Selective toxicity comparative distribution

Selective toxic agents have been developed to protect crops, animals of economic importance, and humans from the vagaries of pests, parasites, and pathogens. Such selectivity is conferred primarily through distribution and comparative biochemistry. 

Another possible use of in vitro developmental toxicity tests would be to select the least developmentally toxic backup from among a group of structurally related compounds with similar pharmacological activity [use (2) in the list above], for example, when a lead compound causes malformations in vivo and is also positive in a screen that is related to the type of malformation induced. However, even for this limited role for a developmental toxicity screen, it would probably also be desirable to have a measure of the comparative matemotoxicity of the various agents and/or information on the pharmacokinetics and distribution of the agents in vivo. 

Maltby et al. (2002) and Van den Brink et al. (2006a) compared SSDs based on acute and chronic laboratory toxicity data for aquatic test species exposed to pesticides. The SSDs were constructed with toxicity data for the most sensitive taxonomic group, because of the specific toxic mode of action of the pesticides selected. The SSDs were used to calculate the hazardous concentration to 5% of the species (HC5) by means of a log-normal distribution model, and comparisons were performed for 2 insecticides and 7 herbicides (Table 6.4). The log-normal model did not fit the diuron (herbicide) short-term L(E)C50 data or the atrazine (herbicide) long-term NOEC data. Consequently, the L(E)C50 HC5 value for diuron and the NOEC HC5 value for atrazine should be interpreted with caution, as well as their acute HC5-chronic... 

There are many cholinesterase inhibitors diminishing both AChE and BuChE activities to a comparable extent. However, there are a number of important exceptions the selectivity of some OP and carbamates for BuChE has been described by Aldridge (A4). Carbamates belong to a group of insecticides having a large variation in their effectiveness. They are biologically active because of their structural complementarity to the active surface of AChE and their consequent reaction as substrates with very low turnover numbers (A4, B2). Some carbamates inhibit selectively either AChE or BuChE (Bll, B22). The toxicity of carbamates is dependent on their ability to carbamylate AChE in different tissues and on other factors such as distribution, detoxification, and metabolization. 

Figure 9.4 Risk assessment for an aquatic environment based on a probabilistic procedure into which the concept of varying sensitivity in multispecies communities is incorporated (Nendza, Volmer and Klein, 1990). Exposure and effects are determined separately from experimental or, if not available, QSAR data. Physico-chemical data and information on bioaccumulation and biotransformation are the input for computer simulations of transport and distribution processes that estimate the concentrations of a potential contaminant in a selected river scenario, using, for example, the EXAMS model (Bums, Cline and Lassiter, 1982). For the effects assessment, the log-normal sensitivity distribution is calculated from ecotoxicological data and the effective concentrations for the most sensitive species are determined. The exposure concentrations and toxicity data are then compared by analysis of variance to give a measure of risk for the environment. Modified from Nendza, Volmer and Klein (1990) with kind permission from Kluwer Academic Publishers, Dordrecht.

The first point especially addresses ecological considerations about the abundance and the distribution of sensitive species in the environmental compartment of concern the second aspect relates to the correct operation of QSAR methods. In the cases of the model contaminant phenol, which was chosen because of the availability of ample experimental data for the comparative exercise, sufficient knowledge is at hand to guide the retrieval of suitable QSARs. For toxicity to fish, the available models vary regarding (a) the endpoints measured - different fish species, different effects (NOEC, LC50, LCioo, ) different durations of the experiments (4 h-30 d), and (b) the various classes of chemicals studied. Because phenol is known to be a polar non-specific toxicant, suitable QSARs for fish (section 5.1) can be selected in a straightforward manner. These models are generally log P -dependent,... 

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