Toxicity animal data extrapolation

The interindividual variability reflects differences in toxicokinetics as well as in toxicodynamics. With respect to toxicokinetic factors, interindividual differences in the metabolism of chemicals are generally considered as the most significant explanatory factor. Hardly any knowledge is available with respect to the factors that influence toxicodynamics. Thus, it is necessary to take such variation into account when extrapolating animal toxicity data to the human simation. 

Vocci, F. and T. Farber. 1988. Extrapolation of animal toxicity data to man. Regul. Toxicol. Pharmacol. 8 389-398. 

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

Because human pharmacokinetic data are often minimal, absorption data from studies of experimental animals-by any relevant route of exposure-might assist those who must apply animal toxicity data to risk assessment. Results of a dermal developmental toxicity study that shows no adverse developmental effects are potentially misleading if uptake through the skin is not documented. Such a study would be insufficient for risk assessment, especially if it were interpreted as a negative study (one that showed no adverse effect). In studies where developmental toxicity is detected, regardless of the route of exposure, skin absorption data can be used to establish the internal dose in the pregnant animal for risk extrapolation to human dermal exposure. For a discussion pertinent both to the development and to the application of pharmacokinetic data, risk assessors can consult the conclusions of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies (Kimmel and Francis 1990). 

Howe, R.B., K.S. Crump, and C. Van Landingham. 1986. GLOBAL86 A Computer Program to Extrapolate Quantal Animal Toxicity Data to Low Doses. Subcontract No. 2-251U-2745. Prepared for U.S. Environmental Protection Agency, Washington, DC. 

This example illustrates two important points. First, malathion is a selectively toxic compound in that it kills insects without harming humans. Second, different species may metabolise drugs in different ways and extreme care must be exercised when extrapolating results from one species to another, notably from animal toxicity data to humans. 

Verification of Uncertainty Factors. As summarized in several publications, uncertainty factors are currently recommended to estimate acceptable intakes for systemic toxicants (1,13,18). The selection of these factors in general reflects the uncertainty inherent with the use of different human or animal toxicity data (i.e., the weight of evidence plays a major role in the selection of uncertainty factors). For example, an uncertainty factor of less than 10 and perhaps even 1 may be used to estimate an ADI if sufficient data of chronic duration are available on a chemical s critical toxic effect in a known sensitive human population. That is to say that this ideal data base is sufficiently predictive of the population threshold dose therefore, uncertainty factors are not warranted. An overall uncertainty factor of 10 might be used to estimate an acceptable intake based on chronic human toxicity data and would reflect the expected intraspecies variability to the adverse effects of a chemical in the absence of chemical-specific data. An overall uncertainty factor of 100 might be used to estimate ADIs with sufficient chronic animal toxicity data this would reflect the expected intra- and interspecies variability in lieu of chemical-specific data. However, this overall factor of 100 might be used with subchronic human data in this case the 100-fold factor would reflect intraspecies variability and a subchronic exposure extrapolation. 

Turesky, R.J. (2005) Interspecies metabolism of heterocyclic aromatic amines and the uncertainties in extrapolation of animal toxicity data for human risk assessment. Mol. Nutr. 

The reference dose (RfD) assumes there is a threshold of exposure below which a chemical does not produce a toxic effect because the body is able to detoxify and/or eliminate it. The reference dose is derived either from a no observed adverse effect level (NOAEL) or from a benchmark dose (BMD) determined in an animal toxicity study. The NOAEL or BMD is divided by at least two uncertainty factors or safety factors a factor of 10 to account for the uncertainty involved in extrapolating from animals to humans, and a second factor of 10 to account for variation in human sensitivity. If the animal toxicity data supporting the NOAEL or BMD are not definitive, a third safety factor of 10 is included. Thus, the RfD is set equal to the NOAEL or BMD divided by 100 alternatively, it is set equal to a number approximating the NOAEL or BMD divided by 1,000. The acceptable daily intake (ADI) is the same as the reference dose. The reference concentration (RfG) refers to the concentration of a pollutant in the air. It differs from the... 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmocokinetic data on tissue doses are considered for interspecies extrapolation. 

This rule holds reasonably well when C or t varies within a narrow range for acute exposure to a gaseous compound (Rinehart and Hatch, 1964) and for chronic exposure to an inert particle (Henderson et al., 1991). Excursion of C or / beyond these limits will cause the assumption Ct = K to be incorrect (Adams et al., 1950, 1952 Sidorenko and Pinigin, 1976 Andersen et al., 1979 Uemitsu et al., 1985). For example, an animal may be exposed to 1000 ppm of diethyl ether for 420 min or 1400 ppm for 300 min without incurring any anesthesia. However, exposure to 420,000 ppm for lmin will surely cause anesthesia or even death of the animal. Furthermore, toxicokinetic study of fiver enzymes affected by inhalation of carbon tetrachloride (Uemitsu et al., 1985), which has a saturable metabolism in rats, showed that Ct = K does not correctly reflect the toxicity value of this compound. Therefore, the limitations of Haber s rule must be recognized when it is used in interpolation or extrapolation of inhalation toxicity data. 

Intermediate-duration oral studies in humans for mirex are lacking. A review of the animal oral intermediate toxicity data for mirex indicates that the available studies are not adequate to derive intermediate oral MRL for mirex. The most suitable study provides a LOAEL of 0.25 mg/kg/day for endocrine effects-dilation of rough endoplasmic reticulum cisternae of the thyroid of weanling Sprague-Dawley rats (Singh et al. 1985). Adjusting the LOAEL of 0.25 mg/kg/day determined from this study with a total uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for animal to human extrapolation, and 10 for interspecies variability) yields an intermediate oral MRL of 0.0003 mg/kg/day, which is lower than the chronic-duration oral MRL of 0.0008 mg/kg/day derived from an NTP (1990) study in rats (see chronic-duration MRL). Therefore, no oral intermediateduration MRL was developed for mirex. 

No information is available on acute oral exposure of humans or animals to bromomethane. Extrapolation from acute inhalation data is probably not appropriate, since some of the effects (both inhalation and oral) are due to point-of-contact irritation. However, acute oral toxicity studies are probably not essential, since oral exposure of humans to acutely toxic levels of bromomethane is not likely to occur due to the high volatility of the compound. 

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. 

The reader is advised to exercise caution in the extrapolation of toxicity data from animals to humans. Species-related differences in sensitivity must be accounted for. Some studies utilized to derive MRLs or otherwise extrapolate data, is dated however, they do represent the body of knowledge regarding chloroform toxicity. In addition, many of the human studies quoted involved clinical case reports in which chloroform was utilized either as an anesthetic or as an agent of suicide. Such doses are clearly excessive and would not be encountered by the general population. These and other issues are addressed in Section 2.10. 

Data from studies in experimental animals are the typical starting points for hazard and risk assessments of chemical substances and thus differences in sensitivity between experimental animals and humans need to be addressed, with the default assumption that humans are more sensitive than experimental animals. The rationale for extrapolation of toxicity data across species is founded in the commonality of anatomic characteristics and the universality of physiological functions and biochemical reactions, despite the great diversity of sizes, shapes, and forms of mammalian species. 

Extrapolation of data from studies in experimental animals to the human situation involves two steps a first step is to adjust the dose levels applied in the experimental animal studies to human equivalent dose levels, i.e., a correction for differences in body size between laboratory animals and humans. A second step involves the application of an assessment factor to compensate for uncertainties inherent in toxicity data as well as the mterspecies variation in biological susceptibility. These two steps are addressed in the following sections. 

The TGD has noted that in practice, relevant data on kinetics and metabolism, especially after dermal and inhalation exposure, are frequently missing. As a consequence, corrections can only be made for differences in bioavailability. There are some pragmatic approaches in order to calculate a NAEL (or LAEL) by extrapolation, when specific data are not available. The methods described are for extrapolating from oral toxicity data since this is the route most often used for repeated dose toxicity studies in animals. The TGD emphasized that it should be noted that insight into the reliability of the current methodologies for route-to-route extrapolation has not been obtained yet, with a reference to the smdy performed by WUschut et al. (1998), see above. 

Extrapolations of therapeutic index and toxicity data from animals to humans are reasonably predictive for many but not for all toxicities. Seeking an improved process, a Predictive Safety Testing Consortium of five of America s largest pharmaceutical companies with an advisory role by the Food and Drug Administration (FDA) has been formed to share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans. In 2007, this group presented to the FDA a set of biomarkers for early kidney damage. 

A weight of evidence approach to assessing reproductive toxicity requires rigorous evaluation of all available data. However, often only limited information is available, and default assumptions must be made because of uncertainties in understanding mechanisms, dose-response relationships at low dose levels and human exposure patterns. Several of these assumptions are basic to the extrapolation of toxicity data from animals to humans, while others are specific to reproductive toxicity. The general default assumptions for reproductive toxicity stated in the IPCS (1995) report are summarized as follows ... 

Human toxicity data, especially the median lethal dose, is extrapolated from animals or from accidental poisoning, homicides and suicides. Extrapolations from animal data are educated estimates which consider the differences in species and building in a safety factor. If a lethal dose is 10 mg/kg in a rat and we consider a human to be 10 times more sensitive 1 mg/kg will have another 10-fold safety margin. Animal testing also involves using what may seem as ridiculous doses in order to cover the safety factor. To find a statistically valid effect which occurs once in one million subjects, several million animals would have to be used, which is exhorbitantly... 

Extrapolation of toxicity data from animals to humans is not completely reliable. For any given compound, the total toxicity data from all species have a very high predictive value for its toxicity in humans. However, there are limitations on the amount of information it is practical to obtain. 

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