Extrapolation to humans

A major objective of a toxicological study is to quantify the effects of the suspect toxicant on a target organism. For most toxicological studies animals are used, usually with the hope that the results can be extrapolated to humans. Once the effects of a suspect agent have been quantified, appropriate procedures are established to ensure that the agent is handled properly. 

Immunotoxicology data most often available for use in risk assessment is derived from experimental animal studies. Although animal models provide an opportunity to establish more reliable exposure estimates and conduct more informative tests than human studies, the level of accuracy that can be achieved using such data in extrapolating to humans is often a matter of debate. In immunotoxicology testing, a set of tests usually referred to... 

Because DMPK properties vary among different species, in vitro human and animal data and in vivo animal data cannot always be extrapolated to human in vivo responses. The three main reasons that drugs fail during clinical trials are (1) lack of efficacy, (2) unacceptable adverse effects, and (3) unfavorable ADME properties. Hence, clinical development is necessary to establish solid experiment-based human exposure and safety data through both short- and long-term monitoring. 

Doses should be selected that are reasonable multiples of the proposed therapeutic dose to be employed, especially since in many cases the amount of material available for testing may be limited and not available in Kg amounts. Preclinical rodent or primate studies should merely provide the flags to monitor during Phase I clinical trials. Reason should prevail, not only in the selection of methods and models for assessing the potential toxicity of the new agents, but also in the use of these data for extrapolation to humans. Whether U.S. industry succeeds or fails in the biotechnology arena will depend on the quick resolution of issues such as... 

Data should be extrapolated to humans with caution... 

Used to derive acute inhalation Minimal Risk Level (MRL) of 0.05 ppm (50 ppb) animal dose extrapolated to human dose according to method of EPA (1989d) values of blood/air partition coefficients assumed to be equal for animals and humans dose adjusted for 1 ess-than-continuous exposure (8 hours/24 hours), and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). 

In Vitro Systems. Different biochemical approaches provide a variety of methods for comparing and evaluating fiber toxicity. Organ cultures, cultured cells, and cells in suspension from humans and animals can be exposed to fibrous materials or, alternatively, cells from treated animals, bacterial cells, and so on can be used. Many hundreds of experiments have been performed, but it is difficult to apply the results, and in many cases extrapolation to humans is not warranted. Nevertheless, cell systems provide excellent data on which to base our understanding of the mechanisms related to fiber-induced disease a few selected examples follow. 

Ethylene chlorohydrin is highly irritating to mucous membranes but produces little reaction on contact with rabbit skin. Toxic amounts can be absorbed through the skin without causing dermal irritation the dermal LDso for rabbits is 68 mg/l. This value extrapolated to humans suggests that a volume slightly more than a teaspoon could be lethal with prolonged contact. ... 

Often PK/PD models are developed using classic PK models to describe plasma concentrations, which is often appropriate when P K samples are obtained during the PD assay so that plasma concentrations are most accurately simulated. A PBPK/PD model may be particularly useful when P K data are not available for a given PD assay, when a PD effect is not related to free plasma concentrations but instead is related to the free concentration in a target tissue, orwhena PK/PD model must be extrapolated to humans. 

Search for and validate animal models to analyse toxicological aspects of reproductive biology to develop appropriate systems that are reproducible, low cost and easier to extrapolate to human disease. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular... 

Experimental models. Comparative studies of toxic phenomena are necessary to select the most appropriate model for extrapolation to humans and for testing and development of drugs and biocides. Taxonomic proximity does not necessarily indicate which will be the best experimental animal because in some cases primates are less valuable for study than are other mammals. 

This maximum legal exposure, often referred to as the Theoretical Maximum Residue Contribution, or TMRC, is compared with established toxicological criteria such as the reference dose (RfD) or Acceptable Daily Intake (ADI) which represent, after analysis of animal toxicology data and extrapolations to humans, the daily exposure that is not considered to present any appreciable level of risk. When it is determined that the TMRC exposure is below the RfD or ADI, the EPA usually considers the risks from the pesticide in question to be negligible and approves the manufacturer s petition to establish a tolerance at or slightly greater than the maximum levels identified from the manufacturer s controlled field trials (Winter, 1992a). 

Estimates of responses at low doses derived from data on laboratory animals and extrapolated to humans are complicated by a variety of factors that differ among species and potentially affect the response to hazardous chemicals. These factors include differences between humans and experimental test animals with respect to life span, body size, genetic variability, population homogeneity, existence of concurrent disease, such pharmacokinetic effects as metabolism and excretion patterns, and the dosing regimen. These factors are discussed further in Section 3.2.1.5. 

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