Target animal studies

Today, in the United States, the FDA is responsible for examining safety and efficacy data before an antibiotic or synthetic chemical may be commercialized for livestock use. This includes studies on formulations, product stability, conventional and genetic toxicity, environmental safety, metabolism, residue studies in target animals, studies on antibiotic resistance in gut microflora and on salmonella shedding in target animals. Similar requirements are part of registering these products in overseas markets. In general, after a product is discovered in the laboratory, many... 

Clinical trials must be conducted to establish safety in each target animal species which, in the majority of cases, will include food-producing species. Although the same types of animal may be involved in both pre-clinical and clinical trials, dear distinctions can be drawn between each type of study. Pre-clinical studies are only conducted in animals that are kept for the purposes of laboratory research, and that are usually maintained in a very controlled environment. Clinical trials, on the other hand, are conducted in animals that are representative of the normal conditions (field conditions) and purposes for which they are maintained. 

Additional animal studies of trichloroethylene following intermediate-duration oral exposure are necessary to further define dose-response relationships. Because developmental neurotoxicity appears to be a sensitive end point, a focus on this end point would be useful. Animals studies following intermediate-duration dermal exposure are necessary. These studies would indicate whether targets following dermal exposure differ compared to inhalation and oral exposure. 

Animal studies have shown that tumors can result from both inhalation (Fukuda et al. 1983 Henschler et al. 1980 Maltoni et al. 1986) and oral exposure (Aima et al. 1994 Henschler et al. 1984 NCI 1976 NTP 1990) to trichloroethylene. Unfortunately, some of these studies (NCI 1976) are limited in that they use carcinogenic epoxide stabilizers with the trichloroethylene, which may contribute to the carcinogenicity. The studies also show different responses depending on the sex, species, and strains of animals used and do not point to a particular target organ for increased tumor incidence. Other studies are flawed because of excess... 

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. 

There is little new with regard to the mu receptor, the main target for opioid drugs. The receptor is remarkably similar in structure and function in all species studied so animal studies will be good predictors for clinical applications. Although there have been suggestions of subtypes of the receptor, the cloned mu receptors have all been identical. 

The identified human studies and the animal studies did not identify the primary target of toxicity for... 

Polyalphaolefin Hydraulic Fluids. No human studies for polyalphaolefin hydraulic fluids were located. Polyalphaolefin hydraulic fluids are used in U.S. military aircraft hydraulic systems thus, there is a potential for occupational exposure. Animal studies were insufficient for determining the primary targets of toxicity. Epidemiology studies examining a number of end points would be useful for identifying targets of toxicity. 

Since the design of the first targeted polyplexes more than 20 years ago [97, 134], numerous efforts have been made to develop polyplexes for use in medical products, both in pharmacological animal studies and in human studies. Therapeutic modalities include ex vivo treatment of isolated human patient cells, localized in vivo treatments, and - currently the most challenging delivery scenario - in vivo targeted intravenous delivery. 

Hexachloroethane has been found in the plasma of workers wearing protective clothing and respiratory protection suggesting that hexachloroethane can be absorbed following inhalation and/or dermal exposure. Based on the minimal effects seen on target tissues (liver and kidney) in animal studies, absorption from the lungs seems to be limited. Dermal absorption was also estimated to be low based on calculated dermal penetration rates. 

Chronic-Duration Exposure and Cancer. No studies were located in humans following chrome-duration exposure to hexachloroethane for any exposure route. No chronic animal studies were conducted using the inhalation route of exposure. In oral studies with rats, the kidney was identified as a primary target organ in males and females (NTP 1989). The kidney damage in male rats was the result of hyaline droplet nephropathy and, accordingly, was not suitable as the basis for an oral MRL. In contrast to acute- and intermediate-duration oral exposure, liver toxicity was not evident in rats following chronic oral exposure. There were no studies of chronic dermal exposure to hexachloroethane. 

Studies in animals confirm that endrin s main target is the nervous system, probably because the brain and other parts of the nervous system contain much fatty tissue, and endrin tends to stay in those tissues. Birth defects, especially abnormal bone formation, have been seen in some animal studies. While there are no human data on birth defects, evidence in rodents suggests that exposure to high doses of endrin during pregnancy could be a health risk to developing fetuses. 

Intermediate-Duration Exposure.No studies are available on the adverse health effects from intermediate-duration exposure in humans by any route. Studies in animals indicate that exposure to endrin via inhalation can be lethal and causes effects on the nervous and respiratory systems, the liver, the brain, adrenals, and kidneys (Treon et al. 1955). Since systemic effects were observed at levels which caused death, data are not sufficient to derive an intermediate-duration inhalation MRL. Animal studies also demonstrate that oral intermediate-duration exposure can lead to death in several species (rat, mouse, hamster, rabbit, monkeys, cat) (Treon et al. 1955). Endrin was lethal in rabbits following dermal exposure (Treon et al. 1955). No other treatment-related disorders are known. Additional studies for oral and dermal routes using a range of exposure levels would be useful in identifying potential target tissues. 

Since no information is available on adverse health effects of endrin aldehyde or endrin ketone following intermediate-duration exposure by the inhalation, oral, and dermal routes in humans or animals, studies using various dose levels and several animal species are needed to identify potential target tissues. 

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