Toxicology Letters 231 (2014) 111–121

Contents lists available at ScienceDirect

Toxicology Letters journal homepage: www.elsevier.com/locate/toxlet

Ethics in biomonitoring for occupational health M. Manno *, F. Sito, L. Licciardi Department of Public Health, Section of Occupational Medicine and Toxicology, University of Naples Federico II, Via S. Pansini, 5, 80131, Naples, Italy

H I G H L I G H T S

G R A P H I C A L A B S T R A C T

 Biomonitoring measures human exposure, effects and susceptibility to chemicals.  Ethical issues may arise during study design, sampling, and interpretation of data.  Critical aspects are informed consent, communication, and management of the results.  The four ethical principles are autonomy, non maleficence, beneficence, and equity.  Ethical decisions require a balance of the interests of all the parties involved.

Phases of a biological monitoring program requiring ethical assessment.The decision on whether the priority is purely occupational health or (also) research/validation of new biomarkers is to be taken early and stated clearly in the process. “Yes” and “no” refer to positive and negative ethical outcome, respectively.

A R T I C L E I N F O

A B S T R A C T

Article history: Received 21 August 2014 Received in revised form 28 September 2014 Accepted 2 October 2014 Available online 18 October 2014

Biological monitoring, i.e., the use of biomarkers for the measurement of systemic human exposure, effects and susceptibility to chemicals has increased considerably in recent years. Biomonitoring techniques, originally limited to a few metals and other chemicals in the workplace, are currently applied to a large number of exposure situations and have become a useful tool for occupational and environmental health risk assessment. Almost any biomonitoring program, however, entails a number of relevant ethical issues, which concern all the phases of the entire process, from the selection of the biomarker to the study design, from the collection, storage and analysis of the biological sample to the interpretation, communication and management of the results, from the (truly?) informed consent of the worker to the independence and autonomy of the occupational health professional. These issues require a balanced assessment of the interests and responsibilities of all the parties, the worker primarily, but also the employer, the occupational health professional, the health authorities and, for research studies on new biomarkers, also the scientists involved. Ideally, decisions of ethical relevance concerning biomarkers should be based on, and respectful of the best scientific, legal and ethical evidence available. When, however, a conflict should arise, before any decision is taken a thorough risk-benefit analysis should be done, at the beginning of the process and after listening to the workers and the management involved, by the occupational physician or scientist, based on his/her professional experience, independent judgement and individual responsibility. ã 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Biological monitoring Ethics Occupational health

Aim/design of the biomonitoring study (exposure, effect, suscepbility, other purpose)

Occupational health

New selecon

No

Research on biomarkers

Selection of workers and biomarkers (Individual or Ethics Commiee assessment) Yes

Informed consent

Drop out

No

Yes

Sample collecon, handling, storage and analysis No

Interpretaon, communicaon and management of the results Yes

For the worker individually (job fitness, health surveillance, change of task/job, etc.)

For the workers collectively (health authority, legal acon/ authority, publicaon of data, etc.

Occupational health protective and preventive action - environmental intervenon - individual protecon tools - 2nd level health surveillance - validaon of (new) biomarker

1. Introduction * Corresponding author. Tel.: +39 0817463838; fax: +39 0817463837. E-mail address: [email protected] (M. Manno). http://dx.doi.org/10.1016/j.toxlet.2014.10.004 0378-4274/ ã 2014 Elsevier Ireland Ltd. All rights reserved.

Human biological monitoring or simply biomonitoring (BM) is the measurement of biomarkers in fluids and tissues of subjects

112

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

exposed to chemicals or other risk factors in the workplace or the general environment. This practice has increased dramatically over the last decades, both quantitatively and qualitatively. Various techniques to measure the uptake of occupational chemicals directly in human body fluids were developed early in the 20th century, among which measurements of lead and a few other chemicals or their metabolites (Angerer et al., 2007). Later, larger scale BM was used in exposure and health surveillance programs or as part of regulatory requirements, particularly for workers of the chemical industry and other specific industrial sectors. From the relatively few papers published in the ‘80s, there are now several thousand papers published in the peer review literature each year, and the trend is still rising. Initially just a tool for assessing exposure, BM is now used also to assess early biological effects from, and individual susceptibility to a vast array of chemicals. Besides, this technique once used only in the occupational setting is currently also applied to explore exposure conditions in the general environment (Sexton et al., 2004). The application of BM in fact has now expanded significantly beyond the boundaries of occupational and environmental health. BM is not only attracting the scientific interest of occupational health professionals (OHP), as well as public health professionals (PHP) in general, but also the increasing attention of workers, consumers and even members of the general public. Clinicians, researchers, governmental and international agencies, and even environmental health activist groups now employ this tool extensively and for a variety of purposes (Nelson et al., 2009). The most common use of BM is for exposure assessment and for validation of the occupational guidance values recommended by national and international agencies such as ACGIH, DFG, and SCOEL among others. In this context the main ethical issues have already been addressed and biomarkers are routinely used for risk assessment without particular problems. In the UK, the Health and Safety Executive (HSE) has even produced a practical guide to set up a BM program (HSE, 1997). As outlined by the National Academy of Sciences, though, the growing information provided by biomonitoring studies in various fields has raised new challenges for scientists, regulators and public health managers. Among these challenges is how to deal with the various ethical issues concerning biomarkers for individual and public health purposes in terms of risk assessment, communication and management (NRC, 2006). A number of high quality review papers on human biological monitoring have also addressed, in general and to different extents, the ethics involved in BM (WHO/IPCS, 2001; NRC, 2006; ACGIH, 2005; IUPAC et al., 2004, 2006, 2007) and international ethical guidelines for human research are available (Council for International Organizations of Medical Sciences (CIOMS), 2002, 2009). Some authors have addressed specific aspects of human biomonitoring for occupational and environmental health, including advantages and limitations (Stokstad, 2004), or specific classes of chemicals (Nordberg et al., 2007; Clarkson et al., 1988). The interacting scientific, ethical and regulatory issues related to BM, and particularly to the use of exposure biomarkers, have been reviewed (Viau, 2005). However, to the best of our knowledge a specific evaluation of the most critical ethical aspects of BM in occupational health (OH), including exposure, effect and susceptibility biomarkers, is not available. Despite its impressive exploitation, however, or probably because of it, BM is not always correctly used or interpreted, and many related scientific and ethical issues are not firmly established yet. The Code of Ethics of the International Commission on Occupational Health (ICOH) published in 2002 (ICOH, 2002) only provides some general, rather basic recommendations and even the current revision of the Code, approved recently by the ICOH Board and to become public soon, does not seem to have changed the situation. The main ethical

questions addressed by the Code are: the general criteria for the selection of biomarkers, their sensitivity and specificity, the riskbenefit dilemma and the issue of the informed consent. According to the Code, “biomarkers must be chosen for their validity and relevance for protection of the health of the worker concerned, with due regard to their sensitivity, specificity and predictive value and should not be used as screening tests or for insurance purposes. Preference must be given, when possible, to non-invasive methods. When invasive tests or tests which involve a risk to the health of the worker are advisable, a risk-benefit analysis for the worker(s) concerned must be done first. In any case biomonitoring is subject to the worker’s informed consent and must be performed according to the highest professional standard” (ICOH, 2002). More specific issues, such as sample collection, storage and analysis, interpretation, communication and management of results, are only briefly mentioned in the Code due to space limitation. Other, increasingly relevant aspects, including the ethical issues raised by the new potential biomarkers being developed by molecular biology and “omics” science and technology, their use and limitations and the specific features of biomarkers used for research are not covered by the Code. The Scientific Committee on Occupational Toxicology (SCOT) of ICOH, whose mission, for twenty years now, has been promoting scientific and professional quality in the exercise of BM, has recently reviewed the use of BM for occupational health risk assessment (Manno et al., 2010). The aim was to provide a basis for an ICOH consensus document on BM by discussing briefly the basic scientific and ethical aspects of BM, among which planning of the study, informed consent, confidentiality and communication issues. In that paper the specificities and potentialities of the three types of biomarkers (exposure, effect and susceptibility) have also been discussed separately. The aim of the present paper is to address those aspects in a more comprehensive way and in more detail, by expanding, integrating and amending, when necessary, the previous document. Moreover, we will discuss here the practical ethical problems encountered in the application of biological monitoring in OH, by outlining those aspects which have reached a general consensus within the scientific and professional occupational health community and focusing on those which have not, still being a matter for discussion or even conflict. Although most ethical issues apply to both occupational and non occupational contexts, discussion here has been limited to the workplace because of the many differences in the two approaches. These include risk perception and awareness (by the worker vs. the citizen), exposure conditions (known vs. unknown sources of exposure), risk-benefit assessment (for the same vs. different individuals), expected outcome in terms of management of the results (individual vs. collective health protection), and professional responsibility (OHP vs. PHP or public health authorities). In order to make the coverage more comprehensive and the reading smoother, we opted to follow the same order usually adopted in the practice of BM, i.e., from study planning and design to sample collection and storage, from laboratory analysis to interpretation, communication and management of results. All articles with the keyword association “biological monitoring” or “biomonitoring” and “ethical issues” or “ethical aspects” in the title/abstract/text from 2004 to 2013 were retrieved from Scopus and PubMed. After reading the abstract, the articles non related to occupational exposure were generally excluded. The other articles were read and those considered to be relevant to the aim of the present review were assessed and quoted, when necessary. Some additional and earlier publications quoted within these articles were also considered and discussed, if relevant. We hope the present paper may stimulate and help those involved in BM during their scientific and professional activity to

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

always consider carefully and possibly solve the many ethical questions they will undoubtedly face. 2. Generalities on ethics in biological monitoring In order to emphasize the relevance of ethics for a correct application and use of BM in occupational health we thought it useful to recall here briefly both the basics of BM and the fundamental principles of bioethics. According to a comprehensive definition, biological monitoring is the repeated, controlled measurement of endogenous or exogenous biochemical markers (biomarkers) in fluids, tissues or other accessible samples from subjects exposed to chemical, physical or biological risk factors in the workplace and/or the general environment (Manno et al., 2010). Biomonitoring includes three different endpoints: exposure, effect, and susceptibility, although exposure is by far the most used and developed. In brief, exposure biomarkers involve the assessment of the amount of a chemical absorbed in the body by measuring the concentration of the actual compound, its metabolites, or their reaction products in human body components or products such as blood, urine, breast milk, saliva, breath, hair, or other samples or tissues. These biomarkers may be indicative of past, recent, current, or cumulative exposure and may have different toxicological significance, indicating, for instance, the absorbed or the biologically active or the target dose. Effect biomarkers are a measurable biochemical, structural, functional, or even behavioral alteration in an organism that, according to its magnitude, may be indicative of a potential or an established health impairment or disease. Finally, a biomarker of susceptibility is a biochemical or biological indicator of an inherent or acquired inability of the organism to respond to a challenge to health resulting from chemical exposure (NRC, 2006). Susceptibility biomarkers may include specific genotypes of drug metabolizing enzymes (CYP, GST, etc.), indicators of a decreased immunoresponse, some oncogenes or tumor suppressor genes and other tests or markers. The use of this rather simple classification into three classes, however, is not always straightforward nor easy to use, and this difficulty may have in some cases a significant ethical impact, as discussed later. Biomedical ethics is based on four principles: autonomy, non maleficence, beneficence, and justice (Beauchamp and Childress, 2001). The relevance of each of these principles for BM will be now briefly addressed.

113

is not easy, however, particularly for workers assigned to a job for which biomonitoring is a compulsory prerequisite to assess their fitness to work. Refuse to participate in this case might imply per se their exclusion from that job (Council of Europe, 1997). Autonomy is also important from the OHP perspective. According to the ICOH Code of Ethics, OHPs “must enjoy full professional independence in the execution of their functions”. This rather obvious requirement, which apparently applies to any medical specialty, is not always easy to ensure, however, in the practice of occupational health. Particularly so in those cases in which the relationship between the OHP and the worker and that between the OHP and the employer, for any reason are colliding. It is never emphasized enough that the protection of worker’s health is the priority in occupational health practice, and biomonitoring is no exception. The full autonomy of the OHP should be, therefore, specifically mentioned, preferably in writing, when the terms of his/her commitment are discussed or signed. 2.2. Beneficence and non maleficence The relevance of BM for these two principles is obvious. A test or a biomarker should be used to the benefit of the workers, without causing any significant adverse effect. The main benefit expected would be the information gained on the actual level of exposure or on the presence of any signs of early biological effects resulting from exposure. Much more rarely it may also be interpreted or perceived in terms of a potential, higher susceptibility to tolerate low or moderate levels of exposure and to develop an effect under otherwise acceptable conditions. Issues related to beneficence and non maleficence are usually present in the same individual and therefore they not only should be balanced one to the other, but also include an assessment of the perceived balance. An even more relevant ethical issue may derive form the fact that sometimes the benefit and the risk resulting from biomonitoring and, also, their perception may not be for the same individual. This may be the case for research studies on new or non validated biomarkers, where the benefit to the worker(s) involved from the new information may not be certain or immediate. The level of risk accepted when using validated biomarkers, therefore, is generally (much) higher than that of new or non validated biomarkers, whose benefit, if any, may be difficult to assess. The ethical relevance for any BM program of an accurate risk-benefit analysis and its perceived balance for all parties involved will be discussed later in more detail.

2.1. Autonomy 2.3. Justice Autonomy represents the subject’s right to be fully informed and aware of the benefits and the risks of a medical procedure in order to decide whether he/she is really willing to participate. Whether he/she is a patient or a worker or a study subject, autonomy is normally pursued by a standard procedure known as informed consent. This procedure, in fact, is not always effective or appropriate. Vulnerable individuals or groups, which are generally per se at a higher health risk, for various reasons are also those with a diminished autonomy. For example, workers under pressure for possible unemployment or for fear of possible future retaliations or for being simply part of an ethnic or socio-cultural minority, may become prone to provide their written “consent” without an adequate conviction or information and, therefore, with no real autonomy. In these cases a key role (and responsibility) must stay with the health professional, be he/she an occupational health professional or a biomarker researcher, depending on the situation. He/she should try and (re)establish a state of trust and make the worker, or the study subject, fully aware of the situation and free in his/her decision. If this cannot be achieved, the only option would be to simply exclude the subject from participating. Such a decision

According to this principle, which in the present context would mainly mean equity, all subjects with the same type or level of risk should be treated equally, independent on their age, sex, cultural or social status. This means that human beings as moral equals should be treated equally unless there is a reasonable justification for treating them differently (Tangwa, 2009). So, equity in BM means for the OHP to give all the workers the same chance to protect their health, according to the resources available and despite the workers’ physical, social, cultural differences. On the other hand, the rational behind using BM as a tool for occupational health risk assessment is apparently the opposite, i.e., to be able to detect inequalities. Indeed the main purpose of BM is the possibility to discriminate between exposed and non exposed workers, healthy and (to become) ill subjects, susceptible and non susceptible individuals. Equity, therefore, does not mean uniformity and, on the contrary, any objective difference among the workers which is relevant for their protection should be taken into account individually. This principle does not apply, however, to the use of generalized screening tests purely aimed to select the workers

114

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

most fit for a given job or undertaking or for mere insurance purposes and therefore these tests should be avoided. In any case, according to the Code of ICOH, any investigation or test which involves a risk to the health of a worker may only be advised “after an evaluation of the benefits and the risks to the worker involved” (ICOH, 2002). Equity also means that risks and benefits should be equally distributed not only among the workers, but also between the workers and the other parties, such as the occupational physician or the employer, in the case of legal responsibility. This is more easily stated than put into practice, as the worker generally has a more limited access to legal and regulatory documentation than other parties. Moreover, public and private interests sometimes are conflicting (Last, 1998) and a limitation of individual freedom may be necessary to prevent risks to third parties. This is the case, for instance, of compulsory biomonitoring for alcohol consumption in specific professions such as drivers. Even legislation in this context is sometimes contradictory. The European Convention on Human Rights states that “the interests and welfare of the human being shall prevail over the sole interest of society or science”. It also states, though, that restrictions to this concept may become necessary “in the interest of public safety, for the prevention of

crime, for the protection of public health or for the protection of the rights and freedoms of others” (Council of Europe, 1997). 3. Study objectives, design and planning Having considered the fundamentals of bioethics as a basis for further discussion, we now address the most relevant ethical issues concerning the various phases of a BM program. The phases of a biological monitoring program requiring ethical assessment are summarized in Fig. 1. 3.1. Aims of the study: research vs. practice in BM As anticipated above, the first critical aspect to consider is the aim of the study, i.e., whether BM is performed for research purposes or for exposure assessment and health surveillance. The two options raise distinct ethical questions with important practical implications. In general, biomarkers research is mainly an inductive process, i.e., it uses a limited multiindividual information, such as that from biomarkers of exposure, to reach a more general knowledge on workplace conditions. Although itmay also help, sometimes, in individual risk assessment when

Fig. 1. Phases of a biological monitoring program requiring ethical assessment. The decision on whether the priority is purely occupational health or (also) research/validation of new biomarkers is to be taken early and stated clearly in the process. “Yes” and “no” refer to positive and negative ethical outcome, respectively.

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

validated biomarkers are included in the protocol. In contrast, medical surveillance is mainly deductive in nature, i.e., it uses general knowledge on, say, a given hazard or group of hazards to look for and possibly gain information on a single individual’s risks, although it may also contribute to improve the general knowledge on that hazard. So, in research studies on biomarkers a test performed in an individual or group of individuals may provide new knowledge that will only be of benefit for other individuals or even future generations. In practice, biomonitoring for health surveillance purposes will provide benefits and risks on the same individual, whereas human research using biomarkers may involve risks for some individuals (those involved in the study) but benefits for others (those to be exposed in the future). The latter approach requires (by the researcher) a much more conservative risk-benefit assessment than the former (by the OHP). This must be made clear in advance to the worker(s) by the researcher/OHP involved. In any case, also the worker participating in a BM program, not just the researcher or the OHP, must be aware of all these aspects, before he/she makes the decision to participate or not (Council for International Organizations of Medical Sciences (CIOMS), 1991). 3.2. Study design and planning The second critical step when starting a new BM program is to ensure an appropriate study design, depending on whether it is for research on new biomarkers or for the implementation of a biomonitoring program using established methods. This step includes the decision on which biomarker(s) should be measured for which hazards, in which biological fluid or tissue, when, where and how many samples should be collected and from which workers. The selection of an appropriate reference group of nonexposed subjects is also mandatory, including a description of the inclusion and exclusion criteria for both exposed and non-exposed subjects. In general, non-invasive and easily collectable samples are usually preferred by both the workers and the OHP. This procedure, however, may not be necessarily the best option. The choice should depend also on other factors. In the case of exposure biomarkers, for instance, the following should be considered in relation with the working conditions: the toxicokinetics of the chemical(s), including its/their route(s) of absorption, metabolism, distribution, accumulation and excretion, the stability and reproducibility of the test, and most importantly the toxicological significance and the validity of the biomarker, i.e., its specificity, sensitivity and predictive value. An early assessment of the purpose and, possibly, of the expected outcome of the BM program is also important. An accurate choice of the statistical methods to be used, including their features and limitations, must be made, based on the size and characteristics of the target population. Finally, a detailed evaluation of the possible ethical constrains, including information, communication and an accurate riskbenefit and cost-benefit analysis, when relevant, are also necessary. All these precautions need to be ensured, as biomarkers are based on scientific evidence but their use also require important practical, non-scientific considerations (Caux et al., 2007). 3.3. Scientific methodology The first ethical requirement of any BM program is a sound scientific approach and methodology. A written protocol should be made early, reporting the selection of the study population or group (including inclusion and exclusion criteria), the validity of the biomarkers to be used, the foreseen impact of the program itself and its expected results in terms of risk assessment, both individually and as a group. It should be made also clear which of the following targets the proposed program is aimed to:

115

i a routine BM program for occupational health (OH) risk

assessment; ii epidemiological research using biomarkers; iii a pure research study to develop or test new biomarkers.

By routine BM programs for OH risk assessment we mean standard BM procedures using validated biomarkers without any health risk to the worker (such as blood lead level or solvents’ urinary metabolites) and which are necessary for the OHP to assess the worker’s fitness to his/her job. Without this information the OHP will not be able to make any evidence-based decision. According to the European directives, the Italian national law and the authors’ experience, this type of protocol does not require formal approval or assessment by an independent external (or internal) ethical board. The ethical evaluation of the OHP responsible for the study is necessary and usually sufficient in this case. Different is the case of epidemiological research using biomarkers or pure research studies on new biomarkers, which require a careful formal case-by-case ethical assessment, although other, more or less rigorous procedures may operate in other countries or parts of the world. So, the ethical approach adopted in the three cases is quite different, a rigorous ethical assessment by an independent external or internal ethical board being unnecessary, recommended or compulsory, respectively. In general, the more uncertain the toxicological significance and validity of the biomarker are, the more strict the ethical assessment and provisions should be. Besides, the uncertainties should be made clear and the expectations limited. Likewise, the closer the biomarker is to the target organ, or the more predictive (i.e., specific and sensitive) the test is of an adverse health effect or disease, the higher the benefit to the worker(s) from the BM study will be. In summary, a detailed assessment and formal approval of the biomonitoring program by a competent ethical committee is usually required in most countries for epidemiological studies and, of course, for human research involving biomarkers, but not necessarily for routine occupational health activities using validated biomarkers such as, for instance, measurements of levels of chemicals or their metabolites in blood or urine, unless some specific risk or requirement is present. This approach resembles that generally used in the clinical context, where, for diagnostic use or for individual health assessment in patients, only invasive and/or new, non validated procedures should require a thorough ethical assessment. 3.4. Predictive validity The most important factor when planning a new BM program for occupational health is probably the predictive value of the biomarker to use. This depends on the biomarker’s sensitivity and specificity but also on the prevalence of the disease or health effect that the biomarker is expected to detect. This is clearly shown by the following example where two tests to assess the worker’s fitness to his/her job are compared. Assuming, very hypothetically for the purpose or the argument, a sensitivity of 80% and a specificity of 98% for both tests and a prevalence of disease/effect of 50% in one case (scenario N. 1) and of 1% in the other (scenario N. 2), the outcome in terms of cost-benefit will be very different, as shown in Table 1. The test with a 50% prevalence of disease, when applied to a group of, say, one hundred workers, will correctly detect as positive forty subjects with the disease/effect, but it will also detect one false positive subject, with a cost-benefit ratio of 1:40 between false and true positive subjects (while as many as ten truly “ill” subjects will not be detected due to the test’s limited sensitivity of 80%). In this case the ethical sustainability of the test would be acceptable to most observers. In contrast, with a 1% prevalence of disease/effect, for each subject correctly detected as

116

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

Table 1 Effect of the prevalence of disease, with sensitivity and specificity unchanged, on the ethical acceptability of a biomarker for use in occupational health. Cost is equivalent to false positive test(s) and benefit is equivalent to true positive test(s) (see text for explaination).

Ethical validity of a BM test Scenario N.1 Prevalence of disease: 50% Sensitivity: 80% (20% false neg.) Specificity: 98% (2% false pos.)

Test Test + -

Scenario N.2 Prevalence of disease: 1% Sensitivity: 80% (20% false neg.) Specificity: 98% (2% false pos.)

Tot.

Test Test + -

Tot.

Dis. +

40

10

50

Dis. +

1

0

1

Dis. -

1

49

50

Dis. -

2

97

99

Tot.

41

59

100

Tot.

3

97

100

Cost-benefit = 1:40

Ethically acceptable

Cost-benefit = 2:1

Ethically unacceptable

positive, as many as two “healthy” subjects would be detected as (false) positive by the test, with a cost-benefit ratio of as much as 2:1. In other words, for each worker actually “protected” by doing the test, two others would be requested to change, or even loose, their job unnecessarily. This would be considered ethically unacceptable by any occupational health standard and, therefore, the use of that particular test should be avoided.

3.5. Biomarker validation The issue of biomarkers’ validation, i.e., of assessing their sensitivity and specificity, has several direct and indirect ethical implications. As discussed by IPCS (WHO/IPCS, 2001) it is a complex exercise, involving all steps from the development of the biomarker in the lab to its testing in animal models, when necessary, and application in humans. To assess biomarker validation one has to consider all the relevant factors, such as toxicological significance (in terms of exposure, effect or susceptibility), intra- and inter-individual variability, external to internal dose relationship (for exposure biomarkers), dose-response curve (for effect biomarkers) and predictive value (especially for susceptibility biomarkers). In general, exposure biomarkers are easier to validate than effect or susceptibility biomarkers, as their sensitivity and specificity are higher. Urinary biomarkers have long been validated for several organic and inorganic substances, including metals, solvents and other occupational and environmental pollutants. For these chemicals reference materials and internationally adopted standard methodologies are available for sampling and analysis (Smolders et al., 2009). In principle, the more validated the biomarker is, the larger the benefit and also its ethical acceptability will be to the workers. In other words, the larger the uncertainty as to the biomarker’s significance, sensitivity and specificity, the more cautious its application should be. Studies on new biomarkers, therefore, deserve an ethical assessment which is significantly different from that required by validated biomarkers.

4. Sample collection, storage, and analysis Another basic ethical requirement of a BM program is its scientific and technical quality. The implementation of standardized protocols and quality control procedures for sampling, storage and analysis is most important to ensure the ethical validity of the program (Holland et al., 2003; Manno et al., 2010). Once the decision is finally taken that the protocol is going to be implemented, a number of methodological issues are to be considered before sampling is actually started. 4.1. Informed consent For invasive or not yet validated biomarkers, once the program’s scientific and ethical content has been approved, a written informed consent must be obtained from each worker involved, both exposed and non exposed. This should contain adequate and clear information on the risks and the benefits to the worker, and any other person involved, from the testing and it should clearly mention the right of the worker to withdraw at any time. The information should cover the objectives and aims of the study, the meaning of the test, the sampling procedure, the possible results and their interpretation. This includes their comparison with appropriate reference values, the foreseen actions in terms of risk management, and the possible consequences in terms of (lack of) job fitness and (loss of) employment. The informed consent form should be filled in by a trained OHP, preferably the occupational physician responsible for the program or one of his/her collaborators. It should be dated and signed both by the worker and the OHP, and a copy should remain with the worker. An informed consent form is not usually required, though, for routine BM procedures with non-invasive validated biomarkers used for standard health surveillance programs (Manno et al., 2010). It should borne in mind, though, that a signed informed consent form does not necessarily ensure a truly aware consent. According to Caux et al. (2007), the workers’ understanding of biomarkers (and their limitations) is often strongly conditioned by excessive expectations and by the workers’ inability to distinguish between validated and non-validated biomarkers. Misunderstandings may also arise if stakeholders (physicians, nurses and researchers especially) inadequately explain the meanings and limitations of biomarkers. So, signing or not signing an informed consent appears to be more a matter of trust rather than an instrument of information and understanding. For example, workers may feel or fear that the biomarkers’ results will be used to screen or exclude them from a job rather than to protect their health (Caux, 2007). Time spent in clear and simple explanations to the workers is precious in these cases, not only to allow for a larger participation and compliance, but also to prepare the workers to any future actions or decisions that the biomarker results may require. Another discriminating factor that may induce or not the worker to participate lies in what he/she believes will be for him/her a benefit, or a lack of benefit, from participation. The lack of an immediate benefit may not be in itself a strong deterrent, but it does not represent an incentive to a voluntary participation either. To avoid this, the features of the program should be explained clearly to the workers: the objective, the expected short-term and long-term outcomes, the risks and the benefits to the individual worker or to the workers as a group. Practical benefits or incentives, such as payment, although are not against the law and are used sometimes to motivate participation, may be considered a selection bias or even unethical in some cases and therefore should be avoided. A compensation for time lost or reimbursement of travel expenses as it is usually the case for blood or other donors, would be acceptable in some cases.

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

(Council of Europe, 1997; Council for International Organizations of Medical Sciences (CIOMS), 1991).

117

the health professionals involved. The risk of contamination or infection from the biological sample, although relatively small, sometimes cannot be ruled out completely.

4.2. Sample collection 4.3. Analysis One important issue to consider is the type of sample to be collected. Blood and urine, for obvious reasons, are traditionally the most common sources used. Blood is relatively easy to collect and has the advantage that it is relevant to the toxicokinetics of almost any chemical. Its collection, though, is invasive, limited in amount and requires a professional expertise. Urine collection is easier, more generous in quantity and repeatable in time (spot samples). Besides, it is non invasive and riskless for the worker and simple for the health professional or researcher, making it the most common sampling procedure used for occupational health (Polkowska et al., 2004). It may also be more informative than other sources in terms of metabolism of the chemical and time of/ from exposure. Depending on the chemical/metabolite’s half-life and the sampling procedure adopted, urinary biomarkers may be indicative of short-, medium-, long-term or even past exposure (Esteban and Castaño, 2009; Barr et al., 2005). Other non invasive sampling matrices, such as exhaled air, hair, sweat, saliva, nails and other fluids/tissues are less common and usually have specific indications. In general, non invasive sampling is cheaper, it does not require any particularly skilled personnel and it is better accepted by the workers, making the collection of the informed consent much easier (Smolders et al., 2009; Rockett et al., 2004; Boumba et al., 2006; Timchalk et al., 2004; Lindstrom and Pleil, 2002; Walker et al., 1999). Breath analysis, for instance, is a relatively new, non-invasive procedure for monitoring workers exposed to volatile chemicals both in laboratory-based studies and for field research. Recent advances in breath sampling and analysis are such that it is likely to become more widely used in the future. In particular, exhaled alveolar breath analysis, for example, not only can provide information about an individual’s exposure to volatile chemicals but also about his/her status of health (Wilson and Monster, 1999). Invasive or more complex sample collection methods are probably the most common reason for a low or insufficient participation to research studies using biomarkers as a tool (Rockett et al., 2004). Non-invasive, more simple methods, including self-collection, will definitely improve participation rates (van Valkengoed et al., 2002; Harty et al., 2000) and also reduce selection bias (Bates et al., 2005). The continuous increase in sensitivity and specificity in analytical chemistry allows today to measure trace levels of chemicals or their metabolites, and their speciation, in almost any kind of biological sample. This has contributed significantly to increase the use of, and the benefit from biomarkers in exposure assessment (WHO/IPCS, 2006; Needham et al., 2005). The increase in sensitivity, besides the obvious advantages, has also a negative impact on the perception of risk as the usually unexperienced and/or uninformed general public often considers, in spite of the well known Paracelsus’ aforisma, the presence of a chemical to be harmful for health independently on its concentration or dose. Risk perception is an important component of any medical decision, including biomonitoring, although its modulating factors and ethical implications are sometimes very difficult to assess, as discussed later. Many other apparently minor factors, such as fluid/tissue size, time of collection, containers used, preservatives and other additives, storage temperature, transport means and time, may affect the quality and stability of the samples and consequently their analytical reliability. All these conditions must be considered with care at the initial planning stage of the BM program, as they may indirectly affect its overall ethical assessment. For example, sample collection and analysis may also be ethically relevant for

As the first ethical requirement for a MB program is, besides a clear objective, also its scientific quality, as repeatedly mentioned before, the same attention has to be payed also to the analytical methodology. Standardized validated methods should only be used for BM. The OHP should make sure that the laboratory has the necessary human and instrumental resources to ensure the quality of the data. Quality control (QC) and quality assurance (QA) procedures, including interlaboratory comparison, use of standard materials, certified personnel and validated methods, should all be implemented to guarantee the reliability of both process and product. Since an important application of biomarkers is to verify that exposure limits are not exceeded, it is important that the results obtained in exposed workers are correctly compared with the corresponding guideline values, i.e., the biological equivalent values, such as BEIs1 (ACGIH, 2005) if available, or those of an appropriate non exposed reference group, known as reference values. It is important, therefore, to ensure that the method of analysis be the same, or at least comparable, with those used in the literature supporting the guideline values. Confounding influences and interferences during the pre-analytical phase of any new biomonitoring program can be minimized by consultation with or recommendations from experienced laboratories (Schaller et al., 2002). 5. Interpretation, communication and management of the results The ethical issues of these three important aspects of any biomonitoring program, although partly overlapping, are complex and therefore will be discussed here separately. 5.1. Interpretation of biomarkers’ data As mentioned above, biomarkers are usually classified into three different types: biomarkers of exposure, effect, and susceptibility. According to some authors or journals (Biomarkers), a fourth group of biomarkers is that of the early indicators of disease. Briefly, biomarkers of exposure are chemicals or metabolites measured in body fluids and reflect the internal dose or the level of contaminant absorbed or bound to a target tissue (adducts). Biomarkers of effect identify early, generally adverse and reversible biological effects on body functions or structures. Finally, biomarkers of susceptibility are aimed to uncover individual genotypes or phenotypes which may/might make a subject more prone to develop an adverse health effect. Special attention should be given to the interpretation and use of data from susceptibility biomarkers, since their ethical aspects are particularly delicate. The critical issue in this context is to ensure a correct balance between the benefit to the worker in terms of health prevention on the one hand, and the cost (or risk) in terms of loss of his/her job on the other. In principle, the management of a BM program should not result in any degree of (unjustified) discrimination or reduction of job opportunities for the workers involved (Van Damme and Casteleyn, 2003; Manno et al., 2010). The type of biomarker is not only associated with its toxicological significance and predictivity, but also with its ethical value and acceptability. It is not always easy, however, to classify biomarkers correctly as indicators of exposure, effect, or susceptibility. The measurement, for instance by the chlorzoxazone test, ofthe CYP2E1 phenotype in vivo in workers exposed to solvents or

118

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

other chemicals as a biomarker of metabolic activity in the liver, although still under validation, is a good example (Lucas et al.,1999). The ratio between the metabolite 6-OH-chlorzoxazone and the parent compound, chlorzoxazone, measured in serum two hours after a single oral dose of the drug, could be interpreted differently, indicating either exposure or effect or susceptibility, depending on the context. In fact CYP2E1 activity may be decreased due to competitive inhibition by other solvents, say, benzene or toluene, which are also metabolized by CYP2E1, in which case the test would just be mainly indicative of exposure. Alternatively, CYP2E1 activity may be non competitively inhibited by attack of the chemical or its reactive metabolites, in which case it may be used as an effect biomarker. Finally, as CYP2E1 activity itself is responsible for the metabolic activation of many toxic chemicals including solvents, anesthetics and others, CYP2E1 phenotype has been investigated in field studies as a potential susceptibility biomarker (Piccoli et al., 2010). So, since the correct interpretation of the test's results may be difficult, the informed consent form should indicate and explain all three different possibilities. To summarize, assessing the predictive value of the test correctly (including prevalence of the disease, sensitivity and specificity of the test) becomes equally important for exposure, effect and susceptibility biomarkers since the final aim is the same: the protection of the workers’ health. A higher ethical priority should be given, however, to avoid that truly ill or susceptible subjects are erroneously admitted to a risky job (false negative individuals) or vice versa, healthy or non-susceptible subjects be erroneously excluded from that job (false positive individuals). 5.2. Data protection and communication This is a critical aspect of any BM program for all the parties involved: the worker, the OHP, the employer, and depending on the circumstances, also other stakeholders, such as the worker’s GP, the health authorities and the scientific and professional community by and large. As a rule, the data belong to the individual providing the sample and it should be his/her decision about who can see them. So, the privacy and confidentiality of the data stored throughout a BM program must be ensured by a number of measures (Reis et al., 2008). Usually, participants’ names are coded prior to data processing and analysis and database access is protected by user passwords. Confidentiality, storage and handling of large coded databases is no more a technical problem due to the potent informatic tools now available but other issues may remain unsolved. Conflicting interests (individual vs. collective, private vs. public, etc.) may arise which are difficult to solve (Last, 1998). Legislation is also vary in different countries, even in the EU. These aspects have been specifically addressed in a number of documents including “ethics and data protection in a number of European countries” compiled within the ESBIO project (ESBIO, 2007). Since national regulations are dishomogeneous, lacking, or even contrasting, any decision on conflicts is generally left to the OHP or the researcher responsible for the BM program. The protection, for instance, of sensitive individual health data (right to privacy), such as for instance positivity for hepatitis B or C virus infection, may create a collision between the need to protect that individual’s health and that to prevent virus transmission to other individuals (right to health). In general, communication of BM data – all data, not just health-related data – to the workers involved should be normally ensured in all cases, although it should be born in mind that even an adequate and complete information might generate an unjustified fear in some cases (Arendt, 2008). The level and form of communication should be different, depending on the type of biomarker, on whether the data are individual or collective, and also accounting for specific legal provisions, if any. In principle, collective and in particular cases

even individual exposure data can and sometimes must be communicated to the relevant persons other than the worker, such as the employer or his/her delegate. Individual health-related results can and, when necessary, should be communicated to the worker’s practitioner for his/her information and provisions, whereas collective health data should be communicated to the employer and to the relevant occupational or public health authorities. Communication of susceptibility data are generally limited to the worker(s) concerned, unless specific provisions are to be followed (vaccination). Another important issue to consider is the ability of the worker to interpret BM information correctly. The issue of perception of biomarker’s significance by the workers has been specifically addressed by Caux et al. (2007) in an interesting article reporting the representation of various ethical concerns in the use of biomarkers by different occupational health stakeholders’ groups. The study was based on focus group interviews and an internet discussion forum. The main concerns of the stakeholders were: confidentiality, interpretation of data, consent and information, and the balance between advantages and disadvantages. The authors proposed an original tridimensional model for assessing the ethical perception of the stakeholders in the use of biomarkers using three different criteria: narrative of science, validation of biomarkers, and protection of workers. The further the test is, on each axis, from the center of the model, the more likely the test is to raise ethical tension. For example, ethical concern may arise from an altered perception by the worker (or other stakeholder) of the biological or clinical significance of the test (axis 1) or its predictive validity (axis 2) or its potential for the protection of the worker (axis 3). The authors suggest that ethical perception could be improved by providing more and better quality information to the workers before they give consent to participation. Communication of individual data to the worker’s GP should be prior approved by the worker himself, preferably in writing. Alternatively, written information (preferably in an accessible form) should be handled to the worker for his/her GP. The possibility of a future use for legal or medical purposes of biological samples obtained from biomonitoring studies should be considered and, when available, should always be communicated to the worker. Communication of collective results may also be a sensitive issue. Publication of collective anonymous data as scientific reports or articles is acceptable or even recommended in principle. It should be mentioned therefore in the protocol of the study and, if necessary, in the informed consent form. The final decision on when and how individual biomonitoring results should be reported to the workers rests with the OHP (for health surveillance programs) or the scientist (for research BM studies). Information should include an explanation of the relationship among external exposure, internal dose and health effects, when known. If the dose-response relationship is not well known, as in the case of new or not yet validated biomarkers, this should be explained to the workers to prevent any false (higher or lower) perception of risk. The issue of confidentiality in biomonitoring research has been specifically addressed by Nelson et al. (2009) by asking a panel to express their feelings on various aspects of biomonitoring, particularly the use and disclosure of individual results. The panelists were mainly concerned that biomonitoring results as part of an individual’s medical record might have consequences for his/her insurance or employment status. There was consensus that individual biomonitoring information should not be given to employers, insurers or others, without the written consent of the worker involved. The panel also recommended that a specific legislation be issued and felt that each study participant should be given the option to freely decide whether or not to receive his/her personal results.

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

119

As for any other phase of a biomonitoring program, also for the management of the results ethical assessment depends on the aim of the study, the type of biomarker and the specific context under consideration. BM data may be used for two general purposes: occupational health risk assessment or research on new biomarkers. Besides, risk can be assessed for either deterministic (toxicity) or stochastic (carcinogenicity) effects. More specifically, within occupational health risk assessment, one or more of the following may be aimed to in a BM program: (i) exposure assessment, (ii) effect measurement, (iii) susceptibility detection, (iv) risk characterization. When BM is part of a routine occupational health program, the duties and responsibility of the OHP are usually better defined, sometimes even by the law. Among these are the specific directives or recommendations developed and issued by the EU for implementation by each individual member states. As a rule, national laws or regulations may be more strict, but cannot be less strict, than the original European directive. Sometimes, however, significant differences may arise in the interpretation or even translation from one language to the other. This has been the case, for instance, of the implementation, at the national level in the early 2000’s, of a European directive on chemical risk assessment, where the threshold for activating the health surveillance of the workers was set at very different levels of risk, depending on the word used in the national law, i.e., slight, very low, or moderate. This discrepancy had per se severe ethical implications in terms of occupational risk management and prevention, since it accepted different standards in different member states. The issue was also raised of whether a law, or any other legal regulation, should be considered as stronger and more binding than an ethical rule despite lacking an adequate scientific base (Manno et al., 2002). In general, although law and ethics are distinct concepts and require a separate analysis, one would assume that the need for an ethical assessment would only arise if, when or where a legal rule on a sensitive issue is not available or clearly applicable, not because of the legal rule itself. A number of additional, subjective, circumstantial factors modulate the relationship between law and ethics in BM:

threshold dose is available, i.e., the level above which the biomarker result will be considered of concern (e.g., a level equal to a BEI1, the biological exposure indices recommended by ACGIH), this information should be given early, preferably before the start of the study (Deck and Kosatsky, 1999). If the results will fall below this level, individual data will be recorded in the personal health document but, according to clinical medicine ethics, they would not necessarily need to be reported to the workers concerned. Vice versa, if the results are above that level, the individual data will have to be communicated to the worker concerned as early as possible. In the case of borderline values the decision will be left to the OHP on whether and how to inform the worker. It is interesting to note, though, that the approaches to data communication used in clinical medicine and in occupational health are different (Morello-Frosch et al., 2009). The traditional ethical model generally used in clinical medicine gives all the responsibility to the clinician, as an expert, to balance the risk and benefit for the patient, assumed to be unexpert, from managing uncertain information or data. In contrast, in the occupational health context a full awareness of the biomonitoring results by the worker is important to improve his/her working behavior and reduce exposure conditions. So, even borderline levels which are of no or negligible toxicological significance should be communicated to the worker. When dealing with no-threshold chemicals, such as carcinogens or mutagens, the results of biomarkers of exposure or effect should be communicated to the worker in all cases, as no level of exposure would be considered without risk, no matter how low the level is. This applies more to effect than to exposure biomarkers. Even more difficult to interpret are susceptibility biomarkers’ data and their use is therefore more prone to misunderstanding and misperception by the workers. Nonetheless they should always be fully communicated as they may be more effective in improving the worker’s behavior. In practice the decision to communicate the data (and hence the related ethical relevance and implications for the OHP) will depend not only on the level of the biomarker or its toxicological significance but also, and more importantly, on its perception by the worker and its potential in terms of risk prevention.

 the purposes of the legal and ethical provisions may be perceived

6. Concluding remarks

5.3. Management of the results

as different or even conflicting, depending on the cultural, economic, or social context;  the time necessary for the legal system to acknowledge the advancements of science may be long, particularly when compared with the rapid development of the medical sciences in general and occupational toxicology in particular;  ethics and law may be considered as inversely related: a community with strong shared ethical values may not need a rigid legal system or structure. Another ethical issue in managing BM data is the responsibility of the OHP in communicating the results in terms of risk for the workers. In general results of exposure biomarkers would be easier to explain than those of effect or susceptibility biomarkers, although they may be less informative in terms of individual risk assessment. Vice versa effect biomarkers’ results are usually more indicative in terms of individual risk, but they may be more difficult to explain to the workers. Even more cumbersome to explain (and, in fact, even to interpret) are susceptibility data. To avoid misinterpretation, communication of individual and collective results should be accompanied by an adequate information on their significance and possible outcome in terms of preventive action. When, for instance, the dose-response relationship is known for a given biomarker, of either exposure or effect, and evidence for a

All areas of occupational health risk assessment, and particularly biomonitoring, are evolving rapidly, mainly due to the fast developments in medical science and technology. More accurate exposure assessment methods and highly sensitive and specific analytical techniques are now available for both exposure and, to a lesser extent, also effect biomarkers. Moreover, the genetic and biochemical mechanisms of individual susceptibility to chemicals, particularly at low levels, are being increasingly understood. This continuous scientific progress, however, does not always provide easy solutions to the ethical questions of old and new concern by the stakeholders involved in BM, i.e., workers, employers, OHPs, health authorities and general public. The main ethical issues and the related potential conflicts of interest in the various phases of a biological monitoring protocol are reported in Table 2. It is important to acknowledge that when a conflict arises it is not ethics per se, nor people showing ethical concern nor those involved in ethical assessment, that create the problem. In fact, a balanced ethical approach may provide an answer to those complex questions which in many cases science, alone, is unable to provide a solution to, due to the many conflicting values and interests involved (Van Damme and Casteleyn, 2003; Van Damme et al., 1995). In any case decisions on ethical issues should be based on sound scientific evidence, or at least the best science available, and the largest possible consensus, no matter how difficult to

120

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

Table 2 Main ethical issues and related potential conflicts of interest in the phases of a biological monitoring protocol. The table should be read vertically, not horizontally. Study design and planning

Sample collection, storage and Interpretation and management of results analysis

Validity of the test (sensitivity, specificity, predictive value) Risk vs. benefit Selection of the study population and controls Ethics committee’ approval Ethics vs. law Conflict of interest

Free informed consent

Toxicological significance (known vs. unknown, individual vs. group, under- or overestimation of risk, etc.) Risk vs. benefit assessment Job fitness assessment Sample collection Environmental protective action Sample storage and protection Susceptibility (health protection vs. unemployment) Sample destruction Communication (to workers, employer, third parties, health authorities, etc.) Sample analysis Individual responsibility

achieve this would be. One option which is valid for one worker may not be valid for the other or for the workers as a group or for the community by and large. There will usually be, though, an alternative option which best fits a compromise among all the different interests. Respecting the principles of autonomy, beneficence, non maleficence and equity will help, but may not be sufficient for the OHP to make the right decision. The specific context and the contrasting ethical values at stake (public vs. private or individual vs. collective interest, health vs. occupation, risk vs. benefit, privacy vs. information, etc.) will also have to be carefully balanced. In some instances, though, even a balanced approach might not be enough to reach a consensus, in which case will not be easy for the OHP to make and motivate clearly, preferably in writing, his/her own choice (or non-choice), but still he/she will have to. A flowchart of the decision making process by the occupational physician for an ethically sustainable selection of biomarkers for use in occupational health protection programs is proposed in Fig. 2. Briefly, if the biomarker (or the protocol) has some relevant ethical issue, it should be assessed whether there is agreement among state-of-the-art scientific evidence, current law and the recommendations of the ICOH Code of ethics. If these three criteria agree, the biomarker or protocol may be implemented. If they do not, an independent ethical assessment will have to be made by the OHP, including a specific risk-benefit analysis. If the assessment is

positive the biomarker will be implemented. If not, the biomarker (or the protocol) will be dropped and another, more sustainable test or set of tests will have to be selected. In conclusion, a thorough ethical assessment is an important aspect of any BM program. It should consider, without exclusions, all the phases of the program: from the aim of the study to the study design, from the collection of the samples to their storage, from the interpretation of the data to their use, both individually and collectively. In most cases the assessment will be straightforward, and so will the resulting outcome in terms of decisions. In other cases the choice may be more difficult or, sometimes, almost impossible. In any case a sound scientific approach is, per se, the first ethical requirement. Research on biomarkers, including their toxicological significance, sensitivity, specificity and predictive value, together with the new promising biomolecular methods, such as the novel “-omics” techniques, are likely to expand the scientific bases of the OHP and, hopefully, reinforce his/her ability to deal in the near future with the challenges of occupational health risk assessment more effectively. However, the advancement of knowledge is likely to also induce new unprecedented ethical issues. Good science will be necessary but not sufficient to provide a solution in all cases and the OHP will have to be prepared, probably more frequently than it is now, to make his/her own mind based primarily on professional experience, independent judgement and individual responsibility.

Does the (selecon of the) biomarker have any ethical relevance? Yes

No

The test is selected and used without any further assessment

Yes

Is there a consensus among science, law and ICOH Code of Ethics? No

Yes Independent ethical assessment by the OHP

Another, more sustainable biomarker (or protocol) has to be selected (e.g. a less invasive or a more validated, sensive, specific or predicve test)

No

Is the (use of the) biomarker jusfied for the worker/group of workers?

Fig. 2. Proposed flowchart for the assessment of the ethical sustainibility of the selection of a biomarker by the occupational health professional and its use in health prevention and protection programs.

M. Manno et al. / Toxicology Letters 231 (2014) 111–121

Conflict of interest The authors declare that there are no conflicts of interest. Transparency document The Transparency document associated with this article can be found in the online version. References ACGIH, 2005. Documentation of the Threshold Limit Values and Biological Exposure Indices, 7th Ed. ACGIH, Cincinnati. Angerer, J., Ewers, U., Wilhelm, M., 2007. Human biomonitoring: state of the art. Int. J. Hyg. Environ. Health 210, 201–228. Arendt, M., 2008. Communicating human biomonitoring results to ensure policy coherence with public health recommendations: analyzing breastmilk whilst protecting, promoting and supporting breastfeeding. Environ. Health 7 (Suppl. 1), S6. doi:http://dx.doi.org/10.1186/1476–069X-7-S1-S6. Barr, D.B., Wilder, L.C., Caudill, S.P., Gonzalez, A.J., Needham, L.L., Pirkle, J.L., 2005. Urinary creatinine concentrations in the U.S. population: implications for urinary biological monitoring measurements. Environ. Health Perspect. 113, 192–200. Bates, M.N., Hamilton, J.W., LaKind, J.S., Langenberg, P., O’Malley, M., Snodgrass, W., 2005. Workgroup report biomonitoring study design interpretation, and communication—lessons learned and path forward. Environ. Health Perspect. 113, 1615–1621. Beauchamp, T.L., Childress, J.F., 2001. Principles of Biomedical Ethics, 5th ed. Oxford University Press, New York. Boumba, V.A., Ziavrou, K.S., Vougiouklakis, T., 2006. Hair as a biological indicator of drug use: drug abuse or chronic exposure to environmental toxicants. Int. J. Toxicol. 25, 143–163. Caux, C., Roy, D.J., Guilbert, L., Viau, C., 2007. Anticipating ethical aspects of the use of biomarkers in the workplace: a tool for stakeholders. Soc. Sci. Med. 65, 344–354. Clarkson, T.W., Friberg, L., Nordberg, G.F., Sager, P.R. (Eds.), 1988. Biological Monitoring of Toxic Metals. Plenum Press, New York. Council for International Organizations of Medical Sciences (CIOMS), 1991. International Guidelines for Ethical Review of Epidemiological Studies. WHO, Geneva. Council for International Organizations of Medical Sciences (CIOMS), 2002. International Ethical Guidelines for Biomedical Research Involving Human Subjects. WHO, Geneva. Council for International Organizations of Medical Sciences (CIOMS), 2009. International Ethical Guidelines for Epidemiological Studies. WHO, Geneva. Council of Europe, 1997. European Convention on Human Rights and Biomedicine. Council of Europe, Oviedo. Deck, W., Kosatsky, T., 1999. Communicating their individual results to participants in an environmental exposure study: insights from clinical ethics. Environ. Res. 80, S223–S229. doi:http://dx.doi.org/10.1006/enrs.1998.3946. Esteban, M., Castaño, A., 2009. Non-invasive matrices in human biomonitoring: a review. Environ. Int. 35, 438–449. ESBIO, 2007. Development of a Coherent Approach to Human Biomonitoring in Europe. Expert team to Support BIOmonitoring in Europe (ESBIO): Final Activity Report http://www.eu-biomonitoring.org. Harty, L.C., Shields, P.G., Winn, D.M., Caporaso, N.E., Hayes, R.B., 2000. Self-collection of oral epithelial cell DNA under instruction from epidemiologic interviewers. Am. J. Epidemiol. 151, 199–205. Holland, N.T., Smith, M.T., Eskenazi, B., Bastaki, M., 2003. Biological sample collection and processing for molecular epidemiological studies. Mutat. Res. 543, 217–234. HSE, 1997. Biological Monitoring in the Workplace: A Guide to its Practical Application to Chemical Exposure. http://www.hse.gov.uk/pubns/books/ hsg167htm. ICOH, 2002. International Code of Ethics for Occupational Health Professionals, International Commission on Occupational Health. IUPAC, 2004. Glossary of terms used in toxicokinetics (IUPAC Recommendations 2003). Nordberg, M., Duffus, J.H., Templeton, D.M. (Eds.), Pure Appl. Chem. 76, 1033–1082. IUPAC, 2006. Glossary of terms relating to pesticides (IUPAC Recommendations 2006). Stephenson, G.R., Ferris, I.G., Holland, P.T., Nordberg, M. (Eds.), Pure Appl. Chem. 78, 2075–2154. IUPAC, 2007. Glossary of terms used in toxicology, 2nd edition (IUPAC Recommendations 2007). Duffus, J.H., Nordberg, M., Templeton, D.M. (Eds.), Pure Appl. Chem. 79, 1153–1341.

121

Last, J.M., 1998. In: Wallace, R.B., Doebbeling, B.N. (Eds.), Ethics and Public Health Policy. In Maxcy-Rosenau-Las Public Health & Preventive Medicine. 14th ed. Appleton & Lange, Connecticut, pp. 35–43. Lindstrom, A.B., Pleil, J.D., 2002. A review of the USEPA’s single breath canister (SBC) method for exhaled volatile organic biomarkers. Biomarkers 7, 189–208. Lucas, D., Ferrara, R., Gonzalez, E., Bodenez, P., Albores, A., Manno, M., Berthou, F., 1999. Chlorzoxazone, a selctive probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9, 377–388. Manno, M., Mutti, A., Apostoli, P., Bartolucci, G.B., Franchini, I., 2002. Occupational medicine at stake in Italy. Lancet 359, 1865. Manno, M., Viau, C., Cocker, J., Colosio, C., Lowry, L., Mutti, A., Nordberg, M., Wang, S., 2010. Biomonitoring for occupational health risk assessment (BOHRA). Tox. Lett. 192, 3–16. Morello-Frosch, R., Brody, J.G., Brown, P., Altman, R.G., Rudel, R.A., Pérez, C., 2009. Toxic ignorance and right-to-know in biomonitoring results communication: a survey of scientists and study participants. Environ. Health 8, 6. doi:http://dx. doi.org/10.1186/1476-069X-8-6. Needham, L.L., Patterson Jr., D.G., Barr, D.B., Grainger, J., Calafat, A.M., 2005. Uses of speciation techniques in biomonitoring for assessing human exposure to organic environmental chemicals. Anal. Bioanal. Chem. 381, 397–404. Nelson, J.W., Scammell, M.K., Altman, R.G., Webster, T.F., Ozonoff, D.M., 2009. A new spin on research translation: the boston consensus conference on human biomonitoring. Environ. Health Perspect. 117, 495–499. Nordberg, G.F., Fowler, B.A., Nordberg, M., Friberg, L. (Eds.), 2007. Handbook on the Toxicology of Metals. 3rd ed. Elsevier. NRC, 2006. Human Biomonitoring for Environmental Chemicals. Committee on Human Biomonitoring for Environmental Toxicants. The National Academies Press, Washington, DC. Piccoli, P., Carrieri, M., Padovano, L., Di Mare, M., Bartolucci, G.B., Fracasso, M.E., Lepera, J.S., Manno, M., 2010. In vivo CYP2E1 phenotyping as a new potential biomarker of occupational and experimental exposure to benzene. Toxicol. Lett. 192, 29–33. Polkowska, Z., Kozlowska, K., Namiesnik, J., Przyjazny, A., 2004. Biological fluids as a source of information on the exposure of man to environmental chemical agents. Crit. Rev. Anal. Chem. 35, 105–119. Reis, M.F., Segurado, S., Brantes, A., Simões, H.T., Melim, J.M., Geraldes, V., Miguel, J. P., 2008. Ethics issues experienced in HBM within Portuguese health surveillance and research projects. Environ. Health 7 (Suppl. 1), S5. doi: http://dx.doi.org/10.1186/1476-069X-7-S1-S5. Rockett, J.C., Buck, G.M., Lynch, C.D., Perreault, S.D., 2004. The value of home-based collection of biospecimens in reproductive epidemiology. Environ. Health Perspect. 112, 94–104. Schaller, K.H., Angerer, J., Drexler, H., 2002. Quality assurance of biological monitoring in occupational and environmental medicine. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 778, 403–417. Sexton, K., Needham, L., Pirkle, J., 2004. Human biomonitoring of environmental chemicals: measuring chemicals in human tissues is the gold standard for assessing exposure to pollution. Am Sci. 92, 38–45. Smolders, R., Schramm, K.W., Nickmilder, M., Schoeters, G., 2009. Applicability of non-invasively collected matrices for human biomonitoring. Environ. Health 8, 8. doi:http://dx.doi.org/10.1186/1476-069X-8-8. Stokstad, E., 2004. Biomonitoring: pollution gets personal. Science 304, 1892–1894. Tangwa, G.B., 2009. Ethical principles in health research and review process. Acta Tropica 112, S2–S7. Timchalk, C., Poet, T.S., Kousba, A.A., Campbell, J.A., Lin, Y., 2004. Noninvasive biomonitoring approaches to determine dosimetry and risk following acute chemical exposure: analysis of lead or organophosphate insecticide in saliva. J. Toxicol. Environ. Health A 67, 635–650. Van Damme, K., Casteleyn, L., 2003. Current scientific, ethical and social issues of biomonitoring in the European Union. Toxicol. Lett. 144 (1), 117–126. Van Damme, K., Casteleyn, L., Heseltine, E., Huici, A., Sorsa, M., van Larebeke, N., Vineis, P., 1995. Individual susceptibility and prevention of occupational diseases: scientific and ethical issues. J. Occup. Environ. Med. 37, 91–99. van Valkengoed, I.G., Morre, S.A., Meijer, C.J., van den Brule, A.J., Boeke, A.J., 2002. Do questions on sexual behaviour and the method of sample collection affect participation in a screening programme for asymptomatic Clamydia tracomatis infections in primary care? Int. J. STD Aids 13, 36–38. Viau, C., 2005. Biomonitoring in occupational health: scientific socio-ethical, and regulatory issues. Toxicol. Appl. Pharmacol. 207, S347–S353. Walker, A.H., Najarian, D., White, D.L., Jaffe, J.M., Kanetsky, P.A., Rebbeck, T.R., 1999. Collection of genomic DNA by buccal swabs for polymerase chain reactionbased biomarker assays. Environ. Health Perspect. 107, 517–520. Wilson, H.K., Monster, A.C., 1999. New technologies in the use of exhaled breath analysis for biological monitoring. Occup. Environ. Med. 56, 753–757. WHO/IPCS, 2001. Biomarkers in Risk Assessment: Validity and Validation. Environmental Health Criteria 222. World Health Organization, Geneva. WHO/IPCS, 2006. Elemental Speciation in Human Health Risk Assessment. Environmental Health Criteria 234. World Health Organization, Geneva.

Ethics in biomonitoring for occupational health.

Biological monitoring, i.e., the use of biomarkers for the measurement of systemic human exposure, effects and susceptibility to chemicals has increas...
929KB Sizes 0 Downloads 9 Views