12th Meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals: Susceptibility to Environmental Hazards

J. Carl Barrett,¹ Harri Vainio,² David Peakall,³ and Bernard D. Goldstein⁴

Part 6: Ethical, Social, and Legal Issues Surrounding Studies of Susceptibility

Introduction: Ethics as a Methodology
Growing Attention to Ethics. Since the early 1980s, there has been a growing wave of concern about the ethics of studies on biomarkers of susceptibility (217-227). Technological advances continue to challenge our sense of what may be deemed "right" and "wrong" or "morally appropriate." These concerns have escalated since the beginning of the 1990s (228-248).

Education in the formal theories, principles, and rules of ethics generally has not been an integral part of graduate training among risk scientists. Even though scientists have tended to focus on "the scientific method" in their work, there are prominent examples of concern with the ethical dimensions of their speciality (249). Notions of "peer review" are well developed and mechanisms for achieving "informed consent" are firmly in place. However, the social consequences, including both potential benefits and harms, have been relatively neglected in many areas of science (250,251).

Utility of Ethics. A brief overview of ethical theories in relation to scientific technologies is provided, with special attention to their application in the field of biomarkers of susceptibility. It will be shown that the discipline of moral philosophy, like the scientific specialty areas comprising the risk sciences, provides us with methodologies for analyzing decisions (e.g., whether or not to implement a new technology) and a philosophical basis for our actions. In practical terms, ethical analysis provides us with the tools through which decisions we make can be tested against ethical theories (and their attendant principles and rules) as a basis for explaining or justifying (moral) actions (252).

Ethical Theories and Principles. Analogous to other disciplines, ethical analysis has a theoretical basis. Stemming from each theory are principles and associated rules, providing a framework for ethical analysis. Empirical data then are testable against these theoretical frameworks. Several theories from the discipline of ethics warrant review in the context of biomarkers of susceptibility.

Deontology, a duty-based theory that specifies obligations to be upheld by members of the profession, is perhaps the most commonly evidenced ethical theory among health professionals. The "scientific ethic," in fact, is deontological (duty based), requiring of scientists, among other things, to be objective, honest, and unbiased in the use of appropriate methods related to their subspecialty area of practice. Physicians, too, are bound by duties that derive from the principles of autonomy (i.e., the right of the individual to make independent choices), beneficence (i.e., the obligation to do good), nonmaleficence (i.e., the obligation to do no harm), and distributive justice (i.e., social equity). The preeminent duty among physicians is to not cause harm to their patients. It is through this duty that the physicians' role extends to that of patient advocate. Autonomy, as more recently interpreted, extends to include involving the patient as a partner in decisions about care. Distributive justice is manifest in the principle of equal access to care, regardless of ability to pay. These brief glimpses of ethics relate to physician-patient relationships (253).

Other relationships among health professionals exist. For example, those engaged in public health have the community's interests to protect, and usually adhere more to the utilitarian theory of ethics requiring that the greatest good be done for the greatest number of people. This practice does not preclude the inclusion in public health of other principles such as autonomy, nonmaleficence, and equity. However, the libertarian ethic has less utility within public health because it holds the individual more important than the community.

The egalitarian ethic holds all community members equally important and upholds the principle of solidarity. It measures the well-being of the group by that of the least well off. As an example of the use of egalitarianism, the U.S. Clean Air Act sets regulatory standards to protect the most susceptible members of the population. The principle of justice that flows from the egalitarian theory provides for equal access to the process of susceptibility assessment; by the same principle, the environmental risks should be fairly distributed across social classes, ethnic groups, and races. Equal outcomes cannot be expected because of the nonegalitarian characteristics of inherited genetic traits. The egalitarian philosophy, however, would strive to compensate for those inequalities through biologically based treatment or by social means.

It becomes evident that, depending on the ethical theory that one draws upon, one can rationalize apparently disparate conclusions. This is where normative professional practices need to be defined as an aid to individual practitioners faced with dilemmas, ethical conflicts, or tensions among various principles deriving from the respective theories. The recently formulated ethics of postmodernism uphold the principle of social specificity. This implies that local, subjective, and sometimes fragmented narratives may be more appropriate in guiding the actions of both scientists and the community than traditional overarching or absolutist theories.

The relational ethic, for those more familiar with moral philosophy, provides a basis for making rational comparisons among the various theories. While it is often heard that "ethics are value neutral," in practice it is generally agreed that ethics are, in fact, value laden. Hence, relational ethics can be especially helpful for identifying the theories and principles most appropriate to the issues in studies of biomarkers of susceptibility.

Distinguishing between "Research" and "Practice." A distinction needs to be drawn between the professional engaged in research and the professional engaged in clinical or public health practice. The latter is often governed by legal requirements especially in the area of public health practice where, for example, tensions can arise between the principle of autonomy (in terms of the right to privacy) and the public's right to know about, for example, a potentially contagious condition that requires isolation or quarantine.

Research is that area of professional pursuit that develops new approaches to prevention, treatment, and cure. Adequate testing is required to assure that significantly more good than harm will result before any new product or technology is made available for general practice or commercial application. Where concern is focused on establishing the sensitivity, specificity, and predictive value of a new test, this constitutes research. Here, access by the individual to his/her findings in the absence of any clear interpretation would be inappropriate and volunteers for such research ought to have been so advised at the time that informed consent was obtained. Any person, including the one who participates in research, who would wish to know the results of the tests then would be required to await the conclusion of the scientific investigation and the availability of the test for general use or practice.

Legal and Regulatory Perspectives. While new technologies may have appeal as "magic bullets" to people with concerns for potential benefit, it is government's role to protect the public from harmful effects. Therefore, the involvement of government in regulating the use of technologies is appropriate in those instances where public exploitation or harm could arise from access to inadequately tested products, promoted in the absence of adequate review. It is the scientists' role to pronounce the time when they deem products or technologies to have been adequately tested and hence safe, reliable, and accurate enough for public use.

There is, however, often a fine line that separates "safe" from "unsafe." No product or technology can be said to be absolutely safe, so regardless of where that cut point is set, more or fewer untoward (and unintended) effects will be seen. Society has to be involved in the decisions that define "acceptable levels of unintended effects" as a consequence of any new technology. It then becomes the burden of those in risk communication to ensure public understanding of any risk associated with a new technology used for identifying susceptibilities or for building risk management policies around susceptibility issues.

Ecosystem Perspective. Aside from the ethical concerns of professionals engaged directly in human-health-related disciplines, indirect concerns that are intricately tied to the ecosystem also must be considered. Whether animal species are appropriately used as sentinels (i.e., to serve as indicator species) for exposure effects on humans, the ecosphere should be seen as life sustaining in itself. Hence, damage to nonhuman species or the ecosphere should be considered as potentially harmful to human life. There is also the deontological ethic that assigns to humans stewardship responsibility for the natural world. Therefore, broader concerns than anthropocentric ethics need to be considered in any ethical analysis.

Context of Macro Nature: Ethical, Social, Legal
Relational. The ethical, social, and legal frameworks of biomarker research will differ depending on the professional and contractual relationships of the participants. Individual relationships, such as between physician and patient, lawyer and client, and researcher and participant, are governed predominantly by a deontological ethic whereby the providing professional has the primary obligation to look after and protect the interest of the individual over all other considerations, including social benefits. This obligation is recognized in law that protects the privacy and confidentiality of the physician-patient and lawyer-client (and, by implication, the researcher-participant) relationship against undue intrusion.

This protection may not be complete, and will vary under different legal, social, and cultural conditions. For example, the patient-physician contract may be influenced by the ethics of the payor of services. This ethic places constraints on the primacy of the deontologic relationship because the utilitarian-based principles seek the use of fiscal resources for the maximum good of the larger population. An additional threat to confidentiality rests in the potential vulnerability of computer-based records in which security may be breached by technological intrusion potentially to the detriment of the patient/client/participant.

The significance of these considerations for studies on biomarkers of exposure, effects, and susceptibility rests in the inherent conflicts and tensions that occur when the payor, courts, employer, or public health laws impose requirements on biomarker data that intrude on the principles of privacy and confidentiality in a way that is beyond the power of the original contractees to prevent, and with consequences potentially detrimental to both parties. In this way, data on genetic susceptibility may be used to exclude workers from certain job opportunities, or patients may find themselves unsuspectedly constrained by public health laws. There is also the consideration that the worker in possession of information on genetic susceptibility or biologic effect may be motivated, in the absence of a full understanding of the limitations of the methods, to seek compensation for injury; this could occur in the absence of documented evidence of exposure to a substance in the workplace because of the lack of accompanying technology to identify exposure.

The prevention and resolution of these difficulties are complex and various depending on the social, legal, and cultural environment. The overriding ethical principle is, however, that the participants in these professional/contractual relationships be made fully aware of these possibilities in agreeing to participate in biomarker studies, and that the legal frameworks adjust to the potential negative outcomes if they stand in the way of accomplishing a desired social goal. The scientist, professional, ethicist, and lawyer should work in concert to address these issues, recognizing the adversarial nature of the process and the desirability of engaging the professional organizations in identifying capable experts to provide testimony.

Social Context. Another level of analysis needed to broaden an understanding of ethical concerns on a macro level is the social context. The implication is that the technologies used to identify susceptibility are shaped by a variety of social processes. On this level of analysis, questions surrounding the intended and unintended social consequences of dealing with susceptible individuals and populations need to be raised. For example, will the results of identifying relevant biomarkers in an individual, community, or population have a beneficial or harmful effect upon current or future employment; compensation status in terms of both private insurance and public social security systems; and, more generally, existing forms of social inequality? In this sense, ethical discussions must consider that these consequences may be beneficial as well as harmful and this should be recognized within the scientific community.

Another aspect within the social context that needs consideration is the interface between the public health needs of a specific community and the duty of professionals to identify as well as to provide for some of these needs. Simply, what ethical demands emerge when professionals are confronted with susceptibility in a particular community? This may expose a tension between utilitarian and deontological theories. For example, on the one hand a public health perspective, driven by utilitarian ethics, upholds the principle of the greatest good for the greatest number. On the other hand, the deontological ethic, which governs health professionals, emphasizes their duty to serve those susceptible in the community as well as to protect a community's right to health.

An intervening ethical theory may be the libertarian theory of rights, which demands that any health decisions taken, whether by professionals or the community, will be absolutely respectful of individual autonomy. Here the emphasis is that to act ethically, decisionmakers need to assume that their future actions enable all persons to attain benefits (on their own initiative).

It is worthwhile in an ethical context to consider the impact of legislative and regulatory measures on communities. In light of the issue of susceptibility, what biological markers appear as important in determining whether a disease should be reportable or notifiable or considered communicable? How does susceptibility status affect regulatory measures or official disease classifications in the field of public health? Answers to these questions should be informed by clear ethical principles. But a tension emerges if a community's rights for distributive justice (i.e., social justice or equity) under the law overrides the social need for trust in the public health professional.

Still another area of concern is the role of the expert in the formation of public health policy. Here, a key issue emerges: at what stage in the production of knowledge about susceptibility factors can experts agree collectively that this knowledge will contribute to more accurate methods of prevention? In this way, the ethical principle of beneficence is upheld. Hence, meeting the need for sensitivity, specificity, and predictive value in this field has meant that an effective contribution to prevention should be able to be recognized. However, other ethical principles besides beneficence need to be considered for experts to be successful in having an impact on the formulation of appropriate prevention policies.

Most definitely, those involved in studies on biomarkers of exposure, effect, and susceptibility should be cognizant of the fact that ethics guidelines may vary across cultures. The sorts of ethical principles upheld by the scientific community of a particular culture may differ significantly from those upheld by their counterparts in another culture. For example, the basic tenets of both contemporary medical and public health ethics are derived from major conceptual developments in Western cultures. Scientists and public health officials from the "developed world" need to recognize this fact when they attempt to compare studies or assess the utility of biomarkers in the "developing world."

Time-related Factors. A third factor in the context of the application of biomarker technology is the evolutionary nature of social, ethical and legal concepts and norms. The fairly recent institution of the principles and practices of informed consent is an example of evolution in the ethical conduct of science. What is considered ethically acceptable or legally permissible at the time an understanding is reached or a contract negotiated may become questioned over the life of the outcome of that contract, years or decades later, because of the maturation of legal, social, or ethical philosophy. Research studies on captive populations or using potentially injurious substances for worthy scientific goals are no longer considered ethically justifiable or legally permissible. Indeed, tort action is proceeding retrospectively.

The status of legal protection of confidentiality is in a state of flux, becoming more secure in some societies and less secure in others. Since it is not possible to foretell at this time the full implications of a biomarker of exposure, effect, or susceptibility, the potential for unforeseen outcomes (detrimental or beneficial) is very real. There is a need to provide legal protection to the participants in the future, provided the contemporary criteria are fulfilled. The alternative is to withhold or delay the use of biomarker technology until greater certainty is achieved.

Process and Content
Self-Regulation. ACCOUNTABILITY. Governments usually relegate control of science to the subspecialty scientific professions. It therefore falls on the shoulders of the scientific organizations to ensure that guidelines exist against which members of the subspeciality groups of scientists can be held accountable (250). Ethics guidelines, standards of practice, and the development of good laboratory practices are designed to help maintain objectivity and scrupulous honesty, so necessary for the advancement of knowledge. Adherence to good practices of record-keeping facilitates the auditing of laboratories and thereby minimizes the chances of misconduct in terms of data handling (i.e., falsification, fabrication, and plagiarism) (254).

CAPTIVE POPULATIONS. It is currently recognized that captive populations should not be included in research because the prior voluntary consent needed for their participation can have little meaning in such circumstances. Furthermore, the scientific validity of findings derived from captive populations may be of questionable generalizability in the context of the imposed constraints under which such participants may live (255,256).

PRIVACY. The privacy of findings from research on biomarkers of susceptibility has perhaps a higher level of personal concern than other personal data. Because such research can have profound ramifications, not only for the research participant him/herself, but also for his/her family (i.e., siblings and offspring), special attention must be given to respecting the participant's right to privacy. In research settings generally, as well as in practice, some level of uncertainty is associated with the findings from susceptibility studies. The confidence with which highly sensitive information can be shared with the person to whom it directly relates is not always optimal. The question, therefore, of whether to share this information (together with its uncertain interpretation) must be raised. Current deliberations around the principle of autonomy suggest that the informed consent process should include the option of whether or not the research participant would want to know his/her results in the presence of no clear interpretation.

Furthermore, whether results for which no treatment can be offered should be provided to research participants is a topic that extends to the underlying principles of screening, where screening should not be undertaken unless something can be offered to remediate the condition. In genetic marker susceptibility studies, genetic counseling can be offered; inheritable conditions are viewed as "treatable" through recommendations of the option of abstention or, more extremely, of sterilization, an option that in the presence of uncertainty, could result in substantial harm to the individual.

SECURITY. The degree to which information is not only to be protected (secured) by researchers, but also the degree to which it is to be shared with research participants should be effectively addressed in applications for ethics review to institutional review boards, or human subjects/research ethics committees. Studies of biomarkers of susceptibility require special attention to these details because of the heightened sensitivity associated with such findings. Indeed, owing to the heightened sensitivity associated with the information gleaned from studies into biomarkers of susceptibility, special care by scientific reviewers might include the question of whether or not the hypothesis or question being proposed by the study warrants being addressed. The latter point flows from the social values that may or may not permit such questions to be addressed from the public purse. The question that then follows is how to handle the private funding for research of a highly sensitive nature.

When research is funded, researchers need sufficient funds to ensure data security and to conduct a study of adequate statistical power. Pilot studies, while necessary for the formulation of a major study proposal, need to be undertaken with as much attention to data security issues as if they were full-scale studies.

Concern about the public demand for tests that are not scientifically validated is especially serious for biomarker studies. Whereas syphilis testing remains a required premarital test in many countries, in part because a treatment is available, this is not the situation for many markers of susceptibility, especially genetic markers. Where genetic markers are not clearly interpretable, more harm than good could result from access to such testing; certainly, in the current state of development, few cures or treatments are possible. Until such time as society recognizes genetic aberrations as a part of the normal range of biological diversity, the desire to eliminate that which can be eliminated within the constraints of respect for life will continue.

RIGHT TO KNOW AND NOT TO KNOW. Do we have the right to know our personal genetic characteristics? The peculiar and highly sensitive nature of such knowledge indicates that certain limits and precautions may need to be considered in view of the serious potential consequences of such disclosures for the individual, for relatives, and for children. Knowledge of an individual's genetic characteristics can, in some cases and, with some limitations, provide knowledge about the genetic characteristics of his/her relatives.

We also can consider that we have the right not to know our own genetic characteristics, the right to a carefree life, and to remain ignorant about our own lot. Because genetic screening could lead to fatalistic or pathological behavior, some people might prefer to remain ignorant of this information. Such an attitude would deserve the same respect as the one that demands the most exhaustive information about one's state of health. If, however, offspring are planned and, say, a 50% chance of transmission of a serious genetic defect exists, should the noncarrying spouse and, for that matter, the carrier, be forced to know or be provided with the information?

SCIENTIFIC INTEGRITY. The importance of ensuring absolute integrity in scientific studies involving highly sensitive information is apparent. Hence, methods of laboratory procedures that minimize the risk of data falsification and fabrication are all the more important. Greater scrutiny (oversight) of these studies is in order.

Conflicting interests must be protected against. These could arise in biomarker studies in which premature results are published and the public demand for the "new" test serves the interests of the manufacturers (and its shareholders or stockholders) at a time when the test results may cause more concern through the inability to interpret the results.

When population-based studies are undertaken to determine the prevalence of any susceptibility factor, unlinked studies might be preferable by virtue of their total anonymity. In drawing biological specimens for these or other studies, however, informed consent dictates adherence also to the principle of veracity and fidelity in honoring commitments to, for example, privacy and to the withholding of, or the communication of, results.

CONTINUING EDUCATION. Because professions are expected to be self regulating, the production of this document is one mechanism by which the continuing education of researchers engaged in studies of biomarkers of susceptibility, as well as their students, can be kept abreast of advances in the field. Constructive criticism of any of the ethics guides presented herein should be encouraged, given that societal values and technology differ and change over time. The need to engage the public and stakeholder interest groups in this discussion, while difficult, cannot be overstressed.

Communication. Communicating and campaigning with different categories of scientific bodies, nonscientific bodies, and other concerned organizations, are as important as the discovery of genetic tests themselves. Satisfying the concerns of those bodies will facilitate the approval and application of those methods, rendering them more effective.

The current practice of genetic techniques offered by researchers for protection, selection, or surveillance of susceptible persons to chemical environmental exposure needs to be scientifically sound with honest information and validated standards. Then these techniques can be presented for peer review.

Researchers also should inform and explain such methods to important groups such as health authorities, general or family physicians, occupational health physicians, trade unions, legislators, and administrators. They should explain the benefits of the work, as well as the risk assessment findings and possible risk management approaches to be considered. Other scientific bodies and researchers can be informed through scientific journals, periodicals, lectures, conferences, and special symposia and workshops.

Information to the general public using mass media techniques can be handled through the public press, radio, and television applying simplified, understandable, and uncomplicated language. Risk communication with the general public should be provided for in lay terms. People who undergo such tests can be informed or not informed depending on their wish to know or not to know. Information to family members, children, and siblings depends mainly on local values and on legal requirements.

Stakeholder Involvement. As a key stakeholder in the development of biomarker technology, the scientist is socially accountable. The whole question of determining biomarkers of exposure, effects, and susceptibility leads to assessments of the health of individuals and populations as well as considerations of the use of biology in social relationships. For example, ethics, as a guiding narrative for those making scientific claims, is situated at the interface between the scientific discourse on susceptibility and the general, social discourse on professional ethics. Within ethics, ethical principles and basic human rights become visible. While ethical principles include autonomy, beneficence, nonmaleficence and distributive justice, basic human rights such as the right to health, the right to work, and the right to privacy emerge concurrently.

As these principles and rights become established as collective values, it is the duty of all stakeholders involved to ensure that they indeed are upheld. One way to ensure this is to maintain open lines of communication among the various groups of stakeholders. Here, the process of implementing the ethical principles of veracity and fidelity become clear.

Science is not value neutral in that the direction of scientific pursuit is determined by a synthesis of the value of knowledge for its own sake and the value of knowledge for social benefit. All stakeholders should be made aware of the nature and limitations of the scientific method: that it functions by observation, hypothesis, and experiment and requires a tightly controlled methodology for it to provide reliable results. By the same token, although investigating a universe that is governed by the absolute laws of nature, science can never provide an absolute result but phrases its conclusions on the best available evidence at the time. These conclusions are likely to change in the future as new hypotheses and subsequent data about the laws of nature are gathered. Science strives to minimize--but can never eliminate--uncertainty. For these reasons, the process of science must be transparent to all participants, including the research participants themselves, witnesses, and communicators of results. Furthermore, in the interests of reliability, credibility, and durability, the understandable demands for the premature release of data, drugs, and technologies must be resisted according to the ethical principle of nonmaleficence.

In advocating for a position favorable to science, medicine, or public health, the scientist should retain the identity and adhere to the standards of science--objectivity, impartiality, and stating limitations and uncertainties--because the audience always will lend the scientist the credibility of science. To abandon these principles may endanger the stature of science in terms of the scientists' obligation to improve the state of humankind. The need for scientists to convey an attitude of "healthy scepticism" should support the role of science in the public interest.

Case Studies
The recognition of biomarkers in combination with the rapid development of new methods in molecular genetics and analytical biochemistry have facilitated the screening of individuals for genetic variations of direct relevance for susceptibility to environmental factors and diseases. These biomarkers can be analyzed at different levels, indicating differences in metabolic conversion of chemicals, differences in uptake and exposure to DNA-binding chemicals, differences in genetic effects of chemicals, and hereditary differences predisposing to diseases. Several case studies are used to exemplify these applications. The concluding section of each case study attempts to draw out relevant ethical tensions or to highlight particular ethical principles.

Metabolic Variation. Chemicals to which people are exposed are primarily detoxified in the liver by essentially two systems--one that converts chemicals with low water solubility to soluble metabolites (cytochrome P450) and one that causes conjugation to glutathione (glutathione S-transferases) and to some other compounds.

Of relevance in the present context is the fact that both enzyme systems embrace genetic variants that affect the efficiency with which potentially harmful chemicals are metabolized or conjugated to innocent or less toxic chemical components. Individuals lacking or carrying variants of some of the genes for metabolism and conjugation exhibit an increased susceptibility to carcinogenic chemicals in the environment. This increased susceptibility has been indicated by the observation of an increase in the binding of the chemicals to DNA, the increase of cytological effects such as chromosome breakage, sister chromatid exchange, formation of micronuclei, and an increase of point mutations (46).

The recognition of individuals who are subjected to a potentially increased risk of cancer from this exposure poses the ethical dilemma common to much of the present development of biomarker applications: how to prevent susceptible individuals (particularly those occupationally exposed) from being exposed to these chemicals. In this context, a tension appears between the human right to work and the ethical principle of nonmaleficence. To resolve this tension, scientists should consider more fully the principle of solidarity. In addition, scientists should work in conjunction with public health officials who, at the same time, tend to uphold the principle of social justice.

Mutations Predisposing to Human Diseases. In the last few years, the characterization of genetic factors involved in human disease has undergone a dramatic development. A great number of genes now have been localized and the DNA to a great extent has been sequenced. The human genome project, HUGO, which implies the sequencing of the total human genome can be expected to provide much new material in this respect. A shortcut in this procedure has been performed with "expressed sequence tag" through which mRNA is used instead of DNA to identify human coding genes. DNA of the coding genes is collected by enzymatic conversion of mRNA to cDNA. With this technique, the work can be focused on the 3 to 4% of the human DNA giving rise to genes. To date, about 50,000 of the 70,000 to 100,000 genes have been identified. This material already has played a crucial role for the characterization of the mismatched repair genes particularly involved in human colorectal cancer (below). This will put the person concerned, the physician, and the administrator into a dilemma on how to handle such information and how to protect the person. If the ethical rules will be applied and the test with its pros and cons explained to the person beforehand, this should provide reasonable resolution to potential dilemmas.

Repeated DNA Sequences. Among genetic variants in the human population giving rise to diseases, repeated DNA sequences have attracted a great deal of attention in recent years. Repeated DNA sequences of relevance in this context of biomarkers concern amplification of coding genes as well as short repeated sequences, minisatellite and microsatellite DNA (134).

Amplification resulting in overexpression of coding genes is a regular phenomenon under certain circumstances (257). The gene for metallothionein protects against heavy metals, and exposure to heavy metals can cause an induction and an amplification of this gene (258). The subsequent increase of the protein therefore can be a biomarker for exposure to heavy metals like cadmium and mercury.

Of pathological importance is the occurrence of amplification particularly of nuclear oncogenes such as c-myc. Such amplification has been suggested as a biomarker of some prognosis value in breast cancer patients (259).

An essential part of the noncoding DNA is built up of short, repeated sequences and some of that DNA exhibits a pronounced instability, particularly involving length alterations. The function of this DNA has been and remains obscure, but in recent years several serious human diseases have been associated with short, repeated DNA sequences, minisatellites (10-100 bp) and microsatellites (2-4 bp).

One case of pathological connection with minisatellites concerns a minisatellite associated with the oncogene ras. Some rare variants of this minisatellite are associated with multiple forms of human cancers. It is thus possible to identify carriers of these rare minisatellite alleles that result in a significantly increased risk for cancer.

Microsatellites are particularly important as biomarkers and the cause of some serious human neurological disorders. The microsatellites are linked to the actual genes involved in the disorders and an extension of the repeated DNA sequences above a certain number causes the disease. An important aspect of this process is the fact that the amplification tends to increase from one generation to the next, making the disease gradually more serious with earlier onset--"genetic anticipation."

These microsatellite-linked diseases involve, for instance, fragile X, which is one of the most prevalent mental retardation conditions, and the well-known Huntington's disease. Huntington's disease causes a neurological disintegration with onset usually in the age range of 40 to 60 years.

The genetic predisposition for these diseases is passed on to 50% of the offspring and appropriate testing will predict disease in the offspring. Only occasionally has it happened that the number of repeated DNA sequences has diminished from one generation to the next. The fact that Huntington's disease (as well as other neurological diseases) is incurable poses many ethical problems at the individual and family level, such as testing the offspring and other family members; offering prenatal diagnosis; or deciding whether or not abortion should be performed.

Traditional debates in this area expose major tensions between the ethical principles of autonomy, expressed by those upholding the right to choose, and nonmaleficence, implicit in those opposing abortion. While this tension has not yet been adequately resolved, scientists as well as public health professionals would benefit from considering how developments in biomarker technology may have the potential to modify this traditional tension. If all stakeholders involved would agree collectively about what is meant by "human life" and when it starts, this awareness would shift the traditional debate into a different ethical arena. Here, deontology guides the scientist to stimulate the public's awareness of autonomy.

Repair Mutations. It has been known for over 25 years that a deficiency of DNA repair can cause cancer. The classical case is the recessive autosomal mutation Xeroderma pigmentosum, which causes a serious skin disease. Patients with the disease lack the ability to repair the DNA lesions caused by ultraviolet light irradiation and they invariably develop skin cancer.

In recent years, several genes involved in the repair of mispaired nucleotides, mismatched repair, have been characterized and localized (260). Mutations in these genes are particularly linked to an elevated risk of colon cancer. The mutations occur as heterozygotes and the tumors are induced as the result of the loss of the wild-type allele. It has been estimated that this mutation is carried by 1 in 200 people, and it thus constitutes one of the most prevalent human disorder mutations. Screening for this mutation is likely to be recommended, at least in families that exhibit a high rate of this specific colon cancer-type linked to deficiency of mismatched repair. Such screening will fulfill the purpose of avoiding malignant growth of tumors by regularly checking the colon. In addition, it is evident that exposure to mutagenic and carcinogenic agents can be expected to increase the risk of cancer to a greater extent in mutant carriers, with possible implications for occupational and lifestyle choices.

The fact that susceptibility studies of colon cancer implicate family members poses the tension already discussed in the preceding section "Right to Know and Not to Know." Nevertheless, varying attitudes about genetic information--and the genetic information itself--should be seen as equally important by both the public health professional and the scientist.

Reliability of Laboratories and Methods. Many of the analyses of genetic variants and genetic disorders at the molecular level require sophisticated laboratory techniques and professional knowledge to properly interpret the data. It is of paramount importance that laboratories involved in such analyses are subjected to quality control to avoid mistakes. For instance, it is critical that analyses of mini- and microsatellite patterns in forensic medicine to identify criminals is performed without any error--the consequences could otherwise be disastrous. It also has been pointed out that, although the chance of two unrelated persons having a similar genetic pattern is very remote, relationship has to be excluded in the analysis (261). On the other hand, correctly performed, these techniques for characterizing individuals genetically constitute invaluable tools in forensic medicine, paternity determination, and epidemiological and population analysis. The proliferation of these techniques and tools, and their use with individuals and populations, demand that the collective scientific value of quality assurance be maintained. In ethical terms, the principle of scientific honesty is most relevant in laboratory settings.

Impact of Genetic Monitoring or Screening on Society. We are doubtless only in the beginning stages of the evolution of the genetic characterization of individuals, but already we can foresee many practical and ethical problems for society. Solutions must be developed with the ethical and moral implications defined explicitly. When social costs are involved, the right of autonomy over such personally significant data should be balanced against the interests of society according to, for example, principles derived from utilitarian, libertarian, or egalitarian theories of ethics.

Among the pressing problems is the question of who will have access to the genetic information of individuals. The initial governing principle here would seem to be autonomy. The principle of autonomy requires respect for the individual's right to privacy. However, a tension emerges when the individual's own actions can have a negative impact on the group. The tension is between the individual's right to privacy and the group's (or the community's) right to know.

For example, the fact that people can obtain information about mutations that are likely to shorten their life expectancy may become important in securing life insurance. Attempts to prevent genetic data from reaching insurance companies are not likely to be successful in that insurance companies can require the right of access to medical records as a condition to considering insurability.

If egalitarian theories are to be followed, the cost of this insurance risk would be shared without penalty across the pool of insured people. If either utilitarian or libertarian theories are adopted, susceptible persons might be excluded from the pool of insured, or they might be charged higher premiums. It could be foreseen that persons who know that they carry a life-shortening genetic condition might purchase large amounts of life insurance and that, in turn, could cause an economic deterioration of the insurance system. Prior consideration of these possibilities might help society to focus on the risks associated with the adoption of technological advances.

Genetic Screening of Workers. The recognition that certain genetic polymorphisms could be identified in humans (e.g., hemoglobin S, G-6-PD deficiency, ₁-antitrypsin deficiency) and could be related to differential susceptibility, led Stokinger (262) to advocate their application in screening for so-called "hypersusceptible workers." Omenn (223) cautioned against the blanket application of such techniques as inadequately predictive of risk, and several critics have noted the importance of controlling workplace exposures instead of removing susceptible workers from the workplace (263). Although unusually susceptible individuals would benefit from not being exposed to the agents that are likely to make them sick, this intent should not be used as an excuse to avoid reducing exposures in the workplace; nor can it be invoked to avoid taking differential susceptibility into account in risk assessment (264). Moreover, none of the genetic screening programs thus far proposed are sufficiently predictive of risk. Hence, any exclusion by virtue of membership in a genotypic class would be discriminatory, at least under United States law.

The elimination of women of child-bearing age from certain occupations is now deemed illegal in the United States and represents an example of what is essentially genetic screening; namely, the elimination of persons with a particular genotype (XX) without regard to their actual susceptibility status.

Ecological Ethics. The emission of harmful chemicals into the environment also should be considered from an ecotoxicological point of view. Particularly, the contamination of the environment with persistent chemicals like some chlorinated hydrocarbons and heavy metals can have serious effects on the ecosystem through bioaccumulation along the food chain. Organisms at the top of the food chain run the risk of acute intoxication, reproductive inability, and behavioral disturbances. These effects on the ecosystem are relevant for the preservation of biological diversity in accordance with the convention of biodiversity accepted by the United Nations conference on environment and development in Rio de Janeiro, 1992. But besides our moral obligation to take into account effects on the ecosystem and biodiversity, the monitoring of ecotoxicological effects often can have relevance to human health.

The human species is also at the top of the food chain and is often exposed in the same way as other species at this trophic level. The recent focus on chlorinated compounds like PCBs, DDT, and tetrachlorodioxin, because of hormonal effects, may serve as a further warning signal for human beings. The deontologic duty of humans to serve as stewards of the environment for their own self interest and that of future generations is highlighted in this context. This duty enhances the right to life of other species.

Ethical Components of Biomarker Project Proposals
Parties responsible for biomarker studies need to ensure that the broad range of persons involved in the planning, implementation, and outcome of projects (the stakeholders) are provided the protection of explicit ethical principles under which a project will be conducted. Persons involved include the study participants, the beneficiaries (including both participants and nonparticipants), the community (special and general), those gathering the data (researchers and surveyors), employers, trade unions, regulators, sponsors, and other potential recipients of the results.

The ethical issues to be addressed include the following:

• autonomy of the participant in participating, including fully informed consent

• beneficence of the project for the persons and institutions affected

• absence of maleficence toward the participants and institutions affected

• assurance of justice (equity among participants and nonparticipants)

• test validity as a function of the target population, including consideration of the degree of risk, exposure, and other factors

• explicit provisions to ensure equal access to participation across race, social class, and gender as appropriate to the attribute under study

• nonabridgement of deontologic (duty-based) obligations of the participants

• scientific integrity and soundness

• confidentiality and security of data, including anonymity and nonlinkage to the individual

• referral for treatment and counseling for a significant incidental medical finding

• assurance that a recognized public health or legal risk will be reported

• formulated response to anticipated questions about biomarker findings

• identification and allocation of legal liability

• formats and pathways for communicating study results, including publication, media and employer

• sponsorship, conflict of interest; clear understanding of deliverables warranted for funding received

• action to be taken in the event of an untoward finding, including employment status

• future mutual obligations of participants in the event of new developments.

        a) Because the issues contained herein are from the scientist's perspective, the attention of other stakeholders is called for.

        b) The positive aspects of biomarker technologies must be emphasized without failing to recognize the potential for their misuse.

        c) There is a need to continue research to produce better evidence concerning susceptibility markers while simultaneously protecting against any misuse of premature or tentative evidence.

        d) The active participation of the public is to be sought in a partnership capacity to ensure the advancement of knowledge concerning biomarkers for identifying susceptible people and populations.

        e) It must be recognized that science is imperfect. Uncertainty is inherent to the scientific method and varies as a function of the evolution of scientific knowledge.

        f) The imperfections of science require humility on the part of scientists. Science is but one part of a number of inputs for decision making.

        g) For every decision that is made, the tension between risk and benefit should be considered.

        h) Good science should be tied to good ethics and vice versa.

        i) An unintended consequence of biomarker technology is that individuals and populations could be discriminated against.

        j) Until the scientists involved with developing a new susceptibility biomarker technology have declared it adequately reliable and accurate and after full peer review, the public should be protected from commercial interests that wish to prematurely release the technology into the market place.

Recommendations
Participants in preparing this report make the following recommendations:

        a) Because a multidisciplinary group assessed the ethical dimensions of each respective subspecialty discipline, this report ought to carry some authoritative weight in the context of professional ethics.

        b) Professionals and their students need to engage in an ongoing dialogue concerning applied ethics.

        c) Legislation needs to be developed to protect all interests against liability that could be judged in hindsight arising from changes in ethical standards and scientific knowledge over time (i.e., against retrospective tort action in soundly conducted studies because of intervening changes in social and ethical standards or advances in scientific knowledge).

        d) There is a need for guidelines concerning biomarker susceptibility studies for use by researchers and practitioners alike, which also would be of use in the training of students. Other agencies that have engaged in related deliberations (such as those concerning the Human Genome Project and the U.S. Office of Technology Assessment), should be sought out for collaboration since they have developed guidelines in the area and related areas.

        e) Every research proposal in the area of biomarker susceptibility should address the ethical dimensions of the proposed study. In addition, strategies for communication, from peer review through individuals and the public, should be documented. Studies in biomarker susceptibility should be audited for adherence to proposed intentions.

        f) Scientists must be vigilant in developing ethics guidelines in that they should ensure equity across all segments of society. All guidelines should be sensitive to cultural differences.

        g) Because of the extremely sensitive (i.e., intimately personal) nature of the information gleaned from biomarker susceptibility studies, extraordinary precautions relating to the privacy of the information are to be exercised.

        h) Specific guidelines on how industry and insurance companies might deal with individuals discovered to have a susceptibility are beyond the scope of this text. However, attention is drawn to this since guidelines in these specific areas may be aided by the discussion contained in this section.