Animal toxicology data, extrapolation

There are many circumstances in which the only information we can develop on toxic hazards and dose-response relationships derives from experiments on laboratory animals. The example of the food additive, presented in the opening pages, is just one of many circumstances in which condition A involves animal toxicology data, and condition B involves a human population, almost always exposed at small fractions of the dose used in animals, and sometimes exposed for much larger fractions of their lifetime than the animals, and even by different routes. Extrapolations under these circumstances should cause individuals trained in the rigors of the scientific method to seek some form of psychological counsel, or, better yet, to return to the laboratory. 

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). 

The extrapolation of animal toxicology data and combination with human exposure data aiay be used to estimate risk for those situations where exposure is likely. Methods for integrating these data as well as the assumptions for extrapolation from the animal studies are dependent upon the safety data. Risk assessment includes consideration of the type of toxicity involved and its potency, species comparisons, time considerations, dose response, kinetics of homeostatic mechanisms, and mechanisms of toxicity. When the essential components for extrapolations are well understood, more precise estimates can be made. In the absence of such understanding, more conservative approaches are appropriate. 

The extrapolation of animal toxicological data to man is always tenuous, but for obvious reasons, animal test models are necessarily used. Unfortunately, there is no single animal model in which effects perfectly correlate with toxicity in children some slippage is bound to occur in comparisons between the results of animal and clinical or human studies. 

There is a clear need to study the effect of brief and prolonged urban air particulate inhalation on healthy and diseased animals to investigate mechanisms of particulate-enhanced infectious and allergic lung disease. These experiments will require better animal models of human disease, as well as improved engineering teclmiques to either harness or create realistic pollution episodes. Finally, in vitro comparisons of human and animal cells will provide a rational basis for extrapolating from animal toxicology data to potential health effects in humans. 

On the basis of the foregoing discussion, it appears that, if traditional criteria for hazard evaluation are applied to the toxicologic data on experimental animals, there is little room for complacency r arding current ambient concentrations of ozone. Functional, biochemical, and structural effects in both pulmonary and extrapulmonary sterns have been reported by numerous investigators at or near concentrations that are at least occasionally achieved in some polluted urban centers. Unfortunately, there are no adequate methods for extrapolating data to obtain reliable quantitative estimates of population risk at environmental concentrations near the standard, and there is no assurance that the risk is zero. 

Many other extrapolation techniques have been used in manipulation of animal lethality data in an effort to generate a reasonable human estimate. By taking a conservative approach with data on deaths at low doses, one can derive estimates for man that are modest and in keeping with clinical judgement. Such methods depend on procedures developed and applied in toxicology. 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

The similarities in response of humans and experimental animals to similar body burdens of CDDs and related chemicals (Table 2-10), along with our understanding of common mechanisms of actions of CDDs in humans and experimental animals lends support to both the relevance of experimental animal toxicology to humans and the use of experimental animal data for establishing MRLs (see Section 2.4.3 for more information on the animal-to-human extrapolations). Acute, intermediate and chronic MRLs for... 

The Cramer classification scheme can be used to make a threshold of toxicological concern (TTC) estimation. TTC is a concept that aims to establish a level of exposure for all chemicals below which there would be no appreciable risk to human health the threshold is based on a statistical analysis of the toxicological data from a broad range of different and/or structurally related chemicals and on the extrapolation of the underlying animal data to a no-effect dose considered to represent a negligible risk to human health. 

Basic problems of animal-to-human extrapolation are in the OTA s report (op. cit.) and comprehensively treated in Edward Calabrese, Principles of Animal Extrapolation (John Wiley and Sons New York, 1983). The particular problem of extrapolation of teratology data from animals to humans is concisely discussed by V. Frankos in his paper FDA perspectives in the use of teratology data for human risk assessment (Fundamental and Applied Toxicology, Vol. 5, 1985, pp 615-25). 

If no estimated human oral toxicological data were available, the Army used an uncertainty factor of 10 for interspecies extrapolation from animals to human (NAS, 1995). This same methodology was used to establish the human LD50 for T-2 toxin, because there has not been an estimated human LD50 by the oral route. 

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