Drinking Water and Health, Volume 8 Pharmacokinetics in Risk Assessment (1987) / Chapter Skim
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I. Introduction: The Problem and an Approach
I. Introduction: The Problem and an Approach
Pages 1-24
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DART I ntroduction : The Problem and an Approach
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The general approach toward that goal developed over time, but it was to be characterized roughly by processes that involved the development of some form of human dosage versus response relationships for undesirable health effects, the assessment of risk for those effects under specified modes of exposure to the chemical in question, and finally, the setting of permissible exposure limits for the chemical in various exposure situations based on some form of societal perception of acceptable risk. To set this chain of procedures into action, it was first necessary to generate some form of trustworthy picture of dosage versus response for the most serious or most sensitive health effect that a chemical might produce in a human target.
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The risk assessment process, therefore, beginning roughly in the 1930s, took the form of an initial review of the epidemiological health effects data available for a given chemical in worker and user populations and of the dose versus response data generated in test animal systems. Somehow, usually by deliberations of a committee of specialists in the health sciences, the body of epidemiological and animal toxicological data for the chemical was assessed for scope and reliability, and then interpreted in terms of the most probable form for the dosage versus response relationship for each serious health effect in the human as a general target.
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For example, at times in the last two decades, total safety factors of 2,000 or 3,000 have been mentioned as being applicable to the apparent NOEL for tumorigenesis in a chronic animal bioassay of a chemical in converting to an estimate of a NOEL for tumorigenesis in human populations. It should be noted that the simplistic form of risk assessment considered up to this point was always generated singly, chemical by chemical, and was also viewed as a prediction that should be validated or rejected as additional animal and human dose versus response data for a chemical were developed.
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4. The fitted equation of the modeler's choice is then used to extrapolate from the high-dose region of animal administered dose versus response down to theoretical response levels at a very low dose.
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All of these points have been well recognized and discussed in the 1970-1986 time frame by scientists concerned with making quantitative risk assessment more meaningful and sound. Therefore, the need has been recognized for moving quantitative risk assessment to a more realistic dimension, particularly by the use of data from metabolic and comparative pharmacokinetic studies of a given chemical which, when combined with chronic bioassay data from animal experiments, can lead to knowledge about the active chemical species that reaches specific target tissues at measurable delivered concentrations (as a function of time)
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Andersen I NTRODUCTION The overall risk assessment process integrates hazard assessment data on chemical toxicity with exposure assessment information (Figure 11. Hazard assessment is the process by which the toxicity of a chemical is determined either by a series of bioassay experiments with intact test animals or by observing increased morbidity/mortality in exposed humans.
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Pharmacokinetic modeling is useful in hazard assessment where it can aid in estimating realistic measures of target tissue dose in exposed animals and be used to support extrapolations to estimate tissue dose in humans. Basically, there seem to be two fundamental assumptions which toxicologists are forced to make in attempting quantitative extrapolations based on animal toxicity experiments.
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With this type of interaction the expected degree of damage, as loss of cellular constituents or accumulation of bound reactive intermediate, should be related to the time integral of tissue exposure to the reactive chemical. This time integral of tissue exposure is also called the area under the tissue concentration curve for the reactive chemical.
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TR + R (T) + K FIGURE 2 Tissue dose metrics and their relation to toxicity.
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ANDERSEN WHAT ARE SOME MEASURES OF TISSUE DOSE ? AUTC PARENT CHEMICAL AUTC STABLE METABOLITE TISSUE CONCENTRATION PARENT TISSUE CONCENTRATION METABOLITE - AUTC REACTIVE METABOLITE AUTC: AREA UNDER TISSUE CURVE FIGURE 3 Some potential tissue dose metrics for toxic chemicals.
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Hazard assessment calculations for human exposures are subsequently conducted based on the expected human target tissue exposures under various exposure conditions. In work in our laboratory in Dayton, Ohio, developing pharmacokinetic models for use in chemical risk assessments, we have relied heavily on use of so-called physiologically based pharmacokinetic models PB-PK models (see H
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A successful model can then be used as an integral part of the hazard assessment process. The take-home lesson here is that pharmacokinetic modeling is not some kneejerk process where the investigator collects blood time course curves and draws limited inferences about the behavior of the chemical in the body by an abstract mathematical curvefitting procedure.
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literature can be helpful for model definition, for drawing conclusions about the nature of appropriate measures of tissue dose, and for providing limited PK information, but it is also replete with experiments which are virtually useless for hazard assessment. If a new approach, such as PBPK modeling, is proposed as an adjunct to existing hazard assessment techniques, it will have data requirements of its own and require some independent experimentation not previously conducted on a routine basis for each chemical for which a risk assessment was planned.
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Genotoxic chemical carcinogens themselves can be further subdivided on the basis of whether parent chemical or a metabolite is the moiety that reacts with DNA. The possibilities include cases where parent chemicals, such as ethylene oxide or dimethylsulfate, are genotoxic; cases where stable metabolites, such as ethylene oxide formed from ethylene or butadiene epoxides formed from butadiene, are genotoxic; and cases where reactive, nonisolatable metabolites, such as the epoxide formed from vinyl chloride or the chloromethylgluthathione formed from methylene chloride, are presumed to be responsible for genotoxicity (Figure 51.
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Thus, equivalent doses on a body weight basis are expected to produce approximately equal tissue exposures expressed as area under the tissue curve of the genotoxic, stable metabolite. This suggests that larger animals should be at the same risk from equivalent doses of these chemicals as smaller animals.
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When reactive metabolites are associated with carcinogenicity, the simplified pharmacokinetic analysis of the effect of animal size on integrated tissue exposure suggests that larger species will be at proportionately less risk than smaller species (National Research Council, 19861. The reason for this dependence is that metabolic production (the numerator)
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In fact, it is essential to have an adequate understanding of the pharmacokinetic characteristics of target tissue exposure before pharmacodynamic models are developed for any kind of toxic response. The mechanisms of carcinogenicity of directly acting genotoxic chemicals are still under active investigation in terms of fundamental questions about the nature of DNA adducts formed, rates of repair of damaged DNA, the presence of critical mutational sites on DNA, etc.
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PK models will have to be developed to link tissue exposure, cell toxicity, enzyme induction, and changes in cell growth kinetics. These coupled PK and pharmacodynamic models of the cancer process should greatly improve cancer risk assessment for most chemical carcinogens.
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This latter metric of tissue dose is dependent on mass action principles and not simply on integrated tissue exposure. Measures of dose related simply to administered dose or total amount metabolized should be viewed with great caution unless there are compelling reasons for believing there is a direct correlation of these very coarse measures of dose with actual tissue exposure.
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1983. Physiologically-based pharmacokinetic modeling: Principles and applications.
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