Chronic toxicology studies

Larson PS, Hennigar GR, Lane RW, et al. 1978. Acute, subchronic, and chronic toxicological studies with Kepone. Toxicot Appl Pharmacol 45(l) 331-332. 

It is most appropriate for the exposure estimates determined from acute probabilistic assessment techniques to be compared with acute single-day RfDs to determine the acceptability of such exposures. Unfortunately, since accurate acute RfDs for most pesticides have not been determined, the exposure estimates are often compared with RfDs derived from longer-term (28 to 90 days) or chronic toxicology studies. In most cases, the acute RfDs may be much higher than those obtained from longer-term studies. This is particularly important in cases where pharmacokinetic factors such as absorption, distribution, biotransformation, and excretion of a pesticide have been established and demonstrate that repeated exposure to the pesticide could cause an increase in... 

Although ICH S6 indicates that chronic toxicology studies of 6 months duration may be sufficient, many Sponsors have been recently requested to conduct nine-month studies. 

One of the most striking observations that can be made of the peptides as a class is their remarkable safety profile. Of all of the peptides currently on the market that were investigated for this analysis (Table 22.1), there was only one observation in the chronic toxicology studies that was not linked to exaggerated pharmacology. Admittedly, our analysis is biased by the fact that only approved compounds were included however, this data set is still very instructive. The observation in question was from enfuvirtide, a 36 amino acid linear peptide derived from the HIV-1 glycoprotein gp41 [15,16],... 

CRITICAL ASSESSMENT OF THE METHOD Inclusion of these investigations of endocrine safety pharmacology is a useful addition to chronic toxicology studies. 

The purpose of sub-acute to chronic toxicology studies is to provide a reliable set of information on the dose levels to be administered in the different phases of clinical development. Further, these studies are a prerequisite for international approval. 

Dose selection for subchronic and chronic toxicology studies should be based on the results from acute toxicity studies and pharmacokinetic evaluations. The three typical dose levels are (a) a no-toxic-effect level, which should be at least equivalent to, and hopefully a multiple of, the proposed human dose, (b) a dose level that produces a toxic effect in clinical observations, clinical pathology, or histopathologic changes, and (c) a dose level between these two. 

The duration for chronic toxicology studies depends on the projected duration of administration to humans (Table 1). The present consensus according to the FDA (5) is that 6-month rodent and nonrodent studies are sufficient for drug candidates intended for long-term human use, provided the candidate is studied in rats, or other appropriate species, to evaluate the potential for tumor production. 

Similarly, chronic toxicology studies in animals have shown no harmful adverse effects associated with medium-chain triglycerides following inhalation or intraperitoneal, oral, and parenteral administration. 

---