Experimental Animal Toxicity Data

TABLE 2 8 Experimental Animal Toxicity Data, Exposure to Ammonia... 

Therefore in practice, normally, animal toxicity data is required (see above). Of course, the differences between humans and other species must always be recognized and taken into account (see below). It may be possible to use in vitro data both from human cells and tissues as well as those from other animals to supplement the epidemiological and animal in vivo toxicity data. However, at present such data cannot replace experimental animal or human epidemiological data. The predictive use of structure-activity relationships is also possible, and it is an approach, which is becoming increasingly important. 

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. 

Chemical data (e.g., physical and chemical properties, structureactivity relationships, and environmental fate and transport), basic toxicity data, and pharmacokinetic data (information on absorption, distribution (including placental and lactational transfer), metabolism, and excretion) should be reviewed. These data are particularly important because reproductive and developmental effects are interpreted in the context of general toxicity data in humans or experimental animals. Pharmacokinetic data for both animals and humans can be helpful in extrapolating exposure levels from one species to another. 

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). 

Has produced liver and kidney injury in experimental animals. Mutation data reported. Sometimes thought to be nonflammable, however, it is a dangerous fire hazard when exposed to heat or flame. Reaction with solid caustic alkalies or their concentrated solutions produces chloracetylene gas, which ignites spontaneously in air. Reacts violently with N2O4, KOH, Na, NaOH. Moderate explosion hazard in the form of vapor when exposed to flame. Can react vigorously with oxidizing materials. To fight fire, use water spray, foam, CO2, dr) chemical. When heated to decomposition it emits toxic fumes of Cl . See also VINYLIDENE CHLORIDE and CHLORINATED HYDROCARBONS, ALIPHATIC. 

No human toxicity data are available for azamethiphos. For experimental animals, toxicity is low for a single oral dose. Prolonged skin exposure may cause skin irritation. Ocular contact may cause eye irritation and pain. 

Cr(III) that occur in blood plasma, but there are no data at the present time to support or refute this possibility. The kinetics of biologically active Cr(III) would not be expected to have a detectable impact on the kinetics of total chromium at the typical total chromium doses given in experimental animal toxicity studies. However, the essentiality of chromium is an important consideration in the development of a global understanding of chromium kinetics and toxicity. 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

The effects of endosulfan have not been studied in children, but they would likely experience the same health effects seen in adults exposed to endosulfan. Data in adults, mostly derived from cases of accidental or intentional acute exposure (ingestion) to large amounts of endosulfan, indicate that the primary target of endosulfan toxicity is the nervous system. The effects are manifested as hyperactivity and convulsions and in some cases have resulted in death (Aleksandrowicz 1979 Blanco-Coronado et al. 1992 Boereboom et al. 1998 Cable and Doherty 1999 Lo et al. 1995 Terziev et al. 1974). These effects have been reproduced in experimental animals. 

The data in animals are insufficient to derive an acute inhalation MRL because serious effects were observed at the lowest dose tested (Hoechst 1983a). No acute oral MRL was derived for the same reason. The available toxicokinetic data are not adequate to predict the behavior of endosulfan across routes of exposure. However, the limited toxicity information available does indicate that similar effects are observed (i.e., death, neurotoxicity) in both animals and humans across all routes of exposure, but the concentrations that cause these effects may not be predictable for all routes. Most of the acute effects of endosulfan have been well characterized following exposure via the inhalation, oral, and dermal routes in experimental animals, and additional information on the acute effects of endosulfan does not appear necessary. However, further well conducted developmental studies may clarify whether this chemical causes adverse developmental effects. 

---