Animal models genotoxic effects

The database for HFC-134a is extensive it contains studies with both human subjects and animal models. Potentially sensitive populations, including patients with COPD and adult and pediatric asthmatic patients, were tested with direct inhalation of HFC-134a from metered-dose inhalers. The response of these groups was no different than that of healthy adults. The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con... 

Therefore, when it became clearly understood that atrazine is neither estrogenic nor a genotoxic, direct-acting carcinogen - and that the atrazine-associated tumor responses appeared only in female SD rats, a strain with a high, normally occurring incidence of mammary tumors - it became important to study the effect of high doses of atrazine on the SD animal model s own endocrine system and hormonal milieu. 

Toxicology, possibly including safety pharmacology and genotoxicity, to evaluate the potential for the leads to cause adverse effects in in vitro or cell-based systems and in vivo or animal models and to determine that the dose levels that cause toxicity are substantially greater than the dose levels needed to elicit the desired pharmacological effect... 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

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