Animal studies safety data

The focus of this chapter has been mainly on data from animal studies. These data are useful primarily to obtain information on mechanisms of action of CLA. In addition, much higher levels of CLA can be tested in animal studies than would be appropriate in humans. In general, the data imply no safety issues for the consumption of Clarinol G-SO by humans. 

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-... 

To determine whether human testing for a new drug or new drug product is reasonable, it is first necessary to conduct preclinical studies and to submit the IND. The necessary information needed to prepare the IND is outlined in Table 1. The IND is to contain information on appropriate prior animal studies for safety evaluation, any available clinical data, adequate drug identification and manufacturing instructions, and a detailed outline of the proposed clinical study, routs of administration, approximate number of patients to be used, and an estimate of the length of treatment and an environmental impact statement. 

Cautious use of pre-clinical data, involving the insertion of safety (uncertainty) factors, provides the basis for selecting doses for the early clinical trials, but the predictive value of animal data is far from perfect, so that in most cases some adverse side effects will be observed in the human trials. Most often those effects are subjective in nature -headache, nausea, muscle pain - and could not have been suspected from animal studies. More serious side effects sometimes occur, and may put a halt to further development of the drug. 

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... 

Historically, the so-called safety factor approach was introduced in the United States in the mid-1950s in response to the legislative needs in the area of the safety of chemical food additives (Lehman and Fitzhugh 1954). This approach proposed that a safe level of chemical food additives could be derived from a chronic NOAEL from animal studies divided by a 100-fold safety factor. The 100-fold safety factor as proposed by Lehman and Fitzhugh was based on a limited analysis of subchronic/chronic data on fluorine and arsenic in rats, dogs, and humans, and also on the assumption that the human population as a whole is heterogeneous. Initially, Lehman and Fitzhugh reasoned that the safety factor of 100 accounted for several areas of uncertainty ... 

In vivo studies are preferably carried out using unrestrained, imanaesthetised animals. Animals can be fitted with transmitters that allow data to be collected by telemetry. As for all animal studies, avoidance or minimisation of pain and discomfort is an important consideration. Information from the toxicological battery of studies, if they have been adequately designed to address safety pharmacology endpoints, can... 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

In addition to toxicity and safety data, the preclini-cal package to start clinical studies also contains information on the pharmacology, the pharmacokinetics and metabolism and the galenical aspects of the compound. As a rule there is evidence of pharmacological activity and, if possible, of therapeutic activity in one or more animal models of disease. Ideally there is also information on the in vivo concentration effect relationship. 

All medication needs to be approved by the Food and Drug Administration (FDA) before it can be released to the public in the United States. Many of the pharmacology studies of a drug s efficacy and safety are first done on laboratory animals. This is because there is much similarity in the anatomy, physiology, and biochemistry of animals and humans, and there is much experimental evidence showing similarity in response to many different drugs. Arguments in a lawsuit that a specific chemical is causally linked to an individual s injury or behavior often use data from animal studies. 

All pharmaceuticals marketed in the United States, including biotechnology products, must be proven safe and effective for their intended use. The FDA requires that all recombinant proteins and other biotechnology products be produced by a manufacturer holding a certified Biologic License Establishment (BLE). The pharmaceutical company is required to collect safety and efficacy data, first in animal studies and subsequently in clinical trials. This information is submitted in a new drug... 

Animal data serve as the springboard to estimating a safe and effective range of doses for human therapeutic purposes. Initial doses in phase 1 studies are based on preclinical pharmacokinetic and safety data. First estimates of safe and effective drug concentrations in plasma in human studies are also based on animal data. The Clinical Studies section in the product label includes information derived from tolerance studies of the drug (phase I), pivotal human data demonstrating efficacy at a defined dose or dose range, and a description of untoward effects observed in... 

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