Animal data

Data from studies in animals according to test guideline methods, particularly if conducted in accordance with principles of GLP, will usually give very good information in order to identify whether a substance would be considered to be, or not to be, corrosive or irritant to the skin or eye in the test species. In general, it is assumed that substances, which are irritant in test guideline studies in animals will be skin and/or eye irritants in humans, and those which are not irritant in test guideline studies will not be irritant in humans. 

There may be a number of skin or eye irritation smdies available for a specific substance, none of which have been performed fully equivalent to a test guideline. If the results from such a batch of studies are consistent, they may, together, provide sufficient information on the skin and/or eye irritation potential of the substance. If the results from such a batch of studies are not consistent, it will be necessary to decide which of the smdies are the most reliable ones. 

Attention should be given to the occurrence of persisting irritating effects. Effects such as erythema, edema. Assuring, scaling, desquamation, hyperplasia, and opacity, which do not reverse within the test period may indicate that a substance will cause persistent damage to the human skin and eye. 

Data from smdies other than skin or eye irritation smdies, e.g., other toxicological smdies on the substance in which local responses of skin, eye, and/or respiratory system were reported, may provide useful information. However, they may not be well reported in relation to, e.g., the basic requirements for information on skin and eye irritation. 

As mentioned previously, there are no test guideline methods for respiratory irritation. Good data, often clearly related to exposure levels, can be obtained on respiratory and mucous membrane irritation, from well-designed and well-reported inhalation studies in animals. Also the Alarie test (Alarie 1973, 1981), an experimental animal test assessing the concentration that results in a 50% reduction of the breathing frequency, may provide useful information on sensory irritation of the upper respiratory tract and the results may be used for hazard identification. 

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Scientific information for the process of establishing OELs may come from human or animal data obtained using different methods, from studies of acute, subacute, and chronic toxicity through various routes of entry. Human data, which is usually the best source, is not easily available, and frequently it is incomplete or inadequate due to poor characterization of exposure and clear dose-response relationships. Human data falls into one of the following categories ... 

Development of subchronic RfDs parallels the development of chronic reference doses in concept the distinction is one of e.xposurc duration. Appropriate studies are evaluated and a subchronic NOAEL is identified. The RfD is derived from the NOAEL by the application of the UFs and MF, as outlined above. When experimental data arc available only for shorter e.xposurc durations than desired, an additional uncertainly factor is applied. This is similar to the application of the uncertainly factor for duration differences when a chronic RfD is estimated from subchronic animal data. On the other hand, if subchronic data are missing and a chronic oral RfD derived from chronic data exists, the chronic oral RfD is adopted as the subchronic oral RfD. Ill this instance, there is no application of an uncertainly factor to account for differences in exposure duration. 

Because the slope factor is often an upper 95 percentile confidence limit of the probability of response based on experimental animal data used in tlie multistage model, tlie carcinogenic risk estimate will generally be an upper-bound estimate. Tliis means tliat tlie EPA is reasonably confident tliat tlie true risk will not exceed the risk estimate derived tlirough use of tliis model and is likely to be less than tliat predicted. 

Source terms for dispersion and other models Uncertainties in effects modeling -Animal data inappropriate for humans (especially for toxicity) Mitigating effects may be omitted... 

The threshold dose of MDMA is 30 mg, but the average dose is 80-150 mg, with some users taking in excess of 200 mg. The lethal dose is estimated (from animal data) to be approximately 6,000 mg. On the street, concentrations of MDMA can vary greatly, and tablets may also contain other substances such as methylenedioxyamphetamine (MDA) and methylenedioxy-ethylamphetamine (MDEA) (Sherlock et al. 1999). The presence of these other substances is often associated with emergency presentations because of their narrower therapeutic windows. 

There are no data on kinetics or metabolism in humans therefore, no conclusions can be drawn as to the relevance of animal data to human metabolism of these compormds. 

Animal data consistently show dibutyltin dichloride to cause dose-dependent developmental toxicity, such as fetal deaths, birth defects, and reductions in fetal weight. 

Although a number of studies have reported the effects of inhalation exposure to methyl parathion in humans, no inhalation MRLs were derived based on human data because of the lack of adequate quantitative exposure information. Animal data were also insufficient to support the derivation of an acute-, intermediate-, or chronic-duration inhalation MRL. 

The chapter covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this chapter. If data are located in the scientific literature, a table of genotoxicity information is included. 

Species The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. 

Musculoskeletal Effects. Very limited data were available regarding the effects of endosulfan on the musculoskeletal system. However, the available animal data did not indicate that this system is adversely affected following either inhalation or oral exposure to endosulfan (FMC 1965, 1967 Hoechst 1984b, 1984c, 1988b, 1989a, 1989c). Thus, persons exposed to endosulfan would not be expected to experience adverse effects on the musculoskeletal system. 

FIGURE 11.2 Loss of flocoumafen residues from quail liver. Depletion of radioactivity from Japanese quail after a single oral dose (14 mg/kg). Data are presented as microgram equivalents of/per gram of tissue and are mean values of two animals. Data collected at day 7 and day 12 were from four animals and three animals, respectively (from Huckle et al. 1989). 

The effects of microsphere size distribution, drug/polymer ratio, and microsphere quality can be easily demonstrated in this laboratory model. Furthermore, as animal data and human clinical trial results are available the model becomes quite useful as a quality control method (46). 

Based on the limited human and animal data, it is not possible to predict whether or not triehloroethylene exposure at levels found in the environment and at hazardous waste sites can result in gastrointestinal effects. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

Steinberg AD, DeSesso JM. 1993. Have animal data been used inappropriately to estimate risks to humans from environmental trichloroethylene Regul Toxieol Pharmacol 18 137-153. 

Uncertainty Eactor (UE) — A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. 

METH-induced changes in neuropeptide levels, selective Dj (SCH 23390) and D2 (sulpiride) dopaminergic receptor antagonists were coadministered. The results are expressed as percent of control to facilitate comparisons each value represents the mean SEM of five to seven animals. Data were subjeeted to either a Student s r-test (figures 4 and 5) or ANOVA analysis followed by a multiple comparisons test (figures 1, 2, and 3). Signifieanee was set at the. 05 level. 

No acute-, intermediate-, or chronic-duration oral MRLs were derived for americium due to the lack of suitable human or animal data regarding health effects following oral exposure to americium. 

The model is based on both human and animal data. However, it is intended for applications to human dosimetry. Applications to other species would require consideration of species-specific adjustments in modal parameters. 

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