Selective toxicity Cumulative

In the rat, testicularatrophy associated with 2,5-HD exposure can occur at cumulative exposure levels below those that produce clinical neurotoxicity. High-level exposure for relatively brief periods produced testicular injury without clinical evidence of distal polyneuropathy (28), whereas chronic low-level exposure produced clinical evidence of distal polyneuropathy without testicular injury (31). In fact, the testicular injury was dose-rate sensitive, whereas the extent of nervous system toxicity was related to the total dose over a range of dose-rates (22, 32). These tissue-selective pharmacokinetic effects may, in part, explain the predominance of neurotoxicity in human exposures to 2,5-HD precursors. In addition, the clinical manifestations of neurotoxicity are obvious, whereas those of testicular injury are subtle. 

With its 2-carbon bridge across the middle, maprotiline (Fig. 12-26) is technically a tetracyclic compound, yet it behaves as a secondary amine TCA (i.e., a relatively selective NE reuptake). The drug s second-generation standing is purely chronological. It has been in the U.S. market since 1981. Amoxapine, which was marketed the same year, is, of course, the N4-demethylated antipsychotic loxapine (Fig. 12-26). It has been suggested the cumulation of the 8-OH metabolite may be responsible for the inhibition of NE uptake and account for the antidepressant effect. Nomifensine, which is a tetrahydroisoquinoline with potential as an inhibitor of NE and DA, but not 5-HT, was withdrawn in 1987 for toxicity reasons. 

FIGURE 5—4 Frequency distribution curves and quantal concentration-effect and dose-effect curves. A. Frequency distribution curves. An experiment was performed on 100 subjects, and the effective plasma concentration that produced a quantal response was determined for each individual. The number of subjects who required each dose is plotted, giving a log-normal frequency distribution (colored bars). The gray bars demonstrate that the normal frequency distribution, when summated, yields the cumulative frequency distribution—a sigmoidal curve that is a quantal concentration-effect curve. B. Quantal dose-effect curves. Animals were injected with varying doses of sedative-hypnotic, and the responses were determined and plotted. The calculation of the therapeutic index, the ratio of the to the ED q, is an indication of how selective a drug is in producing its desired effects relative to its toxicity. (See text for additional explanation.)... 

Cadmium was selected for laboratory experiments as its toxic eifects on insects were well proved (Martoja et al., 1983 Hopkin, 1989 Helidvaara and Vaisanen, 1993). Its effect on production of free radicals has been discussed above. By elimination of zinc from metallothioneins cadmium may indirectly stimulate reactive oxygen particles (Viarengo, 1989). Direct inhibitory effects on detoxifying enzymes have been well documented (Byczkowski and Sorenson, 1984 Palace and Kleverkamp, 1993). Enzyme activity pattern under cadmium stress shows a cumulative eifects of many interacting factors. 

EPA used the relative potency factor (RPF) method in its cumulative hazard assessment of the OPs. The RPF method is based on the assumption of dose additivity, Dose additivity is the agency s assumption when evaluating the joint risk of chemicals that are toxicologically similar and act at the. same target site (EPA, 2001c). Briefly, with the RPF approach, the toxic potency of each chemical is first determined. One chemical, called the index chemical, is then selected. The index chemical provides the basis for comparison. Relative potency is determined by converting the toxic potency of each chemical into toxic equivalents of the index chemical. 

The human toxicology of methanol has been studied [6,71,72]. The skin absorption rate has been reported to be 0.19 m cm2/min [73]. Methanol vapor uptake by the lungs is effective, usually 7080% (74). In the liver, methanol goes through oxidation metabolism catalyzed by alcohol dehydrogenase (an enzyme), producing toxic formaldehyde and formic acid. The accumulation of formic acid leads to acidosis, dama g the nervous system, particularly the optic nerves, and the retina. In the copresence of ethanol, ethanol is selectively metabolized by alcohol dehydrogenase over methanol this delays methanol intoxication and allows detoxication by the natural elimination of methanol via respiration and urination. The methanol elimination half-life is about 23 h [6]. Because of the slow elimination, methanol can be re rded as a cumulative poison [68]. Chronic oq)osure may result in sufficient methanol accumulation in the body, and illness. 

---