Manufacturers Association, the American

Occupational Medical Association, the American Academy of Occupational Medicine, and the Genetic Toxicology Association. * * * * Their comments were evalu-

“Identified by Fortune 500 listing of [1 S compames engaged in manu.

farturing mining, Fortune, vol 103 S0 9, %Iay 4, 1981

* “Identlfled hy Fortune Magazine [,Ist (’, Fm’fune klagazine, i’ol 103,

NO 9, May 4, 1981

● ● “Identified m the flrectory of National (Iruons and F.mployws ,4s50.

oatlon [ 19791 bj the U S Department of I~bor

w “ “ “In view of time ronstramts, these people gale thmr oplmons as indl~ duals rather th~o ~> rq)rewotatlt es of their orgamzatmn

ated for objectivity and relevance to the purpose of

the survey. The questionnaire then was revised to

reflect the results of the review and prepared for

pretest.

The bottom 25 companies in the Fortune 500 were

selected for the pretesting phase, which was administered from February 25 to March 12, 1982. Eleven (44

percent) of the 25 companies responded. Analysis of

the results indicated that the questionnaire was reasonably clear and consistent and that it should provide the data sought. A draft of the final instrument

was reviewed by the OTA project panel, which included representatives from industry, academia, and

labor. Minor format changes were made, and two

questions were deleted. The rest of the survey population was questioned from March 23 to June 8, 1982.

Because the questionnaire’s changes were relatively

minor, the pretest responses were included in the final

analysis.

Instrument. —The questionnaire is a four-page

printed instrument. Two slightly different versions

were used, depending on whether the document was

sent to a company or a union; however, the differences are semantic in nature. (See app. C.) The questionnaire was composed of:

●

●

●

●

●

●

introductory paragraphs, which give instructions

and define terminology;

eight questions on genetic screening and eight on

cytogenetic monitoring;*

a question on actions taken as a result of either

type of testing;

a question relating to the use or development of

genetic tests in animal studies;

a question to determine the major industrial sector in which the companies did business; and

a space for explaining the answer to any question

or providing additional information.

The questionnaire reflected two assumptions. One

was that the individual who would respond to the

questionnaire would be familiar with genetic testing.

This assumption was believed to be appropriate because genetic testing has been widely discussed by

various professional groups concerned with occupational health, including committees within major industrial trade associations. The second was that the

definitions of genetic screening and cytogenetic

“I’he questionnaire used slightly different twmmolo~y for the tests than

used in this report It used the term “biochemical genetic testing” to refer

to genetic screening and the term ‘{cytogenet]c testing” to refer to rjtogenetic momtormg

175
176 ● The Role of Genetic Testing in the Prevention of Occupational Disease

monitoring would be carefully and consistently followed in answering the questionnaire. Because different experts use the terminology in slightly different

ways, these terms were defined in the first paragraph

of the questionnaire. No reason or evidence was found

to invalidate these assumptions.

Confidentiality. —Providing confidentiality to the individuals answering the survey was viewed as crucial

for securing both a high rate of participation and accurate information, particularly in view of the sensitive nature of the subject (l). No identifying marks

were placed on the questionnaire, and respondents

were urged not to do so on their own. Results could

be compiled only in aggregate form. Followup procedures were possible because respondents were asked

to return, separate from the questionnaire, post cards

that named their organization and stated that the questionnaire had been completed and returned.

SURVEY

The questionnaires were sent to 561 chief executive

officers and presidents, with the suggestion that they

route it to the person responsible for health and safety matters. This approach sought to demonstrate the

importance of the survey and to ensure that the questionnaire quickly got to the appropriate person in the

organization, thereby increasing the chances of a timely response.

Questionnaires were accompanied by two one-page

letters-one from OTA’s Director, John H. Gibbons,

and one from NORC’s project director, Cynthia

Thomas—and by a post card and a return envelope.

A list of the names of the members of the project’s

advisory panel also was enclosed. (See app. C for copies

of the questionnaire, letters, and advisory panel membership list.)

NORC began followup procedures on April 19 by

sending 98 letters to nonrespondents. A second effort

involved telephone calls to 200 of the nonrespondents.

The effort concentrated on the top 100 companies of

the Fortune listing and on those in key industrial

groups, such as chemicals, rubber and plastic products, metal manufacturing, and pharmaceuticals.

By the June 8, 1982, cutoff date, 366 organizations

had answered the questionnaire, a 65.2-percent response rate, and 26 organizations had specifically declined to do so, a 4.6-percent refusal rate. Those who

declined generally gave either no reason for refusal

or the reason of corporate policy not to respond to

surveys. Questionnaires from seven more organizations were received after the cutoff date. None of these

organizations reported any testing activity and were

not substantially different from the earlier respondents. Since these reponses were received after the

close of the survey period, they are included as nonrespondents for analysis purposes.

Response pattern

Can the results of this survey be generalized to the

population of Fortune 500 companies, large utility

companies, and major unions? An answer to this involves two additional questions: Are the responses

equally distributed among the groups represented in

the survey? Are characteristics of the respondents different from the nonrespondents? These two questions

are discussed in turn.

Two weeks into the survey, April 13, 1982, approximately one-third (30.5 percent) of the contacted organizations returned the post card indicating they had

participated in the survey. At that time, little variation was seen in the response rate by size or type of

organization. The largest discrepancy was between

the unions, with a 27.3-percent response rate, and the

utility companies, with a 38-percent response rate. By

the close of the survey (June 8, 1982), however, the

discrepancy in response rate became quite noticeable.

The large corporations had the highest response rates:

68 percent for utilities and 61.5 percent for the top

200 companies in the Fortune 500 listing; the unions

and small corporations had the lowest response rates:

36.4 percent for unions and 44 percent among the bottom 300 companies in the Fortune 500 listing. (See

table A-l.) The variation in response pattern between

Table A-1 .—Distribution of Returned Post Cards by Organization Size and Type

Cumulative number of post cards received by:

Apr. 13, 1982 June 8, 1982

Organization size/type Yes No Percent received Yes No Percent received

Fortune 500 companies

Top 200 . . . . . . . . . . . . . . . . . . . . . 65 135 32.50/o 123 77 61 .50/0

Bottom 300 . . . . . . . . . . . . . . . . . . 64 216 28.0 132 168 44.0

Utilities: top 50. . . . . . . . . . . . . . . 19 31 38.0 34 16 68.0

Unions: 11 . . . . . . . . . . . . . . . . . . . 3 8 27.3 4 7 36.4

Total: 561 . . . . . . . . . . . . . . . . . . . 171 30.5 ”/0 293 52.20/o

SOURCE: National Opinion Research Center, survey conducted for OTA, 19S2
App. A—Survey Design and Methodology ● 177

April 13 and June 8 is undoubtedly due to a number

of factors, most probably the followup efforts which

began in the third week of the survey and focused on

the top 100 companies of the Fortune 500 listing and

organizations in selected industrial classifications such

as utilities. Thus, the results of this survey may be

more applicable to the larger manufacturing/mining

and utility companies than to smaller manufacturing/

mining companies and unions.

Analysis of selected characteristics of respondents

compared with nonrespondents is limited to the Fortune 500 companies. Nonrespondents were identified

by the process of elimination using the post card

responses. The 193 nonrespondents included the 38

companies that sent in anonymous questionnaires but

no post card. Respondents and nonrespondents were

compared on the following characteristics: geographic

location, size of organization, and type of industry.

Rates of response and nonresponse did not differ

greatly geographically. (See table A-2.) The largest variation occurred among the Central States where a

5-percentage-point variation occurred between the

nonrespondents and the respondents. For size of company, however, the rate of nonresponses did differ

widely from the rate of responses. (See table A-3. ) For

example, 53 percent of the nonrespondents were in

the smallest companies, compared with 32 percent of

the respondents. This discrepancy was not unexpected, because the followup concentrated on larger

companies and the response rates may reflect these

efforts. Rate of nonresponse did not vary greatly from

rate of response with respect to industry classification. (See table A-4. ) Eleven industries had a slightly

higher rate of response than predicted, as evidenced

by a comparison with the expected response rate (total

company rate). Of these industries, five (chemicals,

petroleum refining, rubber and plastic products, metal

manufacturing, and pharmaceuticals) were the key industries selected for followup activities and the rates

for the remaining six (glass/concrete, electronics, measuring equipment, motor vehicles, aerospace, and office equipment) may be explained by such factors as

the effect of followup based on size of company or

chance.

Thus, whereas the results of the survey may be

more representative of the larger manufacturing/

Table A-2.—Distribution of Nonrespondents, Respondents, and Total Companies by Geographic Location

(based on Fortune 500 companies)

Non respondents Respondents Total companies

Percent of total Percent of total Percent of total

Geographic Iocationa Number nonrespondents Number respondents Number companies

Northeast . . . . . . . . . . . . . . . . . . . . . . . . . . 82 420/o 133 43% 215 430/0

Southeast. . . . . . . . . . . . . . . . . . . . . . . . . . 8 4 22 7 30 6

Central . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 41 111 36 191 38

Mountain . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1 7 2 9 2

West . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 11 34 11 55 11

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 307 500

aThe following are included i n the respective geographic locations

Northeast” Maine, Vermont, New Hampshire, Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Pennsylvania, Maryland, Delaware,

Southeast’ Virginia, North Carolina, South Carolina, Georgia, Florida, Alabama, Tennessee, Mississippi, Louisiana,.

Central” North Dakota, South Dakota, Nebraska, Kansas, Oklahoma, Texas, Montana, Iowa, Missouri, Arkansas, Michigan, Wisconsin, Illinois, Indiana, Ohio, Kentucky,

West V(rginla.

Mounfa/n. Montana, Wyoming, Utah, Colorado, New Mexico, Arizona.

West” Alaska, Hawaii, Washington, Idaho, Oregon, California, Nevada.

SOURCE National Opinion Research Center, survey conducted for OTA, 1982.

Table A-3.—Distribution of Nonrespondents, Respondents, and Total Companies by Size

(based on Fortune 500 companies)

Non respondents Respondents Total companies

Percent of total Percent of total Percent of total

Size of companv , . Number nonrespondents Number respondents Number companies

Fortune 100 . . . . . . . . . . . . . . . . . . . . . . . . 29 15% 71 230/o 100 20 ”/0

Fortune 200 and 300 . . . . . . . . . . . . . . . . 62 32 138 45 200 40

Fortune 400 and 500 . . . . . . . . . . . . . . . . 102 53 98 32 200 40

Total . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 307 500

SOURCE” National Opinion Research Center, suwey conducted for OTA, 1982.
178 The Role of Genetic Testing in the Prevention of Occupational Disease

Table A“4.—Distribution of Nonrespondents, Respondents, and Total Companies by Industry Classification

(based on Fortune 500 companies)

Non respondents Respondents Total companies

Percent of total Percent of total Percent of total

Industry classification Number nonrespondents Number respondents Number companies

Mining, crude oil . . . . . . . . . . . . . . . . . . .

Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Tobacco . . . . . . . . . . . . . . . . . . . . . . . . . . .

Textile. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Apparel . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Furniture . . . . . . . . . . . . . . . . . . . . . . . . . .

Paper, fiber, wood . . . . . . . . . . . . . . . . . .

Publishing, printing . . . . . . . . . . . . . . . . .

Chemicals . . . . . . . . . . . . . . . . . . . . . . . . .

Petroleum refining . . . . . . . . . . . . . . . . . .

Rubber, plastic . . . . . . . . . . . . . . . . . . . . .

Leather . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Glass, concrete. . . . . . . . . . . . . . . . . . . . .

Metal manufacturing . . . . . . . . . . . . . . . .

Metal products . . . . . . . . . . . . . . . . . . . . .

Electronics, appliances . . . . . . . . . . . . . .

Shipbuilding, railroad, and

transportation equipment . . . . . . . . . .

Measuring equipment . . . . . . . . . . . . . . .

Motor vehicles . . . . . . . . . . . . . . . . . . . . .

Aerospace . . . . . . . . . . . . . . . . . . . . . . . . .

Pharmaceuticals . . . . . . . . . . . . . . . . . . . .

Soaps, cosmetics . . . . . . . . . . . . . . . . . . .

Office equipment . . . . . . . . . . . . . . . . . . .

Industrial and farm equipment . . . . . . . .

Musical instruments, toys. . . . . . . . . . . .

Broadcasting, motion pictures . . . . . . . .

Beverages . . . . . . . . . . . . . . . . . . . . . . . . .

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

7

23

1

5

5

1

16

8

12

11

2

1

3

14

11

12

4

4

6

3

6

3

3

23

3

3

3

193

3.670

11.9

0.5

2.6

2.6

0.5

8.3

4.1

6.2

5.7

1.0

0.5

1.6

7.2

5.7

6.2

2.1

2.1

3.1

1.6

3.1

1.6

1.6

11.9

1.6

1.6

1.6

6

31

3

8

4

0

14

5

28

30

4

1

13

24

12

25

5

11

13

11

11

5

10

20

2

3

8

307

2.0%

10.1

1.0

2.6

1.3

—

4.6

1.6

9.1

9.8

1.3

0.3

4.2

7.8

3.9

8.1

1.6

3.6

4.2

3.6

3.6

1.6

3.2

6.5

0.6

1.0

2.6

13

54

4

13

9

1

30

13

40

41

6

2

16

38

23

37

9

15

19

14

17

8

13

43

5

6

11

500

2,6%

10.8

0.8

2.6

1.8

0.2

6.0

2.6

8.0

8.2

1.2

0.4

3,2

7.6

4.6

7.4

1.8

3.0

3.8

2.8

3.4

1.6

2.6

8.6

1.0

1.2

2.2

alndu~trial ~la~~ification is based on Fortune 500 listing for each company; that listing was the Standard Industrial Classification Code

SOURCENational Opinion Research Centefi survey conducted forOTA, 19S2.

mining corporations and private utility companies as Appendix A reference

identified in Fortune magazine listings, the respond- l.Jones, WesleyH., “Generalizing Most Survey Inducement

ents do not appear to differ greatly from the non- Methods: Population Interactions With Anonymity and

respondents in geographic location or type of com- Sponsorship)” Public Opinion Quarter@, spring 1979,

pany. p. 108.
— ..——.

Appendix B

Report From the National Opinion

Research Center

WORKPLACE SURVEY :

BIOCHEMICAL GENETIC OR CYTOGENETIC

TESTING IN THE WORKPLACE --

PAST, PRESENT AND FUTURE

DRAFT REPORT

Prepared by

Cynthia Thoma s

National Opinion Research Center

Submitted t o

The Office of Technology Assessment

Contract Number 233-2450

First Draft : June 10, 1982

Revised; August 20, 1982

179
180 The Role of Genetic Testing in the Prevention of Occupationl Disease

SUMMARY

The National Opinion Research Center has conducted a mail survey of

the 500 largest U.S. Corporations, 11 unions, and 50 utilities to determine

how many organizations have ever engaged in or might be considering the use of

biochemical genetic or cytogenetic testing of employees or potentia l

employees . Ultimately , respondents from 373 organizations replied to the

questionnaire , either by mail or telephone , yielding a response rate o f

64.5%. Twenty-six organizations declined to complete the questionnaire ,

generally citing reasons of time or survey relevance . Six organization s

report that they are presently testing . Two of them are chemical companies ,

two are utilities and two are in the electronics industry . Seventeen

organizations have tested in the past . Only one organization reports current

testing but no past testing . Fifty-nine organizations (16.1% ) might possibl y

test in the future .
———. —

App. B—Report From the National Opinion Research Center ● 181

1 .

the

how

WORKPLACE SURVEY :

BIOCHEMICAL GENETIC OR CYTOGENETIC

TESTING IN THE WORKPLACE --

PAST, PRESENT AND FUTURE

INTRODUCTION

The National Opinion Research Center has conducted a mail survey of

500 largest U.S. corporations, 11 unions, and 50 utilities to determine

many organizations have ever engaged in or might be considering the use of

biochemical genetic or cytogenetic testing of employees or potential

employees. This survey contributes to a larger research effort conducted by

the Office of Technology Assessment for the Committee on Science and

Technology of the U.S. House of Representatives. The research questions the

survey was designed to address include:

(1) the frequency of past, present and anticipated biochemical

and/or cytogenetic testing in the workplace and whether it has

been conducted on a routine, special or research basis;

(2) the names of the tests used, for whom, and for what purpose;

(3) the actions, if any, taken by the company on the basis of the

results of the tests; and

(4) the criteria against which tests have been measured to

determine acceptability for use.

I I . METHODOLOGY

During February a pretest draft of the questionnaire was sent b y

Federal Express to twenty-five organizations in the Fortune 500. Th e

objective was to determine whether the questionnaire could be answered

properly and whether a reasonable rate of response could be expected. Without

any follow-up, approximately 50% of these organizations returned a completed
182 ● The Role of Genetic Testing in the Prevention of Occupational Disease

questionnaire Since only relatively minor changes in the formatting of the

instrument were required, and two items were deleted, we were able to include

these responses in the final analysis .

On March 25, 1982, questionnaires were sent to 475 chief executive

officers of the largest corporations , presidents of 11 unions and chief

executives of 50 utility companies. Questionnaires were accompanied by two

one-page letters , one from the Office of Technology Assessment, signed by John

Gibbons, the Director, and one from NORC, signed by Cynthia Thomas, NORC's

project director, and by a post card and a return envelope. A list of the

names of members of an advisory panel to OTA of experts in genetics,

occupational medicine, and law, also was enclosed.

The letter from OTA introduced the study by stating that the

Committee on Science and Technology of the U.S. House of Representatives had

asked for the assistance of leading organizations in completing the

questionnaire . The CEOs were asked to direct the questionnaires to their

chief executives for health affairs .

NORC's letter mentioned the importance of the study, the confidential nature of the information, and the use of a pre-paid post card to be

returned by the respondent indicating that a questionnaire was completed, in

order to keep the identity of responding organizations separate from the

questionnaires.

Half of the questionnaires were sent by Federal Express and half by

first class mail, since the budget for postage was limited. Two hundred cases

were targeted for follow-up telephone calls, with priority given to companies

in the Fortune 100 and in key industry groups, including those involved in
App. B—Report From the National Opinion Research Center ● 183

chemicals , rubber and plastic products , metal manufacturing, and”

pharmaceuticals .

From the pretest , we learned that the office of the chief executive ,

as suggested in the cover letter, often referred the questionnaire to someone

else in the organization , such as a chief medical officer. Sometimes severa l

subsidiaries had to be consulted before the questionnaire could be completed.

Consequently, it was realistic to expect the questionnaire to take several

weeks or more to be completed after its receipt. To allow enough time for

organizations to respond, the first telephone follow-ups during the main field

period were scheduled for the week of April 19. Up to and including the 20th

of April, 219 post cards and 239 questionnaires had been received.

Telephone follow-up calls were initiated with 200 of the

organizations which had not sent in post cards by April 21. The office of

the chief executive officer was contacted, the purpose of the study and the

urgency of a response was stated, and the respondent, generally an executive

secretary or administrative assistant, was asked to determine whether the

questionnaire had been received and, if so, who now had it. The procedure

usually either resulted in the request for an additional questionnaire, or the

identification of one or a series of executives to whom the questionnaire had

been referred .

Repeated follow-up calls were made to the offices of those reported

to be in possession of the questionnaire , each time allowing a reasonable time

period for the respondent to expedite the return of the post card before a n

additional call was made . Ultimately , 373 questionnaires were returned or the

information required to complete them was obtained by telephone or in a
184 ● The Role of Genetic Testing in the Prevention of Occupational Disease

letter, yielding a response rate of 64 .5%, including the pretest cases. The

number of post cards received was 307, including post cards from the pretest.

Twenty-six organizations declined to complete the questionnaire (4.6%),

generally citing reasons of time or survey relevance .

l Results presented i n

the following tables are based on responses received by June 1 (the first 366

cases). No questionnaires received after that date contained any instances of

testing. An analysis of non-respondents is presented in Appendix A.

1 Specifically, ten organizations stated that their policy is not to reply

to surveys.Three claimed they were not interested or had no time, one

objected to the methodology, and twelve refused by telephone giving no reason.
App. B—Report From the National Opinion Research Center ● 185

III . REVIEW OF Till? LITERATURE : SURVEY DESIGN METHODOLOGY

The survey was designed to obtain accurate responses from a

reasonably high proportion of potential respondents as cost efficiently as

possible, within a limited budget. Several issues related to the selection of

procedures for completing this survey have been addressed in the literature .

We were not able to find any studies dealing with the topic of biochemical

genetic and cytogenetic testing, however. Some of the advice in the

literature , and related approaches chosen for this study, are reviewed below.

Method of Administration

Typicallyserious studies of elite populations (people high in ,

status, income,or education) employ a personal interview, with open ended

questionsfor data collection. , Generally, however, such studies are

concerned with opinions and unusual experiences or perceptions. The

literature on elite interviewing, consequently, focuses on the conduct of

personal interviews and is of little help in providing guidance for this

survey,

2 which was completed by mail with telephone followups.

Most information to be obtained for this study was factual --

whether or not testing had taken place, and if so, what types of testing.

Consequently, the function of the elite respondent, the chief executive

officerwas to provide impetus for the questionnaire to be completed -- ,

principally by routing it to the appropriate official within his organizatio

Therefore,a personal interview was not necessarily appropriate. Indeed, the

2

See ,for example , Lewis Anthony Dexter,Elite and Specialized

Interviewin~ (EvanstonNorthwestern University Press, : 1970).
186 ● The Role of Genetic Testing in the Prevention of Occupational Disease

cost o f data collection was the principal criterion for selecting a method of

administering the instrument. Consequently, a survey by mail was selected as

the approach to data collection.

Obtaining a High Rate of Response

Most of the literature on obtaining high response rates for mail

surveys deals with surveys of the general population, and not with surveys of

organizations. 3 Nevertheless, some of the principles can be applied to

contacts with organizations.

Confidentiality/Anonymity

It is generally believed important to convey to respondents that the

information they provide will remain anonymous (as well as to ensure that it

does), especially when the topic may be a sensitive one. There were indica -

tions that corporations would find this topic of cytogenetic and biochemical

testing sensitive .

4 One study suggests that high income respondents are more

likely to react favorably to assurances of anonymity than those with lo w

incomes and, consequently , to complete questionnaires .

5 It was decided to

protect anonymity by omitting any identifying information on the questionnaire

and by asking respondents to send a post card naming their organization an d

indicating that a questionnaire had been completed .

3 See, for enmple, Don A. Dillman, Mail and Telephone Surveys: The Total

Design Method (New York: John Wiley & Sons, 1978).

4Articles in the New York Times had contributeci to the controversy.

5Wesley H. Jones, “Generalizing Mail Survey Inducement Methods:

Population Interactions with Anonymity and Sponsorship,” Public Opinion

Quarterly (POQ), Spring, 1979, p. 108.
App. B— Report From the National Opinion Research Center ● 187

There are several pitfalls to this approach that should be noted .

First, organizations may return post cards but not questionnaires, and vice

versa. (We received 307 post cards and 373 questionnaires; even some of these

may not have been matched pairs.) Second, organizations which did not return

post cards were contacted by telephone and, in some cases, were re-sent

questionnaires if they could not find them. Some of them may have sent in a

questionnaire without a post card and later completed and returned a second

questionnaire. We have no way to know whether this happened, but believe it

occured in only a couple of cases. It is also possible, of course, for

questionnaires or post cards to be lost in the mail or lost between the desk

of the chief executive officer and the company’s mail room.

Questionnaire Design

Instrument design, it has been found, can be important in dealing

with sensitive questions in an interview. Although methodological work on

this topic generally has dealt with face-to-face interviews of members of the

general population, some findings can be applied to this mail survey. 6 Ther e

are indications, for example, that whether to report any threatening behavior

is not influenced by such factors as question length. Reports on the amount

of a behavior, however,

response categories and

.

seem to be affected

the opportunity for

.

by availability of open–ended

the respondent to explain an

answer. Several questions in the survey were constructed to allow respondents

to explain or qualify their answers.

6 Norman M. Bradburn, et al., —— Improving Interview Method and Questionnaire

Design (San Francisco, Jossey–Bass Publishers, 1980), pp. 18-25.
188 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Importance Factor

The literature suggests that the more important the survey is

perceived to be by the respondent, the more likely (s)he is to complete a

questionnaire.

7 Several methods were used in this survey to convey a sense of

importance to respondents. Sponsorship of the study by the U.S. Congress was

emphasized,along with the possibility that hearings would be held. The

letter from OTA was individually addressed and signed by the Director. The

questionnaire was printed on a folded sheet of paper rather than xeroxed on

separate pages.As noted, some questionnaires were sent by Federal Express

and others by first class mail; both mailing methods indicate that the

communication is important. As shown below, however, the Federal Express

mailing may have conveyed a greater sense of importance than we ultimately

needed. Finally, during telephone followups, the caller once again conveyed

the urgent need for responses to the questionnaire.

‘See, for example Kent L. Tedin and C. Richard Hofstetter, “The Effect Of

Cost and Importance Factors on the Return Rate for Single and Multiple

Mailings,”Public Opinion Quarterly, Spring, 1982, pp. 122-127.
App. B—Report From the National Opinion Research Center ● 189

I v . RESULTS

Response Patterns

It is not easy to gain the attention of the chief executive officer s

of major corporations with a questionnaire, especially when many of them

report receiving hundreds a year and have established corporate policies of

not responding. Table 1 shows the cumulative totals of post cards received by

the end of each weekly time period during the main survey. Separate rates are

shown for organizations which received Federal Express versus first class

mailings . In Table 2, organizations also are listed according to whether they

are among the two hundred largest or three hundred smallest of the

corporations , or whether they are utilities or unions.

It can be seen from Table 1 that organizations that received the

questionnaire by Federal Express held a lead in the post card returns

throughout the survey period, but the size of the lead diminished

significantly after the first week. By the end of week 10, 52.9% of the 293

postcards received had been returned by organizations which had received a

Federal Express mailing; 47% of those returning post cards had received a

first class mailing. The small difference in rates of return suggests to NORC

that Federal Express was not a particularly cost effective method of maillng,

given that it cost $1,450 for the Federal Express mailings and only $50 for

those sent first class. The seventeen additional cases contributed by the more

expensive approach each cost $82 more than the others.

Whether better rates of response were obtained from larger or

smaller companies is of interest. It should be remembered that all of the 200

largest companies received telephone followups, whereas companies in the
190 ● The Role of Genetic Testingin the prevention Of Occupational Disease

bottom 300 were recontacted only if they belonged to a key industry group.

Table 2 shows that, prior to week 3, when telephone follow-ups began,

approximately 33% of the largest organizations had returned post cards,

whereas 28% of the smallest organizations had done so. Over time, the lead of

the largest corporations increased, suggesting that the impact of follow-up

activities was greatest for this group, as it should have been. Of course,

other factors as well may have contributed to the higher response rate of

larger companies. The response rate for utilities was relatively high, at

68%, and for unions low, at 36%.

Response Quality

Coverage

Generally, those responding to the questionnaire with whom we talked

on the telephone attempted to locate someone within the company with the

expertise to answer the questions. Some organizations in the Fortune 500 are

holding companies,’ owning subsidiary organizations that operate

autonomously. Some organizations refused to respond because they

to devote resources to contacting their subsidiaries to ask about

were unable

testing .

Others either answered to the best of their knowledge or made efforts to

contact their subsidiaries. We have no knowledge about the level of effort

employed in completing each questionnaire.

7Fortune includes holding companies in their listings if more than 50% of

revenues are from manufacturing or mining.
App. B—Report From the National Opinion Research Center ● 191

Missing Data

A limitation of an anonymous questionnaire is that it is not

possible to contact the respondent about missing information or unclear

responses. Generally, the proportions of cases missing information on any

particular item was low. On questions 1-6, approximately 3% of respondents

failed to answer each item, generally by leaving it blank. Eight

questionnaires (2%) did not include enough information so that the company

could be classified as a corporation or utility.
Table 1

POST CARDS RECEIVED BY WEEK, BY TYPE OF MAILING,

(MAIN SURVEY ONLY )

Time Period

Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10

3/31 - 4/6 4/7 - 4/13 4/14 - 4/20 4/21 - 4/27 4/28 - 5/4 5/5 - 5/11 5/12 - 5/18 5/19 - 5/25 5/26 - 6/1 6/2 - 6/8

Cumu1. Cumul. Cumul. Cumul. Cumul. Cumul. Cumul. Cumul. Curall.

Number % Number % Number % Number % Number % Number % Number % Number % Number % Number %

PostCards :

Type of

Mailing :

Federa l

Express

First

Class

102 - 171 - 219 - 234 - 245 - 256 - 266 - 275 - 279 - 293 -

68 66.7 96 56.0 118 53.8 124 53.0 128 52.0 134 52.3 138 52.0 146 53.0 148 53. 0 155 52.9

34 32.4 75 43.4 101 46.1 110 47.0 117 48.0 122 48.0 128 48.0 129 47.0 131 47.0 138 47.0
App. B—Report From the National Opinion Research Center ● 193
194 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Testing: Overall Rates

The following tables summarize the answers to the various questions

on testing. Percentages are based on the total number of responses included

in the analysis : 366. The questionnaire contains the precise phrasing of

each question.

Few organizations report current biochemical genetic or cytogenetic

testing; slightly more have conducted any such tests in the past twelve years;

still more anticipate at least a possibility of conducting such tests in the

future . Organizations were instructed on the questionnaire to include in

their answers any instances of testing, so that positive responses can include

isolated instances of testing as well as long term testing programs. Table 3

summarizes these results by type of organization, main industrial

classification , and according to industrial group.

8 Among the six

organizations currently testing (1.6%), two of them are engaged in the

chemical industry as their principal activity. Two others are utilities, and

the other two are in the electronics industry.

Seventeen organizations (4.6%) have tested in the past. Half of

these are in the chemical industry. Of those organizations that have tested

in the past twelve years, five are still testing today. Only one organization

reports current testing hut no testing in the past twelve years.

8Each organization was rated according to the first industrial group into

which it classified itself and then according to other industrial categorie s

listed, up to three . The table shows testing by main (first) industrial

category and, in parentheses, any representation in that industry.
App. B—Report From the National Opinion Research Center ● 195

Table 3

TESTING : CURRENT, PAST AND FUTURE TESTERS

BY ORGANIZATION TYPE AND MAIN INDUSTRY

Current Testing

N = 6

Organization type:

Corporations

Unions

Utilities

Other

Main Industry:

Chemicals

Utilities

Petroleum

Pharmaceuticals

Rubbers, Plastics

Metals

All others (any others)

Total

4

0

2

2

2

0

0

0

0

2

6 (1.8%)

Past Testing Future Testing No Testing

N = 17 N = 59

16 49

0 0

1 9

1

8

1

0

0

0

0

8

17 (5.2%)

11

10

4

3

3

2

26

59 (18.1%)

N = 244

234

5

5

0

14

5

26

8

1

22

244

244 (74.8%)
196 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Fifty-nine organizations (16.1%) may test in the future, they report.

according

conducted

More animal testing is conducted than testing in the workplace,

to answers to question 18 on whether the organization ever has

test on animals. Twenty-four organizations report testing on

animals for chromosomal aberrations; ten have tested for genetic

predisposition to harmful effects from chemicals. Of those testing on

animals, five have ever tested on humans. (See Table 4.)

Table 4

ANIMAL TESTING, BY EVER TESTED IN WORKPLACE

Animal Test for:

Current or

Past Workplace Chromosomal Genetic

Testing aberrations Predisposition

N = 24 N = 10

No 20 9

Yes 4 1
App. B—Report From the National Opinion Research Center . 197

Types of Testing: Biochemical Genetic and Cytogenetic

Organizations that reported some biochemical genetic testing were

asked whether they had ever tested employees for any red blood cell and serum

disorders (A), liver detoxification systems (B), immune system markers (C), or

heterogygous chromosomal instabilities (D). Within each of these four broad

categories A through D, several examples were included. Of those testing,

there were fourteen organizations that have tested for red blood cell and

serum disorders (category A), three in category B, five in category C and no

organizations reporting a test in category D. Those organizations testing in

category A frequently have conducted more than one test within this category,

such as sickle cell trait, G-6-PD, or SAT. The most frequently used test is

that for sickle cell trait, for which ten organizations have tested. G–6-PD

and SAT were both the second most frequently used individual tests. (See

Table 5 for summary of the frequency of individual biochemical genetic tests.)

For each individual test, companies were asked about the purpose of

the testing and the type of employee tested. Testing was usually routine,

less often for research purposes, or conducted for other reasons. These other

reasons are not specified.

The type of employee chosen for testing was most often based on

ethnicity and race for sickle cell testing, and job category for other types

of tests. No organization reported basing a test on employees’ sex.

Organizations that report having conducted cytogenetic testing wer e

asked whether they had looked for chromosomal aberrations (CA), sister

chromatic exchanges (SCE), mutations by assaying the DNA (DNA), mutations by

assaying the enzymes (ENZ), or something else. Four organizations have tested

for chromosomal aberrations and two for SCE. No one claimed to have tested
198 . The Role of Genetic Testing in the Prevention of Occupational Disease
App. B—Report From the National Opinion Research Center ● 199

for mutations, by assaying either the DNA or the enzymes. CA testing was done

for unspecified reasons by three companies; SCE testing was done for research

purposes. Job category was the only one of the three employee-related

characteristics taken into account in deciding whom to test except for sickle

cell. (See Table 6.)

Several questions were asked for each type of testing (biochemical

genetic and cytogenetic) about factors considered in decisions to implement

testing programs and criteria employed in selecting specific tests. All

categories provided received at least one response. Ten responses indicated

that data was reviewed either from animal studies or from epidemiologic

studies in decisions on whether to perform biochemical genetic testing. In

four instances, such reviews were conducted in deciding whether to implement

cytogenetic testing. The various criteria for selecting a particular test

were fairly evenly employed, although cost appears to have been less important

than the various scientific criteria. (See Table 7 for the distribution of

responses.)

Results of Testin g

Organizations have taken a considerable range of actions as a result

of the biochemical genetic or cytogenetic testing programs they have

conducted. The most common action reported is informing an employee of a

potential problem . Eight organizations have taken such an action. Five o f

the categories are related to actions taken to inform the employee or to

protect him, ranging from the most minimum such activity - merely informing

the employee - to the most extreme, that of discontinuing a product.
200 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Employees were informed in eight Instances (out of the 18) and a product was

discontinued only once. In seven cases, an employee was either transferred or

another job was suggested. The actions taken, by frequency, are listed in

Table 8.
App. B—Report From the National Opinion Research Center ● 201

Table 7

TYPE OF TESTING BY

FACTORS/CRITERIA FOR SELECTING TESTS

Factors in implementing testing

Cost benefit analysis

Data from animal studies

Data-epidemiologic studie s

Legal consequences of not

testing

Unions/employee initiative

Other

No response

Biochemical

genetic Cytogenetic

N-17 N-18

Number Number

2

4

6

3

0

2

2

0

3 0

4

a

3

a

2 0

Criteria for selecting tests

Predictive value of test 5 1

Sensitivity of tes t 3 0

Specificity of test 5 1

Scientific consensus 4 2

Cost of test 2 0

Other 4

3

b

No response 2 1

alncludeS reasons related to protecting employees, research ‘indin~s*

blnC~ude~ research findings t13enera~J*
202 The Role of Genetic Testing in the Prevention of Occupational Disease

Table 8

RESULTS OF TESTING

N = 18

Action Type Number

Informed employee

Transferred employee

Personal protection devices

Other action

Suggested other job

Engineering controls

Implemented research program

Discontinued/changed product

8

5

3

3

2

2

1

1

Comments on the Questionnaire/Postcards

Respondents were encouraged to qualify their responses or to comment

on the questionnaire either on the questionnaire itself or on the postcard.

Three companies currently testing provided comments on their questionnaires.

One of them stated that their . . . “Answers should not be taken to imply any

large scale program or problem.” Once mentioned testing for pre-placement and

as a part of annual physicals. The third uses testing in “continuing health

evaluations” of certain employees.

Two former testers offered comments. One claimed that testing had

been used at the request of the State health department for a brief period.
App. B—Report From the National Opinion Research Center ● 203

Another reported sickle cell testing as part of a “preventive medical program”

on certain people of child bearing age.

Seven possible testers made comments. One noted that “what may be

done will depend upon demonstrations that indicated procedures have practical

utility. ” Others expressed observations about the potential for testing in

their organization.

Comments received on post cards and from organizations which have

never tested, and have no plans to test (approximately 37 were received)

ranged from statements that the questions were inappropriate to their

organizations to beliefs that testing had no proven value. Many questioned

the usefulness of the survey. Several organizations felt that the

questionnaire could be misleading becuase information was not requested on how

much testing was done.

v. CONCLUSIONS

There was great uncertainty at the onset of this study as to whether

to expect any cytogenetic or biochemical genetic testing among the major U.S.

corporations, unions and utilities. Six organizations, however, did report

testing. Of the organizations that tested in the past, only one continues to

test , suggesting a tendency for testing to decline. On the other hand, fiftynine organizations answered “possibly” to the question of whether they

anticipated conducting testing in the next five years.

It is interesting to speculate as to why so many organizations may

have stated that they “possibly ” anticipate conducting testing in the nex t

five years , especially since many organizations have dropped their testing
204 The Role of Genetic Testing in the Prevention of Occupational Disease

programs . Some may have chosen to hedge their bets -- as a result of the

current controversy surrounding the issue , perhaps good reasons for testing ,

not now apparent to them, may surface. Perhaps, also , some are not aware of

the issues surrounding testing and simply do not know whether this topic ma y

some day apply to them.
App. B—Report From the National Opinion Research Center 205

APPENDIX A1

ANALYSIS OF NONRESPONDENTS

The analysis of nonrespondents among the Fortune 500 companies is based

upon 193 cases , including 38 companies who sent in anonymous questionnaires

but did not send in postcards identifying themselves as respondents .

Geographically, nonrespondents , like respondents, were spread fairl y

evenly across the country, as shown in Table A-1.

TABLE A-1

LOCATION OF ALL COMPANIES AND NONRESPONDENTS

Region Nonrespondents Companies

Number Proportion Number Proportion

Northeas t 82 42% 215 43%

Southeas t 8 4% 30 6%

Centra l 80 41% 191 38%

Mountain 2 1% 9 2%

West 21 11% 55 11X

The nonrespondents were concentrated in the smaller two hundred

companies. This most probably reflects the fact that our follow-up activities

focused on the larger three hundred companies, in addition to industries in

key industrial groups . The breakdown of nonrespondents by company size is

shown in Table A-2.

1 This appendix was prepared by Ken Cohen.
206 The Role of Genetic Testing in the Prevention of Occupational Disease

TABLE A-2

SIZE OF NONRESPONDING COMPANIES

Nonrespondents

Size of Company Number Proportion

Fortune 100 29 15%

Fortune 200-300 62 32%

Fortune 400-500 102 52%

Companies in the combined key code industries (chemicals, petroleum

refining, rubber and plastic products, metal manufacturing and

pharmaceuticals) had a nonresponce rate of 31%, which is somewhat lower than

the overall nonrepsonse rate of 38.6% for the Fortune 500 companies . (Again,

these companies were the focus of our follow-up efforts). Otherwise,

particular industries did not deviate significantly from the overall rates .

The breakdown by industrial type is given in Table A-3.

Conclusion

These tables to not suggest that any particular type of organization wa s

more likely than any other to refuse to respond to the questionnaire .
—

App. B—Report From the National Opinion Research Center ● 207

TABLE A-3

NONRESPONDENTS BY INDUSTRY TYPE

Nonrespondents Total Companies

Industry Type Number Proportion Number Proportion

10 - Mining, Crude Oil

20 - Food

21 - Tobacco

22 - Textile

23 - Apparel

25 - Furniture

26 - Paper, Fiber, Wood

27 - Publishing, Printing

28 - Chemicals

29 - Petroleum Refining

30 - Rubber, Plasti c

31 - Leather

32 - Glass, Concrete

33 - Metal Manufacturing

34 - Metal Products

36 - Electronics, Appliances

37 - Shipbuilding, Railroad &

Transport Equipment

7

23

1

5

5

1

16

8

11

11

2

1

3

14

11

10

4

3.6%

11.9%

- - -

2.5%

2.5%

- - -

4%

5.7%

5*7%

- - -

- - -

- - -

7.2%

5.7%

5.2%

2%

13

54

4

13

9

1

30

13

40

41

6

2

16

38

23

37

9

2.6%

10.8%

---

2.6%

1.8%

---

6%

2.6%

8%

8%

1.2%

---

3.2%

7.6%

4.6%

7.4%

1.8%
208 Ž The Role of Genetic Testing in the Prevention of Occupational Disease

Total Companies

Industry Type Number Proportion Number Proportion

38 - Measuring Equipment 4 2% 15 2.6%

40 - Motor vehicle s 5 2.5% 19 3.8%

41 - Aerospace 3

- - - 14 2.8%

43 - Soaps, Cosmetics 3 - - - 8 1.6%

44 - Office Equipment 3

- - - 13 2.6%

45 - Industrial & Farm

Equipment 23 11.9% 43 8.6%

46 - Jewelry, Silverwar e o

- - - 0

- - -

47 - Musical Instruments ,

Toys 3

- - - 5 1%

48 - Broadcasting ,

Motion Picture s 3

- - - 6 1.2%

49 - Beverages 3

- - - 11 2.2%
Appendix C

Survey Materials

Trcnwmmr ASSESSMEW fWARO Uungrtd$ of tfie 31ttiteb f%!af~s -HN U. Glf3mw

ITD STP4ENS, A14SKA, CHAIRMAN

O FFICE OF T ECHNOLOGY A SSESSMEN T

-~

MORRIS K. UDAl& ARI?L, VICE CHAIRMAN

ORRIW 0. NATCM. UTAH GEORGE E. f3ROWN, Jm.. WF.

CHAR- McC. MA7?+IA8. J“- MO. JONN O. D(NGEU MICH. WASHINGTON , D.C. 20510

~wARO M. KEN PWDY. MAsS. tiRRy wlNN, Jn.. tiNg.

CR NIZ7 F. HOUING9, S.C. GREN= E. MIwR, OHIO

HOW&30 W. -NQ4. NW. CQOPER EVAMS, lOWA

JoHu IL OlclooNs March 22, 1982

Dear Mr.

The Committee on Science and Technology of the U.S. House of Representatives

has requested this off ice to carry out a comprehensive study of the policy is sues

arising from potentia1 occupationa1 genetic testing. The Committee expects the

study to provide the Congress with full and fair in formation on a complex and

sensitive topic. A crucial component of our study will be information and advice

from leading U.S. corporations. Since your company is a world leader in many areas

relevant to the study, we believe it is extremely important for us to benefit from

any experience you may have with such testing programs.

The Office of Technology Assessment (OTA) is a nonpartisan congressional

agency that assists the Congress in dealing with complex technical issues. OTA is

governed by a bipartisan Congressional board composed of six Representatives and

six Senators. A council of ten members eminent ‘in science, technology, and

education serves in an advisory capacity. This study is also being assisted by an

advisory panel of experts in genetics, occupational. medicine, law, and policy from

industry, labor, and academia. A list of advisory panel members and their

affiliations is enclosed.

We have asked the National Opinion Research Center of the University of

Chicago (NORC) to assist OTA by collecting and processing data via a questionnaire.

The data will be presented to OTA in aggregate form only, and the raw data will be

destroyed.

NORC’S brief questionnaire is attached. We believe it will be most helpful

if you direct it to your chief executive for health affairs. We respectfully

request a response to the questionnaire as soon as possible and are prepared to

share the results of the analysis with you when it is completed.

If you have any questions about the study or about OTA, please “feel free to

contact me at (202) 224-3695, or Geoffrey M. Karny, OTA project director, at (202)

226-2090. Cynthia Thomas, NORC project director, can be contacted about the survey

at (212) 971-8200.

Sincerely,

&

,

John H. Gibbons

209
210 ● The Role of Genetic Testing in the Prevention of Occupational Disease

NORC

National Opinion Research Center University of Chicago

461 Eighth Avenue New York, N. Y 10001 212/971-8200

March 23, 1982

As one of the leading corporations in this country, your organization has

been selected to participate in an important survey we are conducting for the

Office of Technology Assessment (OTA) of the United States Congress on the

state–of-the-art of genetic and cytogenetic testing programs. The enclosed

letter from the OTA describes this study in more detail.

The National Opinion Research Center (NORC) is a not–for-profit academic

research corporation affiliated with the University of Chicago. The oldest

survey research facility established to do social research in the public

interest, NORC has conducted over a thousand studies since its founding in

1941, and has developed careful and systematic methods for ensuring

confidentiality. Names are never associated with responses to questions, and

data collected are used only for statistical purposes.

It is very important that you complete the enclosed brief questionnaire

as soon as possible. Your answers to the questions should include any

instance of testing in your corporation, or in any of your subsidiary

companies.

To ensure confidentiality, the questionnaire carries no identifying

information. Please mail the completed questionnaire in, the prepaid NORC

envelope. Then, complete and mail the enclosed prepaid post-card. This will

inform us that you have participated in the survey by completing a

questionnaire.

If you have any questions about the questionnaire, please feel free to

telephone me at (212) 971-8200.

Thank you very much.

Sincerely yours,

Cynthia Thomas

Project Director
. .

App. C—Survey Materials . 211

NORC/4354 3/82

WORKPLACE SURVEY

INSTRUCTIONS FOR COMPLETING THE QUESTIONNAIRE

The questions concern biochemical genetic and/or cytogenetic testing that may have

been conducted by your company on one or more employees or potential employees.

By conduct we mean do, contract for, or arrange for. By biochemical genetic tests

we mean tests which screen healthy, asymptomatic individuals for the particular

genetic traits listed in question 7, and not standard blood chemistry tests or

tests used solely for diagnosis. Cytogenetic tests are intended to detect

chromosomal aberrations or sister chromatid exchanges.

Do not sign the questionnaire or record any identifying information on it.

Answers should include any instances of testing in your corporation.

Please return the questionnaire to NORC before April 12.

1. Is your company currently conducting biochemical

Yes N O

genetic testing of employees or potentia1

employees ?

2. Has your company conducted any biochemical

genetic testing of employees or potential

employees in the past twelve years?

3 . Does your company anticipate conducting

biochemical genetic testing in the next five Yes No

years?

Possibly

4. Is your company currently conducting cytogenetic

testing of employees or potential employees ? Yes N o

5 . Has your company conducted any cytogenetic Yes

testing of employees or potential employees in

No 

the past twelve years?

6. Does your company anticipate conducting

cytogenetic testing during the next five years? Yes No

possibly

IF YOUR COMPANY NEVER HAS DONE EITHER BIOCHEMICAL GENETIC OR CYTOGENETIC TESTING,

SKIP TO QUESTION 18.

—
212 . The Role of Genetic Testing in the Prevention of Occupational Disease

IF BIOCHEMICAL GENETIC TESTING HAS EVER BEEN DONE, PLEASE ANSWER QUESTIONS 7-11. If NOT, PLEASE

7. Has your company tested workers for . . .

SKIP TO Q. 12.

Yes No

• 1

c1

• 1

A.

B.

c.

D.

any red blood cell and serum disorders, Including sickle cell trait, glucose-6-phosphate

dehydrogenase deficiency (G-6-PD), methemoglobin reductase deficiency, serum alpha-lantitrypsin deficiency (SAT), alpha and beta thalassemias?

any liver detoxification systems, including aryl hydrocarbon hydroxylase inducibility

(AHH), slow VS fast acetylation?

any immune system markers, including allergic respiratory disease, contact dermatitis,

histocompatibility markers (HLA)?

any heterozygous chromosomal instabilities, including Bloom syndrome, Fanconi syndrome,

ataxia-telangiectasia, xeroderma pigmentosum?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., G-6-PD). Answer Questions 8 & 9 FOR EACH. IF more than4

CONDITIONS, RECORD ON ADDITIONAL SHEET OF PAPER.

ENTER SPECIFIC CONDITION NAME HERE--->

Yes No — —Yes —No Yes —No Yea —No

8 . Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purpo.sea (e.g.,

hypothesis testing)?

❑ 0

❑ 0

c) for any other reasons?

9 . Was testing.to detect increased risk of

disease ● ver based on m ● mplope’e . . .

a) job category? ❑ o

b) sex?

c) ethnic or racial background?

❑ !J

10. What factors have been considered in A. Cost benefit analysis n

decisions to implement any biochemi- B. Data suggesting a possible association

cdl genetic testing programs? between chemical exposure and illness

in animal studies

c. Data suggesting a possible association

between chemical exposure and illness

in ● pidemiologic studies

D. Legal consequences of failure to test u

E . Union/employee initiative

F. Something ● lse. What?

Predictive value of the teat D. Scientific consensus

Cost of the teat

11. What criteria were ● mployed

choice of a specific test?

in t h e A.

B.

c.

Sensitivity of the test E.

Specificity of the test F. Something else. What?
—.

App. C—Survey Materials ● 213

IF CYTOGENETIC TESTING HAS EVER BEEN DONE, PLEASE ANSWER QUESTIONS 12-16.IF NOT, PLEASE SKIP TO Q. 18.

12. Has your company tested workers for exposure to chemicals by looking for . . .

A.

B.

c.

D.

E.

chromosomal aberrations

sister chromatid exchanges (SCE)

mutations by assaying the D N A

mutations by assaying the enzymes

something else? What?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., SCE). ANSWER QUESTIONS 13 & 14 FOR EACH. IF MORE THAN

CONDITIONS, RECORD ON ADDITIONAL SHEET OF PAPER.

ENTER SPECIFIC CONDITION NAME HERE--)

1 3 . Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purposes (e.g.,

hypothesis testing)?

c) for any other reasons?

14. Was testing to detect increased risk of

disease ever based on an employees. . .

a) job category?

b) sex?

c) ethnic or racial background?

Yes No — —

❑ lcl

❑ 0

❑ i l

❑ !3

Yes No —

❑ 0

❑ 0

❑ n

❑ n

Yes No .Yes No —

❑ 0

❑ o

❑ 0

❑ 0

❑ 0

15. What factors have been considered in A.

decisions to implement any cytogenetic testing programs?

B.

c.

D.

E .

F .

Cost benefit analysis

Data suggesting a possible association

between chemical exposure and illness

in animal studies

Data suggesting a possible association

between chemical ● xposure and illness

in epidemiologic studies

Legal consequences of failure to teat

Union/employee initiative

Something else. What?

16. What criteria were employed in the

choice of a specific test?

A. Predictive value of the test D. Scientific consensus ❑

B. Sensitivity of the test E. Coat of the test

C. Specificity of the test F. Something ● lee. What? ❑
214 . The Role of Genetic Testing in the Prevention of Occupational Disease

17. Which actions has your company ever taken as a result of biochemical genetic or cytogenetic

testing ?

A. Informed employee of a potential E. Recommended personal protection

problem devices

B. Suggested employee seek job elsewhere F. Implemented a research program

c . Placed an employee or transferred an G. Discontinued a product or changed —

employee to a different job in the

• 1

materials in a product

company

H. Some other action. What? u

D. Implemented engineering controls

18. Has your company ever conducted any testing on whole

animals or their cultured cells for . . . Yes No —

A. chromosomal aberrations or sister chromatid exchanges

as a result of exposure to workplace chemicals? ❑ o

B. genetic predisposition to harmful effects from exposure

to workplace chemicals?

19. What is the major industrial classification of your company (such as chemicals, food

or textiles)?

20. Please use this space for your comments, if any, about these questions.

Thank you for completing this questionnaire. The information you have provided will be held in

strict confidence. Data will be made available to Congress in statistical form only.
App. C—Survey Materials ● 215

T EC H NO LOGY ASSESSMRW E30AR0 aQllguw50[ tbe ?!Mttl !iMIk$ JOHN H. GIBBONS

TED STEVCN!3. AUSKA. CHAlf? MAN

MORRIS K. UDALI- ARIZ.. VICE CHAli?MAN O FFICE OF T ECHNOLOGY A SSESSMEN T

OI?F?IN O. HATcH. UTA H CCORGE E. DROWN. JR. ~.

CHARLES A-C. AA ATH1-% Jm. UO. JoHN D. DING ELI- MlCM. WASHINGTON, D.C. 20510

U)WARD M. KCNNllDY. MA$25. URfl Y WINN. in. KANS.

CRNE5T F. HOLUNOS. S-C CLARCNCIZ E. MIU-ER. OHIO

NOWARO w. CANNON. NW. CCIOPFX EVAJW, IOWA

JONN N. alllams March 22, 1982

Dear Mr.

The Committee on Science and Technology of the U. S . House of Representatives

has requested this o f f i c e to carry out a comprehensive study of the policy is sues

arising from potential occupational genetic testing. The Committee expects the

study to provide the Congress with full and f a i r information on a complex and

sensitive topic . A crucial component of our study will be information and advice

from leading U.S. labor organizations. Since your union is a world leader in many

areas relevant to the study, we believe it is extremely important for us to benefit

from any experience you may have with such testing programs.

The Office of Technology Assessment (OTA) is a nonpartisan congressional

agency that assists the Congress in dealing with complex technical issues. OTA is

governed by a bipartisan Congressional board composed of six Representatives and

six Senators. A council of ten members eminent in science, technology, and

education serves in an advisory capacity. This study is also being assisted by an

advisory panel of experts in genetics, occupational medicine, law, and policy from

industry, labor, and academia. A list of advisory panel members and their

affiliations is enclosed.

We have asked the National Opinion Research Center of the University of

Chicago (NORC) to assist OTA by collecting and processing data via a questionnaire.

The data will be presented to OTA in “aggregate form only, and the raw data will be

destroyed.

NORC’S brief questionnaire is attached. We believe it will be most helpful

if you direct it to your director for health and safety. We respectfully request a

response to the questionnaire as soon as possible and are prepared to share the

results of the analysis with YOU when it is completed.

If you have any questions about the study or about OTA, please feel free

to contact me at (202) 224-3695, or Geoffrey M. Karny OTA Project director} at

(202) 226-2090. Cynthia Thomas, NORC project director, can be contacted about

the survey at (212) 971-8200.

Sincerely,
216 ● The Role of Genetic Testing in the Prevention of Occupational Disease

NORC

National Opinion Research Center “University of Chicago

461 Eighth Avenue New York, N. Y. 10001 212 /971 -8200

March 23, 1982

Dear

As one of the leading unions in this country, you have been selected to

participate in an Important survey we are conducting for the Office of

Technology Assessment (OTA) of the United States Congress on the state-of-theart of genetic and cytogenetic testing programs. The enclosed letter from the

OTA describes this study in more detail.

The National Opinion Research Center (NORC) is a not-for–profit academic

research corporation affiliated with the University of Chicago. The oldest

survey research facility established to do social research in the public

interest, NORC has conducted over a thousand studies since its founding in

1941, and has developed. careful and systematic methods for ensuring

confidentiality. Names are never associated with responses to questions, and

data collected are used only for statistical purposes.

It is very important that you complete the enclosed brief questionnaire

as soon as possible. Your answers to the questions should include any

instance of testing in your union.

To ensure confidentiality, the questionnaire carries no identifying

information. Please mail the completed questionnaire in the prepaid NORC

envelope. Then, complete and mail the enclosed prepaid post–card. This will

inform us that you have participated in the survey by completing a

questionnaire.

If you have any questions about the questionnaire, please feel free to

telephone me at (212) 971-8200.

Thank you very much.

Sincerely yours,

Cynthia Thomas

Project Director
App. C—Survey Materials Ž 217

NORC/4354 3/82

WORKPLACE SURVEY

INSTRUCTIONS FOR COMPLETING THE QUESTIONNAIRE

The questions concern biochemical genetic and/or cytogenetic testing that may have

been conducted by your union on one or more union members or potential members.

By conduct we mean do, contract for, or arrange for. By biochemical genetic tests

we mean tests which screen healthy, asymptomatic individuals for the particular

genetic traits listed in question 7, “ “ and not standard blood chemistry tests or

tests used solely for diagnosis. Cytogenetic tests detect chromosomal aberrations

or sister chromatid exchanges.

Do not sign the questionnaire or record any identifying information on it.

Answers should include any instances of testing in your union.

Please return the questionnaire to NORC before April 12.

1. Is your union currently conducting biochemical

genetic testing of members or potential members? Yes N o

2 . Has your union conducted any biochemical geneti c

testing of members or potential members in th e Yes N o

past twelve years?

3 . Does your union anticipate conducting biochemical

genetic testing in the next five years? Yes N o

Possibly

4 . Is your union currently conducting cytogenetic

testing of members or potential members? Yes N o

5. Has your union conducted any cytogenetic testing

of members or potential members in the past Yes N o

twelve years?

6. Does your union anticipate conducting cytogenetic

testing during the next five years? Yes No

Possibly

IF YOUR UNION NEVER HAS DONE EITHER BIOCHEMICAL GENETIC OR CYTOGENETIC TESTING,

SKIP TO QUESTION 18.

—
218 ● The Role of Genetic Testing in the Prevention of Occupational Disease

IF BIOCHEMICAL GENETIC TESTING HAS EVER BEEN DONE, PLEASE ANSWER QUESTIONS 7-11. IF NOT, PLEASE SKIP TO Q. 12.

7.

Yes No

Has your union tested members for . . .

A.

B.

c.

D.

any red blood cell and serum disorders, including sickle cell trait, glucose-6-phosphate

dehydrogenase deficiency (G-6-PD), methemoglobin reductase deficiency, serum alpha-lantitrypsin deficiency (SAT), alpha and beta thalassemias? ❑ 0

any Liver detoxification systems, including aryl hydrocarbon hydroxylase inducibility

(AHH), slow vs fast acetylation? ❑ 0

any immune system markers including allergic respiratory disease, contact dermatitis,

histocompatibility markers (KM)? ❑ ID

any heterozygous chromasomal instabilities including Bloom syndrome, Fanconi syndrome,

ataxia-telangiectasia,xeroderma pigmentosum?

ENTER BELOW NAME OF EACH SPECIFIC (CONDITION TESTED FOR (e.g., G-6-PD). ANSWER QUESTIONS 8 & 9 FOR EACH.IF MORE THAN 4

(CONDITIONS, RECORD ON ADDITIONAL SKEET OF PAPER.

 SPECIFIC CONDITION NAME HERE-)

8. Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purposes (e.g.,

hypothesis testing)?

c) for any other reasons?

9 . Was testing to detect increased risk of

disease ever based on a member’s . . .

a) job category?

b) sex ?

c) ethnic or racial background?

Yea No — —

❑ n

❑ 0

❑ O

❑ 0

❑ n

❑ ID

10. What factors have been considered in A.

decisions to implement any biochemi- B.

cal genetic testing programs?

c.

D.

E.

F.

❑ 0

❑ o

❑ 0

❑ 0

Yea No Yes No — —

❑ 0

❑ n

❑ 0

❑ 0 ❑ 0

❑ 0

Cost benefit analysis u

Data suggesting a possible association

between chemical exposure and illness

in animal studies

Data suggesting a possible association

between chemical exposure and illness

in epidemiologic studies 1--1

Legal consequences of failure to test

Union member initiative

Something else , What?

11. What criteria were employed

choice of a specific test?

in the A. Predictive value of the test D. Scientific consensus ❑

B. Sensitivity of the test E. Coat of the test ❑

C. Specificity of the test P. Something else. What? ❑
App. C—Survey Materials ● 219

IF’ CYTOGENETIC TESTING HAS EVER BEEN DONE , PLEASE ANSWER QUESTIONS 12-16. IF NOT, PLEASE SKIP TO Q. 18.

1 2 . Has your union tested members for exposure to chemicals by looking for . . .

Yes No

A. chromosomal aberrations

B. sister chromatid exchanges (SCE)

. mutations by assaying the DNA

D. ❑ utatfons by assaying the enzymes ❑ 0

E. something else? What?

ENTER BELOW NAME OF EACH SPECIFIC CONDITION TESTED FOR (e.g., SCE). ANSWKR QUESTIONS 13 & 14 FOR FACE. IF MORE THAN 4

CONDITIONS, RECORD ON ADDITIONAL SHEET Ok’ PAPER.

ENTER SPECIFIC CONDITION NAME HERE-:

13. Was testing done . . .

a) routinely (e.g., yearly) or during

regular specified circumstances?

b) for research purposes (e.g.,

hypotheses testing)?

c ) for any other reasons?

14. Was testing to detect increased risk of

disease ever based on a member’s . . .

a) job category?

b) sex ?

c ) ethnic or racial background?

I I

Yes No Yes — —

❑ o• 1

No Yes No

. —

❑ lcl

❑ n ❑ 0

❑ n ❑ lcl

❑ 0 ❑ n

❑ o

❑ 0 ❑ o ❑ o

15. What factors have been considered in A. Coat benefit analysis

decisions to implement any cytogenetic testing programs?

B. Data suggesting a possible association

between chemical exposure and illness

in animal studies

c. Data suggesting a possible association

between chemical exposure and illness

in epidemologic studies

D). Legal consequences of failure to test

E. Union member initiative

Q. Something else. What?

Yes No —

❑ icl

❑ 0

❑ (3

❑ 0

❑

❑

16. What criteria were employed

choice of a specific test?

in the A. Predictive value of the test • 1 D.

B. Sensitivity of the test E .

C. Specificity of the test F.

Scientific consensus

Cost of the test ❑

Something else . What ? ❑
220 ● The Role of Genetic Testing in the Prevention of Occupational Disease

.7.. Which actions has your union ever taken as a result of biochemical genetic or cytogenetic

Ž

●

✎ ✎ ✎

.

. .

Informed member of a potential

problem

Suggested member seek job

elsewhere

Suggested member seek transfer to

a different job in the corporation u

Recommended corporation implement

engineering controls u

Recommended corporation provide

personal protection devices

F. Recommended corporation implement

a research program

G. Recommended corporation discontinue

a product or change materials in a

produc t

H. Implemented our own research

program

I . Negotiated items C,D, E or F in

a health/safety contract

J. Some other action. What?

❑

8. Has your union ever conducted any testing on whole

animals or their cultured cells for . . . Yes’

A. chromosomal aberrations or sister chromatid exchanges

as a result of exposure to workplace chemicals?

B. genetic predisposition to harmful effects from exposure

to workplace chemicals?

Q9. What are the major industrial classifications (such as chemical, food, or textiles) of

those companies in the Fortune 500 in which your members work?

0. Please use this space for your comments, if any, about these questions.

Thank you for completing this questionnaire. The information you have provided will be held in

strict confidence. Data will be made available to Congress in statistical form only.
●

App. C—Survey Materials . 221

OCCUPATIONAL GENETIC TESTING ADVISORY PANEL

Arthur D. Bloom, M. D., Chair

Professor of Pediatrics

Director of Clinical Genetics

and Development

Columbia University

J. Grant Brewen, Ph.D.

Director

Molecular and Applied Genetics

Laboratory

Allied Chemical Corporation

Eula Bingham, Ph.D .

Professor, Environmental Health

University of Cincinnati

Former Director, OSHA

Patricia Buffler, Ph.D.

Associate Dean for Research

and Associate Professor of

Epidemiology

University of Texas

School of Public Health

Ira Cisin, Ph.D.

Director, Social Research Group

George Washington University

Burford W. Culpepper, M.D.

Assistant Director, Medical

Division

E. I. DuPont de Nemours & Company

James D. English

Associate General Counsel

United Steel Workers of America

Neil Holtzman, M.D.

Associate Professor of Pediatrics

Johns Hopkins University

Thomas O. McGarity

Professor of Law

University of Texas at Austin

Rafael Moure, Ph.D.

Industrial Hygienist

Oil Chemical & Atomic Workers Union

Robert F. Murray, Jr., M.D.

Professor of Pediatrics and Medicine

Chief, Division of Medical Genetics

Howard University

College of Medicine

Elena Nightingale, M.D., Ph.D .

Senior Program Officer

Institute of Medicine

National Academy of Sciences

Gilbert Omenn, M.D., Ph.D.

Science and Public Policy Fellow

The Brookings Institution

William N. Rem, M.D., M.P.H.

Associate Professor of Medicine

Director, Rocky Mountain Center

for Occupational and Environmental Health

University of Utah

Stuart Schweitzer, Ph.D.

Professor and Director

Program in Health Planning

and Policy Analysis

UCLA School of Public Health

Robert Veatch, Ph.D.

Professor, Medical Ethics

The Kennedy Institute of Ethics

Georgetown University

Paul Kotin, M.D.

Consultant

Former Medical Director

Johns-Manville Corporation
222 Ž The Role of Genetic Testing in the Prevention of Occupational Disease

Respondent Comments About Survey

Respondents were asked to comment about any aspect of the survey or

questionnaire in a space provided on the questionnaire and one the postcard.

The following list comprises the totality of comments received from the

respondents. They have been grouped by status of tester: Current Tester,

past Tester, Future Testers with prior testing experience, and No Testing

(Past, Present, Future), Information contained at the end of a quote Is

descriptive information about the respondent provided by the contractor. In

cases where a number of appears, it is the Standard Industrial Classification

(SIC) Code as given by the respondent. The quotes are printed as written by

respondent. No editing has been done.

Comments by present testers

“Answers should not. be taken to imply any large scale program or problem.

Medical/Ind Hygiene depts have done ‘common sense’ preventive sampling and

testing to reassur e employees in specific small areas of company where eve n

low level risk might occur "

-presently biochemica l genetic testing and past biochemica l

genetic testin g

“We do a chemical profile (blood test) that tests 20 different factors (sic)

in the blood and CBC as a matter of course for pre-placement and annual

physical.”

-presently biochemical genetic testing and past biochemical

genetic testing

"Cytogenetic testing is one aspect of continuing health evaluations on

personnel engaged in “hands on” maintenance work in 500 KV electric

transmission lines.”

-presently cytogenetic testing and past cytogenetic testing

Comments by past testers

“Sickle cell trait testing was offered as a service to employees for a brief

period at the request of the state health department. It was never used as a

screening procedure in relation to the job.”

-past biochemical genetic testing
—.

App. C—Survey Materials ● 223

“Only testing has been for sickle trait or mediterranean anemia trait in a few

people of child bearing age as part of preventive medical program not

consistently”.

-past biochemical genetic testing

Comments by companies that anticipate future testing, but have not conducted

any testing to date:

“Company supports research activities relevant to No. 18 through trade

associations and C1lT.”

“Such tests as described in 18A are run on materials and products routinely as

part of an overall safety assessment.”

“Some essential questions have been omitted--namely,

1. are materials being used with chromosomal and/or genetic harmful

effects?

2. is there clinical evidence or even suspicion to justify

performing such tests? (in a given workplace)

3. are tests results indicators (valid and reliable) of actual o r

potential health risks to employees? ”

“18A, “Chromosomal aberrations” may be included in a mutagenic screen on

chemicals or as a followup to mutagenic testing.”

“It is conceivable we may wish to initiate a limited project of cytogenetic or

biochemical genetic testing in employees “exposed” to nuclear radiation in

next 5-10 years. Our stringent monitoring controls on radiation exposure may

not result in this requirement. However, it is just a possibility.”

“What may be done (#3 and #6) will depend upon demonstration that indicated

procedures have practical utility.”

FROM A UNION QUESTIONNAIRE: “(NAME DELECTED BY NORC) Plant may have been

cytogenetic testing by company for which they worked benzene (sic)”

Comments from companies not now, previously, or in the future planning to

test.

It --- Inc. is a multifacility manufacturing co. that is not involved in

genetic testing.” (540, aircraft)

“We do not perform health testing for the specific purpose of detecting

genetic or cytogenetic health effects of occupational exposure to chemicals.

We have not conducted this type of health testing since we have not identified

chemicals to which our employees are exposed that could potentially cause

these genetic health problems.” (563, electric utility)

“I really wonder if the value of this project will compare favorably with the

cost of it - our federal budget deficit is large and we have operated in the

red for decades - this looks like the sort of expenditure the USA could get

along without!” (547, cement and construction materials)
224 Ž The Role of Genetic Testing in the Prevention of Occupational Disease

“Not needed. Virtually no chemical exposure. Operations are light assembly

of prefinished parts of materials”. (612, recreational vehicles)

“Totally out of context with the nature of our business. ” (613, electronic

equipment)

“Does not seem relative to our business”. (616, gas and oil production)

“The need or cause for such testing has never been revealed”. (617, cement)

“Our company presently has done noise level testing at all facilities and

“Blood-Lead Chemistry” and “Chest X-ray” testing of all employees working in

painting rooms on an annual basis”. (618, Hand tools)

“Privacy of individual employees should not be imposed upon unless there is a

clear indication from Public Health authorities that program is warranted and

public is informed in a manner that would educate employees on the need for

it.” (619, books and journals)

“We have no information that any products we produce require any such

testing” . (620, refractories and building materials)

“Company maintains minimal risk environments [through] selective and

controlled use of chemical and physical agents in conjunction with continuing

industrial hygiene appraisals. (622, cross linked plastics)

“Ref. Question #18: The American Petroleum Institute acting on behalf of the

industry, is engaged in a major, on-going program of animal testing. Generic

petroleum products are employed in this toxicology testing program which

includes genetic considerations.” (286, chemicals)

“We are computer and word processing system manufacturers and are not involved

in chemical or genetic work.” (292)

“Thank you for sending questionnaire. However, it does not seem relevant to

our business or to our future plans.” (219; flat glass, fluid system

components, plastic products)

FROM A UNION QUESTIONNAIRE: “Union never conducted tests. Company screening

often by union demand has been limited to clinical tests and biological

monitoring, no cytogenetic or biochemical genetic tests”. (103, union)

“We have conducted and continue to conduct chemical exposure testing on whole

animals and their cultured cells for chromosomal aberrations and sister

chromatid exchanges. This is sometimes done as one part of our toxicological

evaluations conducted to enable the proper planning and management which

assures safe handling and usage of intermediate and product materials.” (453,

petroleum products and petrochemicals)

“We have used these tests as screening procedures in animals. We do not find

them sufficiently validated for use on our employees, or prospective

employees.” (478, petrochemicals)
App. C—Survey Materials Ž 225

“In our opinion none of our Industrial operations are associated with

environmental hazards which indicate any employee health benefit from either

biochemical genetic or cytogenetic testing.” (479, mining, smelting)

“We believe cytogenic (sic) testing methodology to screen human populations

requires further standardization and validation before we would consider using

it in our employee population. As a general principle, we are reluctant to

utilize a test on employees unless we can explain the result and course of

action required. Question 7C was confusing. It was not clear to us what

measurements are envisioned in the category of allergic respiratory disease or

contact dermatitis.” (366, petroleum)

“Due to the great diversity of operations of this corporation, this

questionnaire is not applicable.” (371, no industrial code given)

“We do not engage in any form of biochemical genetic testing or cytogenetic

testing. We are primarily a metal forming industry.” (375)

“I have no questions about the above. As a physician who has been in full time

occupational practice for 33 years I was amazed to read in the lay press that

some union officials were alleging widespread use or plans for use of genetic

testing by industry.” (385, chemicals)

“To date we have not had t-he exposure, and therefore have not seen the need to

do these tests.” (305, Food)

“Attention John Gibbons: How can your organization afford Federal Express

service from zip code 10001 to 10591 - 20 miles to the North of Manhattan.

Signed, A Hard Working Taxpayer” (201, Food processing)

“Our employees are incidentally exposed to degreasers, solvents and non-lead

based paints. We look to NIOSH to define areas where biochemical and other

testing is prudent. We would discontinue use of any product which would

exhibit qualities that would make such testing prudent however we would

perform the testing of any of our employees so exposed.” (207, fabricated

metal products)

“This questionnaire is another example of wasting Federal tax monies. I would

hope that Congress has more important business to conduct than the above

questionnaire. Also there must be a more economic way to mail it than Federal

Express overnight letter at $9.50.” (231, Lumber and Paper mfg.)

“Biochemical genetic testing: If any thing should be done, it would be

accomplished post-natally since appropriate family history would be

available. Cytogenetic testing: would be appropriate in areas of exposure to

potential chromosomal damaging agents (radation, chemicals, etc.)” (403,

manufacturing and resale electricity)

“Is any industry doing this testing?” (118, Food)

“We have reviewed the current data on cytogenetic testing both in animals and

in man and feel that. these techniques are not yet applicable to standard

medical surveillance of workers. It is recognized that the techniques may

have potential value in risk assessment, and we hope that continued research
226 ● The Role of Genetic Testing in the Prevention of Occupational Disease

work will better define that applicability. We feel strongly that current

capabilities in the field do not allow the widespread use of these techniques

at the present time.” (121, manufacture of medical products for the health

care industry, including both devices and drugs)

n - _ Inc. was selected to participate in a survey conducted by NORC for the

Office of Technology Assessment (OTA) of the U.S. Congress on the state of the

art of genetic and cytogenetic testing programs. By error, we received a copy

of the questionnaire to be completed by a Union as well as a copy to be

completed by a corporation.

I was concerned to note that the questionnaires were different in that

questions no. 19 and 20 appearing on the union version of the form were absent

from the corporation version. I am hopeful that any information you received

from the union on these two questions will be deleted from the report to

Congress since the data is obviously biased.

Many corporations have decided not to implement genetic and cytogenetic

programs since the correlation of results of such testing with frank clinical

diseases has not been demonstrated. This lack of predictability can lead to

incorrect conclusions on the part of environmentalists and governmental

agencies in assessing the risk of certain chemicals and substances. does

concur with the scientific literature which indicates that the proportion of

occupational diseases attributable to genetic predisposition ranges from 10 to

20 per cent with diseases attributable to chromosomal aberrations ranging 1 to

5 per cent.

If you have any additional questions, please let me know.” ( )
Appendix D

Background Frequencies for

Chromosomal Aberrations

The data presented in table D-1 are not intended for

direct comparisons of values obtained between laboratories; rather, they are meant to convey a sense of the

range of normal background values for chromosomal

aberrations reported in the literature.

The following abbreviations are used for culture

media: D—Difco; E—Eagle’s basal; [G—Gibco; H—Ham’s

F1O; M–McCoy’s 5A; T-TC 199; and 1640–RPMI

1640.

The following abbreviations are used for aberrations:

(CTD-chromatid breaks; C—chromosome breaks;

R—rings; D-dicentrics; E-exchanges; Cu—"unstable”

aberrations, according to Buckton, et al.; Cs—"stable”

aberrations, according to Buckton, et al,; AC —abnormal cells. All values are percentages. Gaps are not included, except where noted otherwise. In some cases

it has been necessary to recalculate the original data.

A continuous line covering more than one complex

aberration indicates that the aberrations were combined in the resulting frequency.

Table D-1 .—Background Frequencies for Chromosomal Aberrations

Number of Number of Culture Cultur e

Reference

- -

Legator and Hollaender, 1975 .., . . .

Lubs and Samuelson, 1967 . . . . . . . . . . .

subjects cells medium time(hr) CTD C R D E Cu CS AC

— —

— —

6.07

8.3

75

10

31

1,084

1,299

524

52

134

79

10

20

20

68

15

316

11

44

13

5

38

5

6

5

34

34

44

7

35

34

21

75

18

6

5

31

12

4

3

2.291 ?

T

T

?

7

?

T

?

?

M

H

M

E

H

T

T

?

7

?

7

varied

T

?

7

varied

7

1640

H

H

H

?

?

68-72

72

72

72

72

50

56

6.72 1.48 0 0.17 0.17

3,720 5.9 1.0 0,22

29,709

15,754

25,980

7,653

5,200

-13,400

79 7,900

1,000

20 2,000

1,950

7,406

1,430

23,200

12,700

?

1,312

500

38 1,140

500

600

500

34 3,400

34 3,400

8,000

279

5,054

3,400

2,100

15,000

3,600

300

1,800

3,100

2,400

356

297

6.0

~7.0

Littlefield and Goh, 1973 . . .

Mattei, et al., 1979. . . . . . . . . . . . . . . . .

– 3.0 0 0.12 0.32

4.6 1.7 0.71

— —

— —

1,8

4.7

1.3-1.8

1,08

0.93

~ 0.6a

-0. 9

-0 7

Aula and von Koskull, 1976 .., . .

Ayme, et al., 1976 . . . . . . . . . . . . .

Husgafvel-Pursiainen, et al , 1980. . . . . . . . . . .

A Review, 1975 . . . . . . . . . . . . . . . . .

— — — — — — —

2.4 1.4 0.81 — .

———— — — —

— – 0.1 8 0.80 — —

Awa, et al,, 1971 ., . . . . . . . . . . . — — 0.23 0,59 — —

Honda, et al., 1969 . . . . . . . . .

Brandom, et al., 1978a . . . . . . . . .

46-50

~48

2.7 0.4 0.1 0 0.1

— -0.7-0. 2

— —~0.2

0.4 0.2

— —

Brandom, et al., 1978b ., ., . . 50 or 72 — —

— – 0.6 5

0.9 0.2 0 0 0

. — – 0.078 –

— – 00 2 —

~1,1

1,1

—

— —

Brandom, et al., 1972 . . . . . . . . . .

Lloyd, et al., 1972 . . . ... . . .

Bauchinger, et al., 1980 . . . . . . . . . . . .

Burgdorf, et al., 1977 ., ., . . . . . . . .

Nordenson, et al., 1978 ., . . . . . . . .

Tough and Brown, 1965 ......., . . . . .

50 & 72

48

48

— —. — —

— — —

72

72

40-50

— — . — — . 0-3

— — — — 1,6

— — 0.6 0.4 –

— — 0.6 0.8

— — 0.6 0.4 —

— — 1.67 0.5 —

— — 0.4 0.4 –

— — 0,49 0.04 –

— — 0,61 0.09 –

— — 1,4

— — — — 2.5

— 0.18 — — 1.37

— — — — 2.06

— — — — 1.33

— — 2.38

0,4 0.1 —

—

—

—

—

—

—

—

—

—

—

—

—

—

.

—

Tough, et al,, 1979. ...., . . . 40-50 —

68-70

68-70

72

72

56-58

56-68

Forni, et al., 1971a ., . . . . . . . . . . .

Forni, et al., 1971b . . . . . . . . . . . . . . . . . . . .

Picciano, 1979b ... . ., . . .

—

1.1 0.35 0.06 —

—

—

Watanabe, et al., 1980 . . . . . . ., . . . . .

Kucerova, et al., 1977 ... . . . . . . . . .

Sram, et al., 1980. . . . . . . . . . . . . . . .

—

0.97 0.28 —

—

2.15

—

Picciano, 1979a ., . . . . . . . . . 72 0.51 0.08

Mitelman, et al., 1980 ... ... . . . . . . . 72 1,6b — —

— — —

— — 2.9

— — — ~0.67

?

— — — ‘?

— — — 0.67

— — — 6.0

— — — 4.7

72 —

45 l/~ 0.11

Shiraishi and Yosida, 1972. .., . . . . .

Deknudt, et al , 1973 . . . . . . . 0.33 0

45-48 4.46 0,42 — –

48 —

48 & 72 —

O’Riordan and Evans, 197 4

Deknudt and Leonard, 1975 ,

Bui, et al,, 1975 . . . . . . . .

— — —

— — —

— — — —

227
228 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Table D-1 .—Background Frequencies for Chromosomal Aberrations—Continued

Number of Number of Culture Culture

Reference subjects cells medium time(hr) CTD C R D E Cu Cs AC

Bauchinger, et al., 1976 ., . . . . . . . . . . . . . . .

Forni, et al., 1976 . . . . . . . . . . . .

Deknudt, et al., 1977 ...., . . . . . . . . . .

O’Riordan, et al., 1978 . . . . . . . . . . . . . . . . . . .

Forni, et al,, 1980 . . . . . . . . . . . . . . . . . . . . .

Maki-Paakkanen, et al., 1981 . . . . . . . . .

Funes-Cravioto, et al, . . . . . . . . . . . . . . . . . . .

Maki-Paakkanen, et al., 1980 ....., . . . . . . . . .

Hogstedt, et al., 1981 . . . . . . . . . . . . . . . . . .

Thiess, et al., 1981 . . . . . . . . . . . . . . . . . . .

Ducatman, et al., 1975 . . ... . . . . . . . . . . . .

Purchase, et al,, 1976 ......, . . . . . . . . . . . . .

Szentesi, et al,, 1976 . . . . . . . . . . . . . . . . . . . . . .

Hansteen, et al., 1975 ...., . . . ...

Fleig and Thiess, 1978, . . . . . . . . . . . . . . . .

Kucerova, et al,, 1979 ...., . . . . . . . . . . . . .

Anderson, et al,, 1980, . . . . . . . . . . . . . . . . . . .

15

11

20

13

12

12

42

16

15

21

10

19

5

49

44

16

32

20

8

6

1,650

1,075

3,000

1,243

1,130

1,200

4,200

3,200

1,500

2,100

500

1,900

500

2,523

2,988

1,600

3,200

2,000

800

600

H

T

H

H

T

?

T

?

T

T

G

D

48 0.2 – 0.26 — — 0.47

4.88C

2.53 C

—

2-0

4,76

2.4

1.6

1.4

—

—

—

—

—

1.79

2,33

2.1

1.8

1.33

1 17

1.0

0.38

3.47

2.47

1.8

2.5

—

—

8.5

2.0

1.38

0.8

1.4

68-70 – – – – – – –

48 — – — — — — —

45-48 0.08 – — — – 0.8 0.02

48

7

72

72

50

70-72

65-68

48 or 72

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

—

— — —

— — —

0.08 – — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— — —

— —

— —

— —

— —

0.3 2.9

0.53 0.10

0.50 0

0.35 –

0.56 –

48

? 48 — —

— — —

— — —

— —

?

‘?

D

?

?

48 & 72

— —

— — —

First sampling:

Second sampling:

First sampling:

Second sampling:

— — —

— —

0.5 0

0.5 0

0.75 0

0.13 0

8 800

565

1,700

1,900

500

1,400

11,000

1,000

651

1,800

1,594

398

288

Kirkland, et al., 1978 ......, . . . . . . . . . . . 17

19

5

7

22

10

7

18

10

11

4

T 48 — — —

— —

—

—

—

— — —

— — —

— —

Meretoja, et al., 1981 . . . . . . . . . . . . . . . .

Hogstedt, et al., 1980 . . . . . . . . . . . . . . . .

Bauchinger, 1981 ....., . . . . . . . . . . . . . . . .

Waksvik, et al., 1981 . . . . . . . . . . . . . . . . . . . . .

Verschaeve, et al., 1976 . . . . . . . . . . . . . . . .

Thiess and Fleig, 1978 .., . . . . . . . . . .

Cervenka and Thorn, 1974 .., . . . . . . . . . . . . .

Hook, et al., 1974 . . . . . . . . . . . . . . . . .

T

M

H

H

T

?

T

?

64-66

72

48

— —

—

0.16

— — — — —

0.05 0.09 — —

48 — — —

72

70-72

72

72

— 0.3 —

—

—

—

— —

—

—

—

—

—

— — — — —

— — — — —

— — — — —

— — — — —

— — — — — — — —

aExclud1ng CTD and c’

b

lncludes only breaks and exchanges

cGaps Included.

SOURCE Office of Technology Assessment

Appendix D references 38(kV-Systems, ” Radiat. Environ. Bio. 19:23.5-

238, 1981.

Bauchinger, M., et al., “Chromosome Analyses of

Nuclear-Power Plant Workers, ” Int. J. Radiat. Biol.

38:577-581, 1980.

Bauchinger, M., et al., “Chromosome Aberrations in

Lymphocytes After occupational Exposure to Lead

and Cadmium, ” Mutat. Res. 40:57-62, 1976.

Brandom, W. F., et al., “Chromosome Aberrations as

a Biological Dose-Response Indicator of Radiation Exposure in Uranium Miners,” Radiat. Res. 76:159-171,

1978.

Brandom, W. l?., et al., “Somatic Cell Genetics of Uranium Miners and Plutonium Workers, ” in Late Effects

of Ionizing Radition, 1:507-518 (Vienna: international Atomic Energy Agency, 1978).

Brandom, W. F., et al., “Chromosome Aberrations in

Uraniurn Miners Occupationally Exposed to 222Radon, ”

Radiat. Res. 52:204-215, 1972.

Buckton, K. E., et al., "(A Study of the Chromosome

Damage Persisting After X-Ray Therapy for Ankyl -

“A Review of Thirty Years Study of Hiroshima and

Nagasaki Atomic Bomb Survivors, ” J. Radiat. Res.,

Suppl., 1975.

Anderson, D., et al., “Chromosomal Analysis in Vinyl

Chloride Exposed Workers: Results From Analyses

18 and 42 Months After an Initial Sampling, ” Mutat.

Res. 79:151-162, 1980.

Aula, P., and von Koskull, H., “Distribution of Spontaneous Chromosome Breaks in Human Chromosomes ,“

Hum. Genet. 32:143-148, 1976,

Awa, A. A., et al., “Chromosome Aberration Frequency

in Cultured Blood Cells in Relation to Radiation Dose

of A-Bomb Survivors,” Lancet ii:903-905, 1971.

Ayme, S., et al., "Nonrandom Distribution of Chromosome Breaks in Cultured Lymphocytes of Normal

Subjects, ” Hum. Genet. 31: 161-175, 1976.

Bauchinger, M., et al., “Analysis of Structural Chromosome Changes and SCE After occupational LongTerm Exposure to Electric and Magnetic Fields From
App. D—Background Frequencies for Chromosomal Aberrations ● 229

osing Spondylitis, ” Lancet ii:676, 1962.

Bui, T-H., et al., “Chromosome Analysis of Lymphocytes From Cadmium Workers and Itai-itai Patients, ”

Environ. Res. 9:187-195, 1975.

Burgorf, W., et al., “ Elevated Sister Chromatid Exchange Rate in I,ymphocytes of Subjects Treated

With Arsenic, ” Hum. Genet. 36:69-72, 1977,

Cervenka, J., and Thorn, H. L,., “Chromosomes and

Spray Adhesives, ” N. Eng. J. Med. 290:543-545, 1974.

Deknudt, Gh., et al., “Chromosome Aberrations observed in Male Workers Occupationally Exposed to

Lead, ” Environ. Physiol. Biochem. 3: 132-128, 1973,

Deknudt, Gh., et al., “Chromosomal Aberrations in

Workers Professionally Exposed to Lead, ” J. Toxicol. Environ. Health 3:885-8:)1, 1977,

Deknudt, Gh., and Leonard, A., “Cytogenetic Investigations on I.eukocytes of Workers From a Cadmium

Plant, ” Environ. Physiol. Biochem. 5:319-327, 1975.

Ducatman, A., et al., "Vinyl Chloride Exposure and

Human Chromosome Aberrations, ” Mutat. Res.

31 : 163-168, 1975.

Fleig, 1., and Thiess, A. M., “Mutagenicity of Vinyl Chloride: External Chromosome Studies on Persons With

and Without VC Illness, and on VC Exposed Ani -

mals, ” J. Occup. Med. 20:557-561, 1978.

Forni, A., et al., “Chromosome and Biochemical Studies

in Women Occupationally Exposed to Lead, ” Arch.

Environ. Health 3.5: 139-145, 1980.

Forni, A., et al., ‘(Initial Occupational Exposure to Lead:

Chromosome and Biochemical Findings, ” Arch.

Environ. Health 31:73-78, 1976.

Forni, A., et al., “Chromosome Changes and Their Evolution in Subjects With Past Exposure to Benzene, ”

Arch. Environ, Health 23:385-391, 1971,

Forni, A., et al., “Chromosome Studies in Workers Exposed to Benzene or Toluene or Bet}], ” Arch. Environ, Health 22:373-378, 1971.

Funes-Cravioto, F., et al., ‘

{

(chromosome Aberrations

and Sister Chromatid Exchange in Laboratory and

Factory Workers and Their Children ,“ in: H. J. Evans

and L). (D. C ,Lloyd, eds., “Mutagen-induced Chromosome ntw@: [ ‘nit’ (:rsit} Press,

1 978),

Iiansteen, 1-1,., et al., “Effects of l’iny] Ch]oride in hlan:

A (;ytogenetic FolloIv-up StuciJ~, ” Afutat. Res. 31:

163-168, 197.5.

Ho#tedt, B., et al,, “hlicronuclei and Chromosome

,lberrations in Bone kiarroi~’ (;ells and [,ymphocjrtes

of Iiu ma ns F.xposed hlainl~’ to Petroleum \’apors, ”

Hereditas W: 179-187, 1981.

Hogstedt, B., et al., “Cytogenetic Study of Pesticides

in Agricultural it’ork, ” Hereditas 92:1 77-178, 1980.

flonda, ‘I’., et al., ‘((:hromosorne Atwrrations and (:ul -

ture ‘t’irl]e, ” [J’tqq’enf?t, 8:1 17-1 ZLI, 196S.

Hook, E. B., et al., “Negati\7e Outcome of a Blind Assessment of the Association Bet\\reen Spra]r Adheshw Exposure and Human Chromosome Breakage, ” I’ature

(London) 249:165-166, 1974.

Husgaft~el-Pursiainen, K., et al,, “Smoking and Sister

Chromatid Exchange,” }fereditas 92:247-2.50, 1980.

Kirkland, D. J., et al., “Chromosomal []aHla~P and Hair

Dyes, ” Lancet i:124-128, 1978.

Kucerova, hf., W al., “Comparatiife Evaluation of the

Frequency of Chromosomal Aberrations and the

SCF, Numbers in Peripheral I,Jmpho[}tes of \t’ork -

ers occupationally F.xpo5ed to l’ir~Jl (;hloridc illono -

mer, ” ~t~utc? t. ~~S. 67:97-1 ()(), 1979,

Kucero~7a, hf., et al., “Alutagenic Effect of Epichlorohydrin: 11. Analysis of Chromosomal Aberrations in

Lymphocytes of Persons C)ccupationall) Exposed to

Kpichlorohydrin, ” ,Ifutat. Res. 48:35.5-360, 1977.

Legator, M. S., and Ho]]aender, A. (eds. ), “()(>(>l]l);iti()r~:i]

Nlonitoring for (knetic Hazards, ” ,LInn. IA’. 1’. ,Al(a(/.

Sci. 269: 1975.

I,ittlefield, L. G., and Goh, K-O., “CJrtogenetic Studies

in Control Nlen and L1’omen: I, \ ‘ariations in AhPrI’ation Frequencies in 29,709 hleta}~hasri From 305

Cultures ohtained ()~wr a Three-J’rar Period ,“ (jl’ttJgenet. L’ell (knet. 12:1 7-34, 1973.

Lloyd, D. C., et a]., ‘(The In(-idence of [~nstah]e Chromosome Aberrations in Peripheral Blood I.J7mphocytes From [Tnirradiatccl and ()(ucll]l:iti()rl[ill~ I~xposed People, ” Afural. Re.s. 72:.523-532, 1980.

I.uhs, H. A., and Sarnuelson, J., ‘((;hl’or~losor~l[~ ,lbnormalities in [Jymphocjrtes From Normal Fiunlan Sul)-

jects ,“ CJtogenet. 6:402-411, 1967.

kIaki-Paakkanen, J., et a]., “Chromosonlr Aberrations

and Sister Chrornatid Exchanges in I, Pad-k’, ~posed

1$’orkers, ” Hereditas 94:269-27.5, 1 $)81.

hlaki-Paakkanen, J., et al., “’I’(~l~]erl(>-F,x~)os(+(l J1’orkers

and Chromosome Aberration s,” J. ‘f’(~.k ice]. lh]~’iron,

Health 6:775-781, 1980.

Nlattei, N1. G., et al., “Distribution of Spontaneous (’chromosome Breaks in Nlan ,“ q’tog(=mt. [.’(’11 (L’llet.

23:9.5-102, 1979.

Nleretoja, ‘I’., et al., “occupational St~rrne Exposure

and Chromosornal Aberrations ,“ ,kfutat Res, .56: 193-

197, 1977.

Nlitelman, F., et al., “occupational Exposure to Epoxy

Resins Has NO CJ40genetic Effect ,“ ,!lutat. fles. 77’:

345-348, 1980.

lNorclenson, E., et al,, “(1(’c~l[)iitiollal and I;r31i1’orlrllent:i I

Risks In and Around a Snleltrr in Norttwrn SJiTmlen:

11, Chrornosomal Aberrations in J\’ork(~rs Esposed

to Arsenic, ” Herditas 88:47-.50, 1978,

()’Riordan, Al. 1,,, et a]., ‘([;]lr’or~losor~le” Studies on Blood

I,~~mp]~~~~tes of hlen ()(’(’~l~liitiolliill~r h;xposd to

(Yadmiunl,” ,Iluta t Re.s, .58 : 30.5 -:1 1 1, 1978.
230 . The Role of Genetic Testing in the Prevention of Occupational Disease

O’Riordan, M. L., and Evans, H. J., “Absence of Significant Chromosome Damage in Males Occupationally

Exposed to Lead, ” Nature (London) 247:50-53, 1974.

Picciano, D., “Cuytogenetic Investigation of Occupational Exposure to Epichlorohydrin, ” A4uta~. I/es. 66:

169-173, 1979.

Picciano, D., “Cytogenetic Study of Workers Exposed

to Benzene, ” Enkriron. Res. 19:33-38, 1979.

Purchase, I. F. H., et al., “Chromosomal Effects in

Peripheral Lymphocytes, ” Proc. lby. Soc. Med.

69:290-291, 1976.

Shiraishi, Y., and Yosida, T. H., “Chromosomal Abnormalities in Cultured Leukocyte Cells From Itai-itai

Patients, ” Proc. Japan Acad. 48:248-251, 1972.

Sram, R. J., et al., “Cytogenetic Analysis of Peripheral

Lymphocytes in Workers Occupationally Exposed

to Epichlorohydrin, ” Mutat. Res. 70: 115-120, 1980.

Szentesi, I., et al., ‘(High Rate of Chromosome] Aberration in PVC Workers, ” ltfutat. Res. 37:313-316, 1976.

Thiess, A. M., et al., “hlutagenicity Study of Workers

Exposed to Alkylene Oxides (ethylene oxide/propylene oxide) and Derivatives, ” J. OCCUp. Med. 23:

343-347, 1981.

Thiess, A. M., and Fleig, I., “Analysis of Chromosomes

of Workers Exposed to Acrylonitrile, ” Arch. Toxicof.

41:149-152, 1978.

Tough, I. M., and Court Brown, W. M., “Chromosome

Aberrations and Exposure to Ambient Benzene, ”

Lancet i:684, 1965.

Tough, I. M., et al., “Chromosome Studies on Workers

Exposed to Atmospheric Benzene: The Possible Influence of Age,” Europ. J. Cancer 6:49-55, 1970.

Verschaeve, L., et al., ‘(Chromosome Aberrations Induced by Occupationally Low Mercury Exposure, ”

Environ. Res. 12:306-316, 1976.

Waksvik, H., et al., “Chromosome Analyses of Nurses

Handling Cytostatic Agents, ” Cancer Treat Rep. 65:

607-610, 1981.

Watanabe, T., et al., “Cytogenetics and Cytokinetics

of Cultured Lymphocytes From Benzene-Exposed

Workers, ” Int. Arch. Occup. En\~iron. Healt h

46:31-41, 1980.
Appendix E

Background Frequencies for

Sister Chromatid Exchanges

These data are not intended for direct comparisons, but rather to convey a sense of the variability

in the literature.

The following abbreviations are used for culture media: EB—Eagle’ basal; G--Gibco 1A; ii—Ham’s F10;

MEM —Delbecco's minimal essential medium; T-TC 199; and 1640.

Table E-1 .—Background Frequencies for Sister Chromatid Exchanges

Number of Culture

Reference Number of subjects cells/subject medium Bud R ( g/ml) SCE/cel l

Carrano, et al., 1980 . . . . . . . . . . . . . . . . . . . 8 40-80 MEM variable 7.59

Morgan and Crossen, 1977 . . . . . . . . . . . . . . 50 20 H 10 7.9

Crossen, et al., 1977 . . . . . . . . . . . . . . . . . . . . 20 20 G 10 6.37

Lambert, et al., 1978 . . . . . . . . . . . . . . . . . . . . 14 smokers >= 20 ? 100 16,2

29 nonsmokers — 13.1

Husgafvel-Pursiainen, et al., 1980 . . . . . . . . . 43 smokers 30 T 5 9.6

40 nonsmokers 8.1

Goh, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 old 30 ? 3 9.07

23 young 8.05

Butler and Sanger, 1981 . . . . . . . . . . . . . . . . . 19 > 1 5 EB 6 8.4

Butler, 1981 . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 > 2 0 6 8.1-8.7

Burgdorf, et al., 1977 . . . . . . . . . . . . . . . . . . . 44 ~ 1 5 T 30 5,8

Watanabe, et al., 1980 . . . . . . . . . . . . . . . . . . . 7 - 4 0 T 10 11.4

Mitelman, et al., 1980 . . . . . . . . . . . . . . . . . . . 18 20 7 ‘? 8.7

Maki-Paakkanen, et al., 1981 . . . . . . . . . . . . 12 30 ? 5 9.8

Funes-Cravioto, et al. . . . . . . . . . . . . . . . . . . . 15 20 T 7 13.5

6 12.2

Hogstedt, et al., 1981 . . . . . . . . . . . . . . . . . . . 15 30 T 5 8.0

Garry, et al., 1979 . . . . . . . . . . . . . . . . . . . . . . 12 20 MEM 4.5 5.98

Hansteen, et al., 1975 . . . . . . . . . . . . . . . . . . . 16 30 ‘? 2 7.5

Kucerova, et al., 1979 . . . . . . . . . . . . . . . . . . . 8 50 ? ? 9.41

Anderson, et al., 1981 . . . . . . . . . . . . . . . . . . . 6 30 1640 25 6.68

Kirkland, et al., 1981 . . . . . . . . . . . . . . . . . . . . 14 varied 1640 1 50? 10.77

Bauchinger, et al., 1981 . . . . . . . . . . . . . . . . . 22 40 ? 10 7.09

Waksvik, et al., 1981 . . . . . . . . . . . . . . . . . . . . 10 30 7 5 6.5

Sorsa, et al., 1981 . . . . . . . . . . . . . . . . . . . . . . 10 ‘? ? 7 ~8.O

SOURCE Office of Technology Assessment

Appendix E references

Anderson, D., et al., “Chromosomal Analysis in Vinyl

Chloride Exposed Workers: Comparison of the

Standard Technique With the Sister -Chromatic Exchange Technique, “ Mutat. Res. 83:137-144, 1981.

Bauchinger, M., et al., “Analysis of Structural Chromosome Changes and SCE After Occupational LongTerm Exposure to Electric and Magnetic Fields From

380 kV Systems, ” Radiat. Environ. Biophys. 19:235-

238, 1981.

Burgdorf, W., et al., “Elevated Sister Chromatid Exchange Rate in Lymphocytes of Subjects Treated

With Arsenic, ” Hum. Genet. 36:69-72, 1977.

Butler, M. G., and Sanger, W, G., “Increased Frequency of Sister-Chromatid Exchange in Alcoholics ,“

Mutat. Res. 85:71-76, 1981.

Butler, M. G., ‘( Sister-Chromatid Exchange in Four Human Races, ” Mutat. Res. 91:377-379, 1981.

Carrano, A. V., et al., Variation in the Baseline Sister

Chromatid Exchange Frequency in Human Lymphocytes, ” Environ. mutagen. 2:325-337, 1980.

Crossen, P. E., et al., “Analysis of the Frequency and

Distribution of Sister Chromatid Exchanges in Cultured Human Lymphocytes, ” Hum. Genet. 35:345-

352, 1977.

Funes-Cravioto, F., et al., “Chromosome Aberrations

and Sister Chromatid Exchange in Laboratory and

Factory Workers and Their Children, ” in: H. J. Evans

and D.C. Lloyd, eds., "Mutagen-Induced Chromo231
232 . The Ro/e of Genetic Testing in the Prevention of Occupation/ Disease

some Damage in Nlan, ” (Edinburgh: University press,

1978).

Garry, V. F., et al., “Ethylene Oxide: Evidence of Human Chromosomal Effects, ” Environ. Mutagen. 1:

375-382, 1979.

(hh, K-C)., “Sister-Chromatid-Exchange in the Aging

Population, ” J. Med. 12:195-198, 1981.

Hansteen, I-L., et al., “Effects of l~inyl Chloride in Man:

A Cytogenetic Follow-up Study, ” Mutat. lies. 31:163-

168, 1975.

Hogstedt, B., et al., “Nlicronuclei and Chromosome

Aberrations in Bone Nlarrow Cells and Lymphocytes

of Humans Exposed Mainly to Petroleum Vapors, ”

Hereditm 94: 179-187, 1981.

Husgafvel-Pursiainen, K., et al., “Smoking and Sister

Chromatid Exchange, ” Hereditas 92:247-250, 1980.

Kirkland, D. J., et al., “Sister-Chromatid Exchanges

Before and After Hair Dyeing, ” ,Wutat. Res. 90:279-

286, 1981.

Kucerova, NI., et al., ‘(Comparative Evaluation of the

Frequency of Chrornosomal Aberrations and the

SCE Numbers in Peripheral Lymphocytes of Workers occupationally Exposed to Vinyl Chloride Monomer, ” Afutat. Res. 67:97-100, 1979.

Lambert, B., et al., “Increased Frequency of Sister

Chromatid Exchanges in Cigarette Smokers,” kiereditas 88:147-149, 1978.

Maki-Paakkanen, J., et al., “Chromosome Aberrations

and Sister Chromatid Exchanges in Lead-Exposed

Workers, ” Hereditas 94:269-275, 1981.

Mitelman, F., et al., “Occupational Exposure to Epoxy

Resins Has No Cytogenetic Effect, ” kfutat. I?es.

77:345-348, 1980.

Morgan, W. F., and Crossen, P. E., “The Incidence of

Sister Chromatid Exchanges in Cultured Human

Lymphocytes, ” Mutat. Res. 42:305-312, 1977.

Sorsa, M., et al., “Monitoring Genotoxicity in the Occupational Environment, ” Scand. J. G4[ork EnLJiron.

Health 7 (suppl 4):61-65, 1981.

Waksvik, H., et al,, “Chromosome Analyses of Nurses

Handling Cytostatic Agents, ” Cancer Treat, Rep.

65:607-610, 1981.

Watanabe, T., et al., “Cytogenetics and Cytokinetics

of Cultured Lymphocevtes From Benzene-Exposed

Workers, ” Int. Arch, Occup. En\~iron. Health 46:

31-41, 1980.
Appendix F

Screening Tests (Available at Hospitals

or Medical Centers) for Heritable Traits

G-6-PD deficiency

Numerous screening tests have been designed to

identify the glucose-6 -phosphate-dehydrogenase (G-6-PD)

deficient erythrocytes. The most simple, reliable, and

specific screening procedure is the fluorescent spot

test (2), This procedure has been widely employed

(4,9,13, 15) and has been shown to be highly reliable

in detecting the deficiency. It has also been automated

and made available for widespread screening (3,14).

Detection of G-6-PD levels lower than about 50 percent normal is achieved.

Sickle-cell trait

Several screening methodologies for sickle-cell abnormalities have been developed. The procedure consisting of cellulose-acetate electrophoresis (CAE) followed by solubility testing has been favorably regarded because of speed, cost, simplicity, accuracy,

and ability to differentiate the various types of hemoglobin (1). Quantification of hemoglobin types is easily performed. In order to verify the electrophoresis

procedure for HbS, any blood found to have HbS is

subsequently evaluated via the solubility test as HbS

displays abnormal solubility. CAE followed by a solubility test to confirm the presence of HbS has been

the procedure recommended by the National Sickle

Cell Disease Program and the National Hemoglobinopath) Standardization Laboratory at the Centers for

Disease Control (1 1,1 2).

Thalassemias

Pearson, et al, ( 10) have developect an electronic

measurement of mean corpuscular volume (MCV)

which meets the requirements for a screening test for

alpha and beta thalassemic heterozygotes. The procedure is rapid, automated, and inexpensive. It yielded

no false negatives out of a study population of 300.

However, it is possible that false positives may occur

for persons with an iron-deficiency condition. Further,

persons who are so-called "silent carriers” (exhibiting

no clinical symptoms) of alpha or beta thalassemia cannot be detected by this screening test. The frequency

of the silent carrier is thought to be uncommon for

beta thalassemia.

NADH dehydrogenase deficiency

The definitive diagnosis of hereditary methemoglobinemia requires the demonstration of deficient NADH

dehydrogenase activity in red cells. The Hegesh, et al,

(6) assay is considered preferable because of its specificity, accuracy at low enzyme activity levels, and ease

of operation.

Serum alpha1-antitrypsin

(SAT) deficiency

Several reliable, easily administered, and inexpen -

sive tests have been developed for the screening of

large populations for SAT deficiency. All of these tests

are sensitive for the recessive homozygous condition,

but only one of them (8) can reliably detect the intermediate heterozygous Ievels. The authors claim that

this test is a practical screening procedure which could

be applied in large scale.

Slow v. fast acetylation

Urine tests for detecting slow and fast acetylators

have been developed in order to deal with the potential medical problem of slow acetylators being at enhanced risk of developing adverse reactions to isoni -

azid, an antitubercular treatment. The procedure is

straightforward and simple, displaying an excellent

capability to distinguish fast from slow acetylators (7).

HLA typing

The methodology for determining human leukocyte

antigen types is considered simple and is frequently

conducted in numerous medical centers in the United

States. The typical cost is now less than $100 for a complete analysis (5).

Appendix F references

1. Barnes, M. G., Komarmy, 1.., and ,Novak, A. H., “A

Comprehensive Screening Program for Hemoglobinopathies,” JAMA 219:701-705, 1972,

2. Beutler, E., “A series of Net\ Screening Procedures

for Pyruvate Kinase Deficiencyr

, G-6-PD Deficiency

233
234 “ The Ro/e of Genetic Testing in the Prevention of Occupational Disease

and Gluthathione Reductase Deficiency, ” Bfood

28:553-562, 1966.

3. Dickson, L. G., Johnson, L. B., and Johnson, D. R.,

“Automated Fluorometric Method for Screening

for Erythrocyte G-6-PD Deficiency, ” Cljn. Chem.

19:301-303, 1973.

4. Dow, P. A., Petteway, M. B., and Alperin, J. B.,

“Simplified Method for G-6-PD Screening Using

Blood Collected on Filter Paper, ” Amer. J. PathoL

61:333-336, 1974.

5. Harsanyi, Z., and Hutton, H., Genetic Prophec@v:

Beyond the Double Helix (New York: Rawson,

Wade, Publishers, Inc., 1981).

6. Hegesh, E., Calmonovici, N., and Avron, M., ‘(New

Method for Determining Ferrihemoglobin Reductase (NADH-Methemoglobin Reductase) in Erythrocytes,” J. Lab. Clin. Med. 72:339, 1968.

7. Jessamine, A. G., Hodkin, M. M., and Eidus, L.,

“Urine Tests for Phenotyping Slow and Fast Acety -

lators)” Canacl. J. Pub. Hhh. 65:1 19-123, 1975.

8. Lieberman, J., and Mittman, C., “A New ‘DoubleRing’ Screening Test for Carriers of Alpha l-Antitrypsin Variance, ” presented at American Thoracic

Society Meeting, Kansas City, MO.

) Nlay 22, 1972.

9. .

10.

11.

12.

13.

14

15

McIntire, M. S., and Angle, C. R., “Air Lead-Relation

to Lead in Blood of Black School Children Deficient

in G-6-PD, ” Science 17:520-522, 1972.

Pearson, H. A., O’Brien, R. T., and McIntosh, S.,

“Screening for Thalassemia Trait by Electronic

Measurement of Mean Corpuscular Volume,” New

Eng. J. Med. 288(7):351-353, 1973.

Schmidt, R. M., ‘{Standardization in Detection of

Abnormal Hemoglobins: Volubility Tests for Hemoglobin S,” JAMA 225:1255, 1973.

Schmidt, R. M., “Laboratory Diagnosis of Hemoglobinopathies,” JAMA 224:1276-1280, 1973.

Szeinberg A., and Peled, N., “Detection of G-6-PD

Deficiency in the Newborn Using Blood Specimens

Dried on Filter Paper,” Isr. J. Med. Sci. 9:1353-1354,

1973.

Tan, I. K., and Whitehead, T. P., ‘{Automated Fluorometric Determination of G-6-PD and 6-Phosphogluconate Dehydrogenase Acti~rities in Red Blood

Cells, ” Clin. Chem. 18:440-446, 1969.

Yeung, C. Y., Lia, H. C., and Leung, N. K., ‘(Fluorescent Spot Test for Screening Erythrocyte G-6-PD

Deficiency in Newborn Babies,” J. Peal. 76:931-934,

1970.
Appendix G

Other Contractors and Contributors

Other contractors

Four contractors played an important role in this

assessment by contributing to or reviewing the work .

of the principal contractors. They are:

Philip G. Archer, Sc.D,

University of Colorado Medical Center

Denver, Colo.

Epidemiology Resources, Inc.

Chestnut Hill, Mass.

D. R. Jagannath, Ph.D.

Litton Bionetics, Inc.

Kensington, Md.

Marvin S. Legator, Ph.D.

University of Texas Medical Branch

Galveston, Tex.

Other contributors

Many people provided valuable advice and assistance to OTA during this assessment. In particular, we

would like to thank the following:

American Industrial Health Council

Washington, D.C.

Angela Auletta

Environmental Protection Agency

Health and Safety Review Division

Washington, D.C.

Robert C. Barnard

Cleary, Gottlieb, Steen &, Hamilton

Washington, D.C.

Clyde J. Behney

Program Manager, Health Program

Office of Technology Assessment

Fred Bergmann

Program Director, Genetics Program

National Institutes of Health, NIGMS

Bethesda, hid.

Alexander Capron

Executive Director

President’s Commission for the Study of Ethical

Problems in Medicine and Biomedical and

Behavioral Research

Washington, D.C.

Anthony V. Carrano

Biomedical Sciences Division

Lawrence Livermore National Laboratory

Livermore, Calif.

Jerry L. R. Chandler

Office of the Director

National Institute of Occupational Safety and Health

Rockville, Md.

Zsolt Harsanyi

E. F. Hutton Group, Inc.

New York, N.Y.

Peter Infante

Health Standards Program

Occupational Safety and Health Administration

Washington, D.C.

Joseph Irr

Haskell Laboratory

E. I. du Pont de Nemours & Co.

Wilmington, Del.

James Jensen

Professional Staff Member

Subcommittee on Investigations and Oversight

House Committee on Science and Technology

U.S. House of Representatives

Washington, D.C

Bruce W. Karrh

Corporate Medical Director

E. 1. du Pont de Nemours & Co.

Wilmington, Del.

Karl Kronebusch

Health Program

office of Technology Assessment

Max Lyon

Genetic Systems Corporation

Seattle, Wash.

Ken Miller

Worker's Institute for Safety and Health

Washington, D.C.

Thomas Murray

The Hastings Center

Hastings-on-Hudson, N. J’.

Daniel Nebert

National Institute of Child Health and Human

Development

National Institutes of Health

Bethesda, Md.

235
236 ● The Role of Genetic Testing in the Prevention of Occupational Disease

R. Julian Preston

oak Ridge National Laboratory

oak Ridge, Term.

Anthony Robbins

Professional Staff Member

Committee on Energy and Commerce

U.S. House of Representatives

Washington, D.C.

Sheldon Samuels

AFL-CIO

Washington, D.C.

Gail Stetten

Director, Cytogenetics Laboratory

The Johns Hopkins University

Baltimore, Md.

Charles Trahan

General Accounting Office

Washington, D.C.

Theodora Tsongas

Health Standards Program

Occupational Safety and Health Administration

Washington, D.C.

Michael Shodell peter Voytek

Director, Banbury Center Reproductive Effects Assessment Groups

Cold Spring Harbor, N.Y. Environmental Protection Agency

Jane E. Sisk Washington, D.C.

Health Program

Office of Technology Assessment
Index
Index

deficiency, 7, 90

sickle cell, 51, 91

in thalassemia, 91-92

Arsenic (see Chemicals)

Arylamines (see Chemicals )

Aryl hydrocarbon hydroxylase (AH

predictive value of, 18

prvalence of, 19, 172

research on, 1(10

and susceptibilily to lung cancer,

Asbestos (see Chemicals)

H) inducibility, 11, 19

94-9 5

Assessment of occupational studies, 60-6 1

Atomic Bomb Casualty (commission (we Radiation Effect s

Research Foundation

Benzene (see Chemicals)

Body fluids

in detection of genetic traits or abnormalities, 53-54

mutagens in, 18, 75-77

Cadmium (see Chemicals)

Cancer ( S ee also Carcinogenesis 6,19,25

acf:t~’ I;it ion and suscept ihi] it }’ to a rkrla mine -induced, 9.7,

1 ()()-101

a r-j’] hjd roc;t rbon h}’d r-ox }’l:isc (,4 HH ) i nd ucih ilitj’ an d

5Ll S(’(>pt ii)i]itj’ to, 94-9.5, 100

in atomic homh sufn’ilors, 70-71

and car-bon (),x id a t ion abi] i tj’, 96, 100

in Chcmi(’al, smelting, and gold mining t~orkers, 72

and defect il f’ 1) h’ ,,1 rcpa i r, 97

(’arhon oxi(!;ition ahilitj , 1 1

high pre~alence of, ]9, 17 2

implirati(ms for ()(’(’~l~);iti()rl:ll and [’r]\il-ollrllerlt:il health, 96

research orl, 100”

and sus(’eptil)ilit~’ to ranc[~rl 96

(;:il-(>irl[~gf;rlf’sis “

1)~ arsenir, 71

l)j ar>jlilmincs) 9,5

correlation ;t’ith (’llr.{)rllos{)rllal abf’rrat ions and sistf?r

rhromatid cxrhangr (S(:ljl, 69

t)~ f:~)i(:}llor’f)ll~(jr’irl, 72

mutations in, 10, 52-53, 68-69

1)~, pol}(~(.11( aromatir lljr(ir-()(’~irl)()rls, 94

hj linjl chloride monomer, 73

(:hf’rn i(iils

arsenic, 71-72

arj’lamincsl 1 1, :15, 100”

ashfxtos, 5, 23

I)enzenf’, 19, 72,, 121

radmium, 72-7:3

carcinO,g’f:nic, .52-.53

clastogensf 121

differential] susceptihilitj to, 11

(?l>i(;lllorOll\[lr’irl, 72

eth~’lene oxide, 72

genetic damage from, 10, 18, 46, 52.,53

hazardous, 24

lead, 72-73

occupational ekposure to, 6, 24

parathion, 97

pol~c~’clic aromatic 11~[11’o(:;~r’t~orls, 94

uranium 71

~in}’1 chloride 19, 73-74

zinr, 73

(:}l[)li]lf’ster;isf?s, 97

(:hromosornal :il)errations Owc al,so Cjtogenctic studies), lo,

18, 28, 3,5, 37

from arsenic exposllrf’l 71

in atomic bomb surl’iiors, 70-71

t)ii(’k~rOLl[ld frr(lurnries, 227-229 ~tal]lf>)

from hf’nzf~ne e~posure, 72

from cadmium exposurfl, 73

and ca rcinogenicity, 69

disease and, 68-69

from t’~]i(:lllor’ohj[ir’in” exposure, 72

from ethllcnf; oxide exposure, 72

ext r-a }’ chromosome, 79

in unexposed populations, 70

from lifljl chloridf’ monomf~r c~posurel 73-74

(~tlr’orllosorllf~s (Lsflf’ (;hromosoma] ah[~rr:itions)

(;omrnittee on the BiolO~i(’ill ~;fff’cts of ionizing Ril(liat ion,

6, 2.5

(;ongrcss

acts of (see I.egisla t ion )

Ji(lusc (;ommittcr on Srif~l](’f~ iind ‘l’ f’chnolog:, .5, 23, 181

olltions for [see Polirj options )

(:(]tton dust, 121

(:~togenetir studies (sf’f~ ah (knetics ], 1 ( )

on atomic homh surl’i~ors, 70-71

associations hf;t~t”een rh romosoma 1 aberrations and

disease, 68-69

chromosomal studies on groups, 6:)-70

correlation lx3t\$’eerl (’llr-onlosor]]~il il})f’[’l’il t i(jns, sistt)r

chromatid exrhanges, i] nd (’ii rrinog(’n icit~ , 69

economic ek’aluation of, 1.59-160

in exposure to chronic iofI’ radia t ion 71

purpose of, 28

significance of sister rhromatid e~changrs, 47

on unexposed populations, 70

in the ~~’orkplac[), 3S, 37

239
240 ● The Role of Genetic Testing in the Prevention of Occupational Disease

Diseases

association with certain genetic traits, 11

association with human leukocyte antigens (HLA), 19

detection of increased risk, 27-29

differential susceptibility to, 27

economic costs of occupational, 5

genetic damage and risk of, 10, 18-19

health hazards in the workplace, 24-26

use of genetic testing for prevention of, 7-8, 27-29

DNA (deoxyribonucleic acid)

cietection of damage in, 10, 18, 37, 78-79, 171

diseases of repair of, 11, 96-97

role in protein synthesis, 48-49

structure of, 48

unscheduled svnthesis of, in lvmphocvtes, 78

Down’s syndrome, 46

Economic issues, 5, 13-14

benefits and risks, 29

biases and value judgments, 153-154

cost-benefit analyses, 151-152

cost-effectiveness analyses, 152

elements of economic ei’aluation, 154-156

wraluation of cytogenetic monitoring, 159-160

evaluation of genetic screening, 156-159

idcntif}ling and measuring consequences, 152-153

EEOC (see Equal Employment Opportunity Commission)

Ehnpbyserna, 19, 93-94, 101

Environmental Protection Agency (EPA)

estimate of workplace exposure to ionizing radiation, 25

federally funded data bank for epidemiologic studies,

19, 172

(jene-Tox Program, 19, 69, 172

inirentorj’ of hazardous chemicals, 6

research to develop better genetic tests, 18, 171

EPA (we Environmental Protection Agency)

Epidemiologic studies (see Research, epidemiologic studies

in occupational settings)

Equal Employment opportunity Commission (EEOC), 123, 125

Erythrocyte catalase deficiency, 98

Ethical issues, 13

autonomy principle, 142-143

Code of Ethics for Physicians Providing Occupational

hledical Services, 117, 147

compensation of geneticall~’ disadvantaged workers, 146

dubious tests, 144-145

high correlation between genetic endpoints and disease

risk, 145-146

informed consent, 145, 148

justice, 143-144

in medical research, 145

nonmaleficence and beneficence, 143

Fortune 500” companies, 37, 38, 39

G-6 P-D kwe Glucose-6-phosphate dehydrogenase deficiencjr)

(;cnetics (see also C}’togenetic studies)

and ability to detoxif~v chemicals, 50

alleles, 49, .50, 51, 52

as basis of human iariabilit}, 49-.50

body fluids used in detection of traits or abnormalities,

53-54

of cancer, 52-53

cell division, 45

chromosome] aberrations, 46-47

chromosome] instability diseases, 52

DNA damage, 47, 51

DNA repair, 53

Down’s syndrome, 46

of erythrocyte catalase deficiency, 98

genotype, 52

heterozygosity, 51-52

homozygosity, 51

immunoglobulin A deficiency, 97

interaction with physiological processes, 89

karyotyping, 45-46

metabolism of chemical agents, 53

mutations, 51, 52-53, 68-69

paraoxanase polynorphisrn, 97

phenotype, 52

polygenic traits, 52

pseudocholinesterase variants, 98

of red blood cell traits, 89-93

of sickle cell anemia, 51

single gene traits, 51-.52

sister chromatics, 4.5, 47

of superoxide dismutase, 97

of Ta~’-Sachs disease, 51

\ariant genes, 49-50

(;ene-’I’ox Program (see lh~ironmenta] Protection Agency,

Gene-Tox Program)

(;erm cell damage, 79

G]ossary, 237-238

Glucose-6-phosphate dehydrogenase (G-6P-D) deficiency,

7, 11

characteristics of, 90-91

frequency of testing for, in industry, 34

hypothetical distribution of, 58 (figure)

research on, 100

tests for, 233

and worker susceptibility, 27, 90-91

Health hazards

control of, 25-26

t~’pes found in the workplace, 24-26

Hemoglobin

alkylated, 18, 171

mutations, 18, 171

HGPRT mutation in lymphocytes, 18

HI. A (see Human leukocyte antigens)

Human leukocyte antigens (HLA), 11

and risk of disease, 19, 96, 172

tests for, 233

I]~]x~l~]I~oglot~ulin A deficiency, 97

industrial companies, 33

Insecticides, 98

Ionizing radiation

diseases caLIsed by, 19, ,25

effects in atomic bomb sur~’i~’ors, 70-71
Index ● 2 4 1

genetir damage from, 10-1 ], 18, 46

orrupationa] exposure to, 6, 25, 71

I.artic [i[~h}(iI(]g[’niist;-X (I,l)H-X)

automat f~(i testing for, 79, 171

I ,I)H-X (SW I,ii(t ir (it’il~r(il-clg[?ll;is(J-X 1

IJra(i (,wf; (:iwmicais)

I,e,+il issurs (sfw also I,itif+ition), 11-13

husiness necessitj’ and jot) rel:ite(inrss of genetir testingl

124-125, 128-130

(’onfi(icni i:iiit~ of me{iirtii reror(is, 117-118

disclosure of heaith risks, 117

{iu[~ to conduct rne(i ical or genetic testing, 116

mplo\’w arccss to I’rcor’(is , 117, 123

empio~’er iiahiiit\, 113-114

eJIIp]O\r~r rights ami duties, 11, 112, 119

geneti~’ testing anci thr ~rnerdi (iutj (iiiuse Oi’ the

os1{ A(’t , 120

genetir testing and OSIiA st:in(i~ir[is, 121

informe(i consent, 116-11 7

medicai remmtii protert ion :ind r:ite retention, 122-123

ra(’idi anci ethnic (iistrihution of tcstahie genetic traits, 124

rr:isonahif’ a(’(’orllnl(](i:itiorl” ff)r susceptihie fmlpio}rf?f’s, 130

rf;gulation of compdnf’ mmiical and emplownent practices,

118-130

rf’iationship of compifnj doctor-s to empioyer-s anci

emplowx?s , 11.5

right to refuse rx:iminitt ion, 116, 12.5-126

right to refuse hazarxious \\r)r. k, 119

St:ite an(i Federal anti(iiscrimination laws on hiring the

iuin(iirapped, 126-13 0

testing solrij i’or rese:irch, 116

\ a ri:ii]lf’ suscf:ptihilit}’ of empio}~fm in stami:irxis sf?tt ing,

1 Z(). ] ~ 1

t~rork[~r’s compensation ia~t’s, 1 12?-113

i,egisiation

BiinkruptcJ’ .\(’t , 23

(;i\ii Rights Art, 1 ~ 11 ] , 1 ] ~, 1 Yj. I ‘1~

(:onfi(ientialit} of hlmiiciil Information Art ((:;ilif. ), 118

N’:ition;il I,iihoi’ Reiations Act (NI,RAJ, 11 1

X:ition;i] Resciirrh Act, 116

()(’rL]p;iti()niii Siifet~7 ;in(i Health Act K)SH Act), 11-12, 111,

117, 118, 119-123, 143

Rehahi]itiition Art, 12-13, 17, 126-130

i.fx]kt’mia, Eit!

in atomic homh surliiors, 70

from bfmzf’ne f;,xposurw, 72

from ethjif:ne oxi(ie exposurf;, 72

1,it i,+it ion

,4/t] f~nlarlf2 P:ipf~r Co. ~’. Aloo@\’j 124, 125, 129

,4nlf>rican ‘l’f’.x tile .Ilall[ltil(’tt]re[’s lnstifute L’. DonoL’an

((htton msf ciise), 121, 122-123

on iishwtos, 23

Bednarski I. (Wmr:il ,tfofors, 113

Brnzenf’ riisv (.sef; lrrdustrial 1 k1iof7 [kpartnwnt, .4 FL-[.’IO

L. ,4nwriran Petrf)lf?urn Institutf; )

Borel L. k’ibreboard Paper Produrts Corp., 114

[.’otton Dust case (see Ameriran I’extik ,}lan[lfa~’tur-f!t’.s

ln, stitutf: i. DonoLan)

[;rigg’.s [, DukfI Pok~er Co,, 123-124

lnciustriai [ ‘nion L)epartmfJnt, ,4 F’L-{.’10 \ ,ln]elvi[’an

Pf’tJ’Ok’UIJl lnslitutp (Ik’nzf’nf’ (’asf’), 12 J

,\landolidas t, E)kins hdus?rif~.s, lnr. 114

(16KY.’P L’. F;. F;, Black, ltd., 127-12 8

J1’hirfpoo] Corp. i, ,’tlarshall, 119

I,ol%-iirti!’it} piiriiokanasf’, 97

[,~mi)imcytf; tr-iillsf[]l’lll~itiO1l ;issii~, 79

Nl(; tilf; lllogi{)t)irlf’ rlliii, 92-93

}Ionitoring for genf?tic ch:in#’s

as ai(i in idf’nt if ffing ixiz. a rxious suhtanrf’s, 1 ()- 1 1

in :itornic bomh sur\ i\ors, 1()

cjtogenf=t ic, 67-7.5, 1.59-160

fwonomir fwaluation, 159-160

f’l)ici[;lllioiogi[” stu(iifw using, 1 9

f;thic:i] issues in, 14.5, 147

\r gf;nct ic scr-f:rnin~, .5, 7.s, ~:;, J ~

mf~tho(ioiogj’, 10-11, 26, 37

none’,’togenet ir, 18, 75-80

k’aii(iit}’ an[i rf:iiiibiiitl of, 28

hlLltagr3ns

hin(iing to immogiohin, 77

in hocil’ fiuicis, 18, 7.5-77

in fecfw, 77

monitoring of mutations from, 1()

A“A1)lf (iehj(ir-(~g~;rl:ise cieficien(~, 11

rixir:icteristics of, 92-93

tests for, 233

N~itionai Institute for Lnlirorlmf’nt;il f ~[’iilt 11 ,in(i Siiff’tJ’

(N IEHS)

epidemioiogir stu(iies in ()(’(’Up:lt i()lliil sf’ttings, 171-172

feder’aiij tun[ie{i ~iatii hank for f’])i(lf’r?~i(]l(]gi(’stu(iies,

19, 172

rfwarch to del’eiop bf;tter genetic tests, 18, 171

N:itionai Institute for occL]patiorx~i Safet~ ami fiwilth (NIOSH)

f?pidemioiogic studif>s in orrupatiomii sf;ttings, 171-17 2

estimate of w’orker exposure to hazardous chern i(’ii]s, 6

fe[ier:iliy funded diita txink for epi[iemioiogir stL](iies,

19, 172

National ~~cL]patif)na] Hazard SUr\’f’}’ (Notfs) 24

research to (iwwlop hetter genetir trots, 18, 171

National I,abor Reiations Bmirci, 12

Nationai occLlpationa] ]~iiz:]r-d SuJ’\’f?j’ (NOIIS), 24

31atioJ]ai opinion Reswirrh (:enter (NOR(:)

sL]r\w} of genetic tf+sting h~ in(iLlstrJ, 9, 33 175-226

NIEHS (see Nationai InstitL]te for E:r~\ir-or~l~l[;J~tiii Iieaith and

safety)

,NIOSIi (see Nationai Institute for ()[’(’Ll]>:iti()rl:ii Siiff’tJ’ :ind

Heaith)

N’OHS Lsee National occupational Haz:ir{i Sur\w}r), ~-l

NOR(: (SW N;itiona] opinion Research Center)

NL1ciear’ indLlstry, 6

Occupatimlal Safet3 and Health Administration (OSHA),

12, ~J

,Arrms to i+:mplo~tee Exposure and hleciiciti Records

St;irrdard, 117, 118

f>xposure st:in(iard for ethkiene oxki[”, 72

ti~reshoici limit standar[is ;(iopted h~, 1 Z()
242 ● The Role of Genetic Testing in the Prevention of Occupational Disease

office of Technolo~v Assessment (OTA)

assessment of occupational studies, 60-61

contributors and contractors (this report), 235-236

surtrey of genetic testing by industry, 9, 23, 33-40, 175-226

OSHA (see Occupational Safety and Health Administration)

(MH (see Legislation, occupational Safety and Health Act)

()-llA (MW Office of Technology Assessment)

Paraoxanase polymorphism, 97

Parathion (see Chemicals)

Policy options

adopt Federal regulations on protection of human research

subjects, 170

constrain emplo~mlent actions based on genetic testing,

169-170

employers to disclose nature and purpose of medical

procedures, 170-171

(?mp]o.vers to dwnonstrat[! predictilw abilit}’ of tests, 170

encourage troluntar’v guidelines, 16

Federal funding of ;esearch, 171-172

maintain the status qL]o, 14, 16 7

prohibit genetic testing in the ~vorkplace, 1.5-16, 168-16 9

rqjulate genetic testing, 16-18, 169-17 1

stimulate genetic testing technolo~}~, 15, 18-19, 167-168

Poljqclic ~iromatic h@rocarbons (see Chemicals)

Predictability’ (see \’alidit}, reliability, predictil’e \alue)

Protein sj~thesis, 48-49

Pseuclocholinesterase Yariants, 98

Purposes of genetic testing, .27-28, 35, 36, 38-39

Radiation Effects Research Foundation, 70

Radiation (see Ionizing Radiation)

Red cell phosphatase distribution, 99 (figure)

Regulation (sf?e Policy options)

Rt?]iabi]it~~ (see t’alidit}, reliability, predicti~’e \ralue)

Researrb

to d[?~wlop I)etter genetic tests, 18

by employers on enlplo~rees, 17

epiciemiologic studies in occupational settings, 18-19,

171-172

ft?derall~~ funded data bank for epidemiologic studies,

19, 172

priorities, ] $), r~.:~, 80, 100-101, 1 ~~

Respiratorjf tract infections, 97

Risk (it?tf;[’I~~ir~ ~itiol~, 7-8, 27-28, 59-60

SArl’ !stw? Serum alph:i ,-antitrypsin cieficiencj)

S(:E: (see Sister chromiitid exchanges)

Screening for genetic traits

ar(w racy and reliabil it~’ of tests in, 11

aret}~]ation and susceptibilit~’ to ar’~~lamine-ill(iuced bladder

cancer, 95-96

~id~’erse drug reactions and risk of disease from

occupational exposures, 11

ar}~l h~d rocarbon huvdrox~lwe inducibility and susceptibilit~’

to lung’ cancer, 94-95

carbon oxidation abilit~~l 96

II[;r’rlliitologi(’iii” ll~p[:l’s~ls(;epti t}ilitJ~, 96

diseases of DNA repair, 96-97

worwmk [?lraluation of, 156- 15Y

erythrocu~e catalase deficiency and sensitivity to hydrogen

peroxide producing agents, 96

ethical issues in, 144-145, 146

\r. genetic monitoring, 5, 7-8, 23, 28, 57

@cose-6-phosphate dehydrogenase (G-6P-D) deficiency

and hemolytic anemia, 90-91

human leukocyte antigens (HLA) associated With disease

susceptibility, 96

immunoglobulin A deficiency and risk of respiratory tract

infections, 97

lung disease, 93-95

NADH dehydrogenase deficiency and methemoglobinernia,

92-93

paraoxanase polymorphism and risk of parathion

toxicity, 97

pseudocholinesterase \ariants and sensitivity to

insecticidelike compounds, 98

red blood cell traits, 89-93, 100

research on, 100-101

reservations in application of, 99

selection of emp]oyees for, 34-36

serum alpha I-ant itrypsin deficiency}’ and susceptibility to

emphysema, 93-94

sickle cell trait and sickle cell anerniti, 91

superoxide disrnutase, !37

tests in current use, 36-37, .233

thalassemias and erjthroblastic anenlia, 91-92

traits measured in, 11, 19, 89-101

%?cretary of Labor, 11, 12

Sensitivity and specificity of tests, 58

Serum alpha ,-antitrypsin (SAT) deficiency, 11, 19

characteristics of, 93-94

cronomic ekraluation of testing for, 1.fi7-158

frec~uenc~ of use in industr’~~, 34

high prevalence of, 19, 172

ll~p)thetical break-e~en number of cases alerted t~j~

testing for, 157 (table)

research on, I (]1

and susceptibility to emphysema, 93-!]4

t(?sts for, 233

Sickle cell trait, 9, 34

beta-S .g]obin and, so

d incrimination based on, 12

pre~’alence and distribution of, 91

srreening for, 11, 34, 38, 91

tf’sts for, 233

Sister chromatic exchanges (SCL)

b:ickgrouod frequencies, 231 (table)

and ca rcinogenicit.y, 69

definition, 4 i’

testing in industry, 35, 37

in unexposed populations, 70

Spondylitis, ankylosing, 96

State of’ the art (genetic testing), 9-10, 67-101

Super’ oxide dismutase alleles, 97

Sur~wy of genetic testing, 9, 23, 33-40

anal~~sis of nonrespondents, 205-208

animal t(?sting, 196

comments on questionnaire, 202-203”

factors and criteria for test selection, 201 (t:ible)
—

Index ● 2 4 3

‘1’tlwr’rtical iolln(ii~tiorls (of genetic testing], 7, 27, 45-.54

‘111. vr’oi(i ciisww, 96

c)