Environmental Health Ethics in Study of Children

Environmental Health Ethics in Study of Children

Environmental Health Ethics in Study of Children LE Knudsen and M Pedersen, University of Copenhagen, Copenhagen, Denmark DF Merlo, National Cancer Re...

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Environmental Health Ethics in Study of Children LE Knudsen and M Pedersen, University of Copenhagen, Copenhagen, Denmark DF Merlo, National Cancer Research Institute, Genoa, Italy & 2011 Elsevier B.V. All rights reserved.

Abbreviations PCBs REC

polychlorinated biphenyls Research Ethics Committee

Children and Environmental Health: Special Concerns Differential Exposure and Susceptibility of Children In research involving children, it is important to acknowledge that children are not small adults in relation to both exposure and susceptibility. Rapid growth and development of brain and nervous system along with anatomical and physiological changes in several other organs and organ systems differentiate children from adults when studying exposure and susceptibility

to environmental exposure. Children are therefore particularly dependent on their environment and on their caregivers. Also children have a longer life span in which to express illness that may be related with exposure early in life. Studies suggest that exposure to specific environmental factors in early life can increase the risk of chronic adverse health effects later in life (Box 1). Although children may share the same environment as adults, they can be more or less exposed to a variety of chemicals and environmental substances than adults because of their behavior and physiological differences. Although exposure during fetal life and infancy is strongly dependent on the exposure of the pregnant or lactating mother, exposure during childhood and adulthood is also influenced by differences in nutritional and energy requirements, activity level, and the location where activities are taking place. Children, in general,

Box 1 Examples of cases of special childhood vulnerability to environmental exposures. 1. In Minamata bay in Japan, the methylmercury waste resulted in massive exposures of unborn and newborn children resulting in neurodegenerative epidemic outbreak in the area with children and later adults seriously affected with neurologic effects from methylmercury damage of CNS. 2. Exposure to radiation as a result of the Chernobyl nuclear power plant accident where massive amounts of radioactive materials were released into the environment and large numbers of individuals living in Belarus, Russia, and Ukraine were exposed to radioactive iodines, primarily 131I. Iodine-131 concentrated in the thyroid gland of residents of the contaminated areas, with children and adolescents being particularly affected. In the decade after the accident, a substantial increase in thyroid cancer incidence was observed among exposed children in the three affected countries, supporting an association between pediatric thyroid cancer incidence and radiation exposure to the thyroid gland. 3. Consumption of alcohol during pregnancy is associated with a great potential for developmental defects in the unborn child. The critical target organs are the central nervous system and the liver. Fetal alcohol syndrome, fetal alcohol effects, partial fetal alcohol syndrome, alcohol-related neurodevelopmental disorders, static encephalopathy (alcohol exposed), and alcohol-related birth defects are all names for a spectrum of disorders caused when a pregnant woman consumes alcohol. 4. Smoking during pregnancy increases the risk of perinatal mortality, lowers mean birth weight, increases the risk of spontaneous abortion, and has a significant influence of risks of premature delivery and placenta function. Low birth weight, thinness, and short body length at birth has been associated with increased rates of cardiovascular diseases and noninsulin-dependent diabetes in adult life. 5. Exposure to air pollution may cause significant increases in respiratory symptoms and their intensity in sensitive persons. 6. Persistent substances such as lead accumulated in the body of the mother may be redistributed, thus leading to exposure of the unborn child. 7. Pesticides delayed effects on reproductive and immune systems. 8. Cancer risk may increase from higher susceptibility of children. 9. Thalidomide, a drug that was sold during the 1950s and 1960s as a sleeping aid and to pregnant women as an antiemetic to combat morning sickness and other symptoms. It was later (during 1960–61) found to be teratogenic in fetal development. 10. PINCHE concluded that outdoor air pollutants (especially traffic-related), environmental tobacco smoke, allergens, and mercury were high priorities with an urgent need for action. Brominated flame retardants, lead, polychlorinated biphenyls (PCBs) and dioxins, ionizing and solar radiation, and some noise sources were classified as being of medium priority. Some toxins were given low priority, based on few exposed children, relatively mild health effects or an improving situation due to past policy measures. 11. Safety factors in risk assessment may include an extra factor for children.

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have a higher daily intake of food, water, and air along with matters not meant to be eaten, for example, sand or dirt per unit body weight than adults (Table 1). It follows that children cannot be considered and should not be treated as one group given the differences in physiology and physical activity’s influence on the exposure pattern. It is generally recognized that there may be windows of vulnerability or short periods of human development when toxic exposures may substantially alter organ structure or function. Grouping in age groups, for example, in infants (r2 years of age), childhood (42–Z14 years of age), and adolescence (414 years of age) can be useful as a guide for the development of exposure scenarios and baseline values for children. Moreover, during infancy and childhood, substantial maturational changes take place in tissue composition, size, and function. The rates of uptake, distribution, metabolism and excretion of toxins, immune system, DNA repair processes, and cell proliferation and differentiation, etc. are altered in children as compared with adults. Potentially vulnerable systems in infants and young children include the endocrine, reproductive, immune, respiratory, visual, and nervous systems.

Table 1

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Anatomical, biochemical, and physiological differences from adults are more pronounced, the younger the infant. The physiological changes affect children’s exposures and their susceptibility to certain health effects. The agerelated changes in anatomy and behavior are diverse even at a specified age. Some diseases are specific for children and children may respond differently to common illness. Healing and compensation is particularly effective in children and yet adverse environmental exposure and illness in childhood may have far-reaching consequences. Major improvements in the treatment of childhood diseases (e.g., vaccination), nutrition, water quality, and many other factors have resulted in significantly improved survival and lowering of childhood mortality over the recent decades. Increased incidences of, for example, birth defects, cancer, asthma, allergy, and learning disabilities have been reported for developed countries. In general the understandings of the complex relationships between environmental exposures and human health are limited and not easily accessible to researchers and administrators. Especially data on fetal exposure, newborn, and child environmental exposure and shortterm and delayed health effects are scarce. Therefore

Developmental stages and their specific characteristics concerning exposures, vulnerability, and preventive interventions

Developmental stage

Developmental characteristics

Exposure

Vulnerability

Preventive interventions

Preconception

Lack of awareness of gonadal exposure.

All environmental exposures.

Potential for genotoxicity.

Pregnancy

High calorie intake and permeable placenta.

All environmental exposures and ad hoc diagnostic investigations.

Potential for teratogenicity due to embryonic development of various organs and apparatuses.

First three years

Oral exploration, handto-mouth, beginning to walk, and stereotyped diet

Food (milk and baby foods), air (indoor), tap/well water, and mattress/carpets/ floor.

Preschool and school-age child

Growing independence and playground activities.

Food (milk, fruit, and vegetables) and air (indoor and outdoor)

Adolescence

Puberty, growth spurt, risk-taking behavior, and youth employment.

Food (any), air (indoor and outdoor), and water occupational exposure.

Potential for damage to brain (synapses) and lungs (developing alveoli), allergic sensitization, and injuries. Potential for damage to brain (specific synapse formation and dendritic trimming) lungs (volume expansion) and injuries. Potential for damage to brain (continued synapse formation), lungs (volume expansion), and pubertal development and injuries.

Regulations and control on possible sources. Information for adolescents and the general population. Regulation on occupational and other environmental exposures during pregnancy, health information to couples, and health information to pregnant adolescents. Regulations and control on air pollution, provision of safe water and adequate sanitation, and anticipatory advice for injury prevention (parents and caregivers). Regulation and control on outdoor and indoor pollutants and food, and information for parents, schoolteachers, and children. Regulation on child labor, injury prevention, and tobacco smoke and health information and regulations in recreational areas for young people.

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there is a need for environmental research in children. As study subjects, children participating in research have the right to know about the consequences of research to their life and health and the scientists carrying out the research must conform to the ethics of the medical profession to satisfy moral, ethical, and legal requirements. Most of the guidelines promote the following four basic principles of biomedical ethics: autonomy, beneficence, nonmaleficence, and justice. Important ethical issues are information of participants and consent to participate. Follow up and protection of samples and information derived from samples should be discussed in the context of biobanks, where children obtain individual rights when they become adults. There are practical issues on how to best present information on the research study to children in a form they can understand. Differential Autonomy Autonomy is related to respect for the person, and is commonly understood as his/her right to know or not to know, and as his/her freedom in making decisions (to participate in or not to participate in, or withdraw from, the research). For persons with diminished capacity of self-determination (including children who, due to agerelated physical, mental, and psychological development, may not be fully capable of understanding the research issues, benefits, and risks), the right to be protected is in line with this principle. It requires a written informed consent, which again can only be based on adequate and relevant information to potential study participants. Indeed, only truly comprehended information can guarantee a freewill decision after understanding all research implications (intentionality and voluntariness). Planning research on children inevitably requires that special attention is devoted to their capabilities and development. The ability of making independent decisions (understanding and competence) is strictly connected to the process of thinking. Given the variation in development during infanthood, childhood, and adolescence, understanding and determining objectively the child’s capacity to understand complex research issues is a big challenge to researchers. To be able to answer the question ‘‘at what age are children able to make decisions consciously and independently?’’ requires good knowledge of the development of abstract thinking. In early childhood, thinking does not constitute a separate and independent cognitive activity, but is merely subject to practical acts (i.e., concrete actions taken by the child). Four age-related developmentally different phases can be identified. From a few months after birth up to 2½ years of age, motor-sensorial intelligence is predominant. From 2½ to 6 years of age, a child thinks by means of images and focuses on one directly perceived aspect of a given situation (preoperational intelligence). Concrete

notions start appearing at the age of 6–11 years, resulting in what is called orientation in reality. Later in life, activities become intentional and planned. At the age of 12 years, abstract thinking appears, which is built up by the age of 15 years. It enables a child to give independent opinions and to perceive a situation multidimensional. With younger children (aged 15 years) who are not able to fully understand all aspects of the research, the principle of respecting their way of understanding should be taken into due consideration. If a child perceives the research situation as negative, resulting in negative emotions, this should be respected and taken into account. Although for the reasons earlier in the text, autonomy is not within the reach of small children, the opinions of older children are generally asked and taken into account in the medical decisions. Most of the guidelines promote besides autonomy three other basic principles in biomedical ethics: Beneficence/Nonmaleficence The principles of beneficence and nonmaleficence imply the obligation of maximizing possible benefits, protecting participants from potential/predictable harm, and securing their well-being. Justice Justice addresses the issue of fairness of the distribution of research benefits and risks. Only reasons strictly related to research objectives, and not their easy availability or other population-specific characteristics (e.g., ethnic minorities, the socioeconomically less advantaged, gender, etc.), should define the criteria for selection of participants. In environmental as well as therapeutic research, justice is directly linked to the validity of the study, and to the possibility of extrapolating research findings from the study sample to the target population. Research with children should only occur when it cannot be performed on adults, when there is a need to know, and when the results of research with adults can and cannot be extrapolated to children. However, modern biomedical research, including molecular and genetic epidemiology with its complex designs, is difficult to comprehend even for an adult. The fact that it is not simple to formulate the information contained in research protocols in an understandable form for the target groups makes the whole issue of autonomy and informed consent more important. Important ethical issues are information of participants and their consent to participate. Follow up and protection of data (samples and information derived from samples) should be discussed in the context of biobanks, where children obtain individual rights when they become adults.

Environmental Health Ethics in Study of Children

Children as Study Persons Nowadays, it is clear that research with children and on children is necessary within both clinical and environmental fields, to provide age-specific and relevant data regarding the efficacy and safety of medical treatments, and regarding assessment of risk from unintended environmental exposure. The inclusion of children in epidemiological studies and clinical trials were avoided from the doing no harm perspective resulting in lack of appropriate data for risk assessment and for dosing of medicinal compounds. In this context, the stakeholders are many, including children and their parents, physicians and public health researchers, and the society as a whole, with its ethical, regulatory, administrative, and political components (Figure 1). Seeking consent/assent for participation in research is justified by the application of traditional moral theory or principles. 1. Seeking a person’s consent respects their basic right to self-determination (Autonomy). Individuals are best placed to determine what is their best interest and the only justification for infringing this right is to prevent harm to others. 2. Obtaining consent confers benefit by encouraging active participation of individuals in investigation and treatments, which are intended to restore their health (Beneficence).

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3. Obtaining consent protects patients from the physical and psychological harms that may occur as a result of illness or its treatment (Nonmaleficence). 4. Obtaining consent involves treating others in a way in which people would expect to be treated themselves. The universal need to obtain consent also involves treating people justly (Justice). 5. Society and social structures are essential to the existence of the individual. Obtaining consent will broaden the views of the community and its altruism (Community Spirit and Solidarity). Each research project to be conducted in human beings must be carefully reviewed by a research ethics committee (REC) for approval. Since it is unethical to carry out studies that cannot give scientific answers, it is important that these committees consider the following questions: 1. Does the study have a real question or questions? 2. Is the study designed in the best possible way to answer the questions (test the hypotheses)? 3. Will the study work in practice (feasibility)? 4. What are the risks and burdens for the research subjects involved? 5. Are the results of the study to be published in peer review journals? 6. Data protection must be ensured and the eventual future use of data and spare samples must be addressed.

Researchers, statistician, communities, participants representatives Study planning Regulators, politicians, industry Funding Study approval

Recruitments

Research ethics committees (regional and/or institutional)

Study persons, parents or other relatives, school teachers, patients Organizations, nurses, technicians, paediatricians, researchers

Informed assent/consent Researchers, technicians, statisticians Sampling of biological material

Analyses of biological samples

Verification of results Communications of results

Researchers, pediatricians, nurses, technicians, media

Regulators, communities, industry, participants representatives Researchers, pediatricians, nurses, technicians, media

Follow-up

Figure 1 Ethical considerations may be raised at different critical steps of human biomonitoring of children by various groups of stakeholders.

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Environmental Health Ethics in Study of Children

When the REC is convinced that the study is properly designed and the risks for participants will be low or minimal, the study can be approved. A REC should consist of different members with different backgrounds, including pharmacists, statisticians, an ethicist, nurses, and of course medical doctors. The Committee should have members with experience in pediatric research. Informed Consent Informed consent is the process by which an adequately informed person can participate in choices about his/her health care and participation in research. Its purpose is to enable adults to make informed choices about themselves and to safeguard their own best interests, in the full knowledge of risks versus potential benefits. It originates from the legal and ethical right of the patient to direct what happens to his/her body and from the ethical duty of the medical doctor to involve the patient in his/her health care. Consent is required for all medical care; for preventive, diagnostic, or therapeutic measures; and for research. Usually it is necessary to obtain consent in which an individual is specifically asked to consent to the procedure in question. Consent may be implied when an individual presents himself/herself or is presented for a procedure to which general agreement has been obtained or implied. Nevertheless, information about benefits and risks are mandatory. Consent may be written or verbal. Written consent provides some kind of record that the procedure has been discussed but may have no more legal force in some European countries than verbal consent. Nevertheless, most European countries prefer written consent. There is an agreement already respected in most countries that, whenever possible, children should give their own opinion, in the form of written consent, for the studies they attend. However, children, especially unborn, newborn, and small, are clearly unable to consent for research by themselves. Hence, they are dependent on the decisions of their parents or of other legal guardians. Even older children, who can already express their own opinions, are naturally influenced by the people they trust the most. Obtaining informed consent from a child, according to the available guidelines, involves necessarily the child’s assent and parental (or legal guardian’s) consent (proxy consent). In the case of very young children who are unable to assent, parental consent is of course needed in the child’s best interest. This is a challenge for researchers, who are responsible for ensuring informed consent. The notion of proxy consent has been rejected by many ethicists and legalists on the basis of the principle that a ‘‘true consent’’ cannot

be given by another person. However, consensus exists that permission from the guardians is in any case necessary when studying children. Specifically, an informed permission should be obtained from a capable adult responsible for the child’s participation in both therapeutic and environmental research. On top of this, it is generally recommended to seek willingness to participate (assent) from children using an age-appropriate information process. The age of the child research participant is therefore critical in defining the appropriate approach and tools (e.g., information leaflets and abstract forms), to obtain (1) the parents’ (guardians’) informed permission, (2) the child’s assent, and (3) informed consent from older minors. In any case, refusal by a child to participate in a given research should always be respected and taken into account. If a child under the legal age to consent, which may vary between different countries, gives the assent to participate in a research, parents’ informed permission should be obtained because parents know their child the best and therefore can foresee the consequences of participation for the child. There is in fact a chance that children particularly accustomed to obedience may have difficulties in expressing their negative attitude to the researchers in an unfamiliar, possibly intimidating, environment (e.g., hospital and research center). To prevent such a situation, children could give their assent to their parents, possibly at home, in a more comfortable environment. On the next day, parents would give the answers to the researchers. According to this procedure, the enrollment of a child will be possible only after the child’s assent and the parents’ informed permission is obtained. This rule should be applied with the exemption of the situation where parents do not give permission for their child’s participation in therapeutic research. In this case, deontological rules permit that the researcher may resort to the guardianship court to authorize the child’s participation in research that is either life saving or expected to give great benefits. Because children cover a broad age range (i.e., 0–18 years), obtaining a dyad consent for long-term studies must be viewed as a continuous process where children recruited into studies at a young age or before their birth (such as in studies where cord blood is collected and stored) should be asked for their assent repeatedly as they grow older, until they reach the legal age for consent. It is important to realize that autonomy is not simply determined by age. Religious, cultural, and ethnic differences may play an important role. Christian anthropology, for example, recognizes an embryo as a human being since conception, because of the developmental continuity, and rejects the possibility of recognizing such status only at some later period of the fetal development.

Environmental Health Ethics in Study of Children

According to certain philosophical conceptions, the status of a human being is acknowledged only when the full capacity of making a free decision is reached. However, as to when a child reaches such a full capacity is not easily and objectively assessable, and it may be easier to rely on sociodemographic, age-based definitions of the developmental stages, which are, to some extent, subjective. It follows that the ability to give a truly informed consent can be expected from a child aged approximately 13–16 years. This argument is relevant nowadays in research on biomarkers and genetic research on children, given the growing number of biological specimens from people of various ages, stored in specifically dedicated repositories (biobanks) across the world. Obtaining such consent from a capable child may or may not require informed permission from parents or guardians, depending on the local legislation, culture, ethnicity, religion, and the decision of the local or national RECs. Last but not least, a freewill decision is clearly communication-dependent. Obtaining consent requires that the relevant information concerning the research (purposes, benefits, risks, right to withdraw, etc.) be effectively transferred from researchers to participants so that the latter can make their decision. Unfortunately, there is evidence that this is not easily achievable, either in children or adults. Research terminology can be a communication barrier between potential participants and researchers. In addition, environmental research is necessarily multidisciplinary, and therefore various scientific branch-specific jargons appear in research documents. Effective communication of complex concepts requires, whenever possible, the replacement of scientific and technical terms with others that are used in everyday life by the majority of the population. Descriptions of research projects can never be fully exhaustive. The Nuffield Council of Bioethics holds that, even with the best efforts, fully informed consent remains an unattainable ideal, and calls for genuine consent instead of complete consent. This puts extra weight on the ethics and honesty of the scientists carrying out the research. It is their task to make every effort to the best possible understanding between the scientists and research subjects. The most important goal of informed consent is that the participant has an opportunity to be an informed participant in his/her decisions to participate or not participate in the research. Fully valid informed consent has four components: 1. Competence – the person(s) giving consent must be deemed mentally competent to do so. In the case of research on children, the researcher has responsibility for determining whether or not the parent/legal

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representatives are in a fit state of mind to give consent. 2. Information – sufficient information must be given to the person to make an informed choice. It is through communication and the information sheet that the level of information provided is determined. The information sheet, prepared by the researcher, is assessed by the REC although there are few guidelines as to a minimum standard of content. 3. Understanding – the person giving consent must be considered capable of making a reasoned choice. The researcher obtaining consent must judge the level of understanding of the patient(s). 4. Voluntariness – the person giving the consent must do so voluntarily and must recognize that withdrawal from the study is possible at anytime without this affecting care. It is generally accepted that the information given in the informed consent process through the aid of the research information sheets includes a discussion of the following elements: 1. 2.

3. 4.

5.

6.

7.

8.

An invitation to take part in the study. A statement that the study involves research, a clear and understandable explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed (including random allocation to experimental or control treatments), and identification of any procedures that are experimental. A description of any reasonable foreseeable risks or discomforts to the subject. A description of any benefits to the subject or to others, which may reasonably be expected from the research. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained. An explanation (for research involving more than minimal risk) as to whether there are any treatments or compensation if injury occurs and, if so, what they consist of, or where further information may be obtained (a risk is considered ‘minimal’ when the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests). An explanation of whom to contact for answers to pertinent questions about the research and research

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subjects rights, and whom to contact in the event of a research-related injury to the subject. 9. A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled and the subject can withdraw at anytime without penalty or loss of benefits to which the subject is otherwise entitled. 10. A description of the funding of the study and whether the lead investigator is being paid for enrolling subjects into the study. It is essential that consent forms are written in plain language that the research subject can understand. Children and adults can agree (assent) or disagree (dissent) to participate in a clinical or environmental study. However, child’s ‘consent’ (which implies full understanding of their rights and the potential risks associated with their participation in research), can be obtained only when they reach the age of maturity. Until then, they can be enrolled in a study by obtaining permission from their parents or legal guardians. The fundamental ethical principles that are governing medical research in humans have been available to the medical community since the Nuremberg Trial, and specifically to children, since 1989. In addition, the consent form should not contain any exculpatory language. That is, subjects should not be asked to waive (or appear to waive) any of their legal rights, nor should they be asked to release the investigator, sponsor, or institution from liability for negligence. Although consent is often perceived as one-off event, it is better regarded as a continuing process. However, studies involving children cannot rely on the conventional concept of ‘informed consent,’ which implies that a subject is fully capable of making an informed choice. Any study must seek parents’ and children’s agreement to research participation until a child is capable of making autonomous decisions. Therefore, to obtain a ‘real’ consent (child informed assent plus parental informed permission) it is critical to develop and correctly use adult- and child-specific tools (e.g., two information sheets may be required – one for the child and one for the parents/guardian, both addressing the study aims, potential risks, and potential benefits). The key word is ‘informed.’ An informed consent can be given only when truly comprehended information can guarantee a ‘free-will decision’ after understanding all research implications (risks, benefits, rights to opt out, etc.). The ability to give a truly informed consent can be expected from a child aged approximately 13–16 years. Unfortunately there is no agreement on age and there are differences between European countries, with the minor’s will being considered necessary or prevailing over that of the parents or legal representatives at an age that ranges from 7–17 years.

Informed Assent Children, especially unborn, newborn, and small, are clearly unable to consent for research by themselves. Hence, they are dependent on the decisions of their parents or of other legal guardians. Even older children, who can already express their own opinions, are naturally influenced by the people they trust the most. Obtaining informed consent from a child, according to the available guidelines, involves necessarily the child’s assent and parental (or legal guardian’s) consent (proxy consent). In the case of very young children who are unable to assent, parental consent is of course needed in the child’s best interest. This means that there is a consensus agreement that a ‘consent dyad’ is required to conduct research on children. This is a challenge for researchers, who are responsible for ensuring informed consent. Informed assent means a child’s agreement (acquiescence) to research procedures in circumstances where he or she is not legally authorized or lacks sufficient understanding for giving consent competently. When the blood sampling involves a child aged 7 years or older, permission must be obtained from the parent or legal representative and assent must be obtained from the child. Each institution (hospital, university, etc.) has its own responsibility to determine the necessity of obtaining assent from these children. The regulations also state that age, maturity, and psychological state should be considered in the determination of whether children are capable of assenting to the medical procedure. Assent should include the following elements: 1. Helping the patient (child) achieve a developmentally appropriate awareness of the nature of his/her condition. 2. Telling the patient what he or she can expect with tests and treatment(s). 3. Making a clinical assessment of the patient’s understanding of the situation and the factors influencing how he or she is responding. 4. Soliciting an expression of the patient’s willingness to accept the proposed care. Regarding this final point, note that no one should solicit a patient’s view without intending to weigh it seriously. Proxy Consent There is an agreement already respected in most countries that, whenever possible, children should give their own opinion, in the form of written consent, for the studies they attend. However, the notion of proxy consent has been dismissed by many ethicists and legalists on the basis of the principle that a ‘true consent’ cannot be given by another person. However, consensus exists that permission is in any case necessary when studying children (Table 2).

Environmental Health Ethics in Study of Children

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Table 2 Schematic representation of different approaches to the need of the informed permission, assent/consent according to different dominions Dominion

Developmental stages Prenatal

Demography (age in years) Biological relationship and possible forms of permission to research

Adulthooda

Infancy/childhood

Fetus

Newborns

Infants

Childhood

Adolescence

0

0

r2

42–r14

414

Parents:b Informed permission Fetus:

Parents:b Informed permission Infant:

Parents:b Informed permission Child:

Child:

Implicit assent

Implicit assent

Assent

Assent/Consent (age 414) Full capability of free decision (age, maturity)

Philosophy

Status as a human being recognized only when full capability of free decision is reached

Religion Ethics Law

Status as a human being recognized from conception on Ethical regulators: decisions apply to all ages Status as a human and requirement/possibility for individual consent depending on national legislations

a

Adulthood: usually but not always legally defined; Parents: mother or father or legally authorized person.

b

Biobanking Biobanks include collection of identifiable DNA samples or biological samples from where DNA can be isolated, and the possibility to connect molecular markers and lifestyle factors with identifiable individual health data. For example, the Icelandic Biobank Act defines a biobank as a ‘‘collection of biological samples, organic material from human beings, alive or dead, that is permanently preserved.’’ These definitions include three points, which, if combined, create possible concern, especially relating to children: (1) the identifiability of DNA samples, (2) the possibility to connect with health data, and (3) the permanently preserved specimens. Management of such combined data permanently stored, and implications in society, with the general ethical questions of how autonomy and individual rights are looked upon in relation to power and financial gain, are not simple issues. It is self-evident that individual interests and societal and financial interests do not agree in many instances. Whose interests should come first? According to the Declaration of Helsinki, it is clear that it is always the individual who should be respected above everything else. Children have their whole future ahead of them, but do not have an impact on the direction of development in research and on the use of samples and data. Identifiable genetic data are ethically in a special category, because it can be permanently attached to a person. Use of such data may have long-term consequences years after the data are generated, and they should thus be treated with more care than other types of health data.

Samples from children will, no doubt, be a part of biobanks, especially any national biobanks. Thus, any of the issues concerning the planning, development, management, and use of biobanks also concern children. In addition, as discussed earlier in the text, children and unborn children are more vulnerable physically and mentally than adults on account of having less capacity to understand complex issues and long-term consequences, a capacity that is totally lacking in babies, newborn, and unborn children. Furthermore, children have to live in the future that people create. Children cannot themselves choose to be born, or choose their destiny when they are small. It is in the hands of their parents, and even more in the hands of society, through the legislation defining, for example, the value of life. Issues of suffering and, by contrast, the financial costs of screening and care, are often discussed in connection with serious hereditary conditions. What are discussed much less are the ethical costs and what kind of society is preferable. In addition to physical vulnerability, children are at the mercy of adults regarding their mental integrity. Children largely adopt the values and ways of the society they live in, especially through parents, school, and the media. It is, of course, not so much the question of what values are discussed and taught than the question of what values are actually practiced. Indeed, children can be considered as ‘autonomous subjects’ at various ages according to the ‘traditions’ of the ‘moral community’ they live in. The development of children varies a lot, but all small children have less capacity to handle difficult issues. It is partly a question of intelligence, but life experience

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should not be overlooked. Even in early adulthood, people are not fully developed in their inner values and needs. The minds of young children are easily adjusted to the will of respected adults. When fully grown and psychologically mature, people may even represent contrasting values compared to their early age. This may change their earlier views on belonging to a biobank and on use of their samples. Because there are no experiences on long-term storage and use of biobanks at this point, it is difficult even for adults to consider the implications and what may be expected.

Conclusions In addition to the general requirements for good research on humans (necessity, scientifically good planning with as few research subjects as possible, potential benefit overriding potential risks, and approval of an independent REC), and the vulnerability of children (only research benefiting directly children or, with minimal harm, the group they represent) the following key points must be considered when planning research on children: 1. 2.

children should always be respected as persons; an assent/consent from the child and parental permission should be sought whenever possible by using appropriate tools; 3. an abbreviated description of the research for getting research participants’ informed permission/assent/ consent must be written in understandable language according to the age of the target group(s): in studies involving children at least two information sheets are required: one for children and one for their parents/ guardians; 4. enough time should be given for parents and children to discuss the research and consider their participation in a friendly environment; 5. refusal to participate by a child should be respected; 6. the presence of parents should be ensured in the interventions if practically possible, for the child’s comfort and to ensure that the rights of the child are looked after; 7. special attention has to be paid on the most vulnerable children (institutionalized, homeless, impoverished, and dying children); 8. children from different countries or belonging to different ethnic, social, or religious groups should be treated with the same respect; 9. follow-up tools must be considered by researchers to monitor long-term effects in study participants, considering incidental findings; 10. for evaluation of the studies including children, the involvement of a pediatrician in the REC should always take place.

Research with children raises specific questions to the protocol of the study that are to be handled in ethical committees boards, preferable with consultation of relevant expertise (pediatricians, lawyers, statisticians, toxicologists, and psychologists). No best practices in research with children are given and at present the research process is only accepted by the ethical committee not followed/controlled. There is a need to know more about the conception of children and parents on how research is regulated. Informed consent is a prerequisite in all instances – given proxy by parents of children of young age (o6 years) and given accompanied with assent of school children and adolescents. There is a need to know more about the child’s perception of the information given – at different ages. Incentives to participate should be named – for example, ‘the feel good factor’ – for the child provides valuable information to the society. Payment/ Gifts to children participating should be allowed. The refund could be considered comparable to work that also takes up the child’s time. The right to withdraw at anytime of a research process is fundamental for adults but more unclear in relation to children. There is a need to know more about the child’s ‘will.’ In clinical trials with treatment of disease, it may be clear overruling the child’s expression of withdrawal but how about environmental health studies? The child’s right to withdraw/opt out at maturity must be considered and the extent of withdrawal must be clarified (all information collected, new information, etc.). Information about results to parents and children must be agreed on before the study. There may be a difference between cross sectional and longitudinal studies, especially if data and tissue banking is the case. In environmental studies it should be given in all studies either at individual or group level, depending on the sensitivity of the information (stigmatization due to increased disease risk and consequences for employment, insurance, education, and loaning). The child may have the right to be notified of future research plans – or should the decision be delegated to the ethical committee? The ethical committees within Europe are regulated nationally and show wide diversity regarding composition – in some countries no scientific or legal expertise is assured within the committees’ independence – in some instances the researchers’ interest is not challenged versus the interest of the study persons. Recommendations by the ethical committees are not validated and compared even within the same countries. The question about genetic exceptionalism is clearly relevant in relation to autonomy, data protection, etc. of children participating in studies with genetic testing. Exceptionalism may be present regarding environmental health/public health studies versus clinical trials, where

Environmental Health Ethics in Study of Children

the participants normally have an individual interest. This is not the case in many environmental studies where the societal/community interests may override. See also: Children’s Environmental Health: General Overview, Children’s Exposure to Environmental Agents, Children’s Health Risk Assessment: Issues and Approaches, Critical Windows of Children’s Development and Susceptibility to Environmental Toxins, Developmental Programming and the Epigenome, Ethics in Pediatric Environmental Health Research, Issues and Challenges for Determining Environmental Risk Factors and Causes of Disease Among Children, Objectivity and Ethics in Environmental Health Science.

Further Reading Centers for Disease Control CDC and Prevention (2005) Third National Report on Human Exposure to Environmental Chemicals. GA, USA: Department of Health and Human Services. http://www.cdc.gov/ exposurereport/ European Environmental Agency (2002) Children’s health and environment: A review of evidence. Environmental Health Issue Report 29. Copenhagen K, Denmark: EEA. Eskenazi B, Gladstone EA, Berkowitz GS, et al. (2005) Methodologic and logistic issues in conducting longitudinal birth cohort studies: Lessons learned from the Centers for Children’s Environmental Health and Disease Prevention Research. Environmental Health Perspectives 113(10): 1419--1429. Gammelga˚rd A, Knudsen LE, and Bisgaard H (2006) Why do parents enroll their healthy infants in research? A Study of parents’ perceptions of their children’s participation in the COPSAC study. Archives of Disease in Childhood 91: 977--980. Gee D (1999) Children in their environment: Vulnerable, valuable, and at risk. Background briefing children and environmental health. WHO Ministerial Conference Environment & Health. London, 16–18 June. London: WHO Regional Office for Europe, European Environment Agency.

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Greener (2008) Bitter medicine. New regulations aim to address the dearth of clinical safety trials for drugs used in children. EMBO reports 9: 505--508. Knudsen LE, Merlo DF, and Larsen AD (2008) Workshop on ethics and communication in Copenhagen. Environmental Health 1113.3.2007. (Supplement) 1: S1. Lind U, Knudsen LE, and Mose T (2007) Participation in environmental health research by placenta donation–a perception study. Environmental Health 6: 36. Merlo F, Knudsen LE, Bargiel-Matusiewicz K, Niebroj L, and Va¨ha¨kangas K (2007) Ethics in studies with children and environmental heath. Journal of Medical Ethics 33: 408--413. Paulson JA (2006) An exploration of ethical issues in research in children’s health and the environment. Environmental Health Perspectives 114: 1603--1608. Pedersen M, Merlo F, and Knudsen LE (2007) Ethical issues related to biomonitoring studies on children. International Journal of Hygiene and Environmental Health 210: 479--482. Tamburlini G, von Ehrenstein OS, and Bertollini R (eds.) (2002) Children’s health and environment: A review of the evidence (Environmental Issue Report No. 29). A Joint Report from the European Environment Agency and the WHO Regional Office for Europe. Copenhagen: European Environment Agency. WHO (2006) Environmental Health Criteria 237: Principles for evaluating health risks in children associated with exposure to chemicals. Report of WHO. Geneva, Switzerland: WHO

Relevant Websites http://www.cdc.gov/exposurereport/ Centers for Disease Control and Prevention – National report on human exposure to environmental chemicals. http://www.privireal.org/ European Commission, Privireal. http://ohsr.od.nih.gov/guidelines/nuremberg.html OHSR: The Nuremberg Code. http://yosemite.epa.gov/ochp/ochpweb.nsf/content/homepage.htm The Office of Children’s Health Protection, US: Environmental Protection Agency. http://www.wma.net/e/policy/b3.htm World Medical Association. WMA Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects: 52nd WMA General Assembly, WMA, Edinburgh, Scotland.