Maximum tolerated dose , chronic

In a 12-week, subacute toxicity test in rats given intraperitoneal injections of epichlorohydrin, treatment led to a dose-related decrease in haemoglobin values an increase in segmented neutrophils was seen with doses of 56 mg/kg bw and a reduction in the proportion of lymphocytes occurred at doses of 22 and 56 mg/kg bw (Lawrence et al., 1972). An increased leukocyte count was observed in animals exposed chronically to vapours of epichlorohydrin in air at concentrations of 2 mg/m (Fomin, 1966). The maximum tolerated dose in a 13-week subacute study in rats following oral administration of epichlorohydrin was 45 mg/kg bw per day (Oser et al., 1975). 

Manning, C.S., W.E. Hawkins, D.H. Barnes, W.D. Burke, C.S. Barnes, R.M. Overstreet and W.W. Walker. Survival and growth of Japanese medaka (Oryzias latipes) exposed to trichlorethylene at multiple life stages implications of establishing the maximum tolerated dose for chronic aquatic carcinogenicity... 

There has been continuing controversy about the use of the maximum tolerated dose as the highest dose in chronic/cancer bioassays. Essentially, many consider that observation of cancer under conditions that are often unique to the experimental conditions provides little relevant information even in the context of hazard identification for hnmans, which are exposed to much lower doses (often six orders of magnitnde). 

The second type of test is the determination of neuro-toxic esterase activity (NTE), In its simplest form, this involves treatment of the adult hen with a single maximum tolerated dose of the test substance and sub-scquent assay of the brain enzyme after the time of peak inhibition but before substantial resynthesis of new enzyme has occurred (John.son, 1982). The time of peak inhibition, which can be from 3 to 48 hr postdosing (and is determined by the pharmacokinetics of the compound), can often be assessed by observation of the time of onset of cholinergic signs. The threshold level of NTE inhibition at this early stage, which correlates with delayed neurotoxicity, is approximately 80%. No clinical signs are associated with an inhibition of 60% or less. When multiple determinations of NTE are made during chronic exposures, plateau levels are observed after 2 or 3 weeks. If inhibition of NTE in the brain and spinal cord is Ies,s than 50%, delayed neuropathy doe.s not occur. 

As industry sought to develop new, safer and more specific pesticides for agricultural use, toxicology studies became more elaborate, sophisticated and more sensitive. Toxicokinetic principles were used too infrequently in setting doses for subchronic and chronic studies. Maximum tolerated doses used in these tests may have well exceeded the metabolic capacity of the test animal. 

The maximum tolerated dose (MTD) is chosen to result in the deaths of not more than half of the test animals in a chronic toxicity test. Statistical power is decreased when more than 50% of the test population dies. In a carcinogenicity test, the MTD is chosen such that deaths result only from cancer and not from other effects of high-dose exposure. 

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