Intentional Human Dosing Studies for EPA Regulatory Purposes Scientific and Ethical Issues (2004) / Chapter Skim
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7 EPA's Use of Data from Intentional Human Dosing Studies in Risk Assessment
7 EPA's Use of Data from Intentional Human Dosing Studies in Risk Assessment
Pages 144-158
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From page 144... ...
Following that description, the chapter examines the questions of when and how data from intentional dosing studies should be incorporated into EPA's risk-assessment process. The descriptions that follow will show that there is substantial precedent at EPA for using such data in risk assessment; however, although it is important to recognize this historical use, the committee looked beyond precedent to examine anew the questions at hand.
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From page 145... ...
Therefore, decisions to use results from animal studies rest, at least in part, on a "science policy" choice in which results from animal studies are generally assumed to hold for humans unless there is highly convincing evidence to the contrary (NRC, 1983; NRC, 1994) .Taking into account the extensive batteries of animal studies conducted at high doses that are normally required for human risk assessment and the safety factors and conservative assumptions built into the risk-assessment process, this science policy choice generally reflects a cautious stance; but the possibility that animal studies, no matter how complete, may sometimes fail to reveal adverse health effects that are significant for humans cannot be ignored.
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From page 146... ...
. During the 1980s, EPA dropped the use of the term "safety factor" and substituted the concept of "uncertainty factors" (UFs)
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From page 147... ...
Thus, pesticide RfDs derived from animal data generally involve UFA, UFH, and a safety factor to protect children (see Chapter 1)
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From page 148... ...
. IMPLICATIONS OF THE USE OF INTENTIONAL HUMAN DOSING STUDIES IN THE RISK ASSESSMENT PROCESS Assuming that data from a given study meet the criteria for scientific validity and are found to be of adequate quality as demonstrated in Chapter 3, and assuming that they satisfy the ethical requirements described in Chapters 4, 5, and 6, they can be considered for use in risk assessment.
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From page 149... ...
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 150... ...
In general, NOELHU-only studies should not be used for formal risk assessments, unless no other data are available and there is a critical need to develop a tentative risk value. ELIMINATING THE UFA A significant issue arising in connection with the substitution of a NOELHU or LOELHU for a NOAEL derived from an animal experiment concerns the matter of the uncertainty factor to be used.
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From page 151... ...
Replication of study results provides added confidence regarding the sensitivities of the studied populations and the degree to which those populations can be said to represent individuals of average sensitivity, while failure to replicate findings provides a measure of the variability in responses among healthy adult volunteers and a basis for assuring that risks will not be underestimated (because the data from the more sensitive study population would be used for risk assessment)
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From page 152... ...
The need for replication or additional UFs in such circumstances is significantly less compelling than those in which healthy volunteers, not known to have special sensitivities, are the participants in an intentional dosing study. THE CASE OF CHOLINESTERASE INHIBITION EPA's Office of Pesticide Programs has received a body of data from intentional dosing studies in humans sponsored by third parties involving measurements of cholinesterase inhibition induced by certain pesticides (see Chapter 1)
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From page 153... ...
CONCLUSIONS AND RECOMMENDATIONS Data from intentional dosing studies in humans that have been developed using the criteria for scientific and ethical validity elucidated in this report -- and that are shown upon review to be of adequate quality -- can be used within the framework for risk assessment developed by EPA. Use of such data will allow the elimination of the uncertainty factor (UFA)
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From page 154... ...
, and for which it is clear that cholinesterase inhibition is the most sensitive indicator of toxicity, data from intentional human dosing studies may be considered for use in risk assessment. It should be recognized that these circumstances -- in which the most sensitive indicators of toxicity are the acute biological effects of chemicals and in which such effects are readily measurable in ethically acceptable human studies -- are likely to be highly unusual.
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From page 155... ...
Uncertainties regarding these relationships may be dealt with by a requirement for study replication in a different setting or by the use of an uncertainty factor for intraspecies extrapolation (UFH) that is somewhat greater than the usual factor of 10.
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From page 156... ...
For those cholinesterase inhibitors that have been thoroughly investigated in high-quality animal studies (including studies of developmental neurotoxicity) , and for which it is clear that cholinesterase inhibition is the most sensitive indicator of toxicity, data from intentional human dosing studies may be considered for use in risk assessment.
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From page 157... ...
2003. Draft Final Guidelines for Carcinogen Risk Assessment (Ex ternal Review Draft)
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