Occup. Met). Vol. 48, No. 1, pp.

27-30, 1998
Copyright© 1998 Rapid Science Publishers for SOM
Printed in Great Britain. All rights reserved
0962-7480/98

Biomarkers., screening and

ethics
D. Koh and J. Jeyaratnam
Department of Community, Occupational and Family Medicine,
National University of Singapore, Republic of Singapore

Rapid scientific advances, such as those in biomarker technology, have made a

significant impact on the ethics and practice of occupational health. Biomarkers are
extensively used in occupational health practice. In the pre-employment stage,

Downloaded from https://academic.oup.com/occmed/article/48/1/27/1508291 by guest on 17 March 2022

preventive or predictive testing can be performed. Preventive testing aims to avert
accidents that may occur if a medically unfit worker undertakes a job that he is
unable to perform. For safety sensitive jobs, routine testing of a worker's functional
capacity in the actual job would suffice in most cases. However, a recently quotes
application of a test is the screening for mutations of the cardiac myosin-heavy
chain and troponin genes among asymptomatic persons with a family history of
sudden death from hypertrophic obstructive cardiomyopathy. Predictive testing hopes
to forecast the risk of a worker developing an illness. The aims may vary. One aim
may be to exclude a susceptible worker from working in a hazardous environment.
Another aim may be to avoid employment of a worker who is likely to develop an
illness which could lead to higher employer health care costs. A pertinent question
to consider is whether the test undertaken is to benefit the individual or to fulfil
some administrative or financial need. Among exposed workers, screening may be
conducted for biomarkers of exposure or effect. As the aim is to prevent the onset
of clinical illness, the physician must take responsibility for initiating requests for
screening. The appropriate response to the effect of technical and societal advances
on ethics is the updating of ethical guidelines by the profession. However, in the
context of unvalidated biomarkers being used for screening, it may be necessary to
require a regulatory body to ensure that the tests are accurate and effective, and
that they are not used to discriminate against individuals.

Keywords: Genetic testing; markers of effect; markers of exposure; predictive testing; preventive
testing.

Occup. Med. Vol. 48, 27-30, 1998

Received 2 June 1997; accepted in final form 21 July 1997.

INTRODUCTION of such surveillance must be assessed and it must be

In occupational health practice, guidelines for screen-
ing are reasonably well established. The International
Commission on Occupational Health (ICOH) in 1992
published a Code of Ethics for Occupational Health
Professionals.1 This Code of Ethics has a section on
Health Surveillance which is germane to the title of
the paper.
This section states 'The objectives and the details
of the health surveillance must be clearly defined and
the workers must be informed about them. The validity
carried out with the informed consent of the workers
by an occupational health professional approved by
the competent authority. The potentially positive and
negative consequences of participation in screening
and health surveillance programmes should be
discussed with the workers concerned.'
This view is echoed in the guidance on ethics for
occupational physicians prepared by the Faculty of
Occupational Medicine of the Royal College of
Physicians.2 In these guidelines, it is clearly stated that
occupational physicians should 'ensure that any screen-
ing procedures are ethically and clinically justifiable.'

Correspondence and reprint requests to: Dr D. Koh, Department of

Community, Occupational and Family Medicine, National University Evolution of ethical guidelines
of Singapore, Lower Kent Ridge Road, Singapore 0511, Republic of
Singapore. Tel: 65-874-4972; Fax: 65-779-1489; e-mail: cofk- Ethical guidelines are not static. They evolve and must
ohd@nus.sg change with time to adapt to advances in science and
28 Occup. Med. Vol. 48, 1998

society. Indeed, ethical guidelines in occupational Figure 1. Biomarkers, exposure and the individual.
health are continually reviewed and updated. For
example, the guidance on ethics for occupational phy-
sicians of the Faculty of Occupational Medicine, UK,
Exposure marker «— Internal Dose
is currently in its fourth revised edition, and a fifth
edition is being prepared. Effect marker <-- Target organ
One area of rapid technological development is in or system
the use of biomarkers. This has a significant impact Susceptibility, sensitivity <— The Person
on the ethics and practice of occupational health, which
will be discussed.

Medical ethics in the context of preventive

medicine
It is increasingly recognized that medical ethics, which Biomarkers for preventive and predictive
largely originated and was developed for clinical situ- testing

Downloaded from https://academic.oup.com/occmed/article/48/1/27/1508291 by guest on 17 March 2022

ations, requires modifications in public health or
preventive medicine practice.
For instance, a physician may choose to test for
myeloma globulin as an indicator of multiple myeloma-
tosis in a patient consulting for chronic backache and
bone pain. However, there is no justification to
undertake tests for myeloma globulins among well
persons to 'pick up' early cases of multiple myeloma-
tosis in the practice of public health or preventive
medicine as, at present, there is little or nothing that
could be done to benefit an individual so detected.
Unfortunately, such early markers of disease may be
unjustifiably used in pre-employment medical exami-
nations.
This gives rise to a question every occupational
health physician may wish to consider — will the
information obtained from the biomarker test be of
value to the health of the worker?
What is a biomarker?
At this point, it is pertinent to have a clear under-
standing of the definition and scope of a biomarker.
A Committee of the (US) National Research Council
in 19873, described biological markers as indicators
signalling events in biological systems or samples, and
as tools to clarify the relationship between exposure
and health impairment.
They identified three types of biological markers
(Figure 1):
(i) markers of exposure;
(ii) markers of effect and
(iii) markers of susceptibility to disease or
increased sensitivity to certain exposures.
Biomarkers so defined are used to measure these
end points in asymptomatic individuals largely in the
domain of public health and are undertaken for the
prevention of overt disease. Since the measurement of
biomarkers is initiated by the physician, the guiding
ethical principles should be more stringent than those
in clinical situations.
Pre-employment examinations may be undertaken for
purposes of prevention or prediction. Preventive test-
ing aims to prevent accidents or mishaps which may
occur if a medically unfit worker undertakes a job he
or she is unable to perform. These are essentially fitness
to work examinations.
On the other hand, predictive testing hopes to predict
the risk in a worker to develop an illness. The aim of
such tests vary. One reason may be to exclude a
'susceptible' worker from working in a hazardous en-
vironment. Another example could be to avoid the
employment of a worker who is likely to develop an
illness; which could lead to higher health care costs
for the employer.
Preventive testing
Rapid developments in preventive testing can be illus-
trated in the following example. The council on ediical
and judicial affairs of the American Medical Associa-
tion, in a 1991 paper,4 noted that in some cases,
employers might want to use genetic testing to protect
the public's safety. It stated then that 'Genetic tests
are not only generally inaccurate when used for public
safety purposes, but also unnecessary. A more effective
approach to protecting the public's safety would be
routine testing of a worker's actual capacity to function
in a job that is safety sensitive.'
In 1995, a position paper from the Australasian Fac-
ulty of Occupational Medicine5 presented an example
of a possible use of genetic testing associated with job
placement in a safety sensitive job. The example given
was genetic testing for mutations of the cardiac myosin
heavy chain gene and the cardiac troponin gene. This
mutation is screened for in asymptomatic persons with
a family history of sudden death from hypertrophic
obstructive cardiomyopathy. The purpose is to identify
the risk for sudden death, which is important in jobs
such as public transport.
Predictive testing
Currently, there may be a very limited role for genetic
testing for excluding persons genetically susceptible

to occupational illness from the workplace. Although
still debatable, some instances where this is done
include the screening of male workers exposed to
oxidizing chemicals for the sex-linked genetic
abnormality of glucose-6-phosphate dehydrogenase
(G6PD) deficiency.5 Exposure of G6PD deficient
persons to oxidizing chemicals e.g., naphthalene,
may precipitate hemolytic anaemia. Another instance
is the examination of workers exposed to respiratory
irritants for alphai-antitrypsin deficiency.4 Such
persons are more susceptible to chronic obstructive
lung disease.
In these cases, it must be stressed that the use of
biomarkers of susceptibility should not be a substitute
for safe working conditions, but rather, an adjunct
which enables more precise advice to be given to
employees at job placements for selected occupations.
Dr Ross Hawkins, research fellow in genetics at
Cambridge, has predicted that within five years, it will
be possible to identify almost all the damaged genes
that contribute to known diseases.6 Such a situation
will impose a considerable responsibility on the
profession to the ethical use of such technological
developments.
An underlying consideration for an occupational
health physician would be to review the ethics of
requesting a test for a gene marker. For instance, is
the gene marker test undertaken to benefit the indi-
vidual or is it to fulfil some other financial or
administrative need? The mere knowledge that an
individual has a genetic susceptibility to a disease is
not of value unless the capacity to prevent or delay
the onset of that particular disease is currently avail-
able. If not, all that we do would be to turn 'healthy'
people into patients and create a community of
'worried well' persons.
Screening for susceptibility to disease —
another example
The use of N-acetyltransferase polymorphism (related
to the metabolic activation and deactivation of car-
cinogenic arylamines) as a marker for susceptibility to
bladder cancer in workers exposed to carcinogenic
arylamines was discussed in a recent paper.7
The authors noted that while discrimination between
polymorphic phenotypes is generally straightforward,
misclassification, to some degree, cannot be avoided.
Furthermore, although the N-acetyltransferase pheno-
type is a useful predictor of susceptibility, evidence
linking specific N-acetyltransferase polymorphisms
with cancer risk is variable, depending on the exposure
and the population.
There is, in addition, considerable potential for
restriction of employment possibilities based on
gender, race or ethnic group associated with this poly-
morphism. In view of these factors, the authors
concluded that at present, genetic screening of workers
for susceptibility to cancer seems to be an ethically
unacceptable and premature application of science.
D. Koh and J. Jeyaratnam: Biomarkers, screening and ethics 29
Biomarkers to measure exposure and early
effects
The primary purpose of measuring such biomarkers
as a service activity is to prevent the onset of clinical
disease in the working population. As such, it should
be considered as an investigative instrument to be
managed by the physician. Given this background the
physician must take responsibility for initiating the
requests for measurement of biomarkers in the worker.
It is not the responsibility of a laboratory, in other
words a worker should not be in a position to have a
measure of a biomarker undertaken by a laboratory
without the authority of the responsible physician. It
should not be undertaken by insurance companies for
purposes of setting insurance premia because the pri-
Downloaded from https://academic.oup.com/occmed/article/48/1/27/1508291 by guest on 17 March 2022
mary purpose of measuring a biomarker is to delay
or stop the progression of disease, i.e., it is an instru-
ment of prevention.
As such, considering the ethical issues pertaining to
the medical profession, it can only be achieved if the
physician has the control for initiating the measure-
ment of a biomarker. This responsibility charged to
the physician is a fundamental requirement to ensure
the ethical controls required for biomarkers.
Technical considerations. For a biomarker to be consid-
ered as a measure of exposure it needs to fulfil certain
criteria. A correlation between exposure and the
biomarker must be established. It must be possible to
set a 'cut off safe limit so as to enable the biomarker
to be of value in the prevention of overt morbidity as
a consequence of exposure to a toxic agent. These
criteria need to be fulfilled for measures of exposure
and effect. The importance of these criteria is that the
mere detection of an effect or marker of exposure is
of no value in the prevention of morbidity.
The two given examples of technological advances
in biomarker research demonstrate the relevance of
ethical guidelines in the practice of occupational health.
A promising recently-developed biomarker for low
level benzene exposure is urinary trans, trans-muconic
acid.8 Most of the currently available biomarkers are
unable to provide sufficient specificity for monitoring
of low concentrations of benzene exposure. Another
example of a recently proposed biomarker of effect is
urinary clara cell protein as a biomarker for lung
toxicity.9 The reliability of these biomarkers and the
technical limitations of measurements have to be care-
fully validated before they can come into common use.
It must be emphasized that only proven and estab-
lished biomarkers should be used in an occupational
health setting. The ICOH guidelines1 state that 'Bio-
logical tests and other investigations must be chosen
from the point of view of their validity for protection
of the health of the worker concerned, with due regard
to their sensitivity, their specificity and their predictive
value.' In a similar vein, the Faculty of Occupational
Medicine, UK2 states that such procedures should
'fulfil the usual criteria for a valid screening procedure,
30 Ocoup. Med. Vol. 48, 1998
and have adequate quality control of procedures
performed.'
Besides the criteria of voluntary participation, a proc-
ess for dealing with employees in whom abnormalities
are discovered should be established and clearly
understood. Furthermore, 'detailed clinical informa-
tion from such procedures should not be passed on
to the employers where it would be open to misinter-
pretation, but only to a medically qualified adviser',
even then only with the informed consent of the
individual employee.
A need for regulation?
The appropriate response to the effect of technological
and societal advances on ethics is the updating of
ethical guidelines by the relevant professional bodies.
However, this measure, by itself, may not be adequate.
For the context of unvalidated markers being used
as a screening mechanism, it may be necessary to
consider a regulatory body. A national panel on screen-
ing tests can be established. Such a panel could review
the validity of biomarkers as a screening instrument.
This would prevent inappropriate and unvalidated
biomarkers being used for purposes of screening.
The genetic screening panel of the US National
Academy of Sciences has stated that 'There will be a
need for centralized oversight to insure that new
genetic tests are accurate and effective, that they are
performed and interpreted with close to "zero-error"
tolerance, and that the results of genetic testing are
not used to discriminate against individuals.' Such
centralized oversight already exists in some countries.
In the UK for example, an advisory committee on
genetic testing has been formed in the Health Depart-
ment.
REFERENCES
1. International Commission on Occupational Health (ICOH).
International Code of Ethics for Occupational Health Profes-
sionals. 1994, Singapore.
2. Faculty of Occupational Medicine, UK. Guidance on Ethics for
Occupational Physicians. Fourth Revised Edition. London, UK:
FOM,1997.
3. Mercier MJ, Robinson AE. Use of biologic markers for toxic
Downloaded from https://academic.oup.com/occmed/article/48/1/27/1508291 by guest on 17 March 2022
end-points in assessment of risks from exposure to chemicals.
IntArch Occup Environ Health 1993; 65: S7-S10.
4. Council on Ethical and Judicial Affairs, American Medical
Association. Use of genetic testing by employers. JAMA 1991;
266: 1827-1830.
5. Australasian Faculty of Occupational Medicine. Genetic
screening and occupational medicine. A position paper. 1995.
6. The Sunday Times (London). 16 March 1997: 4-7.
7. Vineis P, Schulte PA. Scientific and ethical aspects of genetic
screening of workers for cancer risk: the case of the n-acetyl-
transferase phenotype. J Clin Epidemiol 1995; 48: 189-197.
8. Ong CN, Kok PW, Ong HY, et al. Biomarkers of exposure to
low concentrations of benzene: a field assessment. Occup En-
viron Med 1996; 53: 328-333.
9. Hermans C, Bernard A. Clara cell protein (CC16): charac-
teristics and potential applications as biomarker of lung toxicity.
Biomarkers 1996; 1: 3-8.
10. Anon. Have you had a gene test? Lancet 1996; 347: 133.