Extrapolation of Toxicity Values from Animals to Humans

Extrapolation of Toxicity Values from Animals to Humans... 

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. 

Determination of LC50 value provides an estimate of a chemical s relative toxicity by inhalation. Extrapolation of the LC50 values and the results of acute toxicity studies from animals to humans is valid only to limited degrees. The results of acute inhalation toxicity tests may be summarized in tabular form. They should include all important aspects of the test, as in the case of acute oral toxicity studies. 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

The inhalation RfD is derived from the NOAEL by applying uncertainty factors similar to those listed above for oral RfDs. A UF of 10 is used when extrapolating from animals to humans in addition to the calculation of the human equivalent dose, to account for interspecific variability in scnsiti ity to the toxicant. The resulting RfD value for inhalation exposure is generally reported as a concentration in air in nig/m for continuous, 24 hour/day exposure, although it may be reported as a corresponding inhaled intake (in mg/kg-day). A human body weight of 70 kg and an inhalation rate of 20 m /day are used to convert between an inhaled intake expressed in units of mg/kg-day and a concentration in air expressed in mg/ni. ... 

Agent HD (Sulfur Mustard). RfDe = 7 x 10 mg kg d. A LOiAEL was identified in a two-generation reproductive toxicity study conducted in rats. A total uncertainty factor of 3000 was applied to account for protection of sensitive subpopulations (10), animal-to-human extrapolation (10), LOAEL-to-NOAEL extrapolation (3), and extrapolation from a subchronic to chronic exposure (10). A LOAEL-to-NOAEL UF of 3, instead of the default value of 10, was used because the critical effect (stomach lesions) was considered to be mild in severity and may have been enhanced by the vehicle used (sesame oil in which sulfur mustard is fully soluble) and the route of administration (gavage), which is more likely to result in localized irritant effects. The key study did identify a toxic effect that is consistent with the vesicant properties of sulfur mustard. In none of the other available studies was there any indication of a different effect occurring at a lower exposure level. 

This calculation indicates that the human dose to produce a similar level of effect would not be substantially different from that in sheep. Considered together with the blood ChE activity and toxicity values mentioned above, the evidence is considered sufficient to support the use of an Uncertainty Factor of 1 for animal-to-human extrapolation. 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

The iCp and percentage absorbed values presented in the literature for various substances have been generated from both in vivo and in vitro studies using a wide range of experimental techniques. Studies on human subjects are costly, experimental conditions are more difficult to control and ethical constraints may rule out testing of toxic compounds. If percutaneous data are obtained using animal studies, this presents a number of difficulties associated with the extrapolation of animal data to humans, e.g. animal species variation, different sites of application, differences between shaved versus unshaved skin and differences in skin metabolism. 

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