Subchronic studies

A commercially interesting low calorie fat has been produced from sucrose. Proctor Gamble has patented a mixture of penta- to octafatty acid ester derivatives of sucrose under the brand name Olestra. It was approved by the FDA in January 1996 for use as up to 100% replacement for the oil used in preparing savory snacks and biscuits. Olestra, a viscous, bland-tasting Hquid insoluble in water, has an appearance and color similar to refined edible vegetable oils. It is basically inert from a toxicity point of view as it is not metabolized or absorbed. It absorbs cholesterol (low density Hpoprotein) and removes certain fat-soluble vitamins (A, D, E, and K). Hence, Olestra has to be supplemented with these vitamins. No standard LD q tests have been performed on Olestra however, several chronic and subchronic studies were performed at levels of 15% in the diet, and no evidence of toxicity was found. No threshold limit value (TLV), expressed as a maximum exposure per m of air, has been estabhshed, but it is estimated to be similar to that of an inert hpid material at 5 mg/m. ... 

Subchronic Studies. Although short-term repeated exposure studies provide valuable information about toxicity over this time span, they may not be relevant for assessment of ha2ard over a longer time period. For example, the minimum and no-effects levels determined by short-term exposure may be significantly lower if exposure to the test material is extended over several months. Also, certain toxic effects may have a latency which does not allow their expression or detection over a short-term repeated-exposure period for example, kidney dysfunction or disturbances of the blood-forming tissues may not become apparent until subchronic exposure studies are undertaken. 

Subchronic study Rats/mice/dogs/rabbits 6 months Target organs, delayed effects... 

Yes, 0.45 mg/kg/day was calculated by multiplying the dietary level of 5 ppm (5 mg endosulfan/kg diet) by the food factor for male Wistar rats in a subchronic study of 0.09 kg diet/ kg body weight/day (ERA... 

Subchronic studies that measure Ah receptor-mediated responses, such as thymic atrophy, loss in body weight, and immunotoxicity... 

EPA has derived a chronic oral RfD of 0.001 mg/kg/day for hexachloroethane (IRIS 1995). This value is based on a NOAEL of 1 mg/kg/day for atrophy and degeneration of the renal tubules in rats exposed for 16 weeks (Gorzinski et al. 1985). The NOAEL was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation, human variability, and the use of a subchronic study. EPA places medium confidence in this RfD (IRIS 1995). 

These values are supported by the results of subchronic studies with squirrel monkeys and dogs (Jones et al. 1972). Monkeys and dogs exposed continuously at approximately 15 ppm for 90 d showed no overt clinical signs systemic toxicity consisted of biochemical and/or non-life-threatening histological changes in the liver, spleen, and kidneys. 

Minimal rather than complete protocols tend to be more common in the acute testing of pharmaceutical agents. Drugs will almost always be subjected to at least one subchronic study. Body weight and feed consumption determinations are a standard feature of such studies. Additionally, changes in body weight and feed consumption are more likely in a subchronic than an acute study because the animals are dosed continuously between body weight determinations. 

The objectives of the typical subchronic study fall into three categories. The first is to broadly define the toxicity (and, if one is wise, the pharmacology and hyperpharmacology) of repeated doses of a potential therapeutic agent in an animal model (Traina, 1983). This definition is both qualitative (what are the target organs and the nature of the effects seen ) and quantitative (at what dose levels, or, more important, at what plasma and tissue levels, are effects definitely seen and not seen ). 

These objectives are addressed by the usual subchronic study. Some subchronic studies, however, are unusual in being conceived, designed, and executed to address specific questions raised (or left unanswered) by previous preclinical or early clinical studies. Such a special purpose is addressed separately. 

TABLE 7.2. Numbers of Animals for Chronic and Subchronic Study per Test Group... 

TABLE 7.6. FDA Draft Criteria for a Neurotoxicity Screen as a Component of Short-Term and Subchronic Studies... 

Selecting a subset of animals or test systems from a study to make some measurement (which either destroys or stresses the measured system, or is expensive) at an interval during a study. This may include such cases as doing interim necropsies in a chronic study or collecting and analyzing blood samples from some animals during a subchronic study. 

There have been several subchronic studies of 1,2-dibromoethane. In one, rats and guinea pigs... 

Liver was not examined histologically in the subchronic study used to set concentrations for the NCI chronic gavage bioassay of 1,2-dibromoethane (NC11978). In the NCI (1978) gavage bioassay (discussed in detail in Section 2.2.2.8), a nonneoplastic hepatic lesion, peliosis hepatis, occurred in a small number of treated male and female Osborne-Mendel rats and had an equivocal relationship to... 

The toxicologist usually moves from studies of a single exposure to ones in which animals are exposed on each of 90 consecutive days. The 90-day subchronic study has become a convention in the field. Rodents usually live 2-3 years in the laboratory, so 90 days is about 10% of a lifetime. An enormous amount of 90-day rodent toxicity data have been collected over the past several decades and have played key roles in judging the risks of environmental chemicals. 

The recent change in the method of calculating tolerances within the animal drug program in CVM will have quite a dramatic effect on the permitted tolerances supported by subchronic studies. Table 7 lists a few representative drugs that are currently regulated in food-producing animals. The first column is the no-effect... 

These tolerances are not all being automatically revised in the CFR for several reasons (1) the subchronic studies used to calculate the current tolerances may not meet todays standards, (2) most of these drugs were regulated on the basis of residues of parent drug only, (3) the official methods for monitoring the residues may not meet present standards, and (4) some of the drugs have safety concerns that are not satisfied by subchronic studies. 

The term subacute is not an OECD term. Presumably it relates to a study, which is shorter than a subchronic study, i.e., in OECD terms, it would be a study shorter than 90 days. 

Q2] is employed when extrapolating data from subchronic studies to estimate risk from lifelong exposures. The default value 10, indicating great uncertainty in estimating the NOAELchronic from... 

Vermeire et al. (1999) reviewed several studies comparing NOAELs from chronic and subacute/subchronic studies in order to evaluate the distribution of the extrapolation factor for duration of exposure. The ratios of observed NOAELs from oral studies using historical data for various compounds were calculated. The most likely distribution of the ratios was considered to be lognormal and the parameters of the distributions of the ratios were estimated, see Table 5.8. 

Exposure of the general population to chemicals present in the environment is an example of long-term exposure on a local or regional spatial scale. The general population is mainly exposed to environmental chemicals via oral exposure through food and drinking water and via inhalation from ambient and indoor air. The total body burden can, e.g., be expressed as a total oral intake (the outcome of the exposure assessment). This intake should be compared with a POD derived from preferably long-term studies or at least subchronic studies (outcome of the hazard (effects) assessment). 

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