Toxicity, evaluation animal

As with absorption and distribution, the nature and rate of metabolic transformations vary among individuals and different animal species. Metabolism differences can be extreme, and may be the most important factor accounting for differences in response to chemical toxicity among animal species and individuals within a species. The more understanding toxicologists acquire of metabolism, the more they shall understand the range of responses exhibited by different species and individuals, and the better they shall be able to evaluate toxic risks to humans. 

Potential new drugs that show acceptable toxicity in animals are usually first tested in healthy human volunteers before being investigated in patients. Chapters 3-6 deal with these aspects of new drug development, and it is the purpose of this chapter to consider how safety should be evaluated at the time of the product licence application and in the post-marketing phase. 

The first step in risk assessment is to gather health-related information associated with an exposure. Ideally, hazard identification starts before there is significant use of the agent. The structure of the compound is compared with that of compounds with known toxicity profiles. Cell-based studies are often performed to screen for toxicity. Finally, animal bioassays and human studies are performed to characterize and develop a toxicity profile. Multiple health-related endpoints are evaluated to determine if the compound is associated with adverse effects. Advantages of animal studies include experimental control and accurate knowledge of the dose. 

No studies were located regarding developmental effects of diazinon in humans after oral exposure. Laboratory animal studies with mice provide evidence that exposure to diazinon via mother s milk does not result in neonatal toxicity. Results of toxicity evaluation in rats, mice, hamsters, and rabbits also... 

There are many different examples of species differences in the toxicity of foreign compounds, some of which are commercially useful to man, as in the case of pesticides and antibiotic drugs where there is exploitation of selective toxicity. Species differences in toxicity are often related to differences in the metabolism and disposition of a compound, and an understanding of such differences is extremely important in the safety evaluation of compounds in relation to the extrapolation of toxicity from animals to man and hence risk assessment. 

MDPEA was one of the seven compounds evaluated as to toxicity and animal behavic he University of Michigan under contract from the Army Chemical Cente. Edge wood Arsenal code number was EA-1297. The number... 

The toxicity evaluations of the various compounds were carried out on various animals. The most common test was the LD50 (the dose needed to produce the death of 50% of all tested animals) orally in rats. Cases where other animals or other conditions were applied, will be so noted. 

It is important to use different doses of a chemical or drug to evaluate chemical safety vis-a-vis skin toxicity. Dose levels to be tested for acute dermal toxicity in animals should be sufficient in number, (e.g., three or more and spaced appropriately to produce test groups with a range of toxic effects and mortality rates). The data should permit an acceptable determination of LD50. 

Toxicology studies are conducted to define the safety profile of a candidate and include definition of the no-toxic-effect dose, MTD, potential organs of toxicity, and potential biochemical markers to detect and track toxic events. Most developmental compounds that do not become therapeutic products have unacceptable toxicity in animals or humans. Before the definitive toxicology studies needed to support an IND submission are initiated, a number of animal experiments can be conducted to characterize the potential toxicity of the candidate. These early toxicology evaluations are usually conducted in the same species as used in pharmacology evaluations. As mentioned earlier, the lowest dose that has no toxicity or an acceptable level of toxicity is compared with the dose that gives the desired pharmacologic response in the same animal species to obtain a therapeutic ratio or index for that species. 

Additional studies on chlorine toxicity in animals and, possibly, on human volunteers are needed to better define the health effects of chlorine gas exposure at 0.5-5 ppm, 24 h/d up to 7-10 d. Long-term exposure data for humans and animals is needed to approximate a disabled submarine situation. These studies should include evaluation of short-term effects on pulmonary function and long term effects such as pulmonary fibrosis. As is the case for all irritant toxic gases reviewed in this report. 

When assessing manifestations of toxicity, evaluators might base their conclusions about relevance on the mechanism that produces a toxicological effect however, a basic default assumption is that any manifestation of reproductive or developmental toxicity is relevant to humans unless the mechanism by which it occurs is impossible in humans. For example, if a toxic effect occurs in animals through an inhibition of folic acid synthesis, that effect would not be considered relevant for humans because humans do not synthesize folic acid. It is unusual, however, to have such detailed knowledge about mechanisms of toxicity from experimental animal studies. 

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