Toxicity equivalent , inhibition

Leonards, P.E.G., de Vries, T.H., Minnaard, W., Stuijfzand, S., de Voogt, P., Cofino, W.P, van Straalen, N.M., van Hattum, B. (1995). Assessment of experimental data on PCB-induced reproduction inhibition in mink, based on an isomer- and congener-specific approach using 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalency. Environ Toxicol Chem 14(4) 639-652. 

The procedure involves converting oxon to thion toxicity equivalents by multiplying the oxon value by its relative toxicity (ED of thion r ED,.q of oxon) in Table I. The ED. value is the aermal dose in ug/cnr of total body surface which produces 50% inhibition of red cell ChE activity 72 hours after application. The total thion and oxon level is then divided by the thion toxicity equivalents and the factor is multiplied by the safe level established for thion in Table I. This procedure was conducted for the dislodgeable residues of parathion-paraoxon, methidathion-methidathion oxon, and azinphosmethyl-azinphosmethyl oxon. The safe levels for the total disloggeable residues were determined to be 0.06, 0.2 and 1.6 ug/cm, respectively, for... 

When [ H]-thymidine incorporation was measured in the presence and absence of 10 mM SAAB, no significant difference was observed. If, however, cells were preincubated in the presence of 10 mM SAAB for increasing periods of time, a distinctly biphasic time course was observed (Fig. 9). At present we have no simple explanation for the initial slow decrease in incorporation. Blockage of cell cycle progress in Gi at approx. 2 h before S-phase could account for the second portion of the curve. The observation that S-nitrobenzamide at 6 mM (which gave an approx, equivalent inhibition of uridine incorporation) did not give this effect suggests such a block could be poly(ADP-ribose) synthetase mediated. To test whether this was indeed a Gi block, we treated cells with 10 mM AAB for 8 h, a treatment which caused minimal toxicity (Fig. S), and then released the block and monitored the recovery of [ H]-thymidine... 

Paraquat is embryotoxic to sensitive species of birds. Concentrations equivalent to 0.056 kg/ha applied in oil solution to the surface of eggs of the mallard (Anas platyrhynchos) inhibited development when applied in aqueous solution, paraquat was toxic at a dose equivalent to 0.56 kg/ha. In each case, adverse effects occurred below the recommended field application rate of about... 

The MRL is based on a NOAEL of 0.5 mg/m3 for decreased acetylcholinesterase activity in rats exposed to disulfoton 4 hours/day for 5 days in a study by Thyssen (1978). The NOAEL was adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 30 (3 for extrapolation from animals to humans and 10 for human variability). Inhibition of erythrocyte cholinesterase activity and unspecified behavioral disorders were observed at 1.8 mg/m, and unspecified signs of cholinergic toxicity were observed at 9.8 mg/m. Similar effects were observed in rats or mice exposed to higher concentrations for shorter duMtions (Doull 1957 Thyssen 1978). The NOAEL value of 0.5 mg/m is supported by another study, in which no significant decrease in the activity of brain, serum, or submaxillary gland cholinesterase was found in rats exposed to 0.14-0.7 mg/m for 1 hour/day for 5-10 days (DuBois and Kinoshita 1971). Mild depression of erythrocyte cholinesterase activity was reported in workers exposed by the inhalation and dermal routes (Wolfe et al. 1978). 

This is an equivalent situation to that of the raw material for blood substitutes, and the impurity limits developed for this special application can be used directly. The content of extractable fluorine is a sensitive parameter to characterise the quality of PFCLs. The correlation between the concentration of extractable fluorine in a PFCL and its toxicity was reported by Gervits [19]. Using cell cultures, he was able to correlate the inhibition rate of cell growth to the content of extractable fluorine. Table 2 shows that only very low concentration could be tolerated. 

Also, measurement endpoints such as inhibition concentration related to x% of effect (ICx) compared to a control, can be plotted versus time for each bioassay. Mathematical models for such "toxicity curves" could generate an infinite time Inhibition Concentration related to a x% of effect (°°ICx) for each bioassay. Such data, equivalent to the incipient lethal concentration defined for example by Giesy and Graney (1989), are valuable in terms of long-term environmental impact assessment. 

By the use of radioactively labelled precursor chemicals, the cell s ability to synthesize macromolecules such as DNA, RNA, and proteins, after treatment with the drug, can be measured. A typical result is shown in Fig. 5, for exposure of the cells to the equivalent level of drug found in tumor tissue of a treated animal. The synthesis of new total DNA is selectively and persistently inhibited. Total RNA and protein syntheses are not markedly affected until much higher drug-dose levels, which are frankly toxic to... 

Coprine, isolated from the Coprinus atramentarius mushroom, and identified as hydroxycyclopropyO-L-glutamine ", 135, is the first example of a natural product containing a cyclopropanone equivalent. Coprine inhibits mouse liver aldehyde dehydrogenase in vivo but not in vitro Cyclopropanone hydrate (170), which can be derived from coprine by hydrolysis to 169 (equation 39), inhibits the enzyme both in vivo and in vitro. Cyclopropanone hydrate has thus been proposed as a metabolite of coprine which is the active agent causing the toxic effects ... 

Inhibiting methanol metabolism. Ethanol, which occupies the dehydrogenase enzymes in preference to methanol, competitively prevents metabolism of methanol to its toxic products. A single oral dose of ethanol 1 ml/kg (as a 50% solution or as the equivalent in gin or whisky) is followed by 0.25 ml/kg/h orally or i.v., aiming to maintain the blood ethanol at about... 

Suzuki and colleagues (1986, 1987) have tested the effects of altering methamphetamine p-hydroxylation in rats it appeared that inhibition enhanced the methamphetamine-induced stereotyped behavior. One might conjecture that an equivalent effect could occur in humans with inborn CYP2D6 deficiency if a toxic dose of methamphetamine were applied. Unfortunately, studies of animals do not necessarily help p-hydroxyamphetamine is the main metabolite of amphetamine in rats but not in human liver (see above), and most studies on brain metabolism have not been conducted in human tissue. 

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