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M Dourson

Publications and source records attributed to M Dourson.

7 recordsLinked to original sources
PubMed2002

Guidelines for application of chemical-specific adjustment factors in dose/concentration-response assessment.

This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

Algorithms↗
PubMed2001

Use of human data for the derivation of a reference dose for chlorpyrifos.

In 1998 a panel of experts met to discuss the data available on chlorpyrifos, both human and animal, and to determine the most appropriate endpoints to be used for the derivation of the reference dose (RfD). Since that time, additional data have become available on chlorpyrifos from an experimental study involving humans. Moreover, Food Quality Protection Act (FQPA) considerations need to be addressed, and the appropriate cholinesterase endpoint, whether plasma, red blood cell, peripheral nerve, or brain, has become highly debated. Therefore, Dow AgroSciences, one of the manufacturers of chlorpyrifos, convened a second panel of toxicology and medical experts on June 21, 1999, to consider the presently available scientific literature both published and unpublished on chlorpyrifos and to determine the acute and chronic toxicological RfDs for chlorpyrifos. Four questions were posed to this second panel of experts concerning the available data on chlorpyrifos. (1) Should the RfD for chlorpyrifos be based on acetylcholinesterase (AChE) inhibition or butyrylcholinesterase (BuChE) inhibition as an endpoint for adverse effect? (2) Should the RfDs for chlorpyrifos be based on the data set from three human studies, which are supported by animal data? (3) Should the FQPA safety factor be reduced to 1xbased on animal studies of pre- or postnatal toxicity? (4) If an RfD for chlorpyrifos were to be based on animal data, then is a 10-fold interspecies uncertainty factor necessary? The panel of experts concluded that: (1) inhibition of BuChE is not an adverse effect, and the RfD for chlorpyrifos should be based on AChE inhibition; (2) the RfD for chlorpyrifos should be based on the three available human studies, which are also supported by animal data; (3) the extra FQPA safety factor should be reduced to 1x, because chlorpyrifos shows no pre- or postnatal toxicity of concern at relevant human exposure conditions; and (4) the extra 10-fold safety factor for interspecies variation appears overly conservative because no differences in species sensitivity to chlorpyrifos is evident.

Acetylcholinesterase↗
PubMed1998

Boron tolerable intake: re-evaluation of toxicokinetics for data-derived uncertainty factors.

Boron, which is ubiquitous in the environment, causes developmental and reproductive effects in experimental animals. This observation has led to efforts to establish a Tolerable Intake value for boron. Although risk assessors agree on the use of fetal weight decreases observed in rats as an appropriate critical effect, consensus on the adequacy of toxicokinetic data as a basis for replacement of default uncertainty factors remains to be reached. A critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values. The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3- to 4-fold higher in rats than in humans and data on dynamic differences--in order to modify the default value--are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Additional studies to investigate the toxicokinetics of boron in rats would be useful to provide a stronger basis for replacement of default uncertainty factors for interspecies variation.

Animals↗
PubMed1995

Holistic risk assessment: an emerging process for environmental decisions.

A holistic risk assessment (HRA) strategy is proposed as an alternative, inclusive paradigm which builds upon the traditional risk assessment process described by the National Academy of Sciences. This proposed process expands beyond the traditional process in that it: (i) includes parallel and integrated assessments for ecological risk and human health risks; (ii) recognizes the presence of competing risks that may arise from implementation of risk management decisions; (iii) is an iterative and nonsequential process that highlights the importance of risk characterization and the need for comparisons; (iv) has focus on presenting a series of risk choices that take into consideration parameters specific to exposed populations and ecosystems; and (v) involves communication as the first step between risk assessors and risk managers, with subsequent communication of the results of the assessment to clients and the public. This HRA strategy is illustrated by a case study on methyl mercury. Specific research is proposed for future improvements in this area.

Animals↗
PubMed1988

Reference dose (RfD): description and use in health risk assessments.

For many years the concept of the "acceptable daily intake" has served the toxicological and regulatory fields quite well. However, as approaches to assessing the health significance of exposures to noncarcinogenic substances receive greater scrutiny, some difficulties with this traditional approach have become more apparent. Consequently, the concept of the "reference dose" is introduced in order to avoid use of prejudicial terms (e.g., "safety" and "acceptable"), to promote greater consistency in the assessment of noncarcinogenic chemicals, and to maintain the functional separation between risk assessment and risk management.

Animals↗
PubMedDate not supplied

Mathematical modelling and quantitative methods.

The present review reports on the mathematical methods and statistical techniques presently available for hazard characterisation. The state of the art of mathematical modelling and quantitative methods used currently for regulatory decision-making in Europe and additional potential methods for risk assessment of chemicals in food and diet are described. Existing practices of JECFA, FDA, EPA, etc., are examined for their similarities and differences. A framework is established for the development of new and improved quantitative methodologies. Areas for refinement, improvement and increase of efficiency of each method are identified in a gap analysis. Based on this critical evaluation, needs for future research are defined. It is concluded from our work that mathematical modelling of the dose-response relationship would improve the risk assessment process. An adequate characterisation of the dose-response relationship by mathematical modelling clearly requires the use of a sufficient number of dose groups to achieve a range of different response levels. This need not necessarily lead to an increase in the total number of animals in the study if an appropriate design is used. Chemical-specific data relating to the mode or mechanism of action and/or the toxicokinetics of the chemical should be used for dose-response characterisation whenever possible. It is concluded that a single method of hazard characterisation would not be suitable for all kinds of risk assessments, and that a range of different approaches is necessary so that the method used is the most appropriate for the data available and for the risk characterisation issue. Future refinements to dose-response characterisation should incorporate more clearly the extent of uncertainty and variability in the resulting output.

Animals↗