The ethics of human volunteer studies involving experimental exposure to pesticides: unanswered dilemmas

The controversy about the use of data from human volunteer studies involving experimental exposure to pesticides as part of regulatory risk assessment has been widely discussed, but the complex and interrelated scientific and ethical issues remain largely unresolved. This discussion paper, generated by authors who comprised a workgroup of the ICOH Scientific Committee on Rural Health, reviews the use of human experimental studies in regulatory risk assessment for pesticides with a view to advancing the debate as to when, if ever, such studies might be ethically justifiable. The discussion is based on three elements: (a) a review of discussion papers on the topic of human testing of pesticides and the positions adopted by regulatory agencies in developed countries; (b) an analysis of published and unpublished studies involving human testing with pesticides, both in the peer-reviewed literature and in the JMPR database; and (c) application of an ethical analysis to the problem. The paper identifies areas of agreement which include general principles that may provide a starting point on which to base criteria for judgements as to the ethical acceptability of such studies. However, the paper also highlights ongoing unresolved differences of opinion inherent in ethical analysis of contentious issues, which we propose should form a starting point for further debate and the development of guidelines to achieve better resolution of this matter.     

Pesticide testing on human subjects: weighing benefits and risks

In the debate surrounding testing pesticides on human subjects, two distinct positions have emerged. The first position holds that pesticide experiments on human subjects should be allowed, but only under stringent scientific and ethical standards. The second position asserts that these experiments should never be allowed. In this article, we evaluate what we consider to be the strongest argument for the second position--namely, that the benefits of the experiments are not significant enough to justify the risks posed to healthy subjects. We challenge this argument by examining the benefits and risks of testing pesticides on human subjects. We argue that a study that intentionally exposes humans subjects to pesticides should be permitted if a) the knowledge gained from the study is expected to promote human health; b) the knowledge cannot be reasonably obtained by other means; c) the study is not expected to cause serious or irreversible harm to the subjects; and d) appropriate safeguards are in place to minimize harm to the subjects.     

Occupational exposure to endocrine-disrupting pesticides and the potential for developing hormonal cancers

It is suspected that endocrine-disrupting pesticides are involved in the development of several cancer and noncancer health risks in humans and wildlife. A large number of pesticides show endocrine-disrupting activities. The potential for human and animal exposure to such pesticides is very high. Farmers, as a group, may be particularly at risk, because they are subject to higher-than-average levels of exposure to pesticides over longer-than-average periods. Recent studies have shown that the incidence of hormone-related organ cancers, or hormonal cancers, is elevated among farmers. Exposure to endocrine-disrupting pesticides, particularly to DDT and phenoxy herbicides, is suspected of involvement in some of these hormonal cancers. There is a clear need for a refined epidemiological study that focuses on specific pesticides, accurately assesses exposure, and then examines any association between pesticides and hormonal cancers among farmers.     

Suicide and exposure to organophosphate insecticides: Cause or effect?

BACKGROUND: Suicide using pesticides as agent is recognized as a major cause of pesticide poisoning. METHODS: A literature review of mortality and morbidity studies related to suicide among pesticide-exposed populations, and of human and animal studies of central nervous system toxicity related to organophosphate (OP) pesticides was performed. RESULTS: Suicide rates are high in farming populations. Animal studies link OP exposure to serotonin disturbances in the central nervous system, which are implicated in depression and suicide in humans. Epidemiological studies conclude that acute and chronic OP exposure is associated with affective disorders. Case series and ecological studies also support a causal association between OP use and suicide. CONCLUSIONS: OPs are not only agents for suicide. They may be part of the causal pathway. Emphasizing OPs solely as agents for suicide shifts responsibility for prevention to the individual, reducing corporate responsibility and limiting policy options available for control.     

医学期刊编辑对生物医学研究伦理问题的处理方式调研及建议

【目的】 探讨医学期刊编辑处理生物医学研究伦理问题的方式,为推动确立医学期刊伦理审查规范提供参考。【方法】 通过问卷星向国内医学期刊编辑发放调查问卷,对审稿时和论文出版后处理医学伦理相关问题的方式展开调研。【结果】 共回收问卷230份。调查显示:在审稿阶段,在保护患者隐私方面,英文期刊、中英双语期刊的编辑更注重要求作者提供授权同意相关证明材料;中、英文期刊以及中英双语期刊的编辑对涉及人体试验伦理问题的处理方式都比较规范。但是,对于研究是否获得患者知情同意、动物实验研究是否经过伦理委员会审查、回顾性研究是否需要伦理审查、涉及人的研究是否在临床试验注册中心注册等问题,编辑还需要进一步重视。在论文出版后,编辑发现的医学伦理问题主要是“涉及人的研究未说明是否经过伦理委员会审查”。对论文出版后发现的没有保护患者隐私和没有在临床试验注册中心注册的问题,大部分期刊缺乏相关处理方案。【结论】 编辑应加强对论文知情同意、动物实验伦理、回顾性研究伦理的审查,并审查涉及人的研究是否在临床试验注册中心注册,以推动我国医学期刊的高质量发展。     

Fairness and accountability for reasonableness. Do the views of priority setting decision makers differ across health systems and levels of decision making?

Accountability for reasonableness is an ethical framework for fair priority setting process. This framework has been used to evaluate fairness in several contexts, and a few studies have evaluated its acceptability to decision makers. However, no studies have compared the acceptability of the four conditions of the framework to decision makers across health systems and levels of priority setting. This paper reports the elements of fairness described by 184 decision makers involved in priority setting at the macro-, meso- and micro-levels of priority setting in the Canadian (Ontario), Norwegian and Ugandan health care systems and compares them against the four conditions of ‘Accountability for Reasonableness’ and across levels of decision making, and health care systems.     

Potential developmental neurotoxicity of pesticides used in Europe

Pesticides used in agriculture are designed to protect crops against unwanted species, such as weeds, insects, and fungus. Many compounds target the nervous system of insect pests. Because of the similarity in brain biochemistry, such pesticides may also be neurotoxic to humans. Concerns have been raised that the developing brain may be particularly vulnerable to adverse effects of neurotoxic pesticides. Current requirements for safety testing do not include developmental neurotoxicity. We therefore undertook a systematic evaluation of published evidence on neurotoxicity of pesticides in current use, with specific emphasis on risks during early development. Epidemiologic studies show associations with neurodevelopmental deficits, but mainly deal with mixed exposures to pesticides. Laboratory experimental studies using model compounds suggest that many pesticides currently used in Europe – including organophosphates, carbamates, pyrethroids, ethylenebisdithiocarbamates, and chlorophenoxy herbicides – can cause neurodevelopmental toxicity. Adverse effects on brain development can be severe and irreversible. Prevention should therefore be a public health priority. The occurrence of residues in food and other types of human exposures should be prevented with regard to the pesticide groups that are known to be neurotoxic. For other substances, given their widespread use and the unique vulnerability of the developing brain, the general lack of data on developmental neurotoxicity calls for investment in targeted research. While awaiting more definite evidence, existing uncertainties should be considered in light of the need for precautionary action to protect brain development.     

In utero pesticide exposure and childhood morbidity

In humans, immune development begins early in embryonic life and continues throughout the early postnatal period. Although a number of pesticides have been observed to induce developmental immunotoxicity in mice, few human studies have examined the long term effects of in utero pesticide exposure on childhood morbidity. Empirical evidence suggests that the vulnerable period for toxic insults to the developing immune system extends from early gestation to adolescence in humans and animals. Using data from the Ontario Farm Family Health Study, we examined the relationship between farm couple exposures to pesticides during pregnancy and subsequent health outcomes in their offspring, including: persistent cough or bronchitis, asthma, and allergies or hayfever. No strong associations between pesticide exposures during pregnancy and persistent cough or bronchitis, or asthma were found. There was suggestive evidence that allergies and hayfever appeared to be more common in offspring, especially male offspring, exposed to certain specific pesticides during the period of pregnancy. Nevertheless, given the indirect indicators of pesticide exposure used in this study, and the scarcity of human studies on in utero exposure to pesticides and the development of allergies and other child health outcomes, these findings serve primarily to generate hypotheses for future research.     

Establishment of a blood transfusion center at Kabul (Afghanistan)

Recent events concerning blood transfusion (BT) have led to the number of BT being drastically reduced and to more rigorous checking of blood donations before their use for transfusion. Very few developing countries have been able to set up BT organizations that are both self-sufficient and capable of ensuring a high quality of blood testing. A central blood bank (CBB) was set up in Kabul (Afghanistan) during the 1980s. From 1992 onwards, its activities were curtailed due to the political turmoil, lack of funds and the fact that no blood collection policy was being implemented. A partnership between a development aid agency (Avicen), French public institutions and the local authorities has resulted in the rebirth of this CBB by the injection of financial resources and technical and scientific expertise. An independent committee of BT specialists was responsible for assessing the scientific validity and ethical acceptability of the project. In 1996, the objectives of the project, which had been in operation for one year, were achieved as far as the renovation of the laboratories was concerned. Work has focused mostly on setting up a proper cold chain and on training laboratory technicians in standard biological methods for testing blood from donors (blood group, HIV screening, Ag Hbs, HCV and syphilis). However, due to the shortage of blood donors, it has been difficult to set up a minimum blood bank stock. The results of the first biological tests carried out on the blood of the first 1,281 donors have made it possible to define an appropriate, detailed policy for preventing and controlling the main risks of infection from BT, involving routine testing for HIV, Ag HBs and HCV (0.3% prevalence). BT is a major component of any health care system and it must be reconstructed. The measures proposed here are long-term and require the ongoing participation of all those involved in this project including the local authorities and sources of financial support.     

An expedient and ethical alternative to xenotransplantation

The current voluntary posthumous organ donation policy fails to provide sufficient organs to meet the demand. In these circumstances xenografts have been regarded as an expedient solution. The public perception seems to be that the only impediments to this technology are technical and biological. There are, however, important ethical issues raised by xenotransplantation that need to be considered as a matter of urgency. When the ethical issues raised by using non-human animals to provide replacement organs for human beings are considered in a wider context and the possible alternatives to xenotransplantation are taken into account, a new dimension is added to the debate. In this broader context it is argued that a less ethically problematic solution is to adopt a presumed consent or opt-out organ procurement policy to regulate posthumous organ harvesting from humans. If there are still too few organs available, then the whole question of transplantation must be reassessed.This revised version was published online in October 2005 with corrections to the Cover Date.     

Comparative evaluation of absorbed dose estimates derived from passive dosimetry measurements to those derived from biological monitoring: validation of exposure monitoring methodologies

Passive dosimetry (PD) methods for measuring and estimating exposure to agricultural workers (i.e., persons handling agricultural chemicals and working in treated crops) have been in use since the 1950s. A large number of studies were conducted in the 1950s through 1970s to characterize exposure. Since the 1980s quantitative dermal PD methods are used in conjunction with inhalation PD methods to measure whole-body exposure. These exposure or absorbed dose estimates are then compared to "no effect" exposure levels for hazards identified in toxicology studies, and have become the standard for risk assessment for regulatory agencies. The PD methods used have never been validated. Validation in the context of human exposure monitoring methods means that a method has been shown to measure accurately a delivered dose in humans. The most practical alternative to isolating parts of the body for validating recovery methods is to utilize field exposure studies in which concurrent or consecutive measurements of exposure and absorbed dose have been made with PD and biomonitoring in the same cohorts of individuals. This ensures that a direct comparison can be made between the two estimates of absorbed dose, one derived from PD and the other from biomonitoring. There are several studies available (published and proprietary) employing both of these approaches. Reports involving 14 concurrent or consecutive PD-biomonitoring studies were quantitatively evaluated with 18 different methods of application or reentry scenarios for eight different active ingredients for which measured human kinetics and dermal absorption data existed. This evaluation demonstrated that the total absorbed dose estimated using PD for important handler and reentry scenarios is generally similar to the measurements for those same scenarios made using human urinary biomonitoring methods. The statistical analysis of individual worker PD:biomonitoring ratios showed them to be significantly correlated in these studies. The PD techniques currently employed yield a reproducible, standard methodology that is valid and reliably quantifies exposure.     

Pesticide exposure and child neurodevelopment: summary and implications

Widely used around the world, pesticides play an important role in protecting health, crops, and property. However, pesticides may also have detrimental effects on human health, with young children among the particularly vulnerable. Recent research suggests that even low levels of pesticide exposure can affect young children's neurological and behavioral development. Evidence shows a link between pesticides and neonatal reflexes, psychomotor and mental development, and attention-deficit hyperactivity disorder. Implications include a need for improved risk assessment and health histories by clinicians, greater education at all levels, more common use of integrated pest management, and continued policy and regulatory strategies to mitigate the effects of and the need for pesticides.     

Evaluating health risks from occupational exposure to pesticides and the regulatory response.

In this study, we used measurements of occupational exposures to pesticides in agriculture to evaluate health risks and analyzed how the federal regulatory program is addressing these risks. Dose estimates developed by the State of California from measured occupational exposures to 41 pesticides were compared to standard indices of acute toxicity (LD50) and chronic effects (reference dose). Lifetime cancer risks were estimated using cancer potencies. Estimated absorbed daily doses for mixers, loaders, and applicators of pesticides ranged from less than 0.0001% to 48% of the estimated human LD50 values, and doses for 10 of 40 pesticides exceeded 1% of the estimated human LD50 values. Estimated lifetime absorbed daily doses ranged from 0.1% to 114,000% of the reference doses developed by the U.S. Environmental Protection Agency, and doses for 13 of 25 pesticides were above them. Lifetime cancer risks ranged from 1 per million to 1700 per million, and estimates for 12 of 13 pesticides were above 1 per million. Similar results were obtained for field workers and flaggers. For the pesticides examined, exposures pose greater risks of chronic effects than acute effects. Exposure reduction measures, including use of closed mixing systems and personal protective equipment, significantly reduced exposures. Proposed regulations rely primarily on requirements for personal protective equipment and use restrictions to protect workers. Chronic health risks are not considered in setting these requirements. Reviews of pesticides by the federal pesticide regulatory program have had little effect on occupational risks. Policy strategies that offer immediate protection for workers and that are not dependent on extensive review of individual pesticides should be pursued.     

El registro de los estudios observacionales: es el momento de cumplir el requerimiento de la Declaración de Helsinki

Publication bias is a serious deficiency in the current system of disseminating the results of human research studies. Clinical investigators know that, from an ethical standpoint, they should prospectively register clinical trials in a public registry before starting them. In addition, it is believed that this approach will help to reduce publication bias. However, most studies conducted in humans are observational rather than experimental. It is estimated that less than 2% out of 2 million concluded or ongoing observational studies have been registered. The 2013 revision of the Declaration of Helsinki requires registration of any type of research study involving humans or identifiable samples or data.It is proposed that funding agencies, such as the Fondo de Investigaciones Sanitarias, as well as private companies, require preregistration of observational studies before providing funding. It is also proposed that Research Ethics Committees which, following Spanish regulation, have been using the Declaration as the framework for assessing the ethics of clinical trials with medicines since 1990, should follow the same provisions for the assessment of health-related observational studies: therefore, they should require prospective registration of studies before granting their final approval. This would allow observational study investigators to be educated in complying with an ethical requirement recently introduced in the most important ethical code for research involving humans.     

The dangers to health of fine dust particles in the air

Many scientific studies have been published that connect all kinds of toxicological characteristics offine dust particles, measured in vitro, with lung damage parameters both in animals and humans. These studies do not provide an unequivocal picture on the mechanisms that are responsible for the perceived connection between exposure to fine dust and the degree of illness and death. Without connecting to specific sources of air pollution, this type of study moreover, is only of limited value for drawing up control policy. Even if one or more responsible properties could be determined, it is still unlikely that these would be translated into a standard for permitted levels of concentration in the open air. It is far more likely that such insight will be used for specific source policy aimed at tackling the sources that contribute the most to the harmfulness of the mixture of air pollution.     

Ames, pesticides, and cancer revisited

The case for continuing use of existing levels of pesticides in agriculture, espoused by Bruce Ames, is refuted. Ames' contentions that naturally occurring carcinogens are far more widespread than man-made ones, that pesticides prevent cancer by providing fruits and vegetables at lower costs to the poor, and that animal data on high risks with high doses cannot predict low risks from low doses in humans do not address key issues: 1) fruits and vegetables contain mixtures of carcinogens and anti-carcinogens, and selection effects from human exposures to these mixtures go back more than a million years; 2) exposures from bioconcentrations of biopersistent organochlorines in the food chain create particular risks for meat-eaters, who have higher cancer risks than vegetarians; 3) even low doses from ingestion of produce containing pesticide residues can cause tissue injury, which could itself promote cancer; 4) epidemiologic data show rises in cancer incidences in older people in many countries, major differences in cancer risks between countries, and converging trends in risks for populations migrating to certain countries; 5) studies of pesticide-exposed workers consistently show increased rates of cancers and birth defects and cancers in their offspring; 6) epidemiologic studies based on large databases tend to underestimate risks from environmental causes because of exposure misclassification; 7) exposures to many organochlorines may have pervasive effects on endocrine function; 8) crop yields can be increased with less use of pesticides. Studies demonstrating the latter need replication, and should be supported as part of a coherent government agenda to develop alternative farming methods.     

Desperately seeking targets: the ethics of routine HIV testing in low-income countries

The human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) pandemic, and responses to it, have exposed clear political, social and economic inequities between and within nations. The most striking manifestations of this inequity is access to AIDS treatment. In affluent nations, antiretroviral treatment is becoming the standard of care for those with AIDS, while the same treatment is currently only available for a privileged few in most resource-poor countries. Patients without sufficient financial and social capital -- i.e., most people with AIDS -- die each day by the thousands. Recent AIDS treatment initiatives such as the UNAIDS and WHO "3 by 5" programme aim to rectify this symptom of global injustice. However, the success of these initiatives depends on the identification of people in need of treatment through a rapid and massive scale-up of HIV testing. In this paper, we briefly explore key ethical challenges raised by the acceleration of HIV testing in resource-poor countries, focusing on the 2004 policy of routine ("opt-out") HIV testing recommended by UNAIDS and WHO. We suggest that in settings marked by poverty, weak health-care and civil society infrastructures, gender inequalities, and persistent stigmatization of people with HIV/AIDS, opt-out HIV-testing policies may become disconnected from the human rights ideals that first motivated calls for universal access to AIDS treatment. We leave open the ethical question of whether opt-out policies should be implemented, but we recommend that whenever routine HIV-testing policies are introduced in resource-poor countries, that their effect on individuals and communities should be the subject of empirical research, human-rights monitoring and ethical scrutiny.     

Human testing of pesticides: ethical and scientific considerations

I reviewed ethical and scientific aspects of 6 human pesticide-dosing studies submitted to the Environmental Protection Agency (EPA) for consideration during the pesticide reregistration process. All had serious ethical or scientific deficiencies-or both-including unacceptable informed consent procedures, unmanaged financial conflicts of interest, inadequate statistical power, inappropriate test methods and endpoints, and distorted results. Given today's knowledge of the effects of pesticides, there is no assurance that any such study can be completely free of short-term risks, long-term risks, or both. Therefore, there is no basis for allowing pesticide studies to continue or for using them during the pesticide reregistration process. An EPA committee that is free from political and financial conflicts of interest should review this practice.     

The development of a new method to estimate total daily dose of pesticides in professional turf applicators following multiple and varied exposures in occupational settings

The evaluation of absorbed dose of pesticides in humans requires a knowledge of the kinetics and dynamics of the compound. In some circumstances, data that allow for the estimation of dose may be available from human volunteer studies, although often, it will be based on results from animal studies. If human metabolism data are available, estimates of dose may be more accurate, but it should be recognized that pesticide exposure in an occupational setting may differ from that in a controlled laboratory study. In this study, data from previously published studies are used to evaluate the urinary excretion of 2,4-dichlorophenoxyacetic acid (2,4-D), following single dermal applications to human volunteers. These studies are evaluated with the objective of determining the best method of predicting total absorbed dose following multiple and varied exposures in occupational settings. Further, an alternative to laboratory-controlled human volunteer studies is presented. Data from a third previously published biological monitoring study on six professional pesticide applicators over a 2-week period were used to generate estimates of the urinary excretion of the pesticide 2,4-D that would result from a single dose. The method used to estimate the urinary excretion parameters is a variation of an overlay technique used in pharmacology, and may provide information on the kinetics of other pesticides when it is not possible to conduct human studies. The generated estimates of 24-h urinary excretion of 2,4-D over a 6-day period were remarkably similar to those obtained in controlled studies. Finally, a method was developed to use the generated estimates to determine total absorbed dose of pesticides for an independent group of 95 professional pesticide applicators. This method requires information on the amount of pesticide used for 6 days prior to the collection of two, 24-h urine samples. Received: 31 August 2000 / Accepted: 5 January 2001     

Setting human-health-based groundwater protection standards when toxicological data are inadequate

Toxicological data are not adequate to assess fully the health effects of many of the pesticides that currently contaminate or have the potential to contaminate groundwater. The National Academy of Sciences estimated in 1984 that data to conduct a complete health hazard assessment exist for only 10% of the pesticides currently on the market. Many pesticides have not been tested for their ability to cause cancer, genetic mutation, or birth defects. There are significant gaps in the toxicological data base for the majority of pesticides for which the Environmental Protection Agency proposed health advisories in 1987. To help assure that groundwater standards are adequately protective of human health when toxicological data are not adequate, additional uncertainty factors can be incorporated into such standards. Alternatively, standards can be set at the level of detection. This should be the approach when no data exist to assess major potential health effects. For example, the detection limit could be the standard if no adequate oncogenicity studies have been conducted. In addition, generic standards may be employed when data are inadequate to set chemical-specific standards. New York State has recently taken this innovative generic standard approach.