Toxicological 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. 

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. 

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. 

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). 

For the derivation of EQSs (and similar benchmarks), experimental toxicity data are considered essential. However, for many substances there will be insufficient reliable toxicity data available to meet the prescribed minimum data requirements. In their absence (or to supplement an existing data set), several extrapolative methods may potentially be of assistance. Nevertheless, we recommend extreme caution when extrapolating from calculated values to predicted real toxicity data. Most suggested calculation methods to supplement missing toxicological data are considered unacceptable in EQS derivation. 

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. 

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. 

The 2 CYPIA proteins have been isolated from the livers of a number of animal species, purified, and shown to share extensive structural similarity and to display similar substrate specificity. The human orthologue of CYP1A2 has been isolated from liver and shown to metabolize the same substrates, and to play the same role in carcinogen activation, as the rodent proteins [9]. The human CYPlAl has not been purified but it has been expressed in mammalian cells like the rodent orthologue, it catalyses the oxidation of polycyclic aromatic hydrocarbons and the N-oxidation of aromatic amines [10]. This apparent similarity in substrate specificity between the human and rodent CYPIA proteins would indicate that where CYPIA is involved, toxicological data can, in principle, be extrapolated to man with more confidence. Of the cytochrome P450 proteins so far characterized, the CYPl family appears to be the most conserved within the phylogenetic tree [11]. 

Such factors may change not only the kinetics of an enzyme reaction but also the whole pattern of metabolism, thereby altering the bioavailability, pharmacokinetics, pharmacological activity, or toxicity of a xenobiotic. Species differences in response to xenobiotics must be considered during the extrapolation of pharmacological and toxicological data from experiments in animals to humans. The primary factors in these differences probably are the rate and pattern of drug and xenobiotic metabolism in the various species. 

This guidance clearly illustrates EPA s preference to base regulatoiy decisions on in vivo rat studies. The rat has been selected not on its predictability to human in vivo absorption but rather on its ability to link to other exposure and toxicology data collected in this species. Dermal absorption data collected using procedures similar to those employed with inhalational or oral gavage studies in rats provide a basis for route-to-route extrapolations. 

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. 

Based on these principles, quantitative and qualitative toxicology data on pesticides are generated from animal studies and extrapolated to sian. The extrapolation, however, is usually not direct and stay include several assumptions. Species susceptibility, species metabolism differences, and extrapolations of dose response relationships below the experimental range should be considered (7 ). In a work situation, the husian body burden is determined by the exposure, absorption, and excretion rates. The same is true in animal studies, although continuous exposure is usually incorporated in the study design. Absorption is usually considered relatively complete. Excretion rates are usually specific to the physico-chemical properties of the chemical and the species however differences in excretion rates are not usually incorporated into extrapolations to man ( ). 

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