Ethical Concerns Over Testing on Human Subjects

A Joint Subcommittee of the Scientific Advisory Board and the FIFRA Scientific Advisory Panel recently issued a report to the U.S. Environmental Protection Agency (USEPA) concerning the use of data derived from testing on human subjects. The authors address both scientific and ethical issues pertaining to such research and conclude that as long as certain conditions are met, the deliberate exposure of voluntary subjects to potentially dangerous levels of pesticides can be both scientifically and ethically sound. I argue that there are further ethical problems not adequately addressed in the report. In particular, there are serious concerns about fairness and exploitation in connection with paid volunteers, which also raise questions about the degree to which the conditions of non-coercion and informed consent are likely to be met. The primary aim of this paper is to bring these issues more fully into the discussion. I also consider briefly the constraints placed on legitimate justifications of human studies by the requirement that the promotion of public safety be the ultimate purpose of the studies. This will help to clarify which reasons in support of human studies are in principle legitimate, which will in turn better enable us to weigh them against the ethical concerns about fairness and exploitation.     

Ethical Review of Research on Human Subjects at Unilever: Reflections on Governance

This article considers the process of ethical review of research on human subjects at a very large multinational consumer products company. The commercial context of this research throws up unique challenges and opportunities that make the ethics of the process of oversight distinct from mainstream medical research. Reflection on the justification of governance processes sheds important, contrasting light on the ethics of governance of other forms and context of research.     

The Ethical Conduct of Studies Involving Controlled Human Exposure to Environmental Pollutants

In recent years, the concern for human research subject protection has increased markedly in the United States. The nature of research subject participation in controlled-exposure environmental health research is such that the individual subject bears the risk of participation, while the benefits of such research accrue to society. Therefore, particular attention must be paid when designing studies to protect the health and safety of human research subject. This paper outlines principles for the appropriate selection of pollutants to which humans can be exposed, and the principles that should be used to protect the health and safety of human research subject.     

Conducting Research with Human Subjects in International Settings: Ethical Considerations

Biomedical research in international settings is undergoing expansive growth andmay potentially result in far-reaching benefits, such as direction of researchresources toward solving basic health care needs of world populations. However,key ethical concerns surround this expansion and must be carefully considered byinternational researchers. International research is impacted by differences inlanguage, culture, regulatory structures, financial resources, and possiblyethical standards. Local community leadership involvement in the planning stagesof research is imperative. Especially in resource-poor countries, the researchagenda must be designed to address local needs and provide local benefit.Capacity strengthening efforts, aimed at improving institutional support forethical conduct of human subjects research, must continue to be supported bywealthier nations.     

Issues Related to Chemical Analysis,Data Reporting,and Use: Implications for Human Health Risk Assessment of PCBs and PBDEs in Fish Tissue

Recent reports in the scientific literature and the media, related to elevated levels of polychlorinated biphenyls (PCBs) and polybrominated diethyl ethers (PBDEs) in farmed and wild salmon have had significant impacts on public opinion and consumer behavior, influencing the sales of farmed salmon in North America and Europe. The assessment of contaminants in fatty fish, an important source of omega-3 fatty acids, is therefore an exercise in balancing risks and benefits. Human health risk assessors and risk managers will benefit from an understanding of the level of uncertainty that is integrated into all aspects of evaluating risk in this context. Significant variability exists in the way in which analyses are conducted, how data are reported, and how they are used in risk assessments. We conducted an analytical review of PCB and PBDE data in farmed and wild salmon, and identified critical issues having implications on human health risk assessment from fish consumption. These issues include: analytical methodologies used, quantification issues, reporting of QA/QC information, tissue sampling, nature of tissue analyzed, and laboratory competence. This article reviews and outlines these issues, discusses their implications for human health risk assessment, and recommends the consistent application of analytical fish tissue data in human health risk assessment.     

Ethical Research Issues: Going Beyond the Declaration of Helsinki

La Vaque and Rossiter made a strong, supported argument that it is unethical to use a no treatment control group in a research study if a known, effective treatment is available. Their argument is based on the supposition that the Declaration of Helsinki is the ethical world standard for research with humans. Their argument appears to be straightforward, but is not simple to apply. The issues are very complex, include issues not discussed in their argument, and can lead to a different conclusion as pointed out in this paper. The World Medical Association developed the Declaration of Helsinki as one of their official policies. The Declaration of Helsinki, however, is not accepted as the world ethical standard, as demonstrated by its lack of adoption by many professional associations or even by the United States Federal Government. Perhaps it is not mentioned because its ethical provisions are aspirational rather than mandatory as implied by La Vaque and Rossiter. Researchers and clinicians should also be aware of other ethical issues not directly discussed in the La Vaque and Rossiter paper. The Belmont Report is the basis for the ethical protection of human research subjects for at least 17 federal agencies and does not mention the Declaration of Helsinki. The Belmont Report mentions several ethical principles that form the basis for informed consent, risk/benefit assessment, confidentiality of data, subject selection, Institutional Review Boards, and other protections needed when doing research with human subjects. At least 2 of these core principles have direct implications to the discussion related to the use of placebo controls. The ethical principle of fidelity is also important in guiding research activities with human subjects. Researchers should be familiar with the La Vaque and Rossiter argument, the Belmont Report, and the federal policies developed to implement the provisions of that report, for example, Regulation 45 CFR 46.     

The Value of Human Testing of Pesticides

Recently, the issue of using human volunteers as subjects for studying the potential toxicity of pesticides has received public attention through the media and subsequently in the regulatory arena. The debate has focused on whether such studies are ethical per se and if data from these investigations should be used for regulatory decisions. The precipitating event that prompted the current debate was the enactment of the Food Quality Protection Act (FQPA) of 1996. The FQPA, which amended the two laws governing the regulation of pesticides in the United States, requires the Environmental Protection Agency to reassess all of the nearly 10,000 tolerances (maximum allowable residues in food) and exemptions from tolerances that were in place when the law went into effect. When reassessing tolerances the U.S. Environmental Protection Agency (USEPA) reviews the data, including toxicology, available on each pesticide to determine if they are adequate to allow the Agency to make the necessary safety finding. Historically, it had been considered acceptable to conduct and use data from studies of exposure to chemicals (including pesticides) of human volunteers if these studies were conducted according to specific criteria as outlined in the Helsinki Declaration and Common Rule. Now this philosophy is being challenged and the USEPA is faced with answering the question of whether pesticides should be viewed as different, from an ethical standpoint, from other chemicals, and how such data should be used in the risk assessment process. The following paper makes an argument for the use of human volunteer testing of pesticides applying the logic that, if one wants to protect humans from the potential harm that may occur from eating foods containing pesticides, one must use the best possible data available. There can be little doubt that the best data for predicting the toxicity of a chemical in humans is to obtain and use human data, as long as it is obtained in an ethical manner.     

Practical Issues in the Use of Probabilistic Risk Assessment

Probabilistic risk assessment (PRA) represents an important step in the evolution of risk assessment methodology to assist decision-making at hazardous waste sites. Despite considerable progress in the development of PRA techniques, regulatory acceptance of PRA has been limited, in part because a number of practical issues in its use must yet be resolved. A recent workshop on PRA identified several areas to be addressed, including the need for: (1) better demonstration of the value of PRA in risk management; (2) PRA training and education opportunities; (3) the development of technical criteria for acceptability of a PRA; (4) policy decisions on acceptable risk distributions; (5) ways to deal with risk communication issues; and (6) a variety of technical issues, including ways to include estimates of variability and uncertainty associated with toxicity values. Solutions to many of these issues will require better dialog between risk assessors and risk managers than has existed in the past.     

Application of Ethical Principles to Research using Public Health Data in The Global South: Perspectives from Africa

Existing ethics guidelines, influential literature and policies on ethical research generally focus on real‐time data collection from humans. They enforce individual rights and liberties, thereby lowering need for aggregate protections. Although dependable, emerging public health research paradigms like research using public health data (RUPD) raise new challenges to their application. Unlike traditional research, RUPD is population‐based, aligned to public health activities, and often reliant on pre‐collected longitudinal data. These characteristics, when considered in relation to the generally lower protective ethico‐legal frameworks of the Global South, including Africa, highlight ethical gaps. Health and demographic surveillance systems are examples of public health programs that accommodate RUPD in these contexts. We set out to explore the perspectives of professionals with a working knowledge of these systems to determine practical ways of appropriating the foundational principles of health research to advance the ever growing opportunities in RUPD. We present their perspectives and in relation to the literature and our ethical analysis, make context relevant recommendations. We further argue for the development of a framework founded on the discussions and recommendations as a minimum base for achieving optimal ethics for optimal RUPD in the Global South.     

Using Human Data to Develop Risk Values

One of the criticisms of industry-sponsored human subject testing of toxicants is based on the perception that it is often motivated by an attempt to raise the acceptable exposure limit for the chemical. When Reference Doses (RfDs) or Reference Concentrations (RfCs) are based upon no-effect levels from human rather than animal data, an animal-to-human uncertainty factor (usually 10) is not required, which could conceivably result in a higher safe exposure limit. There has been little in the way of study of the effect of using human vs. animal data on the development of RfDs and RfCs to lend empirical support to this argument. We have recently completed an analysis comparing RfDs and RfCs derived from human data with toxicity values for the same chemicals based on animal data. The results, published in detail elsewhere, are summarized here. We found that the use of human data did not always result in higher RfDs or RfCs. In 36% of the comparisons, human-based RfDs or RfCs were lower than the corresponding animal-based toxicity values, and were more than 3-fold lower in 23% of the comparisons. In 10 out of 43 possible comparisons (23%), insufficient experimental animal data are readily available or data are inappropriate to estimate either RfDs or RfCs. Although there are practical limitations in conducting this type of analysis, it nonetheless suggests that the use of human data does not routinely lead to higher toxicity values. Given the inherent ability of human data to reduce uncertainty regarding risks from human exposures, its use in conjunction with data gathered from experimental animals is a public health protective policy that should be encouraged.     

Ethical issues surrounding controlled human infection challenge studies in endemic low-and middle-income countries

Controlled human infection challenge studies (CHIs) involve intentionally exposing research participants to, and/or thereby infecting them with, micro-organisms. There have been increased calls for more CHIs to be conducted in low- and middle-income countries (LMICs) where many relevant diseases are endemic. This article is based on a research project that identified and analyzed ethical and regulatory issues related to endemic LMIC CHIs via (a) a review of relevant literature and (b) qualitative interviews involving 45 scientists and ethicists with relevant expertise. In this article we argue that though there is an especially strong case for conducting CHIs in endemic (LMIC) settings, certain ethical issues related to the design and conduct of such studies (in such settings) nonetheless warrant particularly careful attention. We focus on ethical implications of endemic LMIC CHIs regarding (a) potential direct benefits for participants, (b) risks to participants, (c) third-party risks, (d) informed consent, (e) payment of participants, and (f) community engagement. We conclude that there is a strong ethical rationale to conduct (well-designed) CHIs in endemic LMICs, that certain ethical issues warrant particularly careful consideration, and that ethical analyses of endemic LMIC CHIs can inform current debates in research ethics more broadly.     

Pathway-Related Factors: The Potential for Human Data to Improve the Scientific Basis of Risk Assessment

The default uncertainty factors used for risk assessment are applied either to allow for different aspects of extrapolation of the dose-response curve or to allow for database deficiencies. Replacement of toxicokinetic or toxicodynamics defaults by chemical-specific data allows the calculation of a chemical-specific “data-derived factor”, which is the product of chemical-specific values and default uncertainty factors. Such chemical-specific composite values will improve the scientific basis of the risk assessment of that chemical, but the necessary chemical-specific data are rarely available. Categorical defaults related to pathways of elimination and mechanisms of toxicity could be used when the overall fate or mechanism is known, but there are no chemical-specific data sufficient to allow replacement of the default, and the development of an overall data-derived factor. The development of pathway-related categorical defaults is being undertaken using data on selected probe substrates for which adequate data are available. The concept and difficulties of this approach are illustrated using data for CYP1A2.     

Ethical Issues in Adolescents' Sexual and Reproductive Health Research in Nigeria

There is increasing interest in the need to address the ethical dilemmas related to the engagement of adolescents in sexual and reproductive health (SRH) research. Research projects, including those that address issues related to STIs and HIV, adverse pregnancy outcomes, violence, and mental health, must be designed and implemented to address the needs of adolescents. Decisions on when an individual has adequate capacity to give consent for research most commonly use age as a surrogate rather than directly assessing capacity to understand the issues and make an informed decision on whether to participate in research or not. There is a perception that adolescents participating in research are more likely to be coerced and may therefore not fully comprehend the risk they may be taking when engaging in research. This paper examines the various ethical issues that may impact stakeholders' decision making when considering engaging adolescents in SRH research in Nigeria. It makes a case for lowering the age of consent for adolescents. While some experts believe it is possible to extrapolate relevant information from adult research, studies on ethical aspects of adolescents' participation in research are still needed, especially in the field of sexual and reproductive health where there are often differences in knowledge, attitudes and practices compared to adults. The particular challenges of applying the fundamental principles of research ethics to adolescent research, especially research about sex and sexuality, will only become clear if more studies are conducted.     

Against the inalienable right to withdraw from research

In this paper I argue, against the current consensus, that the right to withdraw from research is sometimes alienable. In other words, research subjects are sometimes morally permitted to waive their right to withdraw. The argument proceeds in three major steps. In the first step, I argue that rights typically should be presumed alienable, both because that is not illegitimately coercive and because the general paternalistic motivation for keeping them inalienable is untenable. In the second step of the argument, I consider three special characteristics of the right to withdraw, first that its waiver might be exploitative, second that research involves intimate bodily access, and third that it is irreversible. I argue that none of these characteristics justify an inalienable right to withdraw. In the third step, I examine four considerations often taken to justify various other allegedly inalienable rights: concerns about treating yourself merely as a means as might be the case in suicide, concerns about revoking all your future freedoms in slavery contracts, the resolution of coordination problems, and public interest. I argue that the motivations involved in these four types of situations do not apply to the right to withdraw from research.     

Data Fusion Methods for Human Health Risk Assessment: Review and Application

The improved accessibility to data that can be used in human health risk assessment (HHRA) necessitates advanced methods to optimally incorporate them in HHRA analyses. This article investigates the application of data fusion methods to handling multiple sources of data in HHRA and its components. This application can be performed at two levels, first, as an integrative framework that incorporates various pieces of information with knowledge bases to build an improved knowledge about an entity and its behavior, and second, in a more specific manner, to combine multiple values for a state of a certain feature or variable (e.g., toxicity) into a single estimation. This work first reviews data fusion formalisms in terms of architectures and techniques that correspond to each of the two mentioned levels. Then, by handling several data fusion problems related to HHRA components, it illustrates the benefits and challenges in their application.     

Arsenic in Seafood: Speciation Issues for Human Health Risk Assessment

Major sources of arsenic exposure for humans are foods, particularly aquatic organisms, which are called seafood in this report. Although seafood contains a variety of arsenicals, including inorganic arsenic, which is toxic and carcinogenic, and arsenobetaine, which is considered nontoxic, the arsenic content of seafood commonly is reported only as total arsenic. A goal of this literature survey is to determine if generalizable values can be derived for the percentage of total arsenic in seafood that is inorganic arsenic. Generalizable values for percent inorganic arsenic are needed for use as default values in U.S. human health risk assessments of seafood from arsenic-contaminated sites. Data from the worldwide literature indicate the percent of inorganic arsenic in marine/estuarine finfish does not exceed 7.3% and in shellfish can reach 25% in organisms from presumably uncontaminated areas, with few data available for freshwater organisms. However, percentages can be much higher in organisms from contaminated areas and in seaweed. U.S. site-specific data for marine/estuarine finfish and shellfish are similar to the worldwide data, and for freshwater finfish indicate that the average percent inorganic arsenic is generally < 10%, but ranges up to nearly 30%. Derivation of nationwide defaults for percent inorganic arsenic in fish, shellfish, and seaweed collected from arsenic-contaminated areas in the United States is not supported by the surveyed literature.     

Use of Toxicological Data in Estimating Reference Values for Risk Assessment

A number of programs within the U.S. Environmental Protection Agency (USEPA) currently set less-than-lifetime exposure limits in addition to the chronic reference dose (RfD) and reference concentration (RfC). A review of procedures within the USEPA for setting reference values suggests that less-thanlifetime reference values should be more routinely developed and captured in the USEPA's online IRIS database where chronic RfDs and RfCs, as well as cancer slope factors, are currently available. A review of standard testing study protocols was conducted to determine what data were available for setting acute, short-term, and longer-term reference values, as well as chronic values. This review was done from the point of view of endpoints assessed for specific organ systems (both structural and functional), life stages covered by exposure and outcome, durations of exposure covered and the outcomes evaluated for each, and evaluation of latency to response and/or reversibility of effects. This review revealed a number of data gaps and research needs, including the need for an acute and/or short-term testing protocol that can be used to set acute and shortterm reference values, a strategy for when to conduct more extensive testing based on initial screening data or other information (e.g., chemical class, pharmacokinetics, mode of action), additonal standard testing guidlines protocols to allow more complete assessment of certain organ systems and life stages, development of pharmacokinetic data for different life stages, toxicity related to aging, and latency to response, particularly long-term latency as a result of developmental exposures. The implications of this review are discussed relative to characterizing hazard data for setting reference values, and the potential effects on uncertainty factors and low-dose extrapolation.     

Exploitations and their complications: the necessity of identifying the multiple forms of exploitation in pharmaceutical trials

Human subject trials of pharmaceuticals in low and middle income countries (LMICs) have been associated with the moral wrong of exploitation on two grounds. First, these trials may include a placebo control arm even when proven treatments for a condition are in use in other (usually wealthier) parts of the world. Second, the trial researchers or sponsors may fail to make a successful treatment developed through the trial available to either the trial participants or the host community following the trial. Many commentators have argued that a single form of exploitation takes place during human subject research in LMICs. These commentators do not, however, agree as to what kind of moral wrong exploitation is or when exploitation is morally impermissible. In this paper, I have two primary goals. First, I will argue for a taxonomy of exploitation that identifies three distinct forms of exploitation. While each of these forms of exploitation has its critics, I will argue that they can each be developed into plausible accounts of exploitation tied to different vulnerabilities and different forms of wrongdoing. Second, I will argue that each of these forms of exploitation can coexist in single situations, including human subject trials of pharmaceuticals. This lesson is important, since different forms of exploitation in a single relationship can influence, among other things, whether the relationship is morally permissible.