No effect dose

Dioxane is an impurity present in alcohol ethoxy sulfates formed during sulfation of the ethoxylated alcohol. 1,4-Dioxane is a carcinogen in rats and mice [312-314] and has been considered as a possible carcinogen to humans [315-317]. However, the no-effect dose in rats is equivalent to a daily intake of dioxane of 9.6-19.0 mg/kg/day, which corresponds to 0.672 g/day for humans. In other studies it has been determined that the threshold for onset of human toxicity of 1,4-dioxane lies above an intake of 76 mg/kg in adult males [318]. Although it seems to be demonstrated that amounts up to 1000 ppm of... 

Without the availability of animal dafa, how would one decide on the first dose of a molecule (that has never been administered to any animal) to be given to man A frequently used method is to give a volxmteer 10% of the lowest no-effect" dose seen in two or three animal species. How would one decide on the route of administration Some compounds are very toxic to intact veins. How could one give reasonable assurance of safety of a new chemical never before administered to a human The only viable option is to determine tolerance in the veins of lower animals before moving to a volxmteer. Should animal activists not have to put forth their actual protocol for studying a new drug candidate in humans How would they answer the questions raised above ... 

Note that the true no-effect dose may be greater than the NOAEL the latter is in part an artifact of dose selection by the designers of the study. As the acronym suggests the LOAEL is the lowest dose at which some adverse effect is observable. Note also that dose could be any... 

A problem with toxicity produced by an extension of the pharmacology of a compound, is that the conventional use of no-effect doses based on pre-clinical animal studies may not apply. Moreover pre-clinical studies may be complicated by the often understated ranges of response seen across species due to species differences in the receptors, enzymes and ion channels that comprise drug targets. Table 8.1 lists some of these known variations and the consequences range from an exaggerated response, to an absence of a response. 

ECETOC (1995) recommended a factor of 2 to be used in case the extent of the relevant effect is of minor importance, and the slope of the dose-response curve reasonably justifies the assumption that a halving of the LOAEL would be likely to arrive at the no-effect dose. A factor of 3 was recommended as a default value, which would be used in the majority of cases. Extent and severity of the effect at the LOAEL and/or a very flat dose-response curve may justify the use of a higher factor. 

In both mice and rats exposed 6 hours/day 5 days/week for 12 weeks, the no-effect dose was below 150 ppm and the maximum tolerated dose was below 600 ppm. At doses of up to 12 00 ppm there were few signs of overt toxicity, and at necropsy the only treatment related lesions occurred in the liver. Subchronic studies in monkeys showed no exposure-related adverse health effects or reproductive effects after exposure 6 hour/day, 5 days/week for 13 weeks to concentrations of up to 500ppm."... 

No effect dose level, lowest effect level and/or maximum tolerated dose level for maternal toxicity. 

Acute toxicity Usually two species, two routes. Determine the no-effect dose and the maximum tolerated dose. In some cases, determine the acute dose that is lethal in approximately 50% of animals. 

The goals of preclinical toxicity studies include identifying potential human toxicities, designing tests to further define the toxic mechanisms, and predicting the specific and the most relevant toxicities to be monitored in clinical trials. In addition to the studies shown in Table 5-1, several quantitative estimates are desirable. These include the no-effect dose—the maximum dose at which a specified toxic effect is not seen the minimum lethal dose—the smallest dose that is observed to kill any experimental animal and, if necessary, the median lethal dose (LD50)—the dose that kills... 

The existence of "no-effect doses" for toxic compounds is a controversial point, but it is clear that to measure the exposure sufficiently accurately and to detect the response reliably are major problems (see below for further discussion). Suffice it to say that certain carcinogens are carcinogenic after exposure to concentrations measured in parts per million, and the dose-response curves for some nitrosamines and for ionizing radiation appear to pass through zero when the linear portion is extrapolated. At present, therefore, in some cases no-effect levels cannot be demonstrated for certain types of toxic effect. 

At high dose levels to the dam many suckling pups died before weaning, the viability index being zero for the generation. Hence dietary HCB decreased the number of pups that survived to weaning. A minimum, e.g., no effect, dose level of 20 ppm of HCB was established (refs. 95a,b,c). As with other chloroorganics, HCB affects the CNS and with it a variety of essential vital functions. 

As the science of toxicology developed, the requirements for establishing safety became more demanding. At one time the LD50 was sufficient to establish safety. The effect of dose level is very important in toxicology. The effects, which vary from no effect dose (NED) levels to fatal effect, have been summarized in Figure 12-2 (Concon 1988). Two types of substances exist type I shows no beneficial effects and type II shows nutritional and/or therapeutic beneficial effects. 

In the prediction of long-term "no effect" doses there are two important concepts to consider. One is that there are predictable dose relationships between acute, subchronic and chronic toxic effects. Acute toxicity tests refers to studies wherein single or repeated doses are studied 14 days or less. Subchronic (subacute) tests refers to studies wherein the doses are given five-seven days per week for 90 days, Subchronlc studies are also referred to as 13-week, three-month or short-term tests. 

The second concept is that repeated doses of any substance will produce its toxic effects (with the exception of carcinogenicity) in 90 days or not at all. Thus, the lifetime "no effect" dose can be derived from the 90-day "no effect" dose. There are indications that even carcinogenic "activity" may be detected in short-term studies. 

W. Hayes and C. Weil — 1-> have shown (Table VII) that there are useful relationships between LDSO s, ST, LT or lifetime "no effect" doses. 

Table VII. Comparison of Single Dose with 7-Day and 90-Day No Effect Doses (2)...

Table VIIL Prediction of Long-Term "No Effect Doses...

C. Weil t, determined the effective and "no effect" doses of 33 compounds in rats at three months and two years (LT) (.Table IX). These compounds were diverse in chemical structure, pharmacologic type, and toxicity as judged by LDSO s or ST and LT "no effect" doses. 

Short-term no effect dose/factor long term no effect dose... 

The important feature of these data is that there is a 27% chance that the ST given repeatedly will not produce toxic effects in a lifetime and a 95% to 100% likelihood that 1/10 to 1/12 of the ST "no effect" dose can be given repeatedly throughout a lifetime without producing toxic effects. 

Weil al., concerning relationships of LD50 s, ST, and LT "no effect" dose for individual compounds could be seen. 

Based on inhalation data for agent GB, McNamara et al. (1973) calculated the no-effect dose for VX-indnced tremors in hnmans to be 0.34 g/kg. Carnes et al. (1986) suggested that the threshold for muscular tremors in sensitive snbpopnlations, such as infants, may be 0.16 g/kg. McNamara et al. (1973) estimated that the human LD50 and no-death levels for VX were 7.5 pg/kg and 0.94 g/kg, respectively. These estimates were based on extrapolations of LCtso data for GB. 

Repeated exposure to 1.4 mg-min/m produced no eye irritation or injury to laboratory animals (Rosenblatt et al., 1975). hi humans, a Ct of <12 mg-min/m is considered a no-effect dose for eye irritation (McNamara et al., 1975) at ambient temperatures. At higher temperatures ( 32°C), threshold and other biological effects occur at lower concentrations. Cts of 12-70 mg-min/m cause mild reddening of the eyes (McNamara et al., 1975) Cts of 40-90 can cause eye irritation and conjunctivitis after a latency period of 2 to 48 hr and Cts of 90-100 mg-min/m produce moderately severe bums, ulcers, opacity, and perforation after a latency period of 2 to 10 hr (Doull et al., 1980). In some cases there may be a recurrent vascularization and ulceration many years after the initial exposure. 

---