Chronic toxicity study

In additional EPA studies, subchronic inhalation was evaluated ia the rat for 4 and 13 weeks, respectively, and no adverse effects other than nasal irritation were noted. In the above-mentioned NTP chronic toxicity study ia mice, no chronic toxic effects other than those resulting from bronchial irritation were noted. There was no treatment-related increase ia tumors ia male mice, but female mice had a slight increase in bronchial tumors. Neither species had an increase in cancer. Naphthalene showed no biological activity in other chemical carcinogen tests, indicating Htde cancer risk (44). No incidents of chronic effects have been reported as a result of industrial exposure to naphthalene (28,41). 

In 1969, a chronic toxicity study on a cyclamate saccharin (10 1) blend indicated bladder cancer problems in rats. Cyclamate was soon banned by the FDA, but saccharin remained an approved sweetener. In 1977, the FDA proposed a ban on saccharin because of the discovery of bladder tumors in some male rats fed with high doses of saccharin. Because no other nonnutritive sweetener was available at that time, the proposed ban faced strong opposition. 

Chronic Toxicity Studies. With the exception of tumorigenesis, most types of repeated exposure toxicity are detected by subchronic exposure conditions. Therefore, chronic exposure conditions are usually conducted for the following reasons if there is a need to investigate the tumorigenic potential of a material if it is necessary to determine a no-effects or threshold level of toxicity for lifetime exposure to a material and if there is reason to suspect that particular forms of toxicity are exhibited only under chronic exposure conditions. 

A chronic toxicity study for DOSS was performed using beagle dogs [72]. The dogs showed no toxic effects over a one-year period. Not even an effect on gastric mucosa was found (in contradiction to an earlier study [101] see also [102]). 

GL37 Safety repeat dose chronic toxicity Studies to evaluate the safety of residues of veterinary drugs in human food Repeat-dose Chronic Toxicity Testing... 

The single-dose toxicity studies were performed in two mammalian species, rat and mouse, by the route used in clinical practice, that is oral, as well as that ensuring adequate systemic exposure to the drug, that is intravenous. The subacute (3 months) toxicity studies were correctly carried out in the two animal species (rat, dog) in which also the pharmacokinetics was studied. Since in accordance with the International Conference on Harmonization (CPMP/ICH/286/95), 3-month toxicity studies support clinical trials for up to 1 month s duration (the longest duration of drug administration in clinical use), chronic toxicity studies have not been performed. 

CUT (Chemical Industry Institute of Toxicology). 1982. 104-week chronic toxicity study in rats Aniline hydrochloride. Final report. CIIT, Research Triangle Park, NC. 

The duration of such toxicity tests varies. In the USA, the FDA usually recommends a period of up to 2 years, whereas in Europe the recommended duration is usually much shorter. Chronic toxicity studies of biopharmaceuticals can also be complicated by their likely stimulation of an immune response in the recipient animals. In the context of new chemical entities (NCEs, i.e. low molecular weight traditional chemicals), not only can the drug itself exhibit a toxic effect, but so potentially can drug breakdown products. As proteins are degraded to amino acids, any potentially toxicity associated with protein-based drugs is typically associated with the protein itself and not degradation products. 

For avian wildlife, data are incomplete on PAH background concentrations and on acute and chronic toxicity. Studies with mallard embryos and PAHs applied to the egg surface showed toxic and adverse sublethal effects at concentrations between 0.036 and 0.18 pg PAH/kg whole egg (Hoffman and Gay 1981). Additional research is needed on petroleum-derived PAHs and then-effects on developing embryos of seabirds and other waterfowl. There is an urgent need for specific avian biomarkers of PAH exposure (Murk et al. 1996). 

The period of the test depends on whether long- or short-term effects are of interest. Acute toxicity is the effect of a single exposure or a series of exposures close together in a short period of time. Chronic toxicity is the effect of multiple exposures occurring over a long period of time. Chronic toxicity studies are difficult to perform because of the time involved most toxicological studies are based on acute exposures. The toxicological study can be complicated by latency, an exposure that results in a delayed response. 

Chronic toxicity studies were carried out with rats, dogs, and rhesus monkeys (2). In nearly all cases, the principal effect produced was ischemia of some part of the body. 

Carcinogenicity study (often combined with a 2-year chronic toxicity study, usually in the rat)... 

The traditional acute, subchronic, and chronic toxicity studies performed in rodents and other species also can be considered to constitute multiple endpoint screens. Although the numerically measured continuous variables (body weight, food consumption, hematology values) generally can be statistically evaluated individually by traditional means, the same concerns of loss of information present in the interrelationship of such variables apply. Generally, traditional multivariate methods are not available, efficient, sensitive, or practical (Young, 1985). 

Pharmacokinetics. All subchronic and chronic toxicity studies now incorporate (either in the study itself or in a parallel study) evaluation of the basic pharmacokinetics of a compound. This is discussed in detail in Chapter 18. 

A carcinogenicity study is more focused than a chronic toxicity study fewer endpoints are evaluated, and as such it is a simpler study. The key endpoints are actually few. 

Metabolism and pharmacokinetic studies have greater relevance when conducted in both sexes of young adult animals of the same species and strain used for other toxicity tests with the test substance. The number of animals used in metabolism and pharmacokinetic studies would be sufficient to reliably estimate population variability. This usually means a separate (but parallel) set of groups of animals in rodent studies. A single set of intravenous and oral dosing results from adult animals, when combined with some in vitro kinetic results, may provide an adequate data set for the design and interpretation of short-term, subchronic and chronic toxicity studies. 

Body Weight Effects. No specific effects on body weight have been noted in humans. Effects on body weight (decreases) in animals were usually associated with administration of high doses and were not observed in chronic toxicity studies (Chemoff et al. 1979a Deichmann et al. 1970 Goldenthal 1978a Kavlock et al. 1981 NCI 1978 Treon et al. 1955). 

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