Intentional Human Dosing Studies for EPA Regulatory Purposes Scientific and Ethical Issues (2004) / Chapter Skim
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3 Scientific Justification for and Conduct of Intentional Human Dosing Studies
3 Scientific Justification for and Conduct of Intentional Human Dosing Studies
Pages 66-83
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From page 66... ...
However, for ease of explication, scientific and ethical issues are discussed separately in this chapter, with scientific issues the principal concern. Intentional human dosing studies involving potentially toxic substances can, in some circumstances, contribute significant and useful knowledge for regulatory standard setting and other forms of public health protection.
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From page 67... ...
In addition, the committee proposes careful, independent review of study justifications and protocols for all intentional human dosing studies within the scope of EPA's mandate. Before examining the issues involved in providing scientific justifications of and study protocols for intentional human dosing studies, a brief discussion is presented of the types of scientific investigations involving intentional dosing that are typically considered for possible conduct in human populations.
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From page 68... ...
In addition to informing interspecies comparisons, human PK data can shed light on the appropriateness of the intraspecies uncertainty factor, for example, by showing similar PK activity in a wide range of participants. Useful PK data typically can be developed in humans using very low doses of chemicals -- doses that cannot cause adverse effects and often that cannot cause any detectable biological changes in research participants.
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From page 69... ...
At the doses and duration used, however, the response would not be expected to cause an adverse effect in study participants. These biological responses often are referred to as biomarkers for the effects of interest (e.g., neurological effects)
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From page 70... ...
, a no observed adverse effect level (NOAEL) , and possibly an NOEL, although it is expected that any observed effects will not be sustained once exposure ceases (that is, the change is fully reversible)
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From page 71... ...
A LOAELHU is the lowest dose or concentration at which an adverse effect is seen. In terms of the committee's discussion, for intentional human dosing studies there should be high confidence that any anticipated ad verse effect is not serious and is reversible.
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From page 72... ...
JUSTIFICATION FOR INTENTIONAL HUMAN DOSING STUDIES Criteria for Study Justification Justification of intentional human dosing studies depends on the importance of the expected results to a regulatory decision that will protect the public health and a demonstration that other means of acquiring the necessary information are substantially deficient. In the case of intentional human dosing studies conducted for EPA regulatory purposes, ethical and scientific standards demand that every effort be made in advance to ensure that the biological endpoints to be measured are important to the assessment of human risk.
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From page 73... ...
Nonetheless, inhibition thresholds for the onset of particular effects are often controversial. AChE inhibition that mediates neurotoxicity occurs at synapses of central and peripheral nerves, but alterations in plasma and red blood cell cholinesterase activities are commonly monitored as indices of potential central effects in adults and children (Wessels et al., 2003)
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From page 74... ...
. Second, animal models have little value for assessing adverse effects that cannot be objectively measured, such as those that can be known only because they can be reported by study participants (headaches are a prime example, as are feelings of nausea and dizziness)
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From page 75... ...
The committee views ensuring the protection of research participants as an element of the study protocol. BOX 3.2 Criteria for Judging the Adequacy of the Scientific Justification for Intentional Human Dosing Studies 1.
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From page 76... ...
Finally, the overall plan should include documentation of the adequacy of preclinical data for establishing that study participants are not likely to be harmed at the doses selected and that other appropriate safeguards are in place. Aspects of Study Design Five features are critical to designing an intentional human dosing study, including endpoint, dose, and participant selection; study method; and dosing and measurement schedules.
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From page 77... ...
If the objective is to modify uncertainty factors and replace animal data with relevant human data (potentially eliminating the need for the uncertainty factor for animal-to-human extrapolation) , healthy adult humans of, for example, similar age and weights might be most appropriate to represent the average human population.
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From page 78... ...
If, on the other hand, the goal of the study is to set acceptable levels of an air pollutant, it will be critical to focus on sensitive populations because they represent those most clearly at risk and often include individuals with specific medical conditions. Careful review of these conditions
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From page 79... ...
. Study protocols should include justification for participant selection, a description of how potential participants are identified, and a description of the procedures to be used in randomizing participants to dose groups.
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From page 80... ...
All relevant studies conducted by the laboratory, clinic, or funding organization should be reported in at least summary form, even if their findings are not in the interest of those sponsoring the study. Recommendation 3-1: Scientific Validity of Intentional Human Dos ing Studies EPA should issue guidelines for determining whether intentional human dosing studies have been: a.
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From page 81... ...
SUMMARY Three principal types of studies involving intentional dosing of research participants with chemicals have been conducted for EPA regulatory purposes: PK studies; PD studies of low-dose, nonadverse effects; and PD studies designed to elicit an adverse but fully reversible effect. The first two types of studies are likely to pose no identifiable risk to study participants or can be scientifically demonstrated to provide a reasonable certainty that no harm will result to them.
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From page 82... ...
1997. An introduction to the use of physiologically based pharmacokinetic models in risk assessment.
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From page 83... ...
1995. Physiologically based pharmacokinetic and phar macodynamic modeling in health risk assessment and characterization of hazardous substances.
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