No effect dose level

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

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. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

The maximum no observed (non-toxic) effect dose level (NOEL). 

The evaluation of dose-response relationships includes the identification of effective dose levels as well as doses that are associated with low or no increased incidence of adverse effects compared with controls. Many studies identify either the lowest dose causing an adverse effect (lowest-observed-adverse-effect level, or LOAEL) or the no-observed-adverse-effect level (NOAEL) (Calabrese Baldwin,... 

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. 

EXTENSIONS AND COMMENTARY This material, which is certainly a mixture of two diastereoisomeric pairs of racemates since there are two chiral centers present, showed no effects at levels of up to 15 milligrams orally. Doses of 100 mg/Kg were without effects in mice following i.p. injections, although half again this amount proved to be lethal. In rats trained to discriminate LSD from saline, F-2 proved to be about 40 times less potent than the reference compound DOM, requiring some 5 mg/Kg for positive responses. But the human trials were only up to about 0.2 mg/Kg. 

The no observable adverse effect (dose) level (NOAEL) would be lOOmg/kg, with a maximum tolerated dose (MTD) of lOOOmg/kg. 

Evaluate in vivo dose-response range, including dose-response comparison of lead candidates calculation of pharmacologically active doses, e.g., ED50 or ED)0 and therapeutic ratio when combined with no effect or minimum toxic effect dose level. 

Dose selection for chronic studies is very important, because regulatory agencies want one dose to be a no-toxic-effect dose level and another to show frank toxicity. Several approaches are available to select doses, as described in... 

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. 

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. 

The Cramer classification scheme can be used to make a threshold of toxicological concern (TTC) estimation. TTC is a concept that aims to establish a level of exposure for all chemicals below which there would be no appreciable risk to human health the threshold is based on a statistical analysis of the toxicological data from a broad range of different and/or structurally related chemicals and on the extrapolation of the underlying animal data to a no-effect dose considered to represent a negligible risk to human health. 

An evaluation of the dose-response characteristics of chemicals is at the heart of the problem of understanding the health risks they may pose. If for every chemical in the environment we knew the range of no-effect doses and the point at which toxicity begins to appear — the point at which the threshold of toxicity is passed - we could then act to prevent exposures from ever reaching the level at which harmful doses are created (the reader may briefly review Chapter 2 for a discussion of... 

Because the no-effect level can often be only statistically proven to the level of the background noise (recall our discussion in Chapter 1 about spontaneous disease level), it is impossible to statistically prove a zero- or no-effect dose. In fact, as will be touched on later, subtoxic chemical exposure may be beneficial for many chemicals as homeostatic compensatory mechanisms are induced which have a beneficial, not adverse, biological effect. 

Peritoneal macrophages from c57BL/6N mice were incubated in vitro with poly(ICLC) at varying doses. B16-B/6 cells labeled with I -IUDR served as target cells. Levels of drug from 0.001 to 0.1 pg/mL activated macrophages, levels below 0.001 pg/mL had no effect, while levels of 1 pg did not enhance or were inhibitory.22... 

In laboratory tests, appHcation of DMAC to the skin of pregnant rats has caused fetal deaths when the dosages were close to the lethal dose level for the mother. Embryonal malformations have been observed at dose levels 20% of the lethal dose and higher. However, when male and female rats were exposed to mean DMAC concentrations of 31,101, and 291 ppm for 6 h per day over several weeks, no reproductive effects were observed (6). 

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